Professional Documents
Culture Documents
Dementia
Dementia
Dementia
Comprehensive Principles and Practice
Edited by
Bradford C.Dickerson, MD
Associate Professor of Neurology, Harvard Medical School
Director, Frontotemporal Disorders Unit
Co-Investigator, Alzheimers Disease Research Center
Department of Neurology, Massachusetts General Hospital
Boston, MA
and
1
1
Oxford University Press is a department of the University of
Oxford. It furthers the Universitys objective of excellence in research,
scholarship, and education by publishing worldwide.
OxfordNewYork
Auckland Cape Town Dar es Salaam Hong Kong Karachi
Kuala LumpurMadridMelbourneMexico CityNairobi
New DelhiShanghaiTaipeiToronto
With offices in
ArgentinaAustriaBrazilChileCzech RepublicFranceGreece
GuatemalaHungaryItalyJapanPolandPortugalSingapore
South KoreaSwitzerlandThailandTurkeyUkraineVietnam
Oxford is a registered trademark of Oxford University Press
in the UK and certain other countries.
Published in the United States of America by
Oxford University Press
198 Madison Avenue, NewYork, NY 10016
Oxford University Press 2014
All rights reserved. No part of this publication may be reproduced, stored in
a retrieval system, or transmitted, in any form or by any means, without the prior
permission in writing of Oxford University Press, or as expressly permitted by law,
by license, or under terms agreed with the appropriate reproduction rights organization.
Inquiries concerning reproduction outside the scope of the above should be sent to the
Rights Department, Oxford University Press, at the address above.
You must not circulate this work in any other form
and you must impose this same condition on any acquirer.
Library of Congress Cataloging-in-Publication Data
Dementia (Dickerson)
Dementia :comprehensive principles and practice / edited by Bradford C.Dickerson & Alireza Atri.
p. ; cm.
Includes bibliographical references.
ISBN 9780199928453 (alk. paper)
I. Dickerson, Bradford C., editor of compilation. II. Atri, Alireza, editor of compilation. III. Title.
[DNLM:1. Dementia. WM220]
RC521
616.83dc23
2014004364
The science of medicine is a rapidly changing field. As new research and clinical experience broaden our
knowledge, changes in treatment and drug therapy occur. The author and publisher of this work have
checked with sources believed to be reliable in their efforts to provide information that is accurate and
complete, and in accordance with the standards accepted at the time of publication. However, in light of
the possibility of human error or changes in the practice of medicine, neither the author, nor the publisher,
nor any other party who has been involved in the preparation or publication of this work warrants that the
information contained herein is in every respect accurate or complete. Readers are encouraged to confirm
the information contained herein with other reliable sources, and are strongly advised to check the product
information sheet provided by the pharmaceutical company for each drug they plan to administer.
The writing and production of this book have been conducted during early mornings, late nights, weekends,
and several vacations. Dr. Atris contributions to this book were conducted both outside his VA tour of
duty and his Massachusetts General Hospital/Harvard University/National Institutes of Health research
and clinical time. The contents of this book do not represent the views of the Department of Veterans Affairs,
the United States Government, Massachusetts General Hospital, or Harvard Medical School.
987654321
Printed in the United States of America
on acid-free paper
Dedication
To my mother and father, Jeannae and John Dickerson, who showed me the value
and joy of a lifelong love of learning; and my grandmother, Gladys Jastram, and my
great-grandmother, Tillie Sorensen, whose strength and kindness inspired me to try
to be compassionate in every interaction with patients and families.
Brad C. Dickerson
To my father Seyed Ali Atri, who showed me that giving is the greatest joy in
life and that optimism, resilience, and forgiveness are necessary choices; my uncle,
A.Hamid Ghodse, M.D., Ph.D., whose character, integrity, and humanity shine as
an eternal beacon to guide and emulate; and my aunt, Zahra Daneshmand, whose
unconditional kindness, generosity and love sustained and taught me what matters.
Alireza Atri
To all patients, families, caregivers, and colleagues who suffer from and continue to
battle these devastating conditions.
Brad C. Dickerson and Alireza Atri
Contents
The concept of dementia, defined originally to the clinical presentation, diagnosis has
as without mind or madness, has existed been difficult for many clinicians. In recent
since ancient times. The term referred to many years guidelines for diagnosis have been
mental disorders, including schizophrenia, developed for many of the dementias
which was originally termed dementia praecox. caused by neurodegenerative diseases, and
Gradually dementia became more associated they have helped to distinguish among the
with old age and was often termed senility or various dementias. The diagnostic guide-
senile dementia and was considered by many lines for dementias due to frontotemporal
to be a normal consequence of the aging pro- lobar degeneration, Lewy bodies, vascular
cess. However, it became more apparent late changes, and Alzheimers-related patholo-
in the 19th century and early 20th century gies are discussed at length in this volume by
that many dementias occurred earlier in life respected experts. In addition, the American
and were presenile. Others were revers- Psychiatric Association has issued a new ver-
ible or sometimes preventable such as the sion of the Diagnostic and Statistical Manual of
dementia caused by syphilis, if treated early. Mental Disorders (DSM-5) in which they pres-
In the mid-1970s Robert Katzman proposed ent neurocognitive disorders as major and
that presenile dementia and senile dementia minor, and have reclassified the dementias as
due to Alzheimers disease (AD) pathology major neurocognitive disorders.
very likely represented variations of the same In 2011, US President Obama signed the
syndrome differing only in age of onset. The National Alzheimers Project Act (NAPA),
term dementia as it is used now refers to pro- which prescribed the development of a
gressive and severe loss of cognitive abilities National Alzheimers Plan. To that end, a
that prevent affected persons from function- National Advisory Council on Alzheimers
ing normally in society no matter what their Disease was established and developed the
age or the underlying cause. Since AD is the plan, which was issued in May 2012 by the
most common form of dementia, research in Secretary of the Department of Health and
recent years has focused more on AD than Human Services. The United States is now
other dementias, even though they are some- one of about twelve nations that have issued
times closely related or even overlapping national plans. In addition, there are a num-
with AD. ber of subnational plans in various countries,
Because clinical differentiation among the including many state and provincial plans.
dementias is sometimes difficult in practice, The US National Plan, while focusing on
especially in early stages and, often, more Alzheimers disease, does include language
than one underlying cause may contribute addressing Alzheimers diseaserelated
xForeword
Dementia: Comprehensive Principles and illnesses become more prevalent. AD, the
Practice is a clinically oriented book that most common cause of dementia, is thought
has blossomed from the annual Dementia: to affect more than 5 million people in the
A Comprehensive Update continuing medical United States, nearly 1million people in the
education course offered by Harvard Medical United Kingdom, and similar numbers in
School. Now, in its eighteenth year in 2014, other developed nations. In 2010, low esti-
this 3- to 4-day course is organized by fac- mates for dementia-related costs accounted
ulty who specialize in the care of patients for greater than 1% of the world gross
with cognitive and behavioral disorders at domestic product. Without major cures,
Massachusetts General Hospital, Brigham projectionsin the United States as well
and Womens Hospital, McLean Hospital, as globallyestimate potentially crippling
and Edith Nourse Rogers Memorial Veterans dementia-related costs for world economies
Administration Bedford Hospital. We are in the coming decades. But since the authors
also fortunate to include a number of inter- of chapters in this book are all clinicians,
nationally renowned guest faculty from other we look beyond statistics; the devastation
major institutions. This course was begun by wrought by these illnesses upon each patient
Drs. David Caplan, Jeremy Schmahmann, and family is immeasureable. Unfortunately,
and Kirk Daffner in 1997; we are immensely even today with growing public awareness,
indebted to all of them for their mentorship dementing illnesses often escape early diag-
as we enter our fourth year of codirecting the nosis and appropriate clinical care, adversely
course. Motivated by the care of our patients impacting the patients, their families and
and their families, and inspired by the inte- caregivers, health carerelated costs, and
grative review of these topics by faculty and public health in a variety of ways, as dis-
the thought-provoking discussions generated cussed in detail in the following pages.
with attendees and colleagues, we developed This book is designed to improve knowl-
this book by working with course faculty and edge about dementia and competence in its
selected additional experts. clinical management, hopefully translating
Why do we need another book on demen- into improved early detection, accurate diag-
tia? Alzheimers disease (AD) and other nosis, and compassionate comprehensive
dementias are increasingly recognized as a care. Written primarily for clinicians, this
scourge of our time. Few of us will be spared volume takes a multidisciplinary approach
the personal or professional effects of these to understanding dementia and is aimed
conditions. As medical care continues to toward neurologists, psychiatrists, geri-
lengthen life span, these largely age-related atricians, psychologists, nurse specialists,
xiiPreface
internists, primary care physicians, social screening and the mental status exam by
workers, occupational therapists, clinical Mitchell and Atri; neuropsychological test-
pharmacists, research scientists, and other ing by Weintraub; the neuropsychiatry of
health professionals involved in the diag- dementias by Tayeb, Murray, and Price; and
nosis, management, and investigation of imaging and biomarkers in clinical diag-
disease states causing dementia. The orga- nosis by Dickerson. A thorough review of
nization of the book takes an integrative management issues concludes the volume
approach by providing three major parts that with chapters on future directions in phar-
(1)establish the neuroanatomical and cogni- macologic management of AD by Raffi and
tive framework underlying disorders of cog- Aisen; management of behavioral and psy-
nition and behavior, (2)provide fundamental chological symptoms of dementia by Ballard
as well as cutting-edge material covering and Corbett, and Ellison and Greywolf; non-
specific diseases associated with dementia, pharmacological approaches to symptom
and (3) discuss approaches to the diagnosis management by Verma; social service and
and treatment of dementing illnesses that caregiver/family-centered approaches by
are pragmatic and highly relevant to clinical Valois and Galvin; and medico-legal issues
practice. by Fogel.
Part I provides the basic cognitive and We hope that readers find value in not
anatomical foundation upon which the book only the cutting-edge discussions and
builds in subsequent sections. A conceptual evidence-based reviews of the literature by
framework of the functional and anatomi- leaders in the field but also appreciate the
cal organization of the cerebral hemispheres clinical wisdom conveyed by many highly
and their systems is provided by Caplan and experienced investigators and compassion-
Schmahmann, and then specific domains of ate clinicians. The topics relating to clinical
function are reviewed by Budson, Daffner, neurology, psychiatry, geriatrics, psychol-
and Willment, and Heilman, including mem- ogy, and neuroscience research discussed
ory, executive, and motor control systems of here directly bear on present and future
the brain. approaches to the diagnosis and manage-
Part II provides comprehensive reviews of ment of dementia. Specialists will find the
the major dementing diseases, starting with book to be an up-to-date reference work; gen-
Cortes Ramirez and Vonsattel on the neuropa- eralists will obtain valuable principles useful
thology of dementias and McKee on chronic in daily clinical practice; and trainees will be
traumatic encephalopathy. We then continue treated to a one-stop source for learning
with new clinical and basic science concepts the scientific basis of the field of dementing
of frontotemporal dementia and primary pro- diseases, and clinical methods and pearls on
gressive aphasia by Dickerson and Mesulam; how to effectively and compassionately care
posterior cortical atrophy by Tang-Wai, Lake, for patients and caregivers who are affected
and Graff-Radford; parkinsonian demen- by these highly challenging diseases.
tias by Lessig, Litvan, Hanagasi, Bilgic, Appropriate dementia care takes a vil-
and Emre; vascular dementias by DeCarli; lagea village of well-informed and inter-
and cerebral amyloid angiopathy by Etten, ested multidisciplinary clinicians and
Greenberg, and Viswanathan, concluding caregivers. We have endeavored in this book
with rare and rapidly progressive dementias to collate the essential and latest information
by Schmahmann. Finally, a comprehensive and tools to allow our colleagues to better
update is presented by Atri, Wicklund, and affect this comprehensive care in the relent-
Petersen, and Sperling on the AD spectrum less battle against the havoc wreaked by the
from dementia to mild cognitive impairment effects of the dementias. It is a battle that
and preclinical AD. This part contains a par- is not only worthy and noble but is also an
ticular emphasis on the highly contemporary imperative derived from our responsibilities
issues, including the new diagnostic criteria as clinicians to adhere to the principles of
for many of these disorders published in the medical ethics: nonmaleficence, beneficence,
last few years. autonomy, and justice. It is a battle, which
Part III concludes the book with chapters when properly waged, can allow major vic-
focusing on evaluation and management, tories in a small minority, minor victories
including a clinical approach to cognitive in the majority, and meaningful benefits by
Prefacexiii
ameliorating suffering in all. Until we can Joseph Locascio, Barbara Maxam, Dorene
cure, we will care and help in anyway we Rentz, Bruce Rosen, Janet Sherman, Chantal
can, and this book is part of our small contri- Stern, Nagagopal Venna, Liang Yap, Anne
bution to this ongoing effort. Young, Steven DeKosky, Rachelle Doody,
We greatly appreciate the work by our and Dan Mungas. Most important, for their
coauthors, who took time out from their love, support, and positive influences in our
usual activities to contribute to this volume. lives, we thank our families. Brad Dickerson
The efforts of Craig Panner and Marni Rolfes thanks Allison Berger, Molly Dickerson,
at Oxford University Press were invaluable Lilly Dickerson, Jeannae Dickerson, John
in helping us to transform the materials here Dickerson, Jim Dickerson, Sarah Dickerson,
from a course syllabus into the book you are Lewis Berger, Ileana Berger, and Stacie and
reading. Anumber of our friends and mem- the Siebrecht family. Alireza Atri thanks
bers of our laboratories were kind enough to his family and friends, particularly Natalie
provide expert assistance in reviewing and Atri, Taraneh Atri, Bijan Atri, Seyed Ali Atri,
editing drafts of chapters, especially Lynn Nasrin Daneshmand, Ali Atri, Erik, Karine,
(Lili) Shaughnessy, Meghan Mitchell, Steven Lukas and Caroline Alexander, Abbas Atri,
Shirk, and Jessica Dodd. More broadly, Mehrnaz Atri, Glen and Betsy Chatfield,
we thank our mentors whose guidance Wayne and Grace Chatfield, Wayne
and encouragement provided formative D.Chatfield, Ramin and Homa Daneshmand,
influences on our thinking and approach Zahra Daneshmand, Tim Duffy, Hamid,
to patient/family care. Brad Dickerson Barbara, Hossein, Nassrin and Ali-Reza
extends special thanks to the following men- Ghodse, Mansour, Shahnaz, Ellie and Arie
tors and colleagues: Tony Phelps, Sheryl Farahabadi, James Ford, Jessica Ford, Ian
Williams, Bill Greenough, Theresa Jones, Fullmer, Andrew Kayser, Jennifer Harris,
Leyla deToledo-Morrell, Frank Morrell, Jeff and Brenda McConathy, Sally Miller,
Marsel Mesulam, Sandy Weintraub, Martin Tracey and Jeff Milligan, Mahin Moeinazad,
Samuels, Marilyn Albert, Reisa Sperling, Mary Norman, Homa, Vahid and Hamid
Kirk Daffner, Deborah Blacker, Brad Hyman, Noshirvani, Michael Opre, Tahereh Shirvani,
John Growdon, David Caplan, Bruce Price, and Abbas Taheri. We also thank each other
Merit Cudkowicz, Bruce Rosen, Janet for the inspiration, encouragement, and wise
Sherman, Dorene Rentz, Keith Johnson, counsel during this processthe process
Barbara Maxam, Diane Lucente, Rudy and product would not have been nearly as
Tanzi, Matthew Frosch, Bruce Miller, Bill fun or fruitful without the balance, motiva-
Seeley, David Wolk, Lisa Feldman Barrett, tion, and support we provided each other.
and Anne Young. Dr. Dickerson also thanks Last but not least, we acknowledge, with
Liz and George Krupp for their generous great humility, a deep gratitude for the privi-
support. Ali Atri offers special thanks the lege of being entrusted, by thousands of our
following mentors and colleagues: John patients, their families and caregivers, the
Growdon, Reisa Sperling, Martin Samuels, awesome responsibility of counseling and
Daniel Lowenstein, John Engstrom, Cheryl caring for them. We have learned immensely
Jay, Joseph Martin, James Sneyd, Carol from listening and caring for you, and will
Newton, David Caplan, Jang-Ho Cha, unfailingly carry forth this inspired legacy
Merit Cudkowicz, Kirk Daffner, Steven to help others, regardless of their circum-
M. Greenberg, Fran Grodstein, Michael stances, to live their lives better and to dili-
Hasselmo, Albert Hung, Michael Irizarry, gently work towards treatments andcures.
Human beings are members of a whole,
In creation of one essence and soul,
If one member is afflicted with pain
Other members uneasy will remain.
If you have no sympathy for human pain,
The name of human you cannot retain
Saadi Shirazi (Persian/Iranian poet, 11841283)
To cure sometimes
To help often
To console always
Medical proverb of unknown originhas been attributed
to several physicians including Trudeau, Pare and Hippocrates
Hippocrates (Greek physician, 460370 b.c.)
Contributors
(A) (B)
O O X O O X
X O O
X X X X
O X
X X O X O
O O O O
O O X
X X O X X
O OX O O X
X O X O X O
O O O X
X O X O
(C)
rch
n sea
ctio
jun
Reaction time
Con
Pop-out search
2 4 6 8 10 12 14 16
Set size
Figure1.18 Conjunction and pop-out search. In both A and B, the task is to determine whether a red circle is
present. In A, the target is defined as the feature in red; in B, the target is defined by the conjunction of red and
circle. In C reaction time is shown for correct detections of present stimuli as a function of set size, consistent with
parallel search not requiring serial deployment of attention in A and requiring serial deployment of attention in B.
Figure1.19 Cartoon of location of the major cognitive systems in the lateral human cortex.
4
8 3 5
6 1 7
9 2
40 19
10 46 41 39
43
45 44 18
47 52 22 42 17
11 37 19
38 21
20
31
6 4 2
5
8
7
9 24
23 31
32
10 33 30 19
28
12 27 29 18
11 25 17
34 35
36 19 18
38 28 37
20
Motor/Premotor
Hetermodal Association
Paralimbic
Figure3.1 Divisions of the frontal lobe. Figure adapted from Mesulam (1986).
+18 4 VLPFC +48
DLPFC
dACC
HT TP lateral
PAG parietal
FI FI
+4 +6 pre-SMA
DMPFC
+12
Figure3.3 Salience and executive control networks revealed through intrinsic connectivity mapping. Image
adapted from Seeley etal., 2007.
IPS/SPL FEF
AG SMG
V3A IFJ
IFJ
IFG
STG
MT Ins
5 3 3 5
z-score functional connectivity
Dorsal attention network Ventral attention network
Figure3.4 Dorsal and ventral attention networks. Image adapted from Corbetta & Shulman (2011).
Supplementary
motor area
Basal ganglia
(putamen)
Prefrontal
cortex
Inferolateral
temporal lobe
Cerebellum
Semantic memory
Procedural memory
Working memory
Figure 4.9 Semantic, Procedural, and Working Memory. The inferolateral temporal lobes are important in the
naming and categorization tasks by which semantic memory is typically assessed. However, in the broadest
sense, semantic memory may reside in multiple and diverse cortical areas that are related to various types of
knowledge. The basal ganglia, cerebellum, and supplementary motor area are critical for procedural memory.
The prefrontal cortex is active in virtually all working memory tasks; other cortical and subcortical brain regions
will also be active, depending on the type and complexity of the working memory task. In addition to being
involved in procedural memory, the cerebellum is also important for the motoric conditioning. (From Budson
and Price, 2005; permission granted by the New England Journal of Medicine.) (See color plate section)
(A) (B)
Figure6.4 Hallmarks of Alzheimers disease neuropathology:(A) neuritic plaques (about 180m in diameter;
each one replaces an estimated 106 synapses and about 100 neurons). The centrally located core is made up
of aggregates of amyloid-, which results from incomplete degradation of a trans-membrane protein present
in nerve terminals called amyloid- precursor protein (APP). The gene for APP is located on chromosome 21.
(B) Neurofibrillary tangles of Alzheimer and neuropil threads (argyrophilic neurons and threads) consist of
intracellular accumulation of paired helical filaments caused by the hyperphosphorylation of tau. Tau protein is a
phosphoprotein that binds to and promotes polymerization and stability of microtubules. The tau gene is located
on chromosome 17. (Bielschowsky silver stain; original magnification, 630)
(A) (B)
Figure6.5(A) Formalin fixed, lateral aspect of the left half brain of a 53-year-old patient with frontotemporal
lobar degeneration (classical Picks disease). Note the prominent circumscribed atrophy involving the frontal
lobe, rostral temporal lobe, and the inferior parietal lobule. Although atrophic, the pre- and postcentral
gyri, the caudal two thirds of the superior temporal gyrus, and occipital lobe are relatively preserved. (B)
Microphotograph of Pick body containing pyramidal neurons of the third layer of the motor cortex. Pick bodies
are argyrophilic, are labeled with AT8 antibodies directed against phosphorylated tau, or with antibodies
directed against ubiquitinated proteins. They are not labeled with antibodies directed against -synuclein
aggregates, which is in contrast to Lewy bodies. (Bielschowsky silver stain; original magnification, 400)
Figure6.8 Lewy body (brainstem type) is usually round, 830m in diameter, and consists of a cytoplasmic,
hyaline core with or without concentric lamellar bands, and with a peripheral, pale halo. These two Lewy body
containing neurons are from the nucleus coeruleus. One of them has two round Lewy bodies (lower left). The
other has a somewhat bilobulated Lewy body with a visible, basophilic, and dark core (upper right). (LHE stain;
original magnification, 630)
(A) (B) (C)
Figure7.2 Distinctive pattern and morphology of tau immunoreactive neurofibrillary pathology in chronic
traumatic encephalopathy. (A) Tau immunoreactive neurofibrillary degeneration is often most striking at depths
of the sulci accompanied by focal thinning of the cortical ribbon (AT8 immunostain, original magnification, 60).
(B) Subpial tau immunoreactive tangles are found in both neurons and astrocytes (double immunostained section
for GFAP [red] and AT8 [brown] showing colocalization of tau and GFAP [arrow]; original magnification, 350).
(C) Extremely dense NFTs and neuropil neurites are found in the medial temporal lobe structures, including
CA1 of the hippocampus, shown here. Senile plaques are absent (AT8 immunostain, original magnification,
150). (D) NFTs and astrocytic tangles tend to be centered around small blood vessels and in subpial patches
(AT8 immunostain, original magnification, 150). (E) NFTs characteristically involve cortical layers II and III in
association with clusters of tau-positive astrocytic processes (AT8 immunostain, original magnification, 150).
(F)NFT in a Betz cell of primary motor cortex (AT8 immunostain, original magnification, 350). (G) There is often
a striking perivascular clustering of NFTs around small blood vessels (AT8, original magnification, 150).
ALZHEIMERS DISEASE
Figure7.3 How the p-tau pathology of chronic traumatic encephalopathy is distinctive from Alzheimers disease.
(Top row) Alzheimers disease:Double immunostained sections for A (red) and PHF-1 (brown) show diffuse,
relatively uniform cortical distribution of NFTs preferentially involving laminae III and V, without accentuation at
depths of sulci. Small blood vessels at sulcal depths show no clustering of neurofibrillary pathology perivascularly.
There is also no clustering of neurofibrillary pathology in subpial or periventricular regions. (Bottom row) Chronic
traumatic encephalopathy:Sections immunostained for AT8 showing irregular cortical distribution of p-tau
pathology with prominent subpial clusters of p-tau astrocytic tangles, focal accentuation at depths of sulci, and
distribution of NFTs in superficial cortical laminae I-III. Small blood vessels at bottom of cortical sulcus show
prominent perivascular distribution of astrocytic tangles and NFTs (AT8). Double immunostained section for A
(red) and PHF-1 (brown) (center panel) shows dense NFTs without A deposition.
(A) (B) (C)
100 m 100 m
100 m
Figure7.4 The phosphorylated TDP43 pathology of chronic traumatic encephalopathy (CTE). (A, B, D, and E)
Dense pTDP-43 abnormalities are found in the cerebral cortex of stage IV CTE. (C) Dense pTDP-43 pathology
in substantia nigra pars compacta. (F) Pronounced pTDP-43 immunopositive pathology in the periventricular
region of the third ventricle. (All images:50m tissue sections; all scale bars, 100m)
(A) (B)
*
(C) (D)
Figure7.5 The axonal pathology of chronic traumatic encephalopathy (CTE). (AC) Phosphorylated
neurofilament staining (SMI-34) in cerebral white matter of stage III CTE shows marked reduction in axonal
staining and numerous large, irregular axonal varicosities. Asmall arteriole shows marked infiltration with
hemosiderin-laden macrophages (asterisks). (D) Luxol fast hematoxylin blue-stained section of white matter
shows brisk astrocytosis, loss of myelinated fibers, and macrophages around vessel (asterisk). (10m tissue
sections; scale bars:100m)
(A) (D)
(B) (E)
(C) (F)
Figure 8.1 Tau pathology in a case of classical Picks disease prominently affects neuronal and glial cells in
gray matter (A, labeling with AT8 [phosphorylated tau] immunohistochemistry) and also usually demonstrates
prominent abnormalities in white matter (B, labeling with AT8 immunohistochemistry) of frontal and temporal
cortices, including the dentate gyrus of the hippocampus, with sparing of primary cortices particularly Heschls
and calcarine cortex (C, absent labeling with AT8 immunohistochemistry). The hippocampus (D, low-power
hematoxylin and eosin stain) also classically shows dense, smooth-contoured rounded cytoplasmic inclusions
in granule cells of the dentate gyrus (E, high-power hematoxylin and eosin stain), which are labeled with AT8
immunohistochemistry (F).
(A) (B)
RH LH
RH - Lateral
Figure8.3 A58-year-old man presented with behavioral symptoms (including apathy, impulsive eating) and
executive dysfunction. (A) Magnetic resonance imaging (MRI) demonstrated bilateral (right greater than left)
frontal, temporal, and parietal atrophy, quantified with a map of cortical thickness compared to controls. (B)
Fludeoxyglucose positron emission tomography (FDG-PET) showed prominent bilateral (right greater than left)
frontal and temporal hypometabolism. This man was found to have a Q300X (premature termination) mutation
in GRN. He exhibited a 5-year clinical course from first symptoms to death. Postmortem examination revealed
the expected TDP-43 pathology.
Left, Lateral
Figure8.4 A59-year-old man presented with behavioral symptoms (including loss of empathy, aggression, lack
of insight), executive dysfunction, and word-finding difficulties. Shortly thereafter he developed dysarthria and
dysphagia and was found to have clinical evidence of motor neuron disease with bulbar predominance (tongue
weakness, fasciculations, lip weakness, as well as mild shoulder weakness and fasciculations with lower extremity
hyperreflexia and extensor plantar responses). Electromyography showed sharp waves, fibrillation potentials, and
fasciculation potentials in cervical, thoracic, and lumbar myotomes with long-duration, high-amplitude polyphasic
potentials with reduced recruitment and rapid firing. (A) Magnetic resonance imaging (MRI) demonstrated
bilateral (left greater than right) frontal atrophy, quantified with a map of cortical thickness compared to controls.
He exhibited a 3.5-year clinical course from first symptoms to death. (B) Postmortem examination revealed the
expected TDP-43 pathology (TDP-43 immunohistochemistry of dentate gyrus of hippocampus).
(A) (D)
(B)
(E)
(C)
Figure8.5 A50-year-old man presented with unilateral dominant hand apraxia and depression without
rigidity, alien hand syndrome, or eye movement abnormalities, followed shortly by executive dysfunction,
word-finding difficulty, and memory loss. The initial neuroimaging examination revealed markedly asymmetric
dominant hemisphere fludeoxyglucose positron emission tomography (FDG-PET) hypometabolism (A, B, C,
left column) and atrophy (A, B, C, right column) extending from perirolandic and dorsal parietal cortex (A) into
perisylvian cortex (B) and ventral temporal cortex (C) with relative preservation of frontal cortex and striatum.
His symptoms progressed to include marked upper extremity apraxia with the eventual development of rigidity,
aphasia, dysarthria, episodic and semantic memory impairment, compulsive behavior, impulsive eating, and
agitation. Along with the progression of symptoms, atrophy progressed from (D) parietal and posterolateral
temporal over a 4-year interval to include (E) ventral and anterior temporal, insular, and posterior frontal cortex.
(A) (B)
(C) (D)
Left Lateral
Figure8.6 The 50-year-old man described in Figure8.5 exhibited an 8-year clinical course from first symptoms
to death. Despite (A) the clear magnetic resonance imaging (MRI) evidence of initial perirolandic and
parietotemporal atrophy (left greater than right), quantified with a map of cortical thickness compared to controls
with (B) postmortem support for these gross findings, histological examination revealed (C) Pick bodies and (D)
tau immunoreactive pathology consistent with pathological Picks disease.
11.97
CMRglc
1 2 3 4 8.98
5 6 7 8
5.99
9 10 11 12 2.99
13 14 0.00
Figure10.2 Positron emission tomography (PET) scan of a fourth patient with posterior cortical atrophy
demonstrating parietal and occipital hypometabolism.
(A) (B)
Figure14.1 Pathologic appearance of cerebral amyloid angiopathy. (A) Amyloid deposits replace media and
smooth muscle cells causing thickening of the vessel wall (hematoxylin& eosin; original magnification, 20). (B)
Immunoperoxidase staining for amyloid- peptide showing circumferential staining of leptomeningeal blood
vessels (original magnification, 20). (Images courtesy of Dr.Matthew P.Frosch, MGH)
(A) (B) (C)
0 1 2 3 4
Figure17.4 Fludeoxyglucose positron emission tomography (FDG-PET) in mild cognitive impairment (MCI).
Axial section of FDG-PET scans in a cognitively normal individual (A) and individuals with MCI (B) and
dementia (C). Red indicates the greatest areas of metabolism, while blue and black are the least. FDG-PET
hypometabolism is a marker of neuronal injury and dysfunction. Bilateral temporoparietal hypometabolism is
noted in MCI (B, white arrows) and even more so in dementia (C, white arrows) due to Alzheimers disease and
is indicative of an increased rate of progression from MCI to dementia.
0 2 4
Figure17.5 Amyloid imaging in mild cognitive impairment (MCI). Axial section of PiB-PET scans in a
cognitively normal individual (A) and individuals with MCI (B) and dementia (C). PiB is a positron emission
tomography (PET) tracer useful for detecting amyloid deposition in the brain. Brain areas where amyloid is
absent appear blue; brain areas with the greatest tracer uptake appear red, while areas with less tracer uptake
appear green or yellow. Amyloid deposition of the white matter, but not gray matter, is seen in cognitively
normal individuals, creating a clear contrast in radioactivity between gray and white matter (A, short arrow).
When amyloid is deposited in the cortices, as occurs in MCI (B, long arrow) and dementia (C, long arrow) due
to Alzheimers disease, diffuse reduction or loss of the normal gray-white contrast is noted. Amyloid deposition
occurs early in the pathological cascade and before development of symptoms, creating relatively similar
distribution and concentration of deposition between the MCI and dementia subjects.
Abnormal A
Tau-mediated neuron injury and dysfunction
Brain structure
Memory
Clinical function
Biomarker magnitude
Cut points
Normal
Cognitively normal MCI Dementia
Clinical disease stage
Figure17.6 The evolution of biomarkers in the Alzheimers pathological cascade. With the early deposition
of amyloid in the pathological cascade, corresponding biomarkers (low cerebrospinal fluid [CSF], A declines,
and positive amyloid imaging) are detected before the development of clinical symptoms. Following this, there
is a sequence of events characterizing neurodegeneration where evidence of brain dysfunction can be measured
through CSF tau levels or fludeoxyglucose positron emission tomography (FDG-PET). As memory and clinical
function decline, structural changes of the brain are noted on magnetic resonance imaging (MRI). MCI, mild
cognitive impairment. (Reprinted from The Lancet Neurology, Vol. number 9, Clifford R Jack, David S Knopman,
William J Jagust, Leslie M Shaw, Paul S Aisen, Michael W Weiner, Ronald C Petersen, John Q Trojanowski.
Hypothetical model of dynamic biomarkers of the Alzheimers pathological cascade, pages 119128. Copyright
(2010), with permission from Elsevier)
Abnormal
Amyloid- accumulation (CSF/PET)
Synaptic dysfunction (FDG-PET/fMRI)
Tau-mediated neuronal injury (CSF)
Brain structure (volumetric MRI)
Cognition
Clinical function
Normal
Preclinical MCI Dementia
Lateral
Medial
Figure 22.3 Computational neuroscience now offers methods to quantify aspects of brain structure from
magnetic resonance imaging (MRI) scans. The left image depicts cortical thickness measurement from a
T1-weighted MRI scan. The right image shows a map of the areas in yellow and red where the cerebral cortex is
thinner in a group of mild Alzheimers disease dementia patients compared to controls.
Figure22.6 In mild Alzheimers disease, cortical glucose metabolism is typically reduced in the
temporoparietal region, as well as posterior midline and orbitofrontal regions. This now classic finding is
useful clinically in differential diagnosis and may be valuable as an imaging biomarker for early detection of
the metabolic signature of the disease in patients with minimal or no symptoms. This figure shows the largest
reduction in metabolism in yellow, with lesser reductions in red hues from a single patient with mild AD,
displayed on that patients cortical surface as reconstructed from the anatomic magnetic resonance image. Areas
without color exhibited normal metabolism compared to age-matched cognitively intact individuals.
Figure22.7 Fludeoxyglucose positron emission tomography (FDG-PET) can be very useful in the clinical
evaluation of patients with dementia, particularly for the differentiation of Alzheimers disease (AD) versus
frontotemporal dementia (FTD). (A) Cognitively normal older adult; (B) mild AD dementia patient; (C) mild FTD
dementia patient. (Images courtesy of Dr.Keith Johnson, Massachusetts General Hospital)
(A) (B)
Figure22.8 Amyloid positron emission tomography (PET) imaging is revolutionizing dementia research. Pittsburgh
compound B (PiB) scan of (A) a cognitively intact 74-year-old adult demonstrates nonspecific binding (negative),
while a scan of (B) a 73-year-old patient with mild Alzheimers dementia shows robust signal throughout multiple
cortical areas (positive). (Images courtesy of Dr.Keith Johnson, Massachusetts General Hospital)
(A) (B)
Figure22.10 Case 1.Magnetic resonance imaging (MRI) and positron emission tomography (PET) often
provide a reasonably convincing set of biomarkers in early-onset or atypical dementia patient evaluations. In
this 39-year-old woman with familial dementia initially thought to be frontotemporal dementia, (A) an MRI
scan showed relatively mild medial temporal lobe atrophy but prominent bilateral parietal atrophy, and (B) a
fludeoxyglucose positron emission tomography (FDG-PET) scan showed prominent bilateral temporoparietal
hypometabolism, supporting the diagnosis of Alzheimers disease (AD). She was later found to carry a PSEN1
mutation and ultimately was determined to have AD pathology at autopsy.
(A)
(B)
(C)
Figure22.11 Case 2.Serial magnetic resonance imaging (MRI) scans 3years apart show rapid progression of
frontotemporal atrophy in this 31-year-old man who died of frontotemporal dementia at age 33. (A) Aseries of
coronal FLAIR MRI images demonstrates left greater than right temporal lobe atrophy at a time when symptoms
were clearly present but overall function was mildly impaired. (B) Asimilar series of coronal T1-weighted MRI
images demonstrates marked progression of frontal, insular, and temporal atrophy with parietal involvement
at a time when the patient was minimally communicative and dependent for most activities of daily living.
(C) Postmortem histology demonstrated neuronal and glial cell loss with prominent tau immunohistochemical
abnormalities (left), including Pick bodies (middle). The hematoxylin and eosin stained sections (right) also
clearly demonstrated cellular inclusions typical of Pick-type tauopathy.
CSF
amyloid-
level
Figure22.12 Case 3.Biomarkers in a 54-year-old woman with mild cognitive impairment with a clinical
presentation suggestive of frontotemporal dementia. (A) Magnetic resonance imaging (MRI) showed a hint of
hippocampal atrophy unilaterally but was otherwise normal. (B) Fludeoxyglucose positron emission tomography
(FDG-PET) demonstrated bilateral (left greater than right) temporoparietal hypometabolism suggestive of
Alzheimers disease (AD) pathobiology. (C) Cerebrospinal fluid biomarkers were strongly consistent with AD
pathobiology.
Part I
3
4 part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
unexpected, and so on leads the person to the the concept TABLE and the concept TABLE
conclusion that, in order to satisfy the desire, represents real tables. Put somewhat more
she should get up at 7:15. This leads to the formally, it is possible to evaluate whether
behavior of setting an alarm clock for 7:15. the use of table to refer is satisfied by a
Contrast this way of affecting behavior particular item. The word table also enters
with other determinants of behavior, such as into computations that retain the informa-
biological states (e.g., being hungry) and emo- tion table conveys, based upon its form
tional states (e.g., being sad). Biological states (not based on what it represents). The rules
lead to behaviors that one might characterize of language allow the word table to be
as resetting biological parameters:being hun- modified by the word red, itself a repre-
gry leads to eating, and being sleepy leads to sentation of the concept of the color red, to
sleeping. Emotions affect what are here called produce the phrase red table, a representa-
attitudes. Being sad (or happy) may affect tion that retains a connection to both redness
your desire to go to NewYork. Neither bio- and tables. This view of representations is the
logical states nor emotions affect behavior by one expressed in Fodor (1998); readers famil-
constituting the content of beliefs or by deter- iar with Turings (1936) work will recognize
mining the relations between the contents his seminal idea of the computational roles of
of beliefs that enter into the chains of logic items being determined only by their syntac-
and association that underlie the relation of tic properties.
beliefs to behaviors. Emotions may affect the The second way of defining/describing
formation of beliefs (e.g., if a person is afraid cognitive processes is as processes that oper-
of dogs, he may find it harder to believe that ate on categories. A category is a substan-
Fido is harmless), but they do not constitute tive (as opposed to logical) term in a theory
the content of beliefs. of some domain (i.e., understanding of the
These intuitions suggest that there are dif- workings of that domain). Lightning is a
ferent types of forces that affect behavior, category because it is a substantive term in
but they do not provide a general answer to a theory (i.e., in a persons understanding)
the question of what cognitive processes are. of climate.1 Seeing a flash of light as a bright
One way to put the question is: What is it white irregular form is a sensory response to
about a belief that makes having one being in a particular stimulus, but seeing a flash of
a cognitive state, as opposed to an emotion, light as a lightning bolt is an act of perceptual
being affected by which does not put one in identification that categorizes the sensory
a cognitive state? One possible answer is that information. What makes categories special
cognitive processes are processes that oper- is that we know things about them that we
ate on representations. The second is that can exploit for other purposes. Having per-
cognitive processes are processes that oper- ceived a flash of light as a lightning bolt, a
ate on categories. Although both of these def- person knows a lot about the event, and
initions/descriptions may be inadequate in this knowledge can result in behavior in the
part because they may not delineate a set of same way as what was described previously
processes that fall together in a justifiable tax- regarding setting an alarm. A person can
onomy of psychological/neurological states think lightning is a prelude to rain; I will
and processes, they will nonetheless frame count the seconds until I hear thunder and
the discussion because they provide insight know when rain will start, which will lead
into elements of cognition. to taking cover at a particular time.
A representation is an expression that has These definitions/descriptions of repre-
two components: It conveys information sentation and category have some desirable
about something else, and it is possible to features. For instance, the description of rep-
perform operations on it that preserve the resentations excludes items such as smoke as
information that it conveys. In philosophi- a representation of fire, or rings of a tree as
cal terms, it is semantically evaluable (it is representations of the age of the tree. These
possible to determine its reference, exten- items are semantically evaluable (smoke and
sion, truth) and it enters into a computational tree rings convey information about fire and
system by virtue of its syntactic features. tree age, respectively, with some degree of
For instance, a word is a representation. Put reliability), but they do not enter into com-
very informally, the word table represents putational systems based on their forms. The
CHAPTER 1. Cognitive Functions and the Cerebral Cortex 5
description of cognitive processes as operat- information. They operate in sets that con-
ing on categories as defined draws a line at stitute perceptual, motor, memory, and
points that seem reasonable. For instance, if language systems. Control operations set pri-
the output of on-center off-surround retinal mary operations into action, stop and inhibit
ganglion cells can be described as a circle, them, and shift the mind/brain to other
and circle is a category in theories of object operations. Control and primary operations
recognition, the process of transforming the work in tandem on a time scale of at least
output of rods and cones to the output of reti- hundredths of a second.
nal ganglion cells is cognitive.2 This would Covering all cognitive systems, or even
imply that operations that occur very early in one in any depth, is not possible. The opera-
the perceptual process and some that oper- tions of the system that recognizes objects
ate very late in motor execution are cognitive. will be outlined next as an example of a pri-
This seems to be a perfectly reasonable con- mary cognitive system; then a simple task
clusion, insofar as it allows many operations will be described in which object recognition
that are part of specific cognitive domains is required to illustrate the nature of control.
to be considered cognitive. However, not
all operations are cognitive:Transduction of
energy at sensory receptors is not a cogni- Perceptual Identification, Recognition,
tive process, even though it is the first step andCategorization of Visually
in a process that eventuates in categories, PresentedObjects
because the output of a receptor is not itself
a category.3 When compared to other cognitive processes
This effort to define cognition likely (e.g., thinking logically, making decisions
raises more questions than it answers, but it about major life issues, writing a paper), per-
may be useful to review some of the consid- ceptual identification and categorization of
erations that arise when we try to determine visually presented objects appear to be very
what we mean by the term; this introduces simple. However, this process is more com-
concepts such as representation, category, plex than one might think, and it illustrates
and computation based on formal properties how complex even the simplest cognitive
of an item that are ubiquitously associated processes are. The description that follows
with cognitive functions. outlines the major aspects of this process.
Moving on from these abstract consider- The process of perception of visually pre-
ations to actual practice, the term cognitive sented objects begins with transduction of
is applied to a wide set of functions. A par- light by cones and rods in the retina. This
tial list includes the abilities to categorize first step has two properties that determine
elements in the world, to relate categories to much of the process of perceptual iden-
one another, to consciously retrieve events tification. The first is that visual features
and facts from memory, to reason, to com- of the object are segregated at the visual
municate, to set criteria for acting, to plan receptors: Cones are sensitive to color and
actions, and to estimate and monitor the con- rods are not; this requires that later opera-
sequences of ones actions on the physical tions integrate these separated visual ele-
and social world. Cognitive processes rank ments into a single item. The second is that
among the most important of the determi- a three-dimensional object in the world is
nants of human behavior, are the most impor- projected onto the two-dimensional retinal
tant factor in determining the success of the surface; this requires that later operations
human species as a whole, and are arguably reconstruct the three-dimensional object
the most important factor in determining the from its two-dimensional projection.
success of the individual in his or her social Neurologically, the separation of visual
setting in modern industrial and postindus- features of objects continues through lateral
trial societies. geniculate, visual koniocortex (V1), and uni-
At the psychological level, we can distin- modal visual association cortex, in the selec-
guish two main types of cognitive opera- tive sensitivity of magno- and parvo-cellular
tions: primary and control operations. neurons, blobs, interblobs, and other ana-
Primary operations are the basic processes tomically identifiable groupings of neurons.
that activate, transform, store, and retrieve Visual features are derived from complex
6 part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
Figure1.1 Color constancy. The color patches in the top and bottom figures are the same but are
matched differently across the left and right rectangles as a function of the color of the background.
(See color plate section)
Proximity Closure
Good Continuation
a c
d b
Figure1.2 Gestalt principles of proximity, closure, and good continuation. Dots spaced closer
together are seen as lines; lines that form closed shapes are seen as related; lines that are slowly
curved (a-b; c-d) are seen as continuous, while lines that form sharp angles (a-c; b-d) are not.
description. Astructural description can be elongation and distinctive visual features are
thought of as the equivalent, in the domain displayed, and that objects displayed in other
of visual object recognition, of a long-term projections are mentally rotated to match
memory of the form of a word. Just as it is these canonical representations (Fig. 1.8)
necessary to recognize a written or spoken (Humphreys & Riddoch, 1987).
item as a word to access the meaning and Structural descriptions must be sufficiently
other features of that word, it is necessary general to allow visually different items of
to recognize the form of a visually presented the same sort to be perceptually identified as
object to access other features of that object. instances of the same type of an object, and,
This process may be called perceptual at the same time, sufficiently constraining
identification. to exclude items that are similar but not of
There is considerable debate about what the same sort. For instance, each snowflake
structural descriptions of objects consist of. is unique and the structural description of a
Neuropsychological data have been inter- snowflake must be sufficiently broad to allow
preted as suggesting that structural descrip- all snowflakes to be mapped onto it but also
tions are idealized object-centered depictions sufficiently constraining to stop items with
of objects in a canonical projection in certain similarities to snowflakes from being
which the principal axes of symmetry and recognized as snowflakes (e.g., tiny paper
Figure1.3 Shape derived from texture cues. The picture shows a camouflaged flounder.
8 part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
R L R
0 deg
1 2 3 4
10
7
5
6
4 5 6
10
7
7 8 9 8
10
10
10 11 12 4
4
1
Failed to name
(A) (B)
(C) (D)
Copying
Figure1.9 Integrative agnosia. The patient could not name objects in A. Copy (B) is focused on
visually salient features that are misinterpreted with respect to the object. Drawing from memory
(C) is excellent. The deficit lies in perceptual identification of visually presented objects.
believe there are separate semantic memory may not be part of a persons concept of cars.
systems for visual and nonvisual features of This last point leads to a discussion of what
objects (Paivio, 1986). Second, none of these concepts are (note that the ideas of concepts,
features are part of the structural description categories, and word meanings are highly
of a car; they are all accessed through a struc- related).
tural description, according to the model pre- Thinking on the part of clinically oriented
sented. Third, any one of these features may or neurologists about concepts, and the related
CHAPTER 1. Cognitive Functions and the Cerebral Cortex 11
question of the meaning of words, has been properties of a concept) are those that are
heavily influenced by British empiricist phi- individually necessary and jointly sufficient
losophy, which emphasized the associations to classify an item in a category (Aristotle,
between information derived from differ- 1995). This formulation encounters a major
ent sensory modalities in forming a concept problem in practice:The features that are nec-
(Geschwind, 1965a, 1965b). Though there is essary and sufficient for a concept are hard
no agreement about the answer to the ques- to determine. For natural categories, we can
tions What are concepts? and What are turn to experts in the relevant science, but sci-
word meanings?, the philosophical and psy- ence is always incomplete. For human-made
chological literature clearly shows that the items, it is even less clear what these features
view of concepts and word meanings as com- are. Thousands of years of study have failed
binations of perceptual and motor features is to identify such features for almost any non-
too narrow, for two reasons. natural concept (Wittgenstein [1921/1961]
First, concepts are not just combinations of famously discussed the concept game).
features in instances of a concept that have Many alternatives to the Aristotelian view
been experienced, since we can classify new have been proposed (see Margolis and
instances as falling under a concept. It may be Laurence [1991] for readings). One com-
the case that a person has only encountered monly invoked alternative is that concepts
tables made of wood, or tables that cost less are determined by prototypes, whose fea-
than $3,000, but his or her concept of tables tures are not necessarily necessary and suf-
need not include the property made of ficient to determine a concept but are typical
wood or costs less than $3,000; these can be of items that fall under the concept. The idea
considered to be incidental properties of tables that concepts are determined by a prototypi-
that he or she has experienced. Concepts are cal instance and a metric that determines the
counterfactually supporting:If conditions x1 distance of any item from the prototype in a
xn instantiate a concept, the concept would be multidimensional space accounts for a great
instantiated if conditions x1xn occurred, even deal of psychological data regarding recogni-
if those conditions never could occur. If light tion and memory of items. It does, however,
rays could be manipulated to allow objects to have significant limitations. The most impor-
come to a stable position on a surface paral- tant limitation is that prototypes of concepts
lel to the ground (and if something that allows do not combine to form other concepts. The
objects to come to a stable position on a sur- prototypical fish for most Americans is per-
face parallel to the ground is a table), a table haps a trout, perch, salmon, or some other
could be made of light rays (the problem with medium-sized fish; the prototypical pet is a
making a table out of light rays is not that the dog or a cat; but the prototypical pet fish is a
concept of a table does not allow it to be made goldfish or another small fish that survives in
out of light rays, but that light rays cannot be a glass bowl, not the combination of a trout
manipulated in the required way). and a dog. Fodor (1998) has argued that no
Second, concepts are delineated in terms of existing theory answers the question of what
intentions. Tables serve the function of allow- a concept is; in his view, concepts are what-
ing objects to rest on them, but an object is ever the mind locks or resonates to when
not a table simply because it allows objects to presented with prototypical instances. This
rest on it; it requires the intention on some- view serves a number of philosophical pur-
ones part that it be used that way. A tree poses in his work, but it clearly leaves many
stump is not a table unless someone intends basic questions unanswered.
to use it as one; a table can be a desk (and Whatever they are, concepts are related
vice versa) depending on intentions. Fodor to one another. The concept DOG is related
(1998) noted in connection with the concept to the concept ANIMAL by inclusion, to the
to paint, that if you dip a paintbrush into a concept TAIL by possession, and to the con-
jar of paint and apply the paint to a wall with cept FRIEND by association. Tulving (1972)
the intention of painting the wall, you have introduced the concept of semantic mem-
painted the wall but you have not painted the ory to describe a long-term memory system
paintbrush. that contained the organized knowledge a
Aristotle proposed that the set of properties person possess[es] about words and other
that constitutes a concept (i.e., the essential verbal symbols, their meaning and referents,
12 part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
about relations among them, and about rules, intentionality: We see (i.e., perceptually
formulas, and algorithms for the manipula- identify) objects that are visually presented
tion of these symbols, concepts and rela- instances of concepts, which require inten-
tions (p. 386). Concepts can be thought of tion. Once we have perceptually identified
as nodes in a network of associations and an object, we activate the concept it is part of
rule-related information in semantic memory. (what is here called recognition) and often
One aspect of the network within which a categorize it. The concept and its higher level
concept is located that has received consid- categorization then can be used in other cog-
erable attention is its hierarchical structure. nitive processes.
Placing a concept within this hierarchy is The way perceptual identification, recogni-
one aspect of categorization. Concepts can be tion, and categorization of visually presented
categorized at various levels of a hierarchy; objects works is true of all primary cogni-
for instance, Tibetan Terriers are dogs, which tive processes. What differ across cognitive
are mammals, which are animals. For many domains are the specific categories that are
concepts, there is a basic level of catego- activated and the operations whereby this
rization, characterized by items at this level is achieved. Perception of spoken language,
inheriting relatively few features from the for instance, involves activation of catego-
items above them, transmitting many fea- ries such as the sound /b/, the syntac-
tures to the items below them, having con- tic structure called noun phrase, and the
siderable overlap in physical features with discourse-level structure called topic; none
other items at the same level, being the most of these categories are activated when peo-
frequently referenced items in the hierarchy ple identify objects on the basis of the their
that includes them, and other properties. visual properties. As we have reviewed in
For example, most people consider dog to visual object recognition, domain-specific
be the basic level in the hierarchy Tibetan categories are activated by specialized
Terrierdogmammalanimal. subroutines. In the case of language, such
The basic level is relevant to percep- subroutines range from mapping acoustic
tual identification: Most people recognize waveforms onto linguistically relevant fea-
instances of dogs as dogs, not as species. tures of sounds through recognizing the form
However, expertise can change the basic of a sentence and the content of a discourse.
level, with effects on perceptual identifi- The extent to which the subroutines in differ-
cation and object recognition (Tanaka & ent cognitive domains apply the same basic
Gauthier, 1997). The effect of expertise is to mechanisms to different categories is a topic
promote subordinate levels of the hierarchy of study (Anderson etal., 2004).
to basic-level concepts. Since perceptual iden-
tification activates structural descriptions of
basic-level categories, which differ as a func- Control
tion of expertise, what people with different
levels of expertise see differs. Most peo- Processes such as those described previously
ple would see a Tibetan Terrier as a dog. in the area of visual perception are subject to
My wife and Iown Tibetan Terriers and are control. Control processes set goals, set cri-
experts on what they look like, and, for us, teria for success, deploy attention to input,
Tibetan Terrier is the basic-level category in choose operations to accomplish goals, plan
the hierarchy Tibetan Terrierdogmam- sequences of operations and inhibit other
malanimal. My wife and I see Tibetan sequences, and select responses. Control
Terriers as Tibetan Terriers and can spot one operations differ from the basic processes
at 100 paces. reviewed before inasmuch as they do not
A relatively simple cognitive system has operate on a representation or a category
been outlined in this section, showing sev- themselves. Rather, they initiate, termi-
eral of its features. One is that, from the very nate, and enhance processes, such as those
first, the appearance of simplicity is deceiv- described previously, that do.
ing; early aspects of object perception, such Basic processes do not operate normally
as color perception, are themselves com- or, in many cases, do not operate at all, with-
plex processes. A second is that the process out the involvement of control processes.
is shot through and through with effects of This applies even to very early perceptual
CHAPTER 1. Cognitive Functions and the Cerebral Cortex 13
operations. For instance, perceptual identi- allows one to detect and respond to stimuli),
fication and object recognition do not take selective attention (focusing on one of several
place, or, at least, do not take place normally, if stimuli), sustained attention (retaining atten-
an object is not attended (see Wolfe & Bennett tion on one item), divided attention (focus-
[1997], for evidence that unattended objects ing on more than one item at a time, and/
are perceived as feature bundles, not as or switching from deploying attention to
objects). Phenomena such as change blind- one item to deploying attention to another),
ness (failure to notice a difference between and specialized attention processes such as
two images that are identical except for one visually directed attention. The processes
change) provide evidence that items that are of setting goals, setting criteria for success,
unattended are not registered in memory. choosing operations to accomplish goals,
Classic experiments using dichotic listen- and other control processes have also been
ing (playing different sounds to each ear) modeled in ways that include multiple sub-
have shown that subjects cannot report the divisions and subprocesses. As was the case
speech played to the unattended ear if they for basic processes, it is impossible to review
are required to understand speech played the entire range of control processes in this
to the attended ear (Cherry, 1953; Treisman, chapter. Instead, control processes will be
1964), indicating that unattended speech illustrated through one simple example that
is processed only very superficially. This builds on the discussion of visual object rec-
is not to say that unattended items are not ognition. See Chapter 3 for additional dis-
processed at all. Visual attention is attracted cussion of control processes in the context of
to unattended areas in the visual field that executive functions.
are visually dissimilar, or that change rap- Imagine you are placed before a computer
idly, indicating that unattended areas are screen, as shown in Figure1.10, and required
processed to some degree (Wolfe, 1994); to use a mouse to move a curser from the rest-
speech played to an unattended ear affects ing spot (the rectangle) to the picture desig-
short-term memory for items played to the nated by a word you hear over headphones;
attended ear (Macken, Tremblay, Alford, & when you finish one trial, you have to push
Jones, 1999), showing that it is not completely a button to ask for the next. Performing this
blocked out. However, the level to which very simple task requires many steps. One
unattended items are processed is not suffi- possible set of steps is as follows:attending to
cient to sustain the cognitive operations out- the two pictures and processing them to the
lined previously. point of object recognition and concept acti-
Control processes are complex, as we have vation; storing the representations that have
seen is the case with basic processes. For been activated (e.g., the concepts evoked by
instance, attention has been divided along the pictures) in memory for later use; attend-
many lines. Different analyses have argued ing to the spoken word and processing it to
that it includes vigilance (being in a state that the point of activation of its meaning (for
24 24
Cohort condition
20 20 Control condition
16 16
12 12
y (cm)
8 8
Cohort condition
4 Control condition 4
0 0
4 4
20 16 12 8 4 0 4 8 12 16 20 20 16 12 8 4 0 4 8 12 16 20
x (cm) x (cm)
Figure 1.10 (Left) Trajectories of mouse movements toward target (picture) in cases of initial
phonological cohort competitor (pitcher) and noncompetitor (table), showing continuous
attraction of the phonological cohort competitor. (Right) Simulation based on interaction of
phonological representation of target and foil interacting with perception of spoken word.
14 part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
present purposes, its meaning can be consid- process the word, one could stop processing
ered to be the concept it evokes); comparing the pictures or could try to store the sound
the concepts derived from object recognition of the word in memory and return to trying
with the meaning of the word; determining to understand it after one had finished pro-
which concept-meaning pair is most similar; cessing both pictures. In fact, things could,
determining the location of the picture that and probably sometimes do, get much more
corresponds to the concept that most closely complicated. If one were unsure about which
matches the meaning of the word; planning concept-meaning pair or pair of sounds was
a motor action that uses the mouse to move most similar, it might be useful, or neces-
the curser to that picture; and executing that sary, to reanalyze one or both pictures to see
program. whether some other concept, which is closer
The task involves many control processes. to the meaning of the word and/or that has a
The first decision is whether the set of steps different sound, could be evoked by a picture,
outlined is going to be used. Here is another and repeat the whole comparison-picture
set of steps that would accomplish the task, selection-motor planning process. The fact
which differs in the italicized steps: attend- that timing of the processes in this task is flex-
ing to the two pictures and processing them ible and might be changed depending on the
to the point of object recognition and con- results of the operations means that the oper-
cept activation; activating the sound of the ations listed previously have to be scheduled.
word that corresponds to the concepts activated The choice of operations and their order is
by the pictures; storing representations that just one of many control problems that a par-
have been activated (e.g., the sounds evoked ticipant in this simple task must deal with.
by the pictures) in memory for later use; Each of the operations listed in the decom-
attending to the spoken word and recogniz- position of this task requires control, at the
ing its sounds; comparing the sounds derived least in terms of shifting attention. And each
from object recognition with the sounds of of the operations listed in the decomposi-
the word; determining which pair of sounds tion of this task significantly understates the
is most similar; determining the location complexity of that stage of processing and
of the picture that corresponds to the sound has additional control operations embed-
that most closely matches the sound of the ded within it. Consider, for instance, the
word; planning a motor action that uses the response selection process. In many mod-
mouse to move the curser to that picture; and els of this process (Ratcliff, 1978), the decision
executing that program. Aparticipant in the to make a response occurs when evidence in
study would have to decide whether to use a favor of that response reaches a threshold.
semantic/conceptual basis for matching the At the onset of a trial, the evidence favoring
word and the picture, a sound-based basis, or both pictures is equal; as the trial progresses
both. Whatever decision is made, the relevant and the operations described previously are
operations have to be turned on. If a seman- accomplished, evidence accrues favoring one
tic/conceptual mechanism is used, the word picture over another. When evidence for a
has to be processed to the level of meaning; response reaches a threshold, that response
if a sound-based mechanism is used, the is selected. The resting state of the evidence
pictures have to be processed to the level of accumulator is a function of the probabili-
sounds. Even if one were to say that all these ties of the set of choices, and the drift rate
operations happen without control once a of evidence accrual is a function of the effi-
person attends to a picture or a word (which ciency of the basic processes that analyze
is doubtful; it is unlikely that we activate the input; the response threshold, however,
words for every object we perceive), control is under participants control. Older people,
processes are required to compare the sounds for instance, set higher thresholds (are more
or concepts that are the basis for the similar- conservative) than younger people (Ratcliff,
ity judgment. Thapar, & McKoon, 2011).
There is also the issue of the order to do The discussion has focused so far on control
things in. One could process one, or neither, processes that are internal to a task:schedul-
of the pictures before one hears the word; one ing and initiating operations, and setting
could process both pictures before processing certain parameters such as response selec-
the word and, if that made it impossible to tion thresholds. It is worth returning to the
CHAPTER 1. Cognitive Functions and the Cerebral Cortex 15
original outline of control processes and integration of domains seems to be the gen-
to note that these are the last items on that eral case. The experiment described, in which
list: deploying attention to input, choos- a person must move a curser to one of two
ing operations to accomplish goals, plan- pictures upon hearing a word, documents
ning sequences of operations and inhibiting a case in which the output of one domain
other sequences, and selecting responses.4 affects ongoing processing in another. If the
The first two items on the list should not be distracter picture is named by a word that
forgotten: setting goals and setting criteria begins with the same sound as the target, the
for success. During all the activity described trajectory of the curser movement is bowed
previously, the goal of the task must be main- toward the distracter, compared to a situa-
tained, and, at the end of each trial, the fact tion in which the distracter and target start
that the goal of the task has been satisfied with different sounds (Fig. 1.10) (Spivey,
must be established. The total extent of the Grosjean,& Knoblich, 2005). This shows that
control needed in this very simple task is the concepts activated by the pictures activate
hard to estimate; computer-based models words, that matching of the spoken word to
that actually do tasks such as this routinely the pictures is based not only on conceptual
require much more control than experimental properties but also on phonological features
psychologists expect (Meyer & Keiras, 1997a, of these words, and that this match interacts
1997b). either with the perception of the word or the
planning of motor movements. Computer
simulations indicate that it can interact with
Interactions of Different Cognitive Domains the perception of the word (Fig.1.10), which
would indicate that there is a very rapid
Examples of basic and control cognitive interaction of processes that can arise in asso-
functions have been drawn from specific ciation with picture identification (activation
domains such as object recognition and word of the sound of the word that corresponds
recognition. These domains interact; as with to the concept depicted in the picture) with
domain-specific operations themselves, this those that recognize sounds from acoustic
interaction occurs over very short time inter- waveforms.
vals (centiseconds). It is possible to name a
familiar picture in less than 250 milliseconds,
showing that the result of visual object recog- Closing Comments on Cognition
nition and categorization can be forwarded
to word activation in a very short period The presentation to this point begins to illus-
of time. A dramatic example of the interac- trate the nature and the extent of the opera-
tion of one domain (object recognition) with tions that we can call cognitive under some
another (planning movement) is catching an definition of this term. They range from early
object. When a person catches an object, she vision through motor planning and include
not only moves her body, arm, and hand in a memory, language, higher level thought, and
way such that the trajectory of the movement numerous control processes. The presenta-
intersects the trajectory of the object at a point tion begins to illustrate the truly daunting
where the object can be grasped. In addition, complexity of the basic operations, interac-
the person must program the force of the tions, and control processes that occur in frac-
grasp in a way that is related to the nature of tions of a second to produce behavior.
the object:Less force is exerted on an egg than Before moving on to neurological issues,
on a baseball. This means that, if the object is it is worth returning to the point that started
not seen until after it is released, the object this section: that cognition affects behav-
recognition system interacts withthe system ior by creating the content of propositional
that computes the trajectory of the object and attitudes and connecting the propositions in
the motor planning system in the brief period these states to one another. The discussion so
during which the object is perceived and the far does not deal with this but rather focuses
action planned and executed. on lower level aspects of cognition (though
One might expect that domains such as concepts and language would hardly be con-
object recognition, trajectory estimation, and sidered lower level compared to many
motor planning would be integrated, but neurological functions). There are three
16 part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
points about this that deserve additional brief expression, accompany the acquisition of
discussion. stable long-term behaviors, such as habitua-
The first is that processes called cogni- tion (Bailey, Bartsch, & Kandel, 1996). These
tive (applying the criteria at the beginning types of neural events are thought to under-
of the chapter) affect behavior in more than lie long-term memories. Episodic changes
one way. Object perception and language in stimulus conditions and behavioral
comprehension can affect behavior without responses are associated with short-term
running through fixation of belief. If you stimulus- and response-related changes in
respond to the request please pass the salt spike trains, synaptic function, and other
by understanding it, looking for the salt, rec- cellular physiologic markers of plasticity.
ognizing it, and getting and passing it over, Electrophysiological, metabolic, and neu-
you have behaved in response to cognitive rovascular imaging in humans shows sys-
operations that have nothing to do with tematic relations to stimuli and behaviors.
fixation of belief. Fixation of belief, and its These studies provide the basis for models
relation to desires, is one wayperhaps the of the neural substrates for operations of
most important way, but who knows?that the sort described previously. Along with
cognition affects behavior. With an expanded studies of the effects of lesions, these data
vision of how cognition affects behavior, we have clearly documented regional func-
appreciate the pervasiveness of cognitive tional specialization of the brain. Evidence
functions in human life even more. for a more widely distributed basis for cog-
Second, the output of modular processes is nitive functions also exists. Before turning
used to fixate beliefs. Relating the meanings to examples of localized and distributed
of words to one another in propositions is functions, two general issues will be briefly
probably the major source of information in discussed: the determinants of neural
semantic memory, and it requires word rec- involvement in a function, and the nature of
ognition, comprehension, sentence analysis neural networks.
and comprehension, and many other basic The function of an area of the brain is in part
operations. determined by intrinsic properties of the neu-
Third, little is known about how beliefs rons it contains, and in part by their connec-
are fixated. This is what some consider to be tivity (itself partly intrinsically determined).
one of the two highest areas of cognition at The role of intrinsic factors is easy to see at
the frontiers of scientific understanding (the the sensory periphery, where receptor cells
other being consciousness). From a mecha- (e.g., cones, hair cells) contain elements that
nistic point of view, however, the basic types allow for the transduction of particular forms
of operations outlined previouslylawful of energy. The features of cells in more central
transformation of semantically evaluable areas of the brain that allow them to accom-
symbolshave been argued to be the types plish the operations they do is less clear, but
of operation that apply in these processes the finding of cells with specific morphology
(Fodor, 1998). There is some reason to be exclusively (Purkinje cells) or predominantly
hopeful that, if we can understand cognitive (Betz cells) in certain areas suggests that their
operations at lower, domain-specific, levels, intrinsic properties are highly connected or
both psychologically and neurologically, the essential to the functions of those areas. The
features we discover about them will be rel- operations that particular cell layers play in
evant to these higher levels as well. particular functional domains have begun to
be understood by the combination of theo-
retical modeling and experimental studies
Neural Mechanisms (Olson & Grossberg, 1998). These operations
are not completely determined by the input
Overview to these layers, pointing to intrinsic features
of cells in particular cortical layers in differ-
Operations of the sort described previously ent brain regions contributing to the compu-
have been related to neural activity in a tational functions of the neuron. At a larger
variety of ways. Studies in animals have scale level, cytoarchitectonic, receptotonic,
shown that long-term changes in synaptic and other features of cortical organization
numbers and activity, associated with gene are among the intrinsic properties of cell
CHAPTER 1. Cognitive Functions and the Cerebral Cortex 17
Figure1.11(A) Base curve. (B) First-order derivative of A at point of vertical line. (C) Second-order
derivative of A at point of vertical line.
CHAPTER 1. Cognitive Functions and the Cerebral Cortex 19
Figure1.12 Effective stimulus for two cells in V4 (sharp convex curvature oriented to the left).
30
10 10 10
5 deg 0 0 0
90 0 90 4 2 0 2 4
Te ing
No e
ad e
Te ing
No e
ne
ur
Sh n
ur
ad
xt
xt
Light angle (deg) Depth (deg)
Sh
30
30 30
20
20 20
10 10 10
0 0 0
90 0 90 4 2 0 2 4
30
30 30
20
20 20
10 10 10
0 0 0
90 0 90 4 2 0 2 4
Figure1.14(A) Responses to highly effective (top), moderately effective (middle), and ineffective
(bottom) example stimuli as a function of depth cues. Responses remained strong as long as
disparity (black, green, and blue) or shading (gray) cues were present. The cell did not respond
to stimuli with only texture cues (pale green) or silhouettes with no depth cues (pale blue). (B)
Response consistency across lighting direction. The implicit direction of a point source at infinity
was varied across 180 in the horizontal (left to right, black curve) and vertical (below to above,
green curve) directions, creating very different two-dimensional shading patterns. (C) Response
consistency across stereoscopic depth. (D) Response consistency across xy position.
the square, responses in neurons in V2 and same time point at which neural responses
V3 whose receptive fields include the square reach this level (Fig. 1.17) (de Weerd, 2006).
increase over several seconds tothe level seen The process of filling-in surface features has
when the square is filled with thebackground. been related to V1 blobs (areas of V1 that stain
Humans report filling-in of the square at the more intensely for cytochrome oxidase) and
(A) (B)
Binding
Turning from individual visual features to
their integration, the segregation of different
types of visual features that begins in the ret-
ina is maintained throughout retinotopically
projected visual areas. These features must be
1 bound to form object representations. The
notion of binding is complex and refers to
Figure1.16 Troxler stimulus. With fixation
as marked, the central patch fills in with the
functions as diverse as perceptual grouping
texture of the background. of features of the same type under conditions
2.4 4
20
No
Square
10
Square
Baseline
0
Spikes/Sec
5.6 12.8
20
10
0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Time (Sec)
Figure1.17 Correlation between increased neural activity in V2/V3 and perceptual filling-in.
Average activity in stimulus conditions with a gray square over or inside the receptive field (solid
line) and in conditions in which the square, and thus the RF, were physically filled in with texture
(heavy dotted line) in subsets of V2 and V3 neurons with significant activity increases. Fine dots
show baseline activity recorded without any stimulus. Square size is given at the top of the panels.
The horizontal line on top of each abscissa indicates the 12-second stimulus presentation time,
preceded and followed by a 1-second period in which activity was recorded in the absence of a
stimulus. Human observers reported filling-in for the same stimuli as used during physiological
recordings in the monkey in a time range indicated by the shaded zones.
22 part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
where there are ambiguities in possible single-cell responses; they can be related to
boundaries (e.g., cluttered scenes; scenes local cell assemblies, in particular if informa-
with several moving items whose trajecto- tion is coarse coded. Second, the presenta-
ries overlap), through attributing different tion ignored the existence of local feedback,
features (e.g., color, shape) to an individual but the inclusion of such feedback does not
object, to matching responses to percepts. change the essence of the process. Applying
Some of these binding processes, such as this approach to binding of different features
aspects of perceptual grouping, appear to be encounters a number of problems, however.
largely, if not entirely, preattentive, and oth- For instance, the number of possible combi-
ers require attention. A sense of the role of nations of features found in objects has sug-
attention in the binding problem can be gested to many researchers that this approach
gained by considering Treismans influential would lead to a computational explosion and
feature integration theory (FIT) (Treisman is beyond the capacity of the brain. Answers
& Gelade, 1980). The theory maintains that to some of these issues have been proposed
features are coded by position and bound (Reynolds & Desimone, 1999). Evidence that
when attention is directed toward a posi- later, higher order neurons respond to
tion. The theory explains several empirical complex features of stimuli (see discussion of
findings:(1)that greater attention is required face recognition below) supports this class of
when binding is necessary to distinguish tar- models.
gets from nontargets (conjunction search Oscillatory synchrony models maintain
Fig.1.18); (2)that when attention is directed that binding of features involves interactions
elsewhere, illusory conjunctions wrongly among cells and brain areas. Considerable
recombining features of different objects are work has pointed to synchrony of electro-
frequently seen; (3)that cueing the location of encephalographic (EEG) activity in the
a target helps more when a conjunction must gamma frequency range (3060 Hz), and,
be reported than when the targets are defined in some studies, the beta range up to 110
as a disjunction of separate features; and 120 Hz, as the basis for aspects of binding.
(4) that grouping by single features occurs Oscillations that have been related to psy-
in parallel across the field, whereas grouping chological functions have been described
by conjunctions is much less salient and also for both neocortex and allocortex (the
seems to require active attention. olfactory bulb and hippocampus; see Gray
There are two major views regarding the [1994] for review). Singer (1999) reviews
neural basis for binding: feedforward hier- the advantages of synchronous oscillatory
archical convergence (directed line) mod- coding and possible physiological mecha-
els (Barlow, 1972, 1995, presented a classical nisms that could produce it (largely related
statement of this type of model; for a more to lateral inhibitory circuits). Oscillations
recent review, see Riesenhuber & Poggio, in the beta range or their synchronization
1999) and oscillatory synchrony models could themselves be the neural code that
(Singer, 1999). These theories are not incom- represents psychologically relevant features
patible, and it is possible that binding opera- and categories, and they have been argued
tionsor perhaps different types of binding to augment firing rates of individual neu-
operationsare supported by different neu- rons, thus enhancing spike train frequency
ral processes. coding (Fries, 2009). Gamma oscillations are
Feedforward hierarchical convergence related to oscillations at lower frequencies
models are the type of model described (in the theta and alpha ranges), which have
previously regarding reconstruction of been interpreted as resetting gamma cycles
three-dimensional representations. They in psychologically relevant ways such as
claim that earlier, lower order cells send alternating attention (see Fries, 2009, for
information to later, higher order cells review). Synchronous oscillatory patterns
that respond to ever-more-complex aspects have been associated with a wide range
of a stimulus. The discussion of these models of cognitive processes, ranging from early
was simplified in several ways. One is that aspects of perception (Gray & Singer, 1989),
it relied on single-cell tuning curves. These through effects of attention on perception
models do not, however, require that higher (Landau & Fries, 2012) to motor planning
level representations be correlated with (Salenius & Hari, 2003). Different forms of
CHAPTER 1. Cognitive Functions and the Cerebral Cortex 23
(A) (B)
drifted in opposite directions in strabismic
O O X O O X cats in which cortical columns were respon-
X O O
X X X X sive to only one eye.
O X
X X O X O In summary, binding of various types is
O O O O
O O X a ubiquitous operation whose neural basis
X X O X X
O OX O O X appears to involve both localized and distrib-
X O X O X O uted processes.
O O O X
X O X O
Face Recognition
(C)
The third aspect of high-level visual object
ch processing whose neural basis will be briefly
sear
ion reviewed is identification of a specialized set
nct
Reaction time
ju of objects:faces.
Con
There is strong psychological evidence that
Pop-out search face recognition is a specialized perceptual
process. McKone etal. (2009) review evidence
that face identification depends more on con-
figurational aspects of a facethe exact spac-
2 4 6 8 10 12 14 16 ing between featuresthan on individual
Set size
features. This appears as the composite
Figure1.18 Conjunction and pop-out search. In effectthe finding that identification of one
both A and B, the task is to determine whether half of a combination face (in which the top
a red circle is present. In A, the target is defined half of the image contains the top half of one
as the feature in red; in B, the target is defined persons face and the bottom half contains the
by the conjunction of red and circle. In C bottom half of another persons face) is much
reaction time is shown for correct detections
harder when the top and bottom images are
of present stimuli as a function of set size,
aligned to form a face than when they are
consistent with parallel search not requiring
offset; as the part-whole effect, in which
serial deployment of attention in A and
recognition of a face part is better if the part
requiring serial deployment of attention in B.
(See color plate section) had previously been presented in the context
of a face; as sensitivity to spatial changes, in
which spatial distance between parts greatly
synchrony (e.g., onset synchrony, induced affects face identification; and in a perceptual
synchrony) need to be identified and may bias to upright face identification, in which
be related to different cognitive operations subjects identify the upright face when an
(Tallon-Baudry & Bertrand, 1999).6 upright and inverted face are superimposed.
With respect to visual object identification, All these effects are stronger for faces than for
one result pertains to the Gestalt principles other classes of objects (McKone etal., 2009).
that affect perceptual grouping. Gray (1994) The neural basis for face recognition
reviewed evidence that proximity, similarity, involves a specialized area of inferior tem-
common motion, continuity, closure, and seg- poral gyrus (ITG) in macaque and human.
mentation all lead to increases in synchrony In macaque, face-selective cells have been
of firing of cells in striate cortex whose visual identified in parts of ITG (Foldiak, Xiao,
receptive fields do not overlap. He argued Keysers, Edwards, & Perrett, 2004), whose
that these results are evidence for a role for location corresponds to BOLD signal
synchrony in preattentive binding processes increases during viewing of faces (Tsao,
in vision. He cited results of Fries (1997) con- Freiwald, Tootell, & Livingstone, 2006).
necting synchronous activity in visual areas Hasselmo etal. (1989) have shown that some
to control of motor responses as evidence of these neurons are projection and move-
of the biological relevance of these response ment insensitive, indicating they respond to
patterns. Fries (1997) showed that synchro- object-centered representations of faces. In
nous activity in areas 17 and 18 was greater humans, a right-lateralized area in the fusi-
for cells that drove optikokinetic responses to form gyrus (called the fusiform face area
the movement of the one of two gratings that [FFA]) has been identified using fMRI. This
24 part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
area shows greater BOLD signal response mechanism underlying at least part of their
to faces than to other classes of objects that perceptual identification.
have been presented (letter strings, flow-
ers, houses, hands, everyday objects, and Activation of Concepts
others) (Kanwisher, McDermott, & Chun,
1997). The FFA is sensitive to face iden- The two views of neural organizationfeed-
tity (Rotshtein, Henson, Treves, Driver, forward, direct line models, in which infor-
& Dolan, 2005), but not facial expression mation coalesces in individual neurons or
(Winston, Vuilleumier, & Dolan, 2003). It small neural assemblies, and distributed
shows a face inversion effect that correlates models, in which information is carried in
with the behavioral inversion effect (Yovel distributed sets of neuronshave both been
& Kanwisher, 2005) and a composite effect advanced as the basis for the representation
(Schiltz & Rossion, 2006). and activation of concepts.
Face recognition is a naturally develop- The first view is found in the paper that
ing process that resembles general object inaugurated the modern era of behavioral neu-
recognition in a variety of ways:Its input is rologyGeschwinds (1965a, 1965b) paper
three dimensional, mobile, presented from on disconnection syndromes. Geschwind
multiple angles, and often occluded. On the argued that the meanings of wordswhich he
other hand, it is atypical of object recogni- did not distinguish from conceptsconsisted
tion in many ways. All faces have character- of the integration of modality-specific features
istic features (overall shape, location relative of objects (themselves activated in unimodal
to other objects such as parts of the body, association cortex adjacent to koniocortex) in
parts, the geometrical layout of parts, and inferior parietal lobe. The absence of strong
the range of relative spacing between parts). direct connections from unimodal association
Faces convey biologically critical informa- cortex to inferior parietal multimodal associa-
tion about identity and therefore are highly tion cortex in nonhuman species accounted
salient, especially in precocial species in for the absence of words with meaning in
which survival and social adaptation are nonhumans. This theoretical account based
contingent on visually recognizing a mother on neuroanatomy has received mixed empiri-
and a small number of family members. cal support. Lesions in inferior parietal lobule
Faces convey information that is useful in do not cause word comprehension deficits
predicting behavioral responses (e.g., mood, or loss of nominal concepts (for selective
whether a person is lying; Ekman, Friesen, & review, see Binder, Desai, Graves, & Conant,
OSullivan, 1988). Evolutionary psychologists 2009), but the inferior parietal lobule is one
(Duchaine, Cosmides, & Tooby, 2001) and of many areas that are activated by tasks that
others (Caramazza & Shelton, 1998) have require conceptual processing (for reviews,
argued that these features of faces may have see Binder etal., 2009; Binder & Desai, 2011).
fostered the evolution of neural specializa- The strongest evidence regarding the possible
tions for face recognition that do not apply site of neural assemblies that might support
to recognition of more standard classes of the integration of various types of features
objects. People and members of many other into a concept in humans comes from seman-
species attend to faces a great deal, arguably tic dementia, a degenerative disease that pro-
more than to any other class of objects. This gressively affects the anterior temporal lobes,
presumably encourages neutrally special- usually more so in the dominant left hemi-
ized mechanisms for their perceptual iden- sphere (Hodges, Graham, & Patterson, 1995;
tification and memory. It is therefore not Hodges, Patterson, Oxbury, & Funnell 1995;
clear whether perceptual identification of Jefferies & Lambon Ralph, 2006; Mummery
the wide range of objects that we encounter et al., 2000; Snowden, Goulding, & Neary,
relies on specialization of parts of high-level 1989). Patients with semantic dementia show
visual cortex that operate in the way that progressive loss of nominal concepts, evident
the FFA does. However, single cells have no matter what the mode of access (verbal,
been found that respond selectively to other pictorial, conceptual). This area is rarely acti-
classes of objects (Grill-Spector, Kourtzi, & vated by semantic tasks, however (but see
Kanwisher, 2001; Hasselmo, Rolls, Baylis, & Rogers et al., 2006, for an account of these
Nalwa, 1989), pointing to a similar neural apparently discrepant findings).
CHAPTER 1. Cognitive Functions and the Cerebral Cortex 25
Evidence for distributed activity that con- fundamentally from those in other species,
stitutes the neural code for concepts comes which cannot develop the range of intentions
primarily from neurovascular and neuro- that we can; therefore, important aspects of
physiological activation studies. A number the neural basis for human concepts will
of studies have shown regional activation in require human studies.
sensory and/or motor areas that support pro-
cessing of the perceptual features of objects
Overview of Perceptual Identification
or their use. Martin (2007) summarized this
and Object Recognition
model as follows:
This brief review of physiological studies of
Evidence from functional neuroimaging aspects of visual object perception is highly
of the human brain indicates that informa- selective, leaving out the great majority of
tion about salient properties of an object, mechanisms used in this process (e.g., use
such as what it looks like, how it moves, of color, texture, motion, and other fea-
and how it is used, is stored in sensory and tures), discussion of alternate models, and
motor systems active when that informa- even integration of the topics that were dis-
tion was acquired. As a result, object con- cussed (e.g., the role of surfaces in producing
cepts belonging to different categories like three-dimensional object-centered shapes). It
animals and tools are represented in par- is only intended to provide a glimpse of some
tially distinct, sensory- and motor prop- of the features of cortical function and orga-
erty-based neural networks. This suggests nization that underlie this domain-specific
that object concepts are not explicitly rep- function. This section will be concluded by
resented, but rather emerge from weighted reviewing some of these mechanisms.
activity within property-based brain One feature of cortical organization that
regions. However, some property-based these results demonstrate is localization of
regions seem to show a categorical organi- function. Cells in particular brain areas can
zation, thus providing evidence consistent be thought of as performing particular opera-
with category-based, domain-specific for- tions on their input. Returning to the issues
mulations as well. (p.25) raised in the outset of this section, the opera-
tions of these cells are determined by their
In addition to well-known results of this intrinsic features (e.g., the ability of cells in
sort was the finding that reading words V4 to respond to the features they do is an
denoting specific actions involving the intrinsic capacity, not one that can be under-
tongue (lick), finger (pick), and leg (kick) acti- stood by considering their input alone, even
vated regions in premotor cortex that were if the development of this computational
also active when subjects made tongue, fin- capacity requires particular input at a criti-
ger, and leg movements, respectively (Hauk, cal time in development). Although the stud-
Johnsrude, & Pulvermuller, 2004). Damasio ies reported tended to rely on single-cell
(1989) argued that objects were represented recording, as noted several times, there is
as patterns of activity in modality-specific evidence that many operations correspond to
regions of the brain. responses in considerably larger cell assem-
A significant limitation of this litera- blies, which are localized in small areas of
ture is that, as the discussion of concepts in the brain (Georgopoulos, Kalaska, Caminiti,
the section on Perceptual Identification, & Massey, 1982). Localization of function is a
Recognition, and Categorization of Visually well-established feature of the cortical orga-
Presented Objects indicates, concepts are nization that supports all levels of psycholog-
more than just the amalgamation of physical ical functions, from line detection through
features and functional operations but have face recognition and activation of concepts.
features that allow them to be counterfactu- Narrow localization is, however, only part
ally supporting and are delineated in inten- of the basis for cortical support of cognitive
tional terms. Therefore, the way sensory functions. The other aspect of cortical orga-
and motor features of concepts are bound nization is a more widespread basis for sup-
together only captures a part of the neu- porting cognitive operations. Some models
ral basis for concepts. Because of their rela- of cortical organization (e.g., Mesulam, 1990,
tion to intentionality, human concepts differ 1998) have argued that areas as large as the
26 part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
entire perisylvian association cortex (in the language, motor planning, control functions,
case of human language) support particu- and different aspects of memory and atten-
lar cognitive functions, in some cases with tion. These areas are integrated in a number
gradients of involvement toward poles of ways. This chapter has reviewed direct
of these large areas. These models use terms line feedforward hierarchical processing
such as distributed functions or neural and synchronous oscillations, and mentioned
nets to describe cortical organization, and local feedback, as aspects of their integration.
they draw upon mathematical models as Modern models add notions of hubs and
the basis for distributed representations and small world organization to the ways these
processes (McClelland & Rumelhart, 1986; sets of areas interact to support related func-
Rumelhart & McClelland, 1986). tions (Bassett & Bullmore, 2009).
From the point of view of relating cognitive Localized cell groups and larger areas
operations to the brain, two different notions are grouped together into neural systems
of distributed, neural net cortical organi- that involve not only the cortex but also
zation need to be distinguished. One is that cortical-subcortical sets of neurons (see
individual cognitive operations are related to Chapter 2). For instance, the motor system
the activity of distributed neural nets. The includes premotor cortex, motor cortex,
second is that sets of related cognitive opera- basal ganglia and other hemispheric sub-
tions are related to the activity of contiguous cortical areas, and the cerebellum and con-
and directly connected areas of the brain. nected brain stem nuclei. At the highest
To the best of my knowledge, although level of organization, these systems inter-
mathematical models have demonstrated act:Voluntary motor function is determined
that distributed representations are impor- by control operations, is dependent upon
tant candidates as neural mechanisms and input from proprioceptive and vestibular
that these systems can develop gradients systems, and in many cases initiated and
of weights in hidden unit layers as they modified by teleoceptive perceptual process-
engage in what are considered individual ing, especially vision.
processes over time (e.g., Plaut, McClelland, Overall, the basic principles of the corti-
Seidenberg, & Patterson, 1996, in the case cal organization that appears to support
of reading), there is no evidence for distrib- cognitive functions are (a) a high degree
uted systems or for a gradient of activity in of specialization of cellular computational
areas of the brain as large as those envis- capacity (which develops in part based on
aged by Mesulam (1998) that supports indi- input and shows a high, but presumably
vidual cognitive operations. The evidence bounded, degree of plasticity); (b) localized
reviewed indicates that synchronous oscilla- cell groups that accomplish particular opera-
tions appear to unite areas of the brain in tions; (c) feedforward, correlated, and hub/
the service of what may be individual opera- small world organization of contiguous and
tions such as the Gestalt perceptual grouping densely interconnected areas to support
processes, but the synchronous oscillations related cognitive operations; (d) interaction
that apply in these single operation cases of spatially disparate areas into systems;
are quite spatially restricted. More wide- and (e) interaction of systems to accom-
spread synchronous oscillations are observed plish tasks. As far as is known, these basic
in cases where different modalities or opera- features of neural function and organization
tions are involved, but this is an example of apply to all aspects of cognitionboth pri-
the second type of distributed neural nets. mary and control operations.
On the other hand, there is little doubt that
the second of these modes of organization
that sets of related individual cognitive oper- Regional Functional Specialization for
ations are related to the activity of contiguous Cognitive Functions
and directly connected areas of the brain
applies in the cortex. We have seen that This chapter will be concluded with a very
related operations apply in spatially contigu- brief overview of the regional functional spe-
ous and directly connected occipito-temporal cialization of the cortex at the third level of
cortex in the process of object recognition; organization:organization of cortical areas to
the same is true of other sensory modalities, support related cognitive operations.
CHAPTER 1. Cognitive Functions and the Cerebral Cortex 27
Large contiguous areas of the cortex tend phenomenon occurs in reverse:Primary motor
to be devoted to operations of the same sort. cortex receives many afferents from adjacent
A picture of the functions associated with unimodal motor association cortex, where
different cortical regions is presented in aspects of movement are planned.
Figure 1.19. This cartoon, or similar ones, is These factors do not account for all aspects
highly familiar to most clinicians, and details of regional cortical functional specialization,
of some of the functions depicted in it are however. On the surface of things, it does
presented in other chapters. It will not be not appear that different types of control
described further here, but rather a few com- operations could be functionally related by
ments will be made on how these localizations the same types of feedforward mechanisms
arise, as well as some caveats about this image. that apply to perceptual analysis and motor
The localization of these large cognitive planning, making the localization of many
domains is in part attributable to the opera- control operations in prefrontal lobe unlikely
tion of direct-line feedforward processing in to be due to these factors. The same is true of
cell groups with particular patterns of con- the different aspects of language (phonology,
nectivity (Geschwind, 1965a, 1965b; Mesulam, syntax, discourse structure). The location
1990, 1998). On the sensory side, simpler rep- of the default system (see Chapters 3 and
resentations are formed in koniocortex, whose 4)close to a large number of primary systems
efferents synapse exclusively in unimodal sen- and the location of episodic memory encod-
sory association cortex, and cell groups in uni- ing in mesial temporal structures are also not
modal sensory association cortex have many easily attributable to these factors.
reciprocal connections with one another. In A final comment is that, although these
conjunction with feedforward computations, gross functional localizations are quite
this creates large areas of cortex devoted to well documented, ongoing work has con-
higher level visual, auditory, and somas- sistently complicated the picture. The evi-
thetic processing. On the motor side, a similar dence for semantic processing in inferior
Figure1.19 Cartoon of location of the major cognitive systems in the lateral human cortex. (See
color plate section)
28 part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
anterior temporal lobe, for instance, was is not clear that these accounts will identify a set
unexpected; the existence of a default net- of psychological operations that cohere scien-
work was unsuspected. Traditional models tifically. But they are a start. And folk psychol-
of language processing localized spoken ogy and intuitions do not do better:The set of
processes that are called cognitive in practice
language comprehension in posterior supe-
is highly heterogeneous on its face.
rior temporal gyrus (Wernickes area) and
4. Setting response criteria thresholds might
adjacent cortex and speech planning in pos- be considered setting criteria for success,
terior inferior frontal gyrus (Brocas area), but applied within a task, not to the task itself.
both deficit-lesion correlations (Caramazza 5. There is a logical relation between plasticity
& Zurif, 1976) and functional neuroimag- due to altered input and the intrinsic proper-
ing (Stromswold, Caplan, Alpert, & Rauch, ties of cells and their organization that deter-
1986)have shown that aspects of comprehen- mine their functional roles. These intrinsic
sion related to the assignment of sentence features must be sufficiently generally pres-
syntactic structure are supported by Brocas ent in cells to allow cells to perform new
functions when presented with new inputs
area in at least some individuals. Though
at certain points of development. The extent
clinicians can reasonably rely on the picture
to which plasticity applies (e.g., whether non-
in Figure 1.19 and can reasonably expect to koniocortical cells in the auditory system (or
be able to rely on that picture in the future, in the visual system, for that matter) would
exceptions, additions, and modifications of develop the response sensitivity of normally
these localizations are very likely to be doc- wired V1 or rewired A1 cells if they were pre-
umented as we learn more about cognitive sented with thalamic efferents) must reflect
functions themselves and their neural bases. the nature of the experience-mutable, shared
cellular properties that give a cell its compu-
tational potential.
Notes 6. The evidence for the relevance of synchro-
1. Acategory can sometimes be described in terms nous oscillations to these processes is strong
drawn from lower levels of science (e.g., but remains controversial. Controversy arises
lightning can be described in terms drawn for technical reasons (higher level oscillations
from the theory of electromagnetism). The par- may be harmonics of lower frequency, or they
tial success of reductionism does not entail that may be confounded with spike train frequen-
something is not a category:Lightning, and cies; Dong, Mihalas, Qiu, von der Heydt, &
not its electromagnetic reformulation, plays a Niebur, 2008)and because some phenomena
role in theories of climate (all special sciences that would seem to be supported by this pro-
have this structure). cess have not been associated with synchro-
2. The stimuli that provoke these neural nous oscillations (cf. Dong et al., 2008, who
responses are not circles, but the output of the found no evidence for synchrony associated
cells can be considered to correspond to cir- with object stimuli).
cles, subject to noise, which is sufficient for it
to be used as a circle in subsequent computa- References
tions in visual perception. (It is doubtful that
either circles actually exist in either nature or Anderson, J. R., Bothell, D., Byrne, M. D.,
serious models of perception; they are being Douglass, S., Lebiere, C.,& Qin, Y. (2004). An
used here simply as familiar descriptors.) integrated theory of the mind. Psychological
3. On the negative side, these descriptions at least Review, 111, 10361060.
risk circularity, as noted in the text. Operations Angelucci, A., Clasca, F., & Sur, M. (1998).
that preserve the information in a represen- Brainstem inputs into the ferret medial genic-
tation cannot be noncircularly defined as ulate nucleus and the effect of early deaffer-
cognitive operations if what makes some- entation on novel retinal projections to the
thing a representation is that it is subject to auditory thalamus. Journal of Comparative
information-preserving operations and what Neurology, 400, 417439.
makes something cognitive is that it oper- Aristotle. (1995). Categories. In The complete
ates on representations. This problem may be works of Aristotle, 2 vols (J. Barnes, Ed., &
avoided if we say that the operations that pre- J. L. Ackrill, Trans., pp. 324). Princeton,
serve information are not themselves cognitive; NJ:Princeton University Press.
it is the application of an operation to a semanti- Bailey, C.H., Bartsch, D.,& Kandel, E.R. (1996).
cally evaluable item that makes it cognitive. It Toward a molecular definition of long-term
bears repeating after considering these descrip- memorystorage. Proceedings of the National
tions that, even if circularity can be avoided, it Academy of Sciences USA, 93(24), 13441345.
CHAPTER 1. Cognitive Functions and the Cerebral Cortex 29
Barlow, H. B. (1972). Single units and sensa- Duchaine, B., Cosmides, L., & Tooby, J. (2001).
tion: A neuron doctrine for perceptual psy- Evolutionary psychology and the brain.
chology. Perception, 1, 371394. Current Opinion in Neurobiology, 11, 225230.
Barlow, H.B. (1995). The neuron in perception. Ekman, P., Friesen, W.V.,& OSullivan, M. (1988).
In M. S.Gazzaniga (Ed.), The cognitive neuro- Smiles when lying. Journal of Personality and
sciences (pp. 41534). Cambridge, MA: MIT Social Psychology, 54, 414420.
Press. Fei-Fei, L., Fergus, R., & Perona, P. (2006).
Bassett, D.S.,& Bullmore, E.T. (2009). Human One-shot learning of object categories. IEEE
brain networks in health and disease. Current Transactions, Pattern Analysis and Machine
Opinion in Neurology, 22(4), 340347. Intelligence, 28(4), 594611.
Binder, J.R.,& Desai, R.H. (2011). The neurobi- Fodor, J. (1998). Concepts: Where cognitive sci-
ology of semantic memory. Trends in Cognitive ence went wrong. The 1996 John Locke Lectures.
Sciences, 15(11), 527536. Oxford, UK:Oxford University Press.
Binder, J. R., Desai, R. H., Graves, W. W., & Foldiak, P., Xiao, D., Keysers, C., Edwards,
Conant, L. L. (2009). Where is the semantic R.,& Perrett, D.I. (2004). Rapid serial visual
system? A critical review and meta-analysis presentation for the determination of neu-
of 120 functional neuroimaging studies. ral selectivity in area STSa. Progress in Brain
Cerebral Cortex, 19(12), 27672796. Research, 144, 107116.
Brincat, S.L.,& Connor, C.E. (2004). Underlying Fries, P., Roelfsema, P. R., Engel, A. K., Knig,
principles of visual shape selectivity in P., & Singer, W. (1997). Synchronization of
posterior inferotemporal cortex. Nature oscillatory responses in visual cortex corre-
Neuroscience, 7, 880886. lates with perception in interocular rivalry.
Buckner, R. L., Snyder, A. Z., Shannon, Proceedings of the National Academy of Sciences,
B. J., LaRossa, G., Sachs, R., Fotenos, 94(23), 1269912704.
A. F.,...Mintun, M. A. (2005). Molecular, Fries, P. (2009). Neuronal gamma-band synchro-
structural, and functional characterization nization as a fundamental process in cortical
of Alzheimers disease: Evidence for a rela- computation. Annual Review of Neuroscience,
tionship between default activity, amyloid, 32, 209224.
and memory. Journal of Neuroscience, 25, Georgopoulos, A. P., Kalaska, J. F., Caminiti,
77097717. R., & Massey, J. T. (1982). On the relations
Caramazza, A.,& Zurif, E. (1976). Dissociations between the direction of twodimensional arm
of algorithmic and heuristic processes in sen- movements and cell discharge in primate
tence comprehension: Evidence from apha- motor cortex. Journal of Neuroscience, 2(11),
sia. Brain and Language, 3, 572582. 15271537.
Cherry, E. C. (1953). Some experiments on the Geschwind, N. (1965a). Disconnexion syn-
recognition of speech, with one and with two dromes in animals and man. I. Brain, 88,
ears. Journal of the Acoustical Society of America, 237294.
25(5), 975979. Geschwind, N. (1965b). Disconnexion syn-
Connor, C. E., Pasupathy, A., Brincat, S., & dromes in animals and man. II. Brain, 88,
Yamane, Y. (2009). Neural transformation 585644.
of object information by ventral pathway Goebel, R., & De Weerd, P. (2009). Perceptual
visual cortex. In M. S. Gazzaniga (Ed.), The filling-in from experimental data to neural
cognitive neurosciences (4th ed., pp. 455467). network modeling. In M. S.Gazzaniga (Ed.),
Cambridge, MA:MIT Press. The cognitive neurosciences (4th ed., pp. 435
Damasio, A. R. (1989). Time-locked multire- 454). Cambridge, MA:MIT Press.
gional retroactivation: A systems-level pro- Gray, C. M. (1994). Synchronous oscillations
posal for the neural substrates of recall and in neuronal systems: Mechanisms and func-
recognition. Cognition, 33, 2562. tions. Journal of Computational Neuroscience, 1,
De Luca, M., Beckmann, C. F., De Stefano, N., 1138.
Matthews, P.M.,& Smith, S.M. (2006). fMRI Gray, C.M.,& Singer, W. (1989). Stimulus-specific
resting state networks define distinct modes neuronal oscillations in orientation columns
of long-distance interactions in the human of cat visual cortex. Proceedings of the National
brain. Neuroimage, 29, 13591367. Academy of Sciences USA, 86, 16981702.
De Weerd, P. (2006). Perceptual filling-in:More Grill-Spector, K., Kourtzi, N., & Kanwisher, N.
than the eye can see. Progress in Brain Research, (2001). The lateral occipital complex and its
154, 227245. role in object recognition. Vision Research, 41,
Dong, Y., Mihalas, S., Qiu, F., von der Heydt, 14091422.
R., & Niebur, E. (2008). Synchrony and the Grossberg, S. (2003). Filling-in the forms:Surface
binding problem in macaque visual cortex. and boundary interactions in visual cortex. In
Journal of Vision, 8, 116. L. Pessoa& P.de Weerd (Eds.), Filling-in:From
30 part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
perceptual completion to skill learning (pp. 13 McClelland, J. L., Rumelhart, D. E., & PDP
37). NewYork, NY:Oxford University Press. Research Group. (1986). Parallel distributed
Hasselmo, M. E., Rolls, E. T, Baylis, G. C., & processing: Explorations in the microstructure
Nalwa V. (1989). Object-centered encoding of cognition, Vol. 2.Psychological and biological
by face-selective neurons in the cortex in models. Cambridge, MA:MIT Press.
the superior temporal sulcus of the monkey. McKone, E., Crookes, K.,& Kanwisher, N. (2009).
Experimental Brain Research, 75, 417429. The cognitive and neural development of face
Hauk, O., Johnsrude, I., & Pulvermuller, F. recognition in humans. In M. S. Gazzaniga
(2004). Somatotopic representation of action (Ed.), The cognitive neurosciences (4th ed., pp.
words in human motor and premotor cortex. 467482). Cambridge, MA:MIT Press.
Neuron, 41, 301307. Meyer, D. E., & Kieras, D. E. (1997a). A com-
Hodges, J. R., Graham, N., & Patterson, K. putational theory of executive control
(1995). Charting the progression in semantic processes and human multiple-task perfor-
dementia:Implications for the organisation of mance:Part1. Basic mechanisms. Psychological
semantic memory. Memory, 3, 463495. Review, 104, 365.
Hodges, J. R., Patterson, K., Oxbury, S., & Meyer, D.E.,& Kieras, D.E. (1997b). A compu-
Funnell, E. (1992) Semantic dementia: pro- tational theory of executive control processes
gressive fluent aphasia with temporal lobe and human multiple-task performance:Part2.
atrophy. Brain, 115, 17831806. Accounts of psychological refractory-period
Hubel, D.H.,& Wiesel, T.N. (1959). Receptive phenomena. Psychological Review, 104, 749791.
fields of single neurones in the cats striate Mesulam, M.M. (1990). Large-scale neurocogni-
cortex. Journal of Physiology, 148, 574591. tive networks and distributed processing for
Hubel, D.H.,& Wiesel, T.N. (1962). Receptive attention, language, and memory. Annals of
fields, binocular interaction and functional Neurology, 28, 597613.
architecture in the cats visual cortex. Journal Mesulam, M.M. (1998). From sensation to cog-
of Physiology, 160, 106154. nition. Brain, 121, 10131052.
Humphreys, G. W., & Riddoch, M. J. (Eds.). Mummery, C. J., Patterson, K., Price, C. J.,
(1987). Visual object processing: A cogni- Ashburner, J., Frackowiak, R. S., & Hodges,
tiveneuropsychological approach. Hillsdale, J. R. (2000). A voxel-based morphometry
NJ:Erlbaum. study of semantic dementia: Relationship
Ito, M., Tamura, H., Fujita, I., & Tanaka, K. between temporal lobe atrophy and semantic
(1995). Size and position invariance of neu- memory. Annals of Neurology, 47, 3645.
ronal responses in monkey inferotemporal Olson, S.,& Grossberg, S. (1998). A neural net-
cortex. Journal of Neurophysiology, 73, 218226. work model for the development of simple
Jefferies, E., & Lambon Ralph, M. A. (2006). and complex cell receptive fields within cor-
Semantic impairment in stroke aphasia ver- tical maps of orientation and ocular domi-
sus semantic dementia: A case-series com- nance. Neural Networks, 11, 189208.
parison. Brain, 129, 21322147. Paivio, A. (1986). Mental representations: A dual
Kanwisher, N. G., McDermott, J., & Chun, coding approach. Oxford, UK: Oxford
M.M. (1997). The fusiform face area:Amod- University Press.
ule in human extrastriate cortex specialized Pasupathy, A.,& Connor, C.E. (1999). Responses
for face perception. Journal of Neuroscience, to contour features in macaque area V4.
17(11), 43024311. Journal of Neurophysiology, 82, 24902502.
Land, E. (1974). The retinex theory of colour Pasupathy, A., & Connor, C. E. (2002).
vision. Proceedings of the Royal Institute of Great Population coding of shape in area V4. Nature
Britain, 47, 2358. Neuroscience, 5, 13321338.
Landau, A. N., & Fries, P. (2012). Attention Plaut, D.C., McClelland, J.L., Seidenberg, M.S.,&
samples stimuli rhythmically. Current Biology, Patterson, K. (1996). Understanding normal and
22(11), 10001004. impaired word reading: Computational prin-
Macken, W. J., Tremblay, S., Alford, D., & ciples in quasi-regular domains. Psychological
Jones, D.M. (1999). Attentional selectivity in Review, 103, 56115.
short-term memory:Similarity of process, not Ratcliff, R. (1978). A theory of memory retrieval.
similarity of content, determines disruption. Psychological Review, 85, 59108.
International Journal of Psychology, 34, 322327. Ratcliff, R., Thapar, A., & McKoon, G. (2011).
Margolis, E., & Laurence, S. (Eds.). (1991). Effects of aging and IQ on item and asso-
Concepts:Core readings. Cambridge, MA:MIT ciative memory. Journal of Experimental
Press. Psychology:General, 140, 464487.
Martin, A. (2007). The representation of object Reynolds, J.H.,& Desimone, R. (1999). The role
concepts in the brain. Annual Review of of neural mechanisms of attention in solving
Psychology, 58, 2545. the binding problem. Neuron, 24, 1929.
CHAPTER 1. Cognitive Functions and the Cerebral Cortex 31
Riesenhuber, M., & Poggio, T. (1999). Are cor- Tallon-Baudry, C., & Bertrand, O. (1999).
tical models really bound by the binding Oscillatory gamma activity in humans and
problem? Neuron, 24, 8793. its role in object representation. Trends in
Riggs, L. A., & Ratliff, F. (1952). The effects of Cognitive Sciences, 3, 151162.
counteracting the normal movements of the Tanaka, J.W.,& Gauthier, I. (1997). Expertise in
eye. Journal of the Optical Society of America, 42, object and face recognition. In R. L.Goldstone,
872873. P. G.Schyns,& D. L.Medin (Eds.), Psychology
Roe, A. W., Lu, H. D., & Hung, C. P. (2005). of learning and motivation, Vol. 36. Perceptual
Cortical processing of a brightness illusion. mechanisms of learning (pp. 83125). San
Proceedings of the National Academy of Sciences Diego, CA:Academic Press.
USA, 102(10), 38693874. Treisman, A. (1964). Monitoring and storage
Roe, A. W., & Tso, D. Y. (1995). Visual topog- of irrelevant messages in selective atten-
raphy in primate V2: Multiple represen- tion. Journal of Verbal Learning and Behavior, 3,
tation across functional stripes. Journal of 449459.
Neuroscience, 15, 36893715. Treisman, A., & Gelade, G. (1980). A feature-
Rogers, T. T., Hocking, J., Noppeney, U., integration theory of attention. Cognitive
Mechelli, A., Gorno-Tempini, M., Patterson, Psychology, 12(1), 97136.
K.,& Price, C. (2006). The anterior temporal Tsao, D. Y., Freiwald, W. A., Tootell, R. B., &
cortex and semantic memory: Reconciling Livingstone, M. S. (2006). A cortical region
findings from neuropsychology and func- consisting entirely of face-selective cells.
tional imaging. Cognitive, Affective and Science, 311, 670674.
Behavioral Neuroscience, 6, 201213. Tulving, E. (1972). Episodic and semantic
Rotshtein, P., Henson, R.N., Treves, A., Driver, memory. In E. Tulving & W. Donaldson
J., & Dolan, R. J. (2005). Morphing Marilyn (Eds.), Organization of memory (pp. 381403).
into Maggie dissociates physical and iden- NewYork, NY:Academic Press.
tity face representations in the brain. Nature Turing, A.M. (1936). On computable numbers,
Neuroscience, 8(1), 107113. with an application to the Entscheidungs
Rumelhart, D. E., McClelland, J. L., & PDP problem. Proceedings of the London
Research Group. (1986). Parallel distributed Mathematical Society, 2(42), 230265.
processing: Explorations in the microstructure Winston, J. S., Vuilleumier, P., & Dolan, R. J.
of cognition, Vol. 1. Foundations. Cambridge, (2003). Effects of low-spatial frequency com-
MA:MIT Press. ponents of fearful faces on fusiform cortex
Salenius, S.,& Hari, R. (2003). Synchronous cor- activity. Current Biology, 13(20), 18241829.
tical oscillatory activity during motor action. Wittgenstein, L. (1961). Tractatus logico-
Current Opinion in Neurobiology, 13, 678684. philosophicus (D. F.Pears& B.F. McGuinness,
Schiltz, C., & Rossion, B. (2006). Faces are Trans.). New York, NY: Humanities Press.
represented holistically in the human (original work published 1921)
occipito-temporal cortex. NeuroImage, 32, Wolfe, J.M. (1994). Guided search 2.0:Arevised
13851394. model of visual search. Psychonomic Bulletin
Singer, W. (1999). Neuronal synchrony: A ver- and Review, 1(2), 202238.
satile code for the definition of relations? Wolfe, J.M.,& Bennett, S.C. (1997). Preattentive
Neuron, 24, 4965. object files: Shapeless bundles of basic fea-
Snowden, J. S., Goulding, P. J., & Neary, D. tures. Vision Research, 37(1), 2544.
(1989). Semantic dementia: A form of cir- Yamane, Y., Carlson, E.T., Bowman, K.C., Wang,
cumscribed temporal atrophy. Behavioural Z.,& Connor, C.E. (2008). A neural code for
Neurology, 2, 167182. three-dimensional object shape in macaque
Spivey, M. J., Grosjean, M., & Knoblich, G. inferotemporal cortex. Nature Neuroscience,
(2005). Continuous attraction toward phono- 11, 13521360.
logical competitors. Proceedings of the National Yovel, G., & Kanwisher, N. (2005). The neural
Academy of Sciences USA, 102, 1039310398. basis of the behavioral faceinversion effect.
Stromswold, K., Caplan, D., Alpert, N., & Current Biology, 15(24), 22562262.
Rauch, S. (1996). Localiza ion of syntactic Zilles, K., & Amunts, K. (2010). Centenary of
comprehension by positron emission tomog- Brodmanns mapConception and fate.
raphy. Brain and Language, 52, 452473. Nature Reviews Neuroscience, 11(2), 139145.
2
All behaviors are subserved by distributed neu- neurologic function. Understanding the neu-
ral systems that comprise anatomic regions, robiology of subcortical cognition and its
or nodes, each displaying unique architec- clinical manifestations is essential to the evalu-
tural properties, distributed geographically ation and care of patients with dementia and
throughout the nervous system, and linked the neurobehavioral consequences of many
anatomically and functionally in a precise debilitating neurological diseases, including
and unique manner (Geschwind 1965a, 1965b; neurodegenerative diseases associated with
Goldman-Rakic, 1988; Jones & Powell, 1970a; dementia.
Luria, 1966; Mesulam, 1981, 1990; Nauta,
1964; Pandya & Kuypers, 1969; Ungerleider
& Mishkin, 1982). Subcortical structures are White Matter Tracts of the Cerebral
incorporated into the distributed neural cir- Hemispheres
cuits subserving cognition, a realization sup-
ported by the recognition of neurobehavioral Anatomical Organization
syndromes following lesions of cerebral white
matter and subcortical regions, and imaging The white matter tracts in the cerebral
studies in psychiatric patients demonstrating hemispheres are composed of axons cours-
abnormalities in subcortical areas. This chap- ing between cortico-cortical and cortico-
ter presents an overview of the anatomical subcortical territories. Neurons within any
organization in monkey of the white matter cortical area give rise to three distinct catego-
tracts linking different cerebral cortical areas ries of efferent fibers that can be identified
with each other, the connections between the within the white matter immediately beneath
cerebral cortex and subcortical areas, and a the gyrus (Schmahmann & Pandya, 2006).
consideration of the clinical manifestations These are association fibers, striatal fibers,
in patients of lesions in white matter tracts, and a confluence of fibers (the cord) that
the basal ganglia, thalamus, and cerebellum. carries commissural and subcortical (projec-
We regard these as disconnection syndromes: tion) fibers (Fig. 2.1).
focal disruptions of the distributed cortical Association fibers comprise local, neigh-
and subcortical neural circuits that subserve borhood, and long association fibers. Local,
32
CHAPTER 2. Neuroanatomy and Behavioral Neurology of Subcortical Systems 33
Striatal
fibers
Commissural
fibers Striatal
fibers
Thalamic Cord fibers
fibers Subcortical
Pontine bundle
fibers
(B)
Short association/Local U-fibers
Association Neighborhood association
(layer II, III) Long association
or U-fibers, are closely apposed to the under- from them, then travel within one of two
surface of the sixth layer and are directed to major fiber bundles. Fibers in the subcallo-
cortical regions in the same or adjacent gyri. sal fasciculus of Muratoff lead mainly to the
Neighborhood association fibers are distinct caudate nucleus and putamen. Fibers in the
from local U-fibers and are directed to nearby external capsule target the ventral part of
cortical regions; for example, the fibers that thecaudate nucleus, the putamen and claus-
connect the inferior parietal lobule to the trum (Fig. 2.2).
medial parietal cortex. Long association The cord of fibers comprises a dense aggre-
fibers are the named fiber tracts that travel gation of fibers occupying the central core
within the central part of the white matter of of the white matter of the gyrus and con-
the core of the gyrus and link distant cortical tains commissural fibers and the subcortical
areas within the same hemisphere. projection bundle. The commissural bundle
Corticostriatal fibers course initially with travels to the opposite hemisphere via the
the long association fibers before separating corpus callosum or the anterior commissure
34part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
MB CS (A)
CC
CC Cord
CC EC
Cd
1,2
IC EC
Put
Th LF (B)
GPe
GPi
CI
STS
Cord
Figure 2.2 Light field photomicrograph of a CC
coronal hemisphere of a monkey brain stained
for Nissl substance, to show the locations of the SB 1,2
ICa
Muratoff bundle (MB) coursing above the body
of the caudate nucleus and below the corpus
callosum, and the external capsule (EC) situated Put
between the claustrum laterally and the putamen
medially. CC = corpus callosum, Cd = caudate
nucleus, Cl = claustrum, CS = central sulcus,
GPe = globus pallidus external, GPi = globus
pallidus internal, IC = internal capsule,
LF = lateral fissure, Put = putamen, STS = superior
temporal sulcus, Th = thalamus (C)
ICp
(Fig. 2.3). The subcortical bundle (SB) trav-
els within the internal capsule (anterior or
1,2
posterior limb) or the sagittal stratum, and
segregates into thalamic fibers that travel via SB
thalamic peduncles to the thalamus, and a
Put
pontine fiber bundle that courses via the cere-
bral peduncle to the pons. The SB also gives Figure 2.3 Photomicrographs of selected
rise to fibers to other diencephalic and brain- coronal sections of a Rhesus monkey
stem structures. following injection of radioisotope into the
Knowledge of these tracts and their puta- frontal operculum in the precentral aspects
tive functional properties is useful when con- of areas 1 and 2. (A) The cord of fibers is
sidering the clinical consequence of white seen emanating from the injection site, with
matter diseases, and in understanding the some commissural fibers (Comm) continuing
neurobehavioral consequence of subcortical medially towards the opposite hemisphere
through the corpus callosum. (B) The cord
lesions that affect white matter tracts. The fol-
segregates into the commissural fibers and
lowing is a brief anatomical overview of the
the subcortical bundle (SB) that descends
fiber tracts of the brain of Rhesus monkey
into the anterior limb of the internal capsule.
(from Schmahmann & Pandya, 2006). These (C)Caudal to the injection site the subcortical
observations in monkey are supported by bundle continues its course in the posterior
magnetic resonance imaging (MRI) findings in limb of the internal capsule. Note terminations
monkey (Schmahmann, Pandya, et al., 2007), in the putamen. Magnification = 0.5,
and they closely match those in the human bar= 5mm. (Adapted from Schmahmann
brain as determined using diffusion tensor & Pandya, 2006; figure reproduced from
imaging (DTI; e.g., Catani, Howard, Pajevic, Schmahman & Pandya, 2008). CC = corpus
& Jones, 2002; Makris et al., 2005; Thiebaut de callosum, EC= external caspule, ICa = internal
Schotten, DellAcqua, Valabregue, & Catani, capsule, anterior limb, ICp = internal capsule,
2012; Wedeen et al., 2008), probabilistic posterior limb, Put = putamen.
CHAPTER 2. Neuroanatomy and Behavioral Neurology of Subcortical Systems 35
tractography (e.g., Johansen-Berg et al., 2005; SLF I(Fig.2.4A) lies medially situated in the
Lehericy et al., 2004), and resting-state func- white matter of the superior parietal lob-
tional connectivity mapping (Greicius, ule and the superior frontal gyrus. It links
Supekar, Menon, & Dougherty, 2009; Raichle the superior parietal region and adjacent
et al., 2001). There are a few notable excep- medial parietal cortex in a reciprocal man-
tions, however, exemplified by the finding of ner with the frontal lobe supplementary
an apparent inferior fronto-occipital fascicle in and premotor areas. It is thought to play a
humans (Forkel et al., 2012) that has not been role in the regulation of higher aspects of
identified in nonhuman primate tract tracing motor behavior that require information
studies (Schmahmann & Pandya, 2006, 2007). about body part location, and it may con-
tribute to the initiation of motor activity.
Association Fiber Tracts SLF II (Fig. 2.4B) is more laterally situated
and occupies a position in the central core
The long association fiber tracts are the of the hemisphere white matter, lateral to
essential anatomic substrates for the interdo- the corona radiata and above the Sylvian
main communication between cortical areas fissure. It links the caudal inferior parietal
that subserve different behaviors, and they lobule (equivalent in human to the angu-
deserve particular emphasis. lar gyrus) and the parieto-occipital areas,
The superior longitudinal fasciculus (SLF) with the posterior part of the dorsolateral
has three subcomponents: and mid-dorsolateral prefrontal cortex. It
SLF I PEc
PE (C) IPS
6D POa
9 IPS PFG
AS PF
CS
LS 6V CS
AS PFop LS
PS
PS 9/46V SLF III
IOS
44 IOS
STS
LF STS
LF
Figure 2.4 Summary diagrams of the course and composition of the superior longitudinal fasciculus
(SLF) in the Rhesus monkey. (A) SLF I; (B) SLF II; and (C) SLF III. The lateral and medial views of the
cerebral hemispheres show the trajectory of the three components of the SLF and the cortical areas that
contribute axons to these fiber pathways. (Adapted from Schmahmann & Pandya, 2006). AS = arcuate
sulcus, CC = corpus callosum, CF = calcarine fissure, Cing S = cingulate sulcus, CS = central sulcus,
IOS= inferior occipital sulcus, IPS = intraparietal sulcus, LF = lateral fissure, LS = lunate sulcus,
OTS = occipitotemporal sulcus, POMS = parieto-occipital medial sulcus, PS = principal sulcus,
RhF = rhinal fissure, RS = rostral sulcus, SMA = supplementary motor area, STS = superior temporal sulcus
36part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
is thought to serve as the conduit for the of the caudal inferior parietal lobule and
neural system subserving visual aware- extends into the white matter of the supe-
ness, the maintenance of attention, and rior temporal gyrus. It links a number of
engagement in the environment. It pro- high-level association and paralimbic cortical
vides a means whereby the prefrontal cor- areas, including the inferior parietal lobule,
tex can regulate the focusing of attention caudal cingulate gyrus, parahippocampal
within different parts of space. gyrus, and prefrontal cortex. In the human
SLF III (Fig.2.4C) is further lateral and ven- the MdLF may play a role in language, possi-
tral, and it is located in the white matter bly imbuing linguistic processing with infor-
of the parietal and frontal operculum. mation dealing with spatial organization,
It provides the ventral premotor region memory, and motivational valence.
and pars opercularis with higher order The fronto-occipital fasciculus (FOF)
somatosensory input, it may be crucial for (Fig.2.6A) travels above the body and head
monitoring orofacial and hand actions, of the caudate nucleus and the subcallosal
and in the human it may be engaged in fasciculus of Muratoff (Muratoff bundle;
articulatory aspects of language. see Fig. 2.6), lateral to the corpus callosum,
and medial to the corona radiata. It links the
The arcuate fasciculus (AF) (Fig. 2.5A) runs parieto-occipital region with dorsal premo-
in the white matter of the superior temporal tor and prefrontal cortices. The FOF is the
gyrus and deep to the upper shoulder of the long association system of the dorsomedial
Sylvian fissure. By linking the caudal tempo- aspects of the dorsal visual stream, and it
ral lobe with the dorsolateral prefrontal cor- appears to be an important component of the
tex, it may be viewed as an auditory spatial anatomical substrates involved in peripheral
bundle, important for the spatial attributes of vision and the processing of visual spatial
acoustic stimuli and auditory-related process- information.
ing. The AF has historically been regarded as The inferior longitudinal fasciculus (ILF)
linking the posterior (Wernicke) and anterior (Fig. 2.6B) is in the white matter between
(Broca) language areas in the human brain, the sagittal stratum medially and the
and to be involved in conduction aphasia. The parieto-occipital and temporal cortices later-
connectional studies in monkey are consistent ally. It has a vertical limb in the parietal and
with the evolving notion that the AF sub- occipital lobes, and a horizontal component
serves a dorsal stream of linguistic processing contained within the temporal lobe. The ILF
(Saur et al., 2008; Petrides & Pandya, 2009). is the long association system of the ventral
Together with the SLF III, it appears that the visual pathways in the occipitotemporal cor-
AF is engaged in the phonemic aspects of lan- tices. Visual agnosia and prosopagnosia are
guage (sound appreciation and production). two clinical syndromes that may arise from
The extreme capsule (EmC) (Fig. 2.5B) is ILF damage.
situated between the claustrum and the insu- The uncinate fasciculus (UF) (Fig. 2.7A)
lar cortex caudally, and between the claus- is a ventral limbic bundle that occupies the
trum and the orbital frontal cortex rostrally. In white matter of the rostral part of the tempo-
monkey, the extreme capsule is the principal ral lobe, the limen insula, and the white mat-
association pathway linking the middle supe- ter of the orbital and medial frontal cortex.
rior temporal region with the caudal parts By connecting these temporal and prefrontal
of the orbital cortex and the ventral-lateral areas, the uncinate fasciculus may be a cru-
prefrontal cortex, including area 45. These cial component of the system that regulates
areas are homologous to the Wernicke and emotional responses to auditory stimuli. It
Broca language cortices in human. The EmC, may also be involved in attaching emotional
together with the MdLF (see Fig. 2.5), is valence to visual information, is likely to be
thought to be implicated in a ventral stream an important component of the circuit under-
processing of language, concerned with the lying recognition memory, and is implicated
semantic aspects of communication, namely, in cognitive tasks that are inextricably linked
the meanings of words (Weiller, Bormann, with emotional associations (Ghashghaei
Saur, Musso,& Rijntjes, 2011). & Barbas, 2002). The UF has been shown to
The middle longitudinal fasciculus (MdLF) be clinically relevant in disorders of social
(Fig.2.5C) is situated within the white matter and moral cognition, such as psychopathy
CHAPTER 2. Neuroanatomy and Behavioral Neurology of Subcortical Systems 37
(A) CS
IPS
8AD 6D
9/46d TPO LS
AF Tpt
PS
AS
IOS
LF
STS
(B) (C)
RhF RhF
OTS OTS
CF CF
RS RS 23, 30
32
CC POMS CC POMS
24
Cing S Cing S
PG-Opt
CS IPS DP
IPS
8Ad
9/46d CS paAc
9 AS LF LS PS AS Tpt LS
proK
PS 47/12 45 paAlt 47/12 paAr TPO
10 IOS paAlt IOS
EmC TS3 IPro
TS2 TPO PGa
TAa LF MdLF
Insula IPa
IPa
TAa
STS
STS
STS STS
IOS
IOS
TF
TL OTS OTS
Orb S L RhF Orb S L RhF
TH
Orb S M Orb S M
CF
CF
Figure 2.5 Summary diagrams of the course and composition in the Rhesus monkey of the
(A) arcuate fasciculus (AF); (B) extreme capsule (EmC); and (C) middle longitudinal fasciculus
(MdLF). The lateral and medial views of the cerebral hemispheres show the trajectory of the
three components of the SLF and the cortical areas that contribute axons to these fiber pathways.
(Adapted from Schmahmann & Pandya, 2006). AS = arcuate sulcus, CC = corpus callosum,
CF=calcarine fissure, Cing S = cingulate sulcus, CS = central sulcus, IOS = inferior occipital sulcus,
IPS = intraparietal sulcus, LF = lateral fissure, LS = lunate sulcus, Orb S L = lateral orbital sulcus,
Orb S M = medial orbital sulcus, OTS = occipitotemporal sulcus, POMS = parieto-occipital medial
sulcus, PS= principal sulcus, RhF = rhinal fissure, RS = rostral sulcus, STS = superior temporal sulcus
and sociopathy (Motzkin, Newman, Kiehl, This dorsal limbic bundle links the rostral
& Koenigs, 2011; Sarkar et al., 2013), and in and caudal sectors of the cingulate gyrus
psychiatric illness including schizophrenia with each other; with the dorsolateral, orbital,
(Kawashima et al., 2009; Kubicki et al., 2002). and medial prefrontal cortices; and with the
The cingulum bundle (CB) (Fig. 2.7B) nes- parietal, retrosplenial, and ventral tempo-
tles in the white matter of the cingulate gyrus. ral cortices (including the parahippocampal
38part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
RhF
POa Opt
DP
LS
OTS IPS
CF V4D
MST
CS FST
RS PO PS MT
AS V1
LF V3, V2
CC 23 POMS V4
PGm ILF
TEO IOS
TEa V4V
Cing S
IPa TE3
Figure 2.6 Summary diagrams of the course and composition in the Rhesus monkey of the (A)
fronto-occipital fasciculus (FOF); and (B) inferior longitudinal fasciculus (ILF). The lateral, medial,
and basal views of the hemisphere show the trajectory of these fiber pathways and the cortical areas
that contribute axons to them. (Adapted from Schmahmann & Pandya, 2006). AS = arcuate sulcus,
CC = corpus callosum, CF = calcarine fissure, Cing S = cingulate sulcus, CS = central sulcus,
IOS= inferior occipital sulcus, IPS = intraparietal sulcus, LF = lateral fissure, LS = lunate sulcus,
Orb S L = lateral orbital sulcus, Orb S M = medial orbital sulcus, OTS = occipitotemporal sulcus,
POMS= parieto-occipital medial sulcus, PS = principal sulcus, RhF = rhinal fissure, RS = rostral
sulcus, STS=superior temporal sulcus
(A) (B)
RhF STS IOS
OTS
Opt
PG
UF IPS
8Ad 6D
TS1 TEa, IPa
9 9/46d
LF LS
Pro TE1 46d
CS
PS
AS
IOS
STS
IOS
TF
Orb S L 47/120
Perirh TL
RhF OTS
13 28 TH
Am
11 Orb S M
10 25 CF
14
Figure 2.7 Summary diagrams of the course and composition in the Rhesus monkey of the (A)
uncinate fasciculus (UF) and (B) cingulum bundle (CB). The lateral and medial views of the cerebral
hemisphere show the trajectory of these fiber pathways and the cortical areas that contribute axons
to them. (Adapted from Schmahmann & Pandya, 2006). Am = amygdala, AS = arcuate sulcus,
CC= corpus callosum, CF = calcarine fissure, Cing S = cingulate sulcus, CS = central sulcus,
IOS=inferior occipital sulcus, IPS = intraparietal sulcus, LF = lateral fissure, LS = lunate sulcus,
OrbSL= lateral orbital sulcus, Orb S M = medial orbital sulcus, OTS = occipitotemporal sulcus,
Perirh= perirhinal area, POMS = parieto-occipital medial sulcus, Pro = proisocortex, PS = principal
sulcus, RhF = rhinal fissure, RS = rostral sulcus, STS = superior temporal sulcus
temporal region, and the inferotemporal and to a dense aggregation of fibers, termed
preoccipital regions. Projections from pri- the cord, which occupies the central core
mary sensorimotor cortices are directed to of the white matter of the gyrus. The fibers
the putamen; those from the supplementary in the cord separate into two distinct seg-
motor area and association cortices terminate ments: commissural fibers and projection
also in the caudate nucleus. fibers in the subcortical bundle.
The MB and external capsule thus convey
fibers from sensorimotor, cognitive, and limbic Commissural Fibers
regions of the cerebral cortex to areas within
the striatum in a topographically arranged Anterior Commissure
manner. These corticostriatal pathways pro- The anterior commissure (AC) traverses the
vide the critical links that enable different midline in front of the anterior columns of the
regions with the basal ganglia to contribute to fornix, above the basal forebrain and beneath
motor control, cognition, and emotion. the medial and ventral aspect of the anterior
limb of the internal capsule. Its fibers link
the caudal part of the orbital frontal cortex,
Cord Fiber System
the temporal pole, the rostral superior tem-
In addition to association and corticostria- poral region, the major part of the infero-
tal systems, every cortical region gives rise temporal area, and the parahippocampal
40part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
Pu CI Pu
Pu
AC
VS
VS
(D) (E) Cl (F)
Cd Cd
Cd
Pu
Pu Th
Th Pu
GPe
GPi
STN STN CdT
CdT
Figure 2.8 Diagrams illustrating the principle of topographic arrangement of cerebral cortical
projections to the caudate nucleus (Cd) and putamen (Pu) from prefrontal cortex in the Rhesus
monkey. Injections of anterogradely transported isotope tracer were placed in the prefrontal
cortex. From left to rightorbital prefrontal cortex area 47/12 encroaching posteriorly on the
insular proisocortex; medial prefrontal convexity area 32; and area 46d above the midportion of the
principal sulcus. Coronal images through the striatum are shown in the columns below, from rostral
above to caudal at the bottom. Black dots represent terminations in the striatum. (Adaptedfrom
Schmahmann & Pandya, 2006). AC = anterior commissure, CdT = tail of caudate nucleus,
Cl=claustrum, GPe = globus pallidus external, G Pi = globus pallidus internal, STN = subthalamic
nucleus, Th = thalamus, VS = ventral striatum
3. Lesions of the ventral striatum produce involvement of the limbic ventral striato-pal-
disinhibited, irritable, and labile behaviors, lidal system, but it can also occur following
and they are implicated in the neurobiology damage to dorsolateral striatum and may
of addiction (Peoples, Kravitz, & Guillem, reflect connections with the medial prefrontal
2007) and obsessive-compulsive disorder and anterior cingulate regions.
(Remijnse et al., 2006). These disturbances of
social and emotional function (behaviors with Motor and behavioral consequences of palli-
limbic valence) reflect the ventral striatal con- dotomy are also determined by lesion loca-
nections with the orbital and medial prefron- tion. Posterior and ventrolateral regions
tal cortices concerned with drive, motivation, (linked to motor cortical areas) have a benefi-
emotional aspects of performance, inhibition cial impact on bradykinesia but no influence
of inappropriate responses, and reward- on cognitive performance (Lombardi et al.,
guided behaviors. Apathy most likely reflects 2000). Rostral and dorsomedial GPi lesions
44part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
(linked to prefrontal cortical areas 9 and 46) The CM/Pf nuclei are linked with the basal
produce impaired semantic fluency, math- ganglia in tightly connected functional cir-
ematical ability, and memory under condi- cuits. A sensorimotor circuit links putamen
tions of proactive interference. Left-sided with CM through the ventrolateral part of the
lesions produce deficits in verbal fluency internal segment of the globus pallidus (GPi).
and verbal encoding (Trpanier, Saint-Cyr, Cognitive circuits link the caudate with Pf
Lozano, & Lang, 1998). And bilateral palli- through the dorsal GPi and through the sub-
dotomy, while generally effective at reduc- stantia nigra pars reticulata (Sidibe, Pare, &
ing the disabling features of Parkinsons Smith, 2002). A limbic circuit links the ventral
disease (Scott, Gregory, & Hines, 1998), can striatum with the Pf through the rostrome-
result in prominent behavioral changes, dis- dial GPi, and midline nuclei receiving input
inhibition, reckless and socially inappropri- from the periaqueductal gray and spinotha-
ate behaviors, apathy, poor judgment, and lamic tract are involved in processing the
lack of insight (Ghika et al., 1999). motivational-affective components of pain
(Bentivoglio, Kultas-Ilinsky, & Ilinsky, 1993;
Lenz & Dougherty, 1997; Willis, 1997).
Thalamus
Limbic Thalamic Nuclei
The neurobehavioral syndromes resulting
from thalamic lesions may be understood The functions of the anterior nuclear group
by considering the functional properties ventral, medial, and dorsal (AV, AM, and AD
of the thalamic nuclei as determined by nuclei), and the lateral dorsal (LD) nucleus
tract-tracing investigations in monkeys, and are determined by their reciprocal anatomic
physiological and clinical studies in patients. connections with limbic structures in the
Thalamic nuclei have been grouped into five cingulate gyrus, hippocampus, parahip-
functional classes:reticular and intralaminar pocampal formation, entorhinal cortex, ret-
that subserve arousal and nociception; lim- rosplenial cortex, orbitofrontal and medial
bic nuclei concerned with mood and motiva- prefrontal cortices, and with subcortical
tion; specific sensory nuclei; effector nuclei structures, including the mamillary bodies
concerned with movement and aspects of and amygdala (Locke, Angevine,& Yakovlev,
language; and associative nuclei participat- 1961; Yakovlev & Locke, 1961; Yakovlev,
ing in high-level cognition (Schmahmann, Locke, Koskoff, & Patton, 1960; Yeterian &
2003; Fig. 2.9; Table 2.1). Pandya, 1988). The magnocellular part of the
medial dorsal nucleus (MDmc), parts of the
medial pulvinar, and parts of the VA nucleus
Anatomical Features and Connections are also reciprocally interconnected with the
cingulate gyrus and other components of the
Reticular Thalamic Nucleus limbic system and thus may also be consid-
ered limbic. Like their cortical and subcorti-
This nuclear shell surrounds thalamus and cal counterparts (Devinsky& Luciano, 1997;
conveys afferents from cerebral cortex. It Mesulam, 1988), limbic thalamic nuclei are
contributes to synchrony and rhythms of tha- likely to be essential for learning and memory,
lamic neuronal activity and is relevant in the emotional experience and expression, drive,
pathophysiology of epilepsy (Huguenard & and motivation. The tuberothalamic artery
Prince, 1997) and neural substrates of con- irrigates these nuclei as well as the mammil-
sciousness (Llinas& Ribary, 2001). lothalamic and ventral amygdalofugal tracts
that link the anterior thalamic nuclei with the
Intralaminar Thalamic Nuclei
limbic regions, accounting for the profound
The paracentral (Pcn), central lateral (CL), amnestic and limbic deficits resulting from
centromedian (CM), parafascicular (Pf), and tuberothalamic stroke.
midline nuclei such as paraventricular, rhom-
boid, and reunions play a role in autonomic
Specific Sensory Thalamic Nuclei
drive. They receive afferents from brainstem,
spinal cord, and cerebellum and have recip- The specific sensory nuclei include the medial
rocal connections with cerebral hemispheres. geniculate nucleus (MGN), lateral geniculate
CHAPTER 2. Neuroanatomy and Behavioral Neurology of Subcortical Systems 45
VA Re
Re (Edy)
(Edy) (L.po) VA
VAmc Cem (L.po)
AD CeM (L.po.mc) MTT
(Co) (Co) VAmc
(A.d) AV MTT
VLa (L.po.mc)
CL (A.Pr) (V.o.a/p) VLa VLa
(iLa.o) (V.o.a/p) VLp (V.o.a/p)
R VLp Pv
(Pm) (V.o.i)
(Rt) (V.o.i)
VLp
MD R (V.im)
(M) MD Pc VLp
(M) (iLa.o) (V.im) (Rt) MD VPLa R
(M) (V.c.a.e) (Rt)
AV VLp CL VPM
CL (A.Pr) (D.im) VPLa
(iLa.o) (V.c.a.e) (iL.a) (V.c.a.i)
LD VLp VPLp
(D.sf) (D.im) (V.c.p.e)
CL Pla
(iLa.v/p) (Pu.o) LP
Plm (D.c)
(Pu.m) LP Plm
(D.c) (Pu.m)
Ventral Pll
(Pu.l)
H1134 H1124
Gpi H1110
Gpi
Gpi
MTT MTT
Re MTT VA ST
(Edy) (L.po) ZI
(Zi)
VM VLa Cem RN
Cem (V.o.m)
(Co) (V.o.a/p) (Co)
VLp
Pv Pf (V.o.i) Pf VMb VLp R
(Pm) (Pf) Pv (Pf) (V.c.pc.i) (V.im) (Rt)
VLp (Pm)
(V.im) R VPLa VMb
CM (Rt) (V.c.a.e) Pf (V.c.pc.i)
CL (Ce) VPLa CL CM (Pf)
(iL.a.p) (iL.a.v/p) (Ce) CM VPLa
MD (V.c.a.e) VPM (V.c.a.e)
(M) VPM MD VPM (Ce) R
(V.c.a.i) (V.c.a.i) (Rt)
(V.c.a.i) H (M) H
(Hb) L CL
VPLp (Hb) Pla VPLp
VPLp
Pla (V.c.p.e) (Li) (iLa.c) (Pu.o)
Pla (V.c.p.e) (V.c.p.e)
L CL (Pu.o)
(Li) (iLa.c)
Plm Plm
(Pu.m) Pll (Pu.m)
(Pu.l) Plm Pll Pll
(Pu.m) (Pu.l) (Pu.l)
Dorsal
LD VLp
(D.sf) (D.im)
LD CL LP
(D.sf) VLp Pll
(V.im) (iLa.c) (D.c)
LP R (Pu.l)
(D.c) (Rt)
LP R
MD (Rt)
MD CL (D.c) R
(M) Pim
(iLa.p) VPLa (Rt) (Pu.m) Pla VPLp
(M) (V.c.a.e) (Pu.o) (V.c.p.e)
PLa
(Pu.o) VPLp
H (V.c.p.e) Pla
(Hb) VPLp (Pu.l) PIi
L (Pu.v)
CM VPM (V.c.p.e) (Li) Po
Pf
(Pf) (Ce) (V.c.a.i) (Li.por) Pli
Sg (Pu.v)
VPI (Li) LGd
PC (V.c.pc.e) Pg (G.l)
MG (pG)
Zi (G.m) R
(Zi) LGd (Rt)
(G.l)
Caudal
Figure2.9 Diagram illustrating the nuclei of the human thalamus. Horizontal sections are seen
above, from ventral to dorsal. Coronal sections below proceed from rostral to caudal. The revised
nomenclature correlates with terminology used in the monkey. An earlier nomenclature is shown in
parentheses. (Adapted from Jones, 1997; figure reproduced from Schmahmann & Pandya, 2008)
46part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
nucleus (LGN), and ventroposterior nuclei The VPL and VPM nuclei are reciprocally
(lateral, medial, and inferiorVPL, VPM, interconnected with primary somatosensory
andVPI). cortices; VPL serves body and limbs, and
Medial geniculate nucleus connections with VPM serves head and neck (Jones & Powell,
primary and association auditory cortices 1970b). Gustatory function is subserved by
infer a role in higher level auditory process- the parvicellular division of VPM (Pritchard,
ing as well as in elementary audition (Hackett, Hamilton, Morse, & Norgren, 1986). The
Stepniewska, & Kaas, 1998; Mesulam & somatotopy of these nuclei is precise, and
Pandya, 1973; Pandya, Rosene, & Doolittle, lacunar infarcts of the inferolateral artery pro-
1994). The lateral geniculate projects to primary duce focal sensory deficits. The VPI nucleus
and secondary visual cortices (Kennedy & is linked with the rostral inferior parietal
Bullier, 1985). It also receives projections back lobule and the second somatosensory area
from visual areas (Shatz& Rakic, 1981), indi- in the parietal operculum (SII; Schmahmann
cating that higher order processing can influ- & Pandya, 1990; Yeterian & Pandya, 1985)
ence visual perception at an early stage. and with the frontal operculum engaged in
CHAPTER 2. Neuroanatomy and Behavioral Neurology of Subcortical Systems 47
(Pandya, Rosene, & Doolittle, 1994) and mul- LP and PO nuclei that project to both superior
timodal superior temporal cortices (Yeterian and inferior parietal lobules. Rostral parietal
& Pandya, 1991), and with the cingulate, para- subdivisions receive projections from ventral
hippocampal (Yeterian & Pandya, 1988), and regions within these thalamic nuclei, caudal
insula cortices (Mufson & Mesulam, 1984). parietal afferents arise from the dorsal parts
Aphasia (Ojemann, Fedio, & Van Buren, of these nuclei, and the intervening cortical
1968), spatial neglect (Karnath, Himmelbach, levels receive projections from intermediate
& Rorden, 2002), and psychosis (Guard etal., positions within the nuclei. A similar topo-
1986) may result from PM lesions. The lat- graphic arrangement is present also in the
eral pulvinar (PL) is linked with posterior medial pulvinar projections to the inferior
parietal (Asanuma, Andersen, & Cowan, parietal lobule (Fig. 2.11).
1985; Schmahmann & Pandya, 1990), supe-
rior temporal (Yeterian & Pandya, 1991), and
medial and dorsolateral extrastriate cortices Clinical Features of Thalamic Lesions
(Yeterian & Pandya, 1997), and the superior
colliculus (Robinson & Cowie, 1997). It is C. Miller Fisher (19132012) first described
engaged in the integration of somatosensory neglect (modified anosognosia and hemia-
and visual information. Inferior pulvinar (PI) somatognosia), global dysphasia, confu-
is linked with temporal lobe areas concerned sion, and visual hallucinations in patients
with visual feature discrimination, and with with thalamic hemorrhage (Fisher, 1959).
ventrolateral and ventromedial extrastriate Accounts followed of thalamic demen-
areas concerned with visual motion (Cusick, tia from prion diseases (Martin, 1997) and
Scripter, Darensbourg, & Weber, 1993; behavioral changes in patients with thalamic
Yeterian & Pandya, 1997). It also receives tumors (Nass et al., 2000; Ziegler, Kaufman, &
input from retinal ganglion cells (Cowey, Marshall, 1977), but these lesions are seldom
Stoerig, & Bannister, 1994) and visual neu- confined to thalamus. Focal lesions in thala-
rons of the superior colliculus (Robinson & mus occur in the setting of ischemic infarc-
Cowie, 1997). The anterior pulvinar (pulvinar tion. There are four main vascular syndromes
oralis, PO) is interconnected with intramo- of the thalamus. A review of these vascular
dality somatosensory association cortices in syndromes illustrates the behavioral roles of
the rostral part of the inferior parietal region, the different thalamic nuclei and highlights
and with the second somatosensory area the clinical relevance of the thalamic affer-
(SII; Acuna, Cudeiro, Gonzalez, Alonso, & ent and efferent connections (Schmahmann,
Perez, 1990; Asanuma, Andersen, & Cowan, 2003; Fig. 2.12; Table 2.2).
1985; Schmahmann & Pandya, 1990; Yeterian
& Pandya, 1985). The PO nucleus may be Tuberothalamic Artery Infarction
important in the appreciation of pain, as are
the suprageniculate, limitans, and posterior These patients demonstrate fluctuating
nuclei (Jones, 1985). levels of consciousness, disorientation in
Sensorimotor, effector, limbic, and asso- time and place, and personality changes,
ciative regions of cerebral cortex are there- including euphoria, lack of insight, apathy,
fore linked with distinctly different sets of lack of spontaneity, and emotional uncon-
thalamic nuclei. Thalamic projections to the cern (Bogousslavsky, Regli, & Assal, 1986;
posterior parietal lobe exemplify this concept Bogousslavsky, Regli, & Uske, 1988; Graff-
(Schmahmann& Pandya, 1990). Connections Radford, Damasio, Yamada, Eslinger, &
become progressively elaborated as one Damasio, 1985; Graff-Radford, Eslinger,
moves from rostral to caudal within both Damasio, & Yamada, 1984; Lisovoski et al.,
the superior and the inferior parietal lobules. 1993) (Fig. 2.13A and B). New learning and ver-
Rostral areas concerned with intramodal- bal and visual memory are impaired. Amnesia
ity somatosensory processing are related to is greater following left thalamic lesions, along
modality-specific thalamic nuclei, whereas with anomia, impaired comprehension, fluent
caudal regions, concerned with complex func- and meaningless discourse with semantic and
tions, derive their input from multimodal and phonemic paraphasic errors, neologisms, and
limbic nuclei (Fig. 2.10). This rostral-caudal perseveration. In contrast, repetition and read-
cortical topography is represented within the ing aloud are preserved. Acalculia, buccofacial
CS IPS
PS AS
LS
LF
STS
Cld
sm LD LD VLc
Csl VLc VLc VLc
MD CL
MD m CL
CL VPLo MD oc VPLo CL
pc MD VPLc
VPLo
CM VPM
CM VPM VPI CM
VPM
VPM VPI
VPI
VLps
sm
VLos
LP
MD CL LD LP
LP MD
PM
H VPLc
pl CM PO SM VPLc
pf CM VPM MDmt
VPLc
PO
VPMpc
pf
GMpc
LP
H MD
PM
Li PM LP
VPLc
PL
PO Li R PL
PM
Pl PO
R H
SG GMpc Li
GM SG
Pt
Pl
St
St
PM
PL
PM
PL
PARIETAL
CORTICAL S1 Area PF Area PG Area PG-Opt
REGION
PRINCIPAL Sensory Sensory Associative Associative
THALAMIC Ventral posterior Ventral posterior Pulvinar medialis (PM) Pulvinar medialis (PM)
NUCLEAR medial (VPM) medial (VPM) Lateral posterior (LP) Lateral posterior (LP)
AFFERENTS Ventral posterior Effector Effector
inferior (VPI) Ventral lateral Ventral lateral
Associative (caudal (VLc) and (pars postrema) (VLps)
Pulvinar oralis (PO) pars postrema (VLps)) Intralaminar
Lateral posterior (LP) Paracentralis (Pcn)
Pulvinar medialis (PM) Limbic
Lateral dorsal (LD)
Anterior nuclei
PUTATIVE Primary Intramodality Multimodal somatosensory Multimodal associative
FUNCTIONAL unimodal association within and visual: for integration and paralimbic: visual
PROPERTIES somatosensory somatosensory of visual and cutaneo- spatial and somesthetic
domain: for kinesthetic spatial stimuli invested with
graphesthesia, information emotional and
stereognosis motivational valence
(A) (B)
1
DM
VA
VA VL VP 6
P
DM 5
VL
LGB 8 7
6 7 8 9
VP IL 2
3
5 3 4 P
1 2
9
4
(C) (D)
Ca
F Put
Pl Put R
R
P Pm
m
a Apr Lpo
Fa Lpo
M Pt
Co T
IML T voi Voe
Vo Voe
Do
M Vim
Pt M
Ce
p mc Vc Vce
m T Ce Dc
p M pc
H IML
m
Cp HI IML
Pu Pu
R
Paramedian
Figure 2.12 Thalamic vascular supply. Schematic diagram of the lateral (A) and dorsal (B) views
of the four major thalamic arteries, and the nuclei they irrigate, according to Bogousslavsky, Regli,
and Uske (1988). 1 = carotid artery, 2 = basilar artery, 3 = P1 region of the posterior cerebral artery
(mesencephalic artery), 4 = posterior cerebral artery, 5 = posterior communicating artery, 6 =
tuberothalamic artery, 7 = paramedian artery, 8 = inferolateral artery, 9 = posterior choroidal artery.
DM, dorsomedial nucleus; IL, intralaminar nuclear complex; P, pulvinar; VA, Ventral anterior; VL,
Ventral lateral; VP, ventral posterior complex. The illustrations in C and D from De Freitas and
Bogousslavsky (2002) are an adapted version of the conclusions of von Cramon, Hebel, and Schuri
(1985) regarding the patterns of irrigation by the thalamic arterial supply to the thalamic nuclei.
(Composite image from Schmahmann, 2003)
Nasreddine & Saver, 1997). Sensory loss may posterior column sense (position, vibration).
be the sole clinical manifestation, involve all These strokes produce a flexed and pronated
modalities, or impair spinothalamic sensa- thalamic hand (Foix & Hillemand, 1925)
tion (temperature, pinprick) without loss of with the thumb buried beneath the other
52part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
TABLE 2.2 Thalamic Arterial Supply and Principal Clinical Features of Focal Infarction (From
Schmahmann, 2003)
Thalmic Blood Vessel Nuclei Irrigated Clinical Features Reported
(A) (B)
(C) (D)
Figure2.13(A) Diffusion weighted image (DWI) of left tuberothalamic artery territory infarction
(right of diagram). (B) DWI showing infarction bilaterally in the territory of the polar branch of the
tuberothalamic artery, likely representing an example of the paramedian artery irrigating both the
paramedian and tuberothalamic territories. (C) Right paramedian artery territory infarction, seen
on T2-weighted magnetic resonance imaging. (D) Acute infarction in the left inferolateral artery
territory on DWI. (From Schmahmann & Pandya, 2008)
ataxia, rubral tremor, dystonia, myoclonus, 2006) can produce corticothalamic discon-
and chorea (Neau & Bogousslavsky, 1996). nection and complex behavioral syndromes
Spatial neglect has been reported (Karnath, (Chukwudelunzu, Meschia, Graff-Radford,
Himmelbach, & Rorden, 2002). & Lucas, 2001; Schmahmann, 1984; Tatemichi
Damage to thalamic fiber pathways may et al., 1992). Disorders of eye movement
have clinical consequences. The mamillotha- result from medial thalamic lesions destroy-
lamic tract (MMT) connects the anterior tha- ing descending tracts from motor and pre-
lamic nuclei with the mamillary body, which motor cortices to the midbrain nuclei of
is linked with hippocampus and entorhinal Darkschewitz and the interstitial nucleus of
cortex. The MMT and fornix bind the ante- Cajal (upgaze and downgaze), and the rostral
rior thalamic nuclei into the neural system nucleus of the medial longitudinal fasciculus
for learning and memory. The ventral amyg- in the tectum (downgaze) (Bogousslavsky,
dalofugal pathway links the amygdala with Regli, & Uske, 1988; Fisher, 1959; Guberman
the medial part of MD, and damage contrib- & Stuss, 1983; Leigh & Zee, 1983).
utes to amnesia and emotional dysregula-
tion (Graff-Radford, Tranel, Van Hoesen, &
Brandt, 1990). Lesions of the superior, medial Cerebellum
and inferior, and lateral thalamic peduncles
and of the anterior limb of the internal cap- The cerebellum is subcortical only in the
sule (conveying prefrontal and anterior cin- sense that it is distinct from cerebral cor-
gulate interactions; Schmahmann & Pandya, tex (Fig. 2.14). The traditional view that
54part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
(A) x=2
100 90 80 70 60 50 40 30 (B)
z= IV
V IV V
0 0
III VI III
10 VI 10
20 20
VIIAt I,II
I,II
VIIB F
30 30 VIIAt
VIIB X X
40 40
VIIIA VIIIA
50 VIIIB 50 IX
IX
VIIIB
60 60
y= 100 90 80 70 60 50 40 30
(C) (D)
y = 52 60 50 40 30 20 10 0 10 20 30 40 50 60
0 0
IV V
10 10 V
V IV
VI VI
20 20 G F F
VI
G
z = 30 Cr I X Cr I 30 X
D E E
40 40 D
IX
50 Cr II 50
VIIB IX IX
IX
60 VIIB 60
VIIIB VIIIA VIIIA VIIIB
VIIIB VIIIA
x = 60 50 40 30 20 10 0 10 20 30 40 50 60
(E) z = 33 60 50 40 30 20 10 0 10 20 30 40 50 60 (F)
V IV V
IV V
30 30
VI
40 40
X X
50 50
IX D IX
D
y = 60 60
VIII VIII
70 70
VIIB VIIB VIIB
80 Cr I 80
90 90 Crus II
Cr II
100 100
x = 60 50 40 30 20 10 0 10 20 30 40 50 60
Figure 2.14 Images of the human cerebellum on magnetic resonance imaging (left) and
postmortem cryosection (right). The cerebellum is sectioned in the sagittal plane 2 mm to the right
of midline in A and B; in the coronal plane 52 mm behind the anterior commissureposterior
commissure (AC-PC) line in C and D; and in the transverse plane 33 mm below the AC-PC line
in E and F. Cerebellar fissures are demarcated and the lobules are designated. Deep cerebellar
nuclei are identified in the cryosection brain: D, dentate nucleus; E, emboliform nucleus; F, fastigial
nucleus; G, globose nucleus. (From Schmahmann et al., 1999; Schmahmann et al., 2000)
CHAPTER 2. Neuroanatomy and Behavioral Neurology of Subcortical Systems 55
cerebellar function is confined to the coor- anterior lobe and part of lobule VI receive
dination of voluntary motor activity has afferents from motor and premotor cortices,
evolved (Schmahmann, 1991, 1997). Evidence whereas the association areas in the prefron-
from patients has made it plain that cerebel- tal and posterior parietal cortices are linked
lar pathology is related to intellectual and predominantly with crus I and crus II of
emotional deficits in addition to motor inco- the posterior lobe (Allen& Tsukahara, 1974;
ordination. The wider role of the cerebellum Kelly & Strick, 2003) (Fig. 2.16). Once con-
in nervous system function has far-ranging veyed to the cerebellar cortex, these streams
implications for understanding the neural of information are acted upon by the cerebel-
substrates of higher order behavior and neu- lar corticonuclear microcomplexes (Ito, 1984),
ropsychiatric disorders. There appears to be and then transmitted via the deep cerebellar
a double dissociation in the organization of nuclei to thalamus, on their way back to the
motor and nonmotor functions in the cerebel- cerebral cortex.
lum, a conclusion derived from clinical neu- Cerebellar projections to thalamus arise
rology as well as anatomy, physiology, and from fastigial and interpositus nuclei as well
functional imaging studies. as from the dentate nucleus, and they are
directed not only to the cerebellar recipient
VL but also to CL, Pcn, the CM-Pf complex,
Connectional Neuroanatomy of the and MD that have efferent projections to
Cerebellum association cortices. The cerebellar dentate
nucleus sends projections through thalamus
It is now known that cerebellar connections to different areas of the frontal lobe in the
with the cerebral cortex are not confined to monkey (Middleton& Strick, 1997). The dor-
motor-related cortices projecting through somedial part of the dentate nucleus sends its
basis pontis nuclei to cerebellum, and dentate projections to the motor cortex, whereas the
nucleus of cerebellum sending efferents back ventrolateral and ventromedial parts of the
through VL thalamus to motor cortex. Rather, dentate nucleus are connected with the pre-
the association and paralimbic regions of the frontal cortex, including area 9/46 (Kelly &
cerebral cortex have topographically orga- Strick, 2003). Further anatomical details of
nized feedforward projections through the the cerebrocerebellar linkage and of the oli-
nuclei in the basis pontis into the cerebellum, vary inputs to cerebellum may be found
as well as feedback projections from the cer- elsewhere (Schmahmann, 1996, 2006, 2013;
ebellum. Association cortex projections arise Schmahmann & Pandya, 1997b; Voogd &
from the prefrontal, posterior parietal, supe- Glickstein, 1998).
rior temporal polymodal regions, and dorsal Resting state functional connectivity mag-
parastriate cortices. Paralimbic projections netic resonance imaging (rs-fcMRI) extends
arise from the posterior parahippocampal these anatomical investigations to humans
cortex, limbic regions of the cingulate gyrus, by using the physiological feature of fluctu-
and the anterior insular cortex involved ating blood oxygen leveldependent (BOLD)
in autonomic and pain modulation sys- signal to infer anatomical connectivity. These
tems (Schmahmann, 1996; Schmahmann & studies show that activity in the cerebel-
Pandya, 1997a, 1997b). These corticopontine lar anterior lobe (most notably in lobules III
pathways are funneled through the cerebro- through V), the adjacent part of lobules VI,
cerebellar circuit within multiple parallel and lobule VIII correlates with sensorimo-
but partially overlapping loops converging tor regions of the cerebral cortex. In con-
with topographic ordering throughout the trast, activity in the cerebellar posterior lobe
pons, whereas the motor corticopontine pro- (mostly Crus I and II of lobule VII) corre-
jections are mostly in the caudal half of the lates with prefrontal, parietal, and temporal
pons (Brodal, 1978; Schmahmann& Pandya, association areas and the cingulate gyrus
1997b; Schmahmann, Rosene, & Pandya, (Habas et al., 2009; Krienen & Buckner, 2009;
2004)(Fig. 2.15). OReilly, Beckmann, Tomassini, Ramnani,
A precise pattern of organization is prob- & Johansen-Berg, 2010). Further, cerebellar
ably present also in the pontine projections correlations with intrinsic functional con-
to the cerebellar cortex, although this still nectivity networks in the cerebral hemi-
remains to be demonstrated. The cerebellar spheres reveal a pattern such that lobules VI,
56part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
IPS
Cing S
PS LS CS PS OTS
AS
CS STS STS
LF Orb S.
STS
(a) (b) (c) (d)
Rostral
P
PM
I
M
II
CF L
III
DM
IV
DL
PM
V
NRTP
VI
V
EDL
VII
D
VIII
IX
Caudal
Figure 2.15 Diagram of the projections to the basis pontis from selected regions within the
cerebral association areas. The pons is the obligatory synaptic step in the feedforward limb of the
cerebrocerebellar circuit. Radiolabeled amino acids (shaded black area in the cerebral hemispheres)
were placed in the medial and lateral parts of the rostral prefrontal cortex (area 10) in A; in the cortex
buried within the rostral upper bank of the superior temporal sulcus (area TPO1) in B; in cortex buried
within the lower bank of the intraparietal sulcus (area POa, or MIP) in C; and in the parahippocampal
gyrus (areas TF/TL) in D. The label was transported in an anterograde fashion and terminated (black
dotes) in the ipsilateral half of the basis pontis from rostral level I to caudal level IX. Each cerebral area
is connected with a unique and distributed subset of pontine neurons. The projections appear to be
arranged in an interdigitating, but not overlapping manner. (From Schmahmann, 1996). AS = arcuate
sulcus, Cing S = cingulate sulcus, CF = calcarine fissure, CS = central sulcus, D = dorsal nucleus,
DL = dorsolateral nucleus, DM = dorsomedial nucleus, EDL = extreme dorsolateral nucleus, IPS =
intraparietal sulcus, L = lateral nucleus, LF = lateral fissure, LS = lunate sulcus, M = medial nucleus,
NRTP = nucleus reticularis tegmenti pontis, Orb S = orbital sulcus, OTS = occipitotemporal sulcus,
P = peduncular nucleus, PM = paramedian nucleus, PS = principal sulcus, STS = superior temporal
sulcus, V = ventral nucleus.
CHAPTER 2. Neuroanatomy and Behavioral Neurology of Subcortical Systems 57
(A) (B)
M1 Area 46
CS
FEF I I II
SPS
9
46
8 M1arm
PS
II III
10 12 PMVarm III
AS
IV
15 IV
Crus I V
STS
5 mm V Crus I
VI VI
Crus II
X
P 7.5 P 8.0 D P 8.5 P 8.5 X
M
1 mm
Figure2.16(A) Lateral view of a cebus monkey brain (top) to show the location of injections of
McIntyre-B strain of Herpes simplex virus type 1 in the primary motor cortex, ventral premotor
cortex, and areas 9 and 46. The resulting retrogradely labeled neurons in the cerebellar dentate
nucleus (below) are indicated by solid dots. (From Middleton and Strick, 1997)(B) Flattened
views of cerebellar cortex of monkey showing areas labeled in anterograde and retrograde fashion
following injection of neurotropic virus tracers in the primary motor cortex at left, and prefrontal
cortex area 46 at right. (Adapted from Kelly & Strick, 2003)
Crus I and Crus II, and lobule IX correlate emotional regulation in the cerebellum repre-
with the executive control network; lobule sents a major departure from earlier conven-
VI with the salience network; and lobule IX tional wisdom. In sum, the cerebellar anterior
with the default network (Buckner, Krienen, lobe and parts of medial lobule VI, together
Castellanos, Diaz, & Yeo, 2011). Task-based with lobule VIII of the posterior lobe and
functional MRI studies indicate that the cer- the globose and emboliform nuclei (or, more
ebellar anterior lobe, adjacent parts of lobule accurately the interpositus nucleus in the
VI, and lobule VIII are activated in sensorim- experimental animal), constitute the senso-
otor tasks; lobules VI and VII in the posterior rimotor cerebellum. Lobule VII (that includes
lobe are active during language, spatial, and Crus Iand Crus II of lobule VIIA, and lobule
executive function tasks; and affective pro- VIIB), parts of lobule VI, and the ventral part
cessing engages the posterior lobes, includ- of the dentate nucleus constitute the ana-
ing the vermis (Stoodley & Schmahmann, tomical substrate of the cognitive cerebellum.
2009; Stoodley, Valera, & Schmahmann, 2012) The limbic cerebellum appears to have an
(Fig. 2.17). Working memory and executive anatomical signature in the fastigial nucleus
functions engage lobules VI and VII, lan- and the cerebellar vermis, particularly the
guage recruits posterolateral cerebellum on posterior vermis. Lobule IX is likely part of
the right, and spatial tasks recruit it on the the default mode network, and lobule X is an
left. Affective/emotional processing and essential node in the vestibular system.
pain and autonomic functions involve lob- There are few published details regard-
ules VI and VII in the vermis more than the ing the anatomical organization of cerebel-
hemispheres (Moulton et al., 2011). lar white matter at the systems level, that is,
The anterior lobe is not engaged in cogni- which parts of the cerebellar white matter
tive tasks; the posterior lobe is not involved convey afferent and efferent fibers to which
in motor tasks with the exception of parts specific cerebellar lobules. Nuclei in the ros-
of lobule VI and the second sensorimotor tral part of the basis pontis project via the
representation in lobule VIII (Stoodley & middle cerebellar peduncle (MCP) to the
Schmahmann, 2009, 2010; Stoodley, Valera,& posterior lobe of the cerebellum, and those
Schmahmann, 2010, 2012). This recognition in the caudal basis pontis project to the ante-
that sensorimotor control is topographically rior cerebellum (Bechterew, 1885; Takahashi,
separate and distinct from cognitive and Song, Folkerth, Grant, & Schmahmann,
58part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
Motor
y = 55
Language
y = 68
Spatial
y = 64
Spatial
y = 78
Working
Memory
y = 60
2013), but more precise information concern- with lobule VI (Fig. 2.18A) likely engaged in
ing MCP organization remains to be eluci- motor control in a manner possibly equiva-
dated. Similarly, the degree to which there lent to premotor regions of the cerebral cortex
is anatomical and functional differentiation (Schmahmann, MacMore, Gardner, & Vangel,
within the superior cerebellar peduncle effer- 2009; Schmahmann, MacMore, & Vangel, 2009;
ents to thalamus is not presently known. Stoodley & Schmahmann, 2009; Stoodley,
The topographical organization of motor, Valera, & Schmahmann, 2012). There is a sec-
cognitive, and affective domains in cerebel- ond sensorimotor area identified by physiol-
lum (Schmahmann, 1991, 2004) suggests that ogy and functional imaging, located in lobule
defining the arrangement of the cerebellar VIII at the medial part of the posterior lobe
white matter pathways that connect with (Grodd, Hlsmann, Lotze, Wildgruber, & Erb,
extracerebellar structures will be of great 2001; Snider & Eldred, 1952). Oculomotor
interest. abnormalities along with prominent vestibu-
lar symptoms (vertigo, nausea, emesis) arise
from lesions that involve lobules IX and X
Clinical Features of Cerebellar of the posterior and flocculonodular lobes
Lesions (Duncan, Parker, & Fisher, 1975; Lee et al.,
2006). Remarkably, large lesions in the major
The cerebellar motor syndrome of gait ataxia, expansion of the cerebellar hemisphere (i.e.,
appendicular dysmetria, dysarthric speech, lobules Crus I and II and lobule VIIB in the
and oculomotor abnormalities results from posterior lobe; Fig. 2.18B) do not result in the
lesions that affect the anterior lobe of the cerebellar motor syndrome. Indeed, when
cerebellum, notably lobules I through V, these patients are examined a few days after
(A)
(B)
(C)
Figure 2.18 Diffusion weighted magnetic resonance image of cerebellar infarction. (A) Reference
diagram in the horizontal plane of the major cerebellar lobular groupings (top left: superior, to bottom
right: inferior). The anterior lobe (lobules I through V) is shaded black; lobule VI of the posterior lobe
is shaded gray; lobules VII through IX of the posterior lobe, and lobule X (flocculonodular lobe) are
not shaded. (B) Stroke in the territory of the superior cerebellar artery, involving the anterior lobe
(cerebellar lobules IV) and part of the posterior lobe. This patient had a cerebellar motor syndrome,
scoring 20 of possible 120 points on the Modified International Cooperative Ataxia Rating Scale
(MICARS; Schmahmann, Gardner, MacMore, & Vangel, 2009; Schmahmann, MacMore, & Vangel,
2009; Trouillas et al., 1997). (C) Stroke in the posterior inferior cerebellar artery territory, sparing the
anterior lobe. The patient was motorically normal, with a MICARS score of 1. (Reproduced from
Schmahmann & Pandya, 2008)
60part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
stroke, and the vestibular symptoms have Schmahmann, 2002; van Harskamp, Rudge,
subsided, it can be difficult to detect any sign & Cipolotti, 2005; Limperopoulos et al., 2006;
of a motor disorder (Schmahmann, MacMore, Tavano et al., 2007; Tedesco et al., 2011).
& Vangel, 2009), a straightforward clinical Deficits in emotional expression in patients
finding that defies two centuries of dogma with strokes and neurodegenerative lesions
about the cerebellar role being confined exclu- have also been linked to involvement of the
sively to motor coordination. cerebellar system (Parvizi, Anderson, Martin,
The other side of the double dissociation Damasio, & Damasio, 2001; Parvizi, Joseph,
is that the cerebellar cognitive affective syn- Press, & Schmahmann, 2007).
drome (CCAS; Schmahmann & Sherman, The posterior fossa syndrome repre-
1998) occurs following lesions of the cerebel- sents a particularly acute form of the CCAS
lar posterior lobe, but not the anterior lobe (Levisohn, Cronin-Golomb, & Schmahmann,
(Exner, Weniger, & Irle, 2004; Schmahmann 2000; Pollack, 1997; Riva & Giorgi, 2000; Wisoff
& Sherman, 1998). The CCAS is characterized & Epstein, 1984). Within 48 hours following
by deficits in executive function, visual spatial surgical resection of midline tumors of the
performance, linguistic processing, and affec- cerebellum, children develop mutism, buc-
tive dysregulation. Executive impairments cal and lingual apraxia, apathy, and poverty
include deficits in working memory, motor of spontaneous movement. Emotional labil-
or ideational set shifting, and perseveration. ity is marked by rapid fluctuation between
Verbal fluency is impaired to the point of irritability and agitation to giggling and easy
telegraphic speech or mutism. Visuospatial distractibility. The range of neuropsychiatric
disintegration impairs attempts to draw or impairments in the setting of cerebellar lesions
copy a diagram, conceptualization of figures falls into five major behavioral domains: atten-
can be disorganized, and some patients dis- tional control, emotional control, social skill
play simultanagnosia. Anomia, agrammatic set, autism spectrum disorders, and psychosis
speech, and abnormal syntactic structure are spectrum disorders (Schmahmann, Weilburg,
observed, with abnormal prosody charac- & Sherman, 2007; Table 2.3).
terized by high-pitched, hypophonic whin- The cerebrocerebellar system thus consists
ing. Abnormal modulation of behavior and of discretely organized parallel anatomic sub-
personality is notable with posterior lobe systems that serve as the substrates for differ-
lesions that involve the vermis and fastigial entially organized functional subsystems (or
nucleus. This manifests as flattening of affect loops) within the framework of distributed
alternating or coexistent with disinhibited neural circuits. This anatomical organiza-
behaviors such as overfamiliarity, flamboy- tion is the substrate for dysmetria of thought
ant and impulsive actions, and humorous theory (Schmahmann, 1991, 1996, 2000, 2004,
but inappropriate and flippant comments. 2010) and the notion of the universal cer-
Regressive, childlike behaviors and obses- ebellar transform. This idea holds that the
sive-compulsive traits can be observed. cerebellum plays an essential role in automa-
Autonomic changes are noted following tization and optimizing behavior around a
lesions of the fastigial nucleus and vermis, homeostatic baseline according to context;
manifesting as bradycardia and syncope, or that the cerebellum modulates cognition and
tachycardia in the setting of acquired panic emotion in the same way that it coordinates
disorder (Schmahmann & Sherman 1998; motor control; and that disruption of the neu-
Schmahmann, Weilburg, & Sherman, 2007). ral circuitry linking the cerebellum with the
The principal features and clinical relevance association and paralimbic cerebral regions
of the CCAS as defined by Schmahmann and prevents the cerebellar modulation of func-
Sherman (1998) have been replicated in adults tions subserved by the affected subsystems,
with stroke (Malm et al., 1998; Neau, Arroyo- thereby impairing the regulation of move-
Anllo, Bonnaud, Ingrand, & Gil, 2000), in ment, cognition, and emotion. This loss of
children who have undergone excision of cer- the cerebellumizing of behavior leads not
ebellar tumors (Levisohn, Cronin-Golomb, only to gait and appendicular ataxia, dysar-
& Schmahmann, 2000; Riva & Giorgi, 2000; thria, and oculomotor abnormalities when
Scott et al., 2001), and in other acquired and the motor cerebellum is involved but also
developmental disorders of the cerebel- to the various aspects of the cerebellar cog-
lum (Allin et al., 2001; Chheda, Sherman, & nitive affective syndrome (Schmahmann &
CHAPTER 2. Neuroanatomy and Behavioral Neurology of Subcortical Systems 61
Sherman, 1998)when the cognitive and lim- related areas of different cortical and subcor-
bic cerebellar regions are damaged. tical nodes. Note that there is, by and large,
no cross-modal communication within sub-
cortical nodes (e.g., thalamic nuclei do not
Conclusions communicate with each other), although a
possible exception has been reported in the
Two overarching principles govern the clini- striatonigostriatal system (Haber, Fudge, &
cal manifestations resulting from lesions McFarland, 2000). Given that behavior is the
of the subcortical nodes of the distributed result of complex interactions between dif-
neural circuits discussed in this chapter. ferent functional domains, at some point in
First, each node is engaged in multiple the anatomy of cognition, mood must inform
loops of information processing with ana- movement, strategy must rely on memory,
tomically and functionally distinct regions and so on. The problem of segregated loops
of the cerebral cortex and other subcortical in cortical-subcortical interactions is resolved
nodes. The topography of the lesion within by the cerebral cortical association areas that,
the node itself determines which behav- alone among the many nodes of the distrib-
ioral domain is affected. Second, the histol- uted neural system, facilitate the integration
ogy of each node enables a computation, or of information across multiple domains in
transform, that is unique to that node. Loss a feedforward and feedback manner. This
of the nodal transform by a lesion therefore capability is made possible by the associa-
affects the motor/cognitive/affective out- tion fiber pathways, which are themselves
come in a manner that is specific to the node. exclusive to the cerebral cortex.
Amore detailed discussion of the theoretical
underpinnings of the behavioral neurology
of these subcortical areas can be found in Acknowledgments
Schmahmann and Pandya (2008). It is worth
restating, however, that a cortical area can Supported in part by RO1 MH067980,
be defined by its pattern of subcortical and MH64044, the Sidney R.Baer Jr. Foundation,
cortical connections; that lesions of subcorti- the National Organization of Rare Disorders,
cal structures mimic deficits resulting from the National Ataxia Foundation, and the
lesions of the cerebral cortex; and that there MINDlink and Birmingham Foundations.
are qualitative differences between the clini- The assistance of Jason MacMore, BA, is
cal manifestations of lesions in functionally gratefully acknowledged.
62part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
infarction of the genu of the internal cap- cortices in the Rhesus monkey:The structure
sule. Journal of Neurology Neurosurgery and and organization of the hippocampal com-
Psychiatry, 71(5), 658662. missures. Journal of Comparative Neurology,
Clarke, S., Assal, G., Bogousslavsky, J., Regli, F., 233(1), 3047.
Townsend, D.W., Leenders, K.L.,& Blecic, S. Devinsky, O., & Luciano, D. (1997). The con-
(1994). Pure amnesia after unilateral left polar tributions of cingulate cortex to human
thalamic infarct:Topographic and sequential behavior. In B. Vogt & M. Gabriel (Eds.),
neuropsychological and metabolic (PET) cor- Neurobiology of cingulate cortex and limbic thala-
relations. Journal of Neurology Neurosurgery mus (pp. 527556). Boston, MA:Birkhuser.
and Psychiatry, 57(1), 2734. Dujardin, K., Sockeel, P., Devos, D., Delliaux, M.,
Cosgrove, G. R., & Rauch, S. L. (2003). Krystkowiak, P., Destee, A., & Defebvre, L.
Stereotactic cingulotomy. Neurosurgery Clinics (2007). Characteristics of apathy in Parkinson's
of North America, 14(2), 225235. disease. Movement Disorders, 22(6), 778784.
Cowey, A., Stoerig, P., & Bannister, M. (1994). Duncan, G. W., Parker, S. W., & Fisher, C. M.
Retinal ganglion cells labelled from the (1975). Acute cerebellar infarction in the PICA
pulvinar nucleus in macaque monkeys. territory. Archives of Neurology, 32(6), 364368.
Neuroscience, 61(3), 691705. Engelborghs, S., Marien, P., Pickut, B. A.,
Cronin-Golomb, A., Corkin, S., & Growdon, Verstraeten, S.,& De Deyn, P.P. (2000). Loss
J. H. (1994). Impaired problem solving in of psychic self-activation after paramedian
Parkinson's disease: Impact of a set-shifting bithalamic infarction. Stroke, 31(7), 17621765.
deficit. Neuropsychologia, 32(5), 579593. Exner, C., Weniger, G.,& Irle, E. (2004). Cerebellar
Cummings, J. L., & Benson, D. F. (1984). lesions in the PICA but not SCA territory
Subcortical dementia. Review of an emerging impair cognition. Neurology, 63(11), 21322135.
concept. Archives of Neurology, 41(8), 874879. Filley, C. M. (2001). The behavioral neurol-
Cusick, C.G., Scripter, J.L., Darensbourg, J.G.,& ogy of white matter. New York, NY: Oxford
Weber, J.T. (1993). Chemoarchitectonic subdi- University Press.
visions of the visual pulvinar in monkeys and Filley, C.M. (2012). Behavioral neurology of white
their connectional relations with the middle matter (2nd ed.). New York, NY: Oxford
temporal and rostral dorsolateral visual University Press.
areas, MT and DLr. Journal of Comparative Fisher, C.M. (1959). The pathologic and clinical
Neurology, 336(1), 130. aspects of thalamic hemorrhage. Transactions of
D'Esposito, M., Verfaellie, M., Alexander, the American Neurological Association, 84, 5659.
M. P., & Katz, D. I. (1995). Amnesia follow- Fisher, C. M. (1978). Thalamic pure sensory
ing traumatic bilateral fornix transection. stroke:Apathologic study. Neurology, 28(11),
Neurology, 45(8), 15461550. 11411144.
Deecke, L., Schwarz, D. W., & Fredrickson, Foix, C.,& Hillemand, P. (1925). Les arte`res de
J. M. (1977). Vestibular responses in the laxe encephalique jusquau dience phale
Rhesus monkey ventroposterior thalamus. II. inclusivement. Revue Neurologique (Paris), 2,
Vestibulo-proprioceptive convergence at tha- 705739.
lamic neurons. Experimental Brain Research, Foltz, E. L., & White, L. E., Jr. (1962). Pain
30(23), 219232. "relief" by frontal cingulumotomy. Journal of
DeFreitas, G., & Bogousslavsky, J. (2002). Neurosurgery, 19, 89100.
Thalamic infarcts. In G. Donnan, B. Norving, Forkel, S.J., Thiebaut de Schotten, M., Kawadler,
J. Bamford, & J. Bogousslavsky (Eds.), J.M., Dell'acqua, F., Danek, A.,& Catani, M.
Subcortical stroke (pp. 255285). New York, (2012). The anatomy of fronto-occipital con-
NY:Oxford University Press. nections from early blunt dissections to con-
Djerine, J. (1892). Contribution l'tude temporary tractography. Cortex, doi:10.1016/j.
anatomo-pathologique et clinique des differ- cortex.2012.09.005. Epub ahead of print.
entes varits de ccit verbale. Mmoires de la Francois, C., Tande, D., Yelnik, J., & Hirsch,
Socit de Biologie, 4, 6190. E. C. (2002). Distribution and morphology
Djerine, J., & Roussy, G. (1906). Le syndrome of nigral axons projecting to the thalamus in
thalamique. Revue Neurologique (Paris), 14, primates. Journal of Comparative Neurology,
521532. 447(3), 249260.
Delgado, M.R. (2007). Reward-related responses Garcin, R. (1955). [Cerebello-thalamic syndrome
in the human striatum. Annals of the NewYork caused by localized lesion of the thalamus;
Academy of Sciences, 1104, 7088. sign of so-called main creuse and its symp-
Demeter, S., Rosene, D.L.,& Van Hoesen, G.W. tomatologic value]. Revue Neurologique (Paris),
(1985). Interhemispheric pathways of the 93(1), 143149.
hippocampal formation, presubiculum, and Garcin, R., & Lapresle, J. (1954). [Sensory
entorhinal and posterior parahippocampal syndrome of the thalamic type and with
64part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
hand-mouth topography due to localized Graybiel, A. M. (1998). The basal ganglia and
lesions of the thalamus]. Revue Neurologique chunking of action repertoires. Neurobiology
(Paris), 90(2), 124129. of Learning and Memory, 70(12), 119136.
Gazzaniga, M. S. (1967). The human brain is Greicius, M. D., Supekar, K., Menon, V., &
actually two brains, each capable of advanced Dougherty, R. F. (2009). Resting-state func-
mental functions. When the cerebrum is tional connectivity reflects structural connec-
divided surgically, it is as if the cranium con- tivity in the default mode network. Cerebral
tained two separate spheres of consciousness. Cortex, 19(1), 7278.
Scientific American, 217(2), 2429. Grodd, W., Hulsmann, E., Lotze, M., Wildgruber,
Gazzaniga, M.S. (2000). Cerebral specialization D.,& Erb, M. (2001). Sensorimotor mapping
and interhemispheric communication: Does of the human cerebellum: fMRI evidence
the corpus callosum enable the human condi- of somatotopic organization. Human Brain
tion? Brain, 123(Pt. 7), 12931326. Mapping, 13(2), 5573.
Geschwind, N. (1965a). Disconnexion syndromes Growdon, J. H., & Corkin, S. (1987). Cognitive
in animals and man. I. Brain, 88(2), 237294. impairments in Parkinson's disease. Advances
Geschwind, N. (1965b). Disconnexion syndromes in Neurology, 45, 383392.
in animals and man. II. Brain, 88(3), 585644. Guard, O., Bellis, F., Mabille, J. P., Dumas, R.,
Ghashghaei, H.T.,& Barbas, H. (2002). Pathways Boisson, D., & Devic, M. (1986). [Thalamic
for emotion:Interactions of prefrontal and ante- dementia after a unilateral hemorrhagic lesion
rior temporal pathways in the amygdala of the of the right pulvinar]. Revue Neurologique
Rhesus monkey. Neuroscience, 115(4), 12611279. (Paris), 142(10), 759765.
Ghika, J., Ghika-Schmid, F., Fankhauser, H.,Assal, Guberman, A.,& Stuss, D. (1983). The syndrome
G., Vingerhoets, F., Albanese, A.,...Favre, of bilateral paramedian thalamic infarction.
J. (1999). Bilateral contemporaneous pos- Neurology, 33(5), 540546.
teroventral pallidotomy for the treatment Gutrecht, J.A., Zamani, A.A.,& Pandya, D.N.
of Parkinson's disease: Neuropsychological (1992). Lacunar thalamic stroke with pure cer-
and neurological side effects. Report of four ebellar and proprioceptive deficits. Journal of
cases and review of the literature. Journal of Neurology Neurosurgery and Psychiatry, 55(9),
Neurosurgery, 91(2), 313321. 854856.
Ghika-Schmid, F., & Bogousslavsky, J. (2000). Habas, C., Kamdar, N., Nguyen, D., Prater,
The acute behavioral syndrome of anterior K., Beckmann, C. F., Menon, V., & Greicius,
thalamic infarction:Aprospective study of 12 M.D. (2009). Distinct cerebellar contributions
cases. Annals of Neurology, 48(2), 220227. to intrinsic connectivity networks. Journal of
Giguere, M., & Goldman-Rakic, P. S. (1988). Neuroscience, 29(26), 85868594.
Mediodorsal nucleus:Areal, laminar, and tan- Haber, S. N., Fudge, J. L., & McFarland, N. R.
gential distribution of afferents and efferents (2000). Striatonigrostriatal pathways in pri-
in the frontal lobe of Rhesus monkeys. Journal mates form an ascending spiral from the
of Comparative Neurology, 277(2), 195213. shell to the dorsolateral striatum. Journal of
Goldman-Rakic, P. S. (1988). Topography of Neuroscience, 20(6), 23692382.
cognition: Parallel distributed networks in Hackett, T.A., Stepniewska, I.,& Kaas, J.H. (1998).
primate association cortex. Annual Review Thalamocortical connections of the parabelt
Neuroscience, 11, 137156. auditory cortex in macaque monkeys. Journal of
Goldman-Rakic, P. S., & Porrino, L. J. (1985). Comparative Neurology, 400(2), 271286.
The primate mediodorsal (MD) nucleus and Heilman, K. M., & Sypert, G. W. (1977).
its projection to the frontal lobe. Journal of Korsakoff's syndrome resulting from bilateral
Comparative Neurology, 242(4), 535560. fornix lesions. Neurology, 27(5), 490493.
Graff-Radford, N. R., Damasio, H., Yamada, Hodges, J. R., & McCarthy, R. A. (1993).
T., Eslinger, P. J., & Damasio, A. R. (1985). Autobiographical amnesia resulting from
Nonhaemorrhagic thalamic infarction. bilateral paramedian thalamic infarction.
Clinical, neuropsychological and electro- Acase study in cognitive neurobiology. Brain,
physiological findings in four anatomical 116(Pt. 4), 921940.
groups defined by computerized tomogra- Hugdahl, K.,& Wester, K. (2000). Neurocognitive
phy. Brain, 108(Pt. 2), 485516. correlates of stereotactic thalamotomy
Graff-Radford, N. R., Eslinger, P. J., Damasio, and thalamic stimulation in Parkinsonian
A.R.,& Yamada, T. (1984). Nonhemorrhagic patients. Brain and Cognition, 42(2), 231252.
infarction of the thalamus: Behavioral, ana- Huguenard, J.,& Prince, D. (1997). Basic mecha-
tomic, and physiologic correlates. Neurology, nisms of epileptic discharges in the thalamus.
34(1), 1423. In M. Steriade, E. G.Jones,& D. A.McCormick
Graff-Radford, N. R., Tranel, D., Van Hoesen, (Eds.), Thalamus, Vol. 2. Experimental and
G. W., & Brandt, J. P. (1990). Diencephalic clinical aspects (pp. 295330). New York,
amnesia. Brain, 113(Pt. 1), 125. NY:Elsevier.
CHAPTER 2. Neuroanatomy and Behavioral Neurology of Subcortical Systems 65
Ilinsky, I.A.,& Kultas-Ilinsky, K. (1987). Sagittal the frontal lobe in the Rhesus monkey.
cytoarchitectonic maps of the Macaca Experimental Brain Research, 29(34), 299322.
mulatta thalamus with a revised nomencla- Krienen, F. M., & Buckner, R. L. (2009).
ture of the motor-related nuclei validated by Segregated fronto-cerebellar circuits revealed
observations on their connectivity. Journal of by intrinsic functional connectivity. Cerebral
Comparative Neurology, 262(3), 331364. Cortex, 19(10), 24852497.
Ito, M. (1984). The cerebellum and neural control. Kubicki, M., Westin, C.F., Maier, S.E., Frumin,
NewYork, NY:Raven Press. M., Nestor, P.G., Salisbury, D.F.,...Shenton,
Jenike, M. A., Baer, L., Ballantine, T., Martuza, M. E. (2002). Uncinate fasciculus findings in
R. L., Tynes, S., Giriunas, I.,...Cassem, schizophrenia: A magnetic resonance diffu-
N. H. (1991). Cingulotomy for refractory sion tensor imaging study. American Journal of
obsessive-compulsive disorder. A long-term Psychiatry, 159(5), 813820.
follow-up of 33 patients. Archives of General Kumar, K., Toth, C., & Nath, R. K. (1997).
Psychiatry, 48(6), 548555. Deep brain stimulation for intractable pain:
Johansen-Berg, H., Behrens, T. E., Sillery, E., A 15-year experience. Neurosurgery, 40(4),
Ciccarelli, O., Thompson, A.J., Smith, S.M.,& 736746; discussion 746737.
Matthews, P.M. (2005). Functional-anatomical Kumral, E., Evyapan, D.,& Balkir, K. (1999). Acute
validation and individual variation of diffu- caudate vascular lesions. Stroke, 30(1), 100108.
sion tractography-based segmentation of the Kunzle, H.,& Akert, K. (1977). Efferent connec-
human thalamus. Cerebral Cortex, 15(1), 3139. tions of cortical, area 8 (frontal eye field) in
Johnson, M. D., & Ojemann, G. A. (2000). The Macaca fascicularis. A reinvestigation using
role of the human thalamus in language and the autoradiographic technique. Journal of
memory:Evidence from electrophysiological Comparative Neurology, 173(1), 147164.
studies. Brain and Cognition, 42(2), 218230. Lapresle, J., & Haguenau, M. (1973).
Jones, E. (1985). The thalamus. New York, Anatomico-chemical correlation in focal tha-
NY:Plenum Press. lamic lesions. Zeitschrift fr Neurologie, 205(1),
Jones, E. (1997). A description of the human 2946.
thalamus. In M. Steriade, E. G. Jones, & Lee, H., Sohn, S.I., Cho, Y.W., Lee, S.R., Ahn,
D. A. McCormick (Eds.), Thalamus, Vol. B. H., Park, B. R., & Baloh, R. W. (2006).
2. Experimental and clinical aspects (pp. 425 Cerebellar infarction presenting isolated ver-
499). NewYork, NY:Elsevier. tigo: Frequency and vascular topographical
Jones, E.G.,& Powell, T.P. (1970a). An anatomi- patterns. Neurology, 67(7), 11781183.
cal study of converging sensory pathways Lehericy, S., Ducros, M., Krainik, A., Francois,
within the cerebral cortex of the monkey. C., Van de Moortele, P.F., Ugurbil, K.,& Kim,
Brain, 93(4), 793820. D.S. (2004). 3-D diffusion tensor axonal track-
Jones, E.G.,& Powell, T.P. (1970b). Connexions ing shows distinct SMA and pre-SMA projec-
of the somatic sensory cortex of the Rhesus tions to the human striatum. Cerebral Cortex,
monkey. 3.Thalamic connexions. Brain, 93(1), 14(12), 13021309.
3756. Leigh, R.,& Zee, D. (1983). The neurology of eye
Karnath, H.O., Himmelbach, M.,& Rorden, C. movements. Philadelphia, PA:FA Davis.
(2002). The subcortical anatomy of human Lenz, F., & Dougherty, P. (1997). Pain process-
spatial neglect: Putamen, caudate nucleus ing in the human thalamus. In M. Steriade,
and pulvinar. Brain, 125(Pt. 2), 350360. E. G. Jones, & D. A. McCormick (Eds.),
Kawashima, T., Nakamura, M., Bouix, S., Thalamus, Vol. 2. Experimental and clinical
Kubicki, M., Salisbury, D. F., Westin, aspects (pp.617651). NewYork, NY:Elsevier.
C. F.,...Shenton, M. E. (2009). Uncinate fas- Leventhal, C. M., Baringer, J. R., Arnason,
ciculus abnormalities in recent onset schizo- B. G., & Fisher, C. M. (1965). A case of
phrenia and affective psychosis: A diffusion Marchiafava-Bignami disease with clini-
tensor imaging study. Schizophrenia Research, cal recovery. Transactions of the American
110(13), 119126. Neurological Association, 90, 8791.
Kelly, R. M., & Strick, P. L. (2003). Cerebellar Levisohn, L., Cronin-Golomb, A., &
loops with motor cortex and prefrontal Schmahmann, J.D. (2000). Neuropsychological
cortex of a nonhuman primate. Journal of consequences of cerebellar tumour resection
Neuroscience, 23(23), 84328444. in children: Cerebellar cognitive affective
Kennedy, H., & Bullier, J. (1985). A syndrome in a paediatric population. Brain,
double-labeling investigation of the afferent 123(Pt. 5), 10411050.
connectivity to cortical areas V1 and V2 of Levy, R.,& Dubois, B. (2006). Apathy and the func-
the macaque monkey. Journal of Neuroscience, tional anatomy of the prefrontal cortex-basal
5(10), 28152830. ganglia circuits. Cerebral Cortex, 16(7), 916928.
Kievit, J.,& Kuypers, H.G. (1977). Organization Limperopoulos, C., Robertson, R. L., Estroff,
of the thalamo-cortical connexions to J.A., Barnewolt, C., Levine, D., Bassan, H.,&
66part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
du Plessis, A. J. (2006). Diagnosis of inferior Mesulam, M. M., & Pandya, D. N. (1973). The
vermian hypoplasia by fetal magnetic reso- projections of the medial geniculate complex
nance imaging: Potential pitfalls and neuro- within the sylvian fissure of the Rhesus mon-
developmental outcome. American Journal of key. Brain Research, 60(2), 315333.
Obstetrics and Gynecology, 194(4), 10701076. Middleton, F. A., & Strick, P. L. (1994).
Lisovoski, F., Koskas, P., Dubard, T., Dessarts, Anatomical evidence for cerebellar and basal
I., Dehen, H., & Cambier, J. (1993). Left ganglia involvement in higher cognitive func-
tuberothalamic artery territory infarc- tion. Science, 266(5184), 458461.
tion: Neuropsychological and MRI features. Middleton, F.A.,& Strick, P.L. (1997). Cerebellar
European Neurology, 33(2), 181184. output channels. International Review of
Llinas, R., & Ribary, U. (2001). Consciousness Neurobiology, 41, 6182.
and the brain. The thalamocortical dialogue Motzkin, J. C., Newman, J. P., Kiehl, K. A., &
in health and disease. Annals of the NewYork Koenigs, M. (2011). Reduced prefron-
Academy of Sciences, 929, 166175. tal connectivity in psychopathy. Journal of
Locke, S., Angevine, J. B., Jr., & Yakovlev, P. I. Neuroscience, 31(48), 1734817357.
(1961). Limbic nuclei of thalamus and connec- Moulton, E., Elman, I., Pendse, G., Schmahmann,
tions of limbic cortex. II. Thalamocortical pro- J., Becerra, L., & Borsook, D. (2011).
jection of the lateral dorsal nucleus in man. Aversion-related circuity in the cerebel-
Archives of Neurology, 4, 355364. lum:Responses to noxious heat and unpleas-
Lombardi, W. J., Gross, R. E., Trepanier, L. L., ant images. Journal of Neuroscience, 31(10),
Lang, A. E., Lozano, A. M., & Saint-Cyr, 37953804.
J. A. (2000). Relationship of lesion loca- Mufson, E.J.,& Mesulam, M.M. (1984). Thalamic
tion to cognitive outcome following connections of the insula in the Rhesus mon-
microelectrode-guided pallidotomy for key and comments on the paralimbic connec-
Parkinson's disease:Support for the existence tivity of the medial pulvinar nucleus. Journal
of cognitive circuits in the human pallidum. of Comparative Neurology, 227(1), 109120.
Brain, 123(Pt. 4), 746758. Murthy, J. M. (1988). Ataxic hemiparesis-
Luria, A. (1966). Higher cortical functions in man. -ventrolateral nucleus of the thalamus: yet
(B. Haigh, Trans.). NewYork, NY:Basic Books. another site of lesion. Stroke, 19(1), 122.
Makris, N., Schlerf, J. E., Hodge, S. M., Muslimovic, D., Post, B., Speelman, J. D., &
Haselgrove, C., Albaugh, M. D., Seidman, Schmand, B. (2007). Motor procedural learn-
L.J.,...Schmahmann, J.D. (2005). MRI-based ing in Parkinsons disease. Brain, 130(Pt. 11),
surface-assisted parcellation of human 28872897.
cerebellar cortex: An anatomically speci- Nadeau, S.E.,& Crosson, B. (1997). Subcortical
fied method with estimate of reliability. aphasia. Brain and Language, 58(3), 355402;
Neuroimage, 25(4), 11461160. discussion 418423.
Malm, J., Kristensen, B., Karlsson, T., Carlberg, B., Naeser, M.A., Palumbo, C.L., Helm-Estabrooks,
Fagerlund, M.,& Olsson, T. (1998). Cognitive N., Stiassny-Eder, D.,& Albert, M.L. (1989).
impairment in young adults with infratento- Severe nonfluency in aphasia. Role of the
rial infarcts. Neurology, 51(2), 433440. medial subcallosal fasciculus and other white
Martin, J. (1997). Degenerative diseases matter pathways in recovery of spontaneous
of the human thalamus. In M. Steriade, speech. Brain, 112(Pt. 1), 138.
E. G. Jones, & D. A. McCormick (Eds.), Nasreddine, Z.S.,& Saver, J.L. (1997). Pain after
Thalamus, Vol. 2. Experimental and clinical thalamic stroke:Right diencephalic predomi-
aspects (pp.653687). NewYork, NY:Elsevier. nance and clinical features in 180 patients.
Mega, M. S., & Cummings, J. L. (1994). Neurology, 48(5), 11961199.
Frontal-subcortical circuits and neuropsychi- Nass, R., Boyce, L., Leventhal, F., Levine, B., Allen,
atric disorders. Journal of Neuropsychiatry and J., Maxfield, C.,...George, A. (2000). Acquired
Clinical Neurosciences, 6(4), 358370. aphasia in children after surgical resection of
Mesulam, M. (1988). Patterns in behavioral left-thalamic tumors. Developmental Medicine
neuroanatomy: Association areas, the limbic and Child Neurology, 42(9), 580590.
system, and hemispheric specialization. In M. Nauta, W. (1964). Some efferent connections
Mesulam (Ed.), Principles of behavioral neurol- of the prefrontal cortex in the monkey. In
ogy (pp. 170). Philadelphia, PA: F. A. Davis. J. M. Warren & K. Akert (Eds.), The frontal
Mesulam, M. M. (1981). A cortical network for granular cortex and behavior (pp. 397409).
directed attention and unilateral neglect. NewYork, NY:McGraw-Hill.
Annals of Neurology, 10(4), 309325. Nauta, W.J.,& Domesick, V.B. (1984). Afferent
Mesulam, M.M. (1990). Large-scale neurocogni- and efferent relationships of the basal gan-
tive networks and distributed processing for glia. Ciba Foundation Symposium, 107, 329.
attention, language, and memory. Annals of Naville, F. (1922). Etudes sur les complications
Neurology, 28(5), 597613. et les sequelles mentales de lencephalite
CHAPTER 2. Neuroanatomy and Behavioral Neurology of Subcortical Systems 67
(2013). Frontotemporal white-matter micro- Schmahmann, J.D., Doyon, J., Toga, A., Evans,
structural abnormalities in adolescents with A., & Petrides, M. (2000). MRI atlas of the
conduct disorder:Adiffusion tensor imaging human cerebellum. San Diego, CA: Academic
study. Psychological Medicine, 43(2), 401411. Press.
Saur, D., Kreher, B. W., Schnell, S., Kummerer, Schmahmann, J.D., Gardner, R., MacMore, J.,&
D., Kellmeyer, P., Vry, M. S.,...Weiller, C. Vangel, M.G. (2009). Development of a brief
(2008). Ventral and dorsal pathways for lan- ataxia rating scale (BARS) based on a modi-
guage. Proceedings of the National Academy of fied form of the ICARS. Movement Disorders,
Science USA, 105(46), 1803518040. 24(12), 18201828.
Schell, G. R., & Strick, P. L. (1984). The origin Schmahmann, J.D.,& Leifer, D. (1992). Parietal
of thalamic inputs to the arcuate premotor pseudothalamic pain syndrome. Clinical
and supplementary motor areas. Journal of features and anatomic correlates. Archives of
Neuroscience, 4(2), 539560. Neurology, 49(10), 10321037.
Schmahmann, J.D. (1984). Hemi-inattention from Schmahmann, J. D., MacMore, J., & Vangel,
right hemisphere subcortical infarction. Boston, M. (2009). Cerebellar stroke without motor
MA:Society of Neurology and Psychiatry. deficit: Clinical evidence for motor and
Schmahmann, J.D. (1991). An emerging concept. non-motor domains within the human cer-
The cerebellar contribution to higher func- ebellum. Neuroscience, 162(3), 852861.
tion. Archives of Neurology, 48(11), 11781187. Schmahmann, J. D., & Pandya, D. N. (1990).
Schmahmann, J. D. (1996). From movement Anatomical investigation of projections from
to thought: Anatomic substrates of the cer- thalamus to posterior parietal cortex in the
ebellar contribution to cognitive processing. Rhesus monkey: A WGA-HRP and fluo-
Human Brain Mapping, 4, 174198. rescent tracer study. Journal of Comparative
Schmahmann, J.D. (Ed.). (1997). The cerebellum Neurology, 295(2), 299326.
and cognition. International review of neurobiol- Schmahmann, J. D., & Pandya, D. N. (1997a).
ogy (Vol. 47). San Diego, CA:Academic Press. Anatomic organization of the basilar pontine
Schmahmann, J. D. (2000). The role of the cer- projections from prefrontal cortices in Rhesus
ebellum in affect and psychosis. Journal of monkey. Journal of Neuroscience, 17(1), 438458.
Neurolinguistics, 13, 189214. Schmahmann, J. D., & Pandya, D. N. (1997b).
Schmahmann, J.D. (2003). Vascular syndromes The cerebrocerebellar system. International
of the thalamus. Stroke, 34(9), 22642278. Review of Neurobiology, 41, 3160.
Schmahmann, J. D. (2004). Disorders of the Schmahmann, J.D.,& Pandya, D.N. (2006). Fiber
cerebellum: Ataxia, dysmetria of thought, pathways of the brain. New York, NY: Oxford
and the cerebellar cognitive affective syn- University Press.
drome. Journal of Neuropsychiatry and Clinical Schmahmann, J.D.,& Pandya, D.N. (2007). The
Neurosciences, 16(3), 367378. complex history of the fronto-occipital fascic-
Schmahmann, J.D. (2006). Cerebellum and spi- ulus. Journal of the History of the Neurosciences,
nal cord - principles of development, anatom- 16(4), 362377.
ical organization, and functional relevance. Schmahmann, J. D., & Pandya, D. N. (2008).
In A. Brice & S. Pulst (Eds.), Spinocerebellar Disconnection syndromes of basal ganglia,
degenerations:The ataxias and spastic paraplegias thalamus, and cerebrocerebellar systems.
(pp. 160). NewYork, NY:Elsevier. Cortex, 44(8), 10371066.
Schmahmann, J. D. (2010). The role of the cer- Schmahmann, J. D., Pandya, D. N., Wang,
ebellum in cognition and emotion: Personal R., Dai, G., D'Arceuil, H. E., de Crespigny,
reflections since 1982 on the dysmetria of A.J.,& Wedeen, V.J. (2007). Association fibre
thought hypothesis, and its historical evolu- pathways of the brain: Parallel observations
tion from theory to therapy. Neuropsychology from diffusion spectrum imaging and autora-
Review, 20(3), 236260. diography. Brain, 130(Pt. 3), 630653.
Schmahmann, J. D. (2013). Cerebellum and Schmahmann, J. D., Rosene, D. L., & Pandya,
ataxia. In H. R. Jones, T. M. Burns, M. D. N. (2004). Motor projections to the
J. Aminoff, & S. L. Pomeroy (Eds.), The basis pontis in Rhesus monkey. Journal of
Netter Collection of medical illustrations, Frank Comparative Neurology, 478(3), 248268.
H. Netter, MD, Vol. 7. Nervous system Part 1, Schmahmann, J. D., & Sherman, J. C. (1998).
Brain (2nd ed., pp. 177197). Philadelphia, The cerebellar cognitive affective syndrome.
PA:Elsevier/Saunders. Brain, 121(Pt. 4), 561579.
Schmahmann, J. D., Doyon, J., McDonald, Schmahmann, J. D., Smith, E. E., Eichler,
D., Holmes, C., Lavoie, K., Hurwitz, F.S.,& Filley, C.M. (2008). Cerebral white
A.S.,...Petrides, M. (1999). Three-dimensional matter: Neuroanatomy, clinical neurology,
MRI atlas of the human cerebellum in pro- and neurobehavioral correlates. Annals
portional stereotaxic space. Neuroimage, of the New York Academy of Sciences, 1142,
10(3Pt.1), 233260. 266309.
CHAPTER 2. Neuroanatomy and Behavioral Neurology of Subcortical Systems 69
Schmahmann, J.D., Weilburg, J.B.,& Sherman, Sperry, R.W. (1964). The great cerebral commis-
J. C. (2007). The neuropsychiatry of the cer- sure. Scientific American, 210, 4252.
ebellum - insights from the clinic. Cerebellum, Spiegel, E. A., Wycis, H. T., Orchinik, C., &
6(3), 254267. Freed, H. (1956). Thalamic chronotaraxis.
Scott, R., Gregory, R., Hines, N., Carroll, C., American Journal of Psychiatry, 113(2), 97105.
Hyman, N., Papanasstasiou, V., .
.
.
Aziz, T. Stoodley, C. J., & Schmahmann, J. D. (2009).
(1998). Neuropsychological, neurological and Functional topography in the human cerebel-
functional outcome following pallidotomy for lum:Ameta-analysis of neuroimaging stud-
Parkinson's disease. A consecutive series of ies. Neuroimage, 44(2), 489501.
eight simultaneous bilateral and twelve uni- Stoodley, C. J., & Schmahmann, J. D. (2010).
lateral procedures. Brain, 121(Pt. 4), 659675. Evidence for topographic organization in the
Scott, R. B., Stoodley, C. J., Anslow, P., Paul, cerebellum of motor control versus cognitive
C., Stein, J. F., Sugden, E. M., & Mitchell, and affective processing. Cortex, 46(7), 831844.
C. D. (2001). Lateralized cognitive deficits Stoodley, C. J., Valera, E. M., & Schmahmann,
in children following cerebellar lesions. J.D. (2010). An fMRI study of intraindivid-
Developmental Medicine and Child Neurology, ual functional topography in the human cere-
43(10), 685691. bellum. Behavioural Neurology, 23(12), 6579.
Selemon, L. D., & Goldman-Rakic, P. S. (1990). Stoodley, C. J., Valera, E. M., & Schmahmann,
Topographic intermingling of striatonigral J. D. (2012). Functional topography of the
and striatopallidal neurons in the Rhesus cerebellum for motor and cognitive tasks:An
monkey. Journal of Comparative Neurology, fMRI study. Neuroimage, 59(2), 15601570.
297(3), 359376. Strick, P.L. (1976). Anatomical analysis of ventro-
Shatz, C. J., & Rakic, P. (1981). The genesis of lateral thalamic input to primate motor cortex.
efferent connections from the visual cor- Journal of Neurophysiology, 39(5), 10201031.
tex of the fetal Rhesus monkey. Journal of Takahashi, E., Song, J. W., Folkerth, R. D., Grant,
Comparative Neurology, 196(2), 287307. P. E. & Schmahmann, J. D. (2013). Detection
Sidibe, M., Pare, J.F.,& Smith, Y. (2002). Nigral of postmortem human cerebellar cortex and
and pallidal inputs to functionally segregated white matter pathways using high angular
thalamostriatal neurons in the centromedian/ resolution diffusion tractography: A feasibil-
parafascicular intralaminar nuclear complex ity study. Neuroimage, 68, 105111.
in monkey. Journal of Comparative Neurology, Tatemichi, T. K., Desmond, D. W., Prohovnik,
447(3), 286299. I., Cross, D. T., Gropen, T. I., Mohr, J. P., &
Siwek, D.F.,& Pandya, D.N. (1991). Prefrontal Stern,Y. (1992). Confusion and memory loss
projections to the mediodorsal nucleus of the from capsular genu infarction: A thalamo-
thalamus in the Rhesus monkey. Journal of cortical disconnection syndrome? Neurology,
Comparative Neurology, 312(4), 509524. 42(10), 19661979.
Smith, E.E., Salat, D.H., Jeng, J., McCreary, C.R., Tavano, A., Grasso, R., Gagliardi, C., Triulzi, F.,
Fischl, B., Schmahmann, J. D.,...Greenberg, Bresolin, N., Fabbro, F.,& Borgatti, R. (2007).
S.M. (2011). Correlations between MRI white Disorders of cognitive and affective devel-
matter lesion location and executive func- opment in cerebellar malformations. Brain,
tion and episodic memory. Neurology, 76(17), 130(Pt. 10), 26462660.
14921499. Tedesco, A.M., Chiricozzi, F.R., Clausi, S., Lupo,
Smith, J.G.,& McDowall, J. (2006). When artificial M., Molinari, M.,& Leggio, M.G. (2011). The
grammar acquisition in Parkinsons disease is cerebellar cognitive profile. Brain, 134(Pt. 12),
impaired:The case of learning via trial-by-trial 36723686.
feedback. Brain Research, 1067(1), 216228. Thiebaut de Schotten, M., Dell'Acqua, F.,
Snider, R. S., & Eldred, E. (1952). Valabregue, R.,& Catani, M. (2012). Monkey
Cerebrocerebellar relationships in the mon- to human comparative anatomy of the frontal
key. Journal of Neurophysiology, 15(1), 2740. lobe association tracts. Cortex, 48(1), 8296.
Solomon, D. H., Barohn, R. J., Bazan, C., & Tobias, T. J. (1975). Afferents to prefrontal cor-
Grissom, J. (1994). The thalamic ataxia syn- tex from the thalamic mediodorsal nucleus
drome. Neurology, 44(5), 810814. in the Rhesus monkey. Brain Research, 83(2),
Spangler, W.J., Cosgrove, G.R., Ballantine, H.T., 191212.
Jr., Cassem, E. H., Rauch, S. L., Nierenberg, Trepanier, L.L., Saint-Cyr, J.A., Lozano, A.M.,&
A.,& Price, B.H. (1996). Magnetic resonance Lang, A.E. (1998). Neuropsychological conse-
image-guided stereotactic cingulotomy for quences of posteroventral pallidotomy for the
intractable psychiatric disease. Neurosurgery, treatment of Parkinson's disease. Neurology,
38(6), 10711076; discussion 10761078. 51(1), 207215.
Sperry, R. (1984). Consciousness, personal iden- Trouillas, P., Takayanagi, T., Hallett, M.,
tity and the divided brain. Neuropsychologia, Currier, R. D., Subramony, S. H., Wessel,
22(6), 661673. K.,...Manyam, B. (1997). International
70part iFunctional Neuroanatomy and Cognitive Neuroscience of Dementia
Cooperative Ataxia Rating Scale for phar- incident Parkinson's disease cohort. Brain,
macological assessment of the cerebellar 130(Pt. 7), 17871798.
syndrome. The Ataxia Neuropharmacology Willis, W.J. (1997). Nociceptive functions of tha-
Committee of the World Federation of lamic neurons. In M. Steriade, E. G.Jones,&
Neurology. Journal of the Neurological Sciences, D. A. McCormick (Eds.), Thalamus, Vol.
145(2), 205211. 2. Experimental and clinical aspects (pp. 373
Ungerleider, L., & Mishkin, M. (1982). Two 424). NewYork, NY:Elsevier.
cortical visual systems. In D. Ingle, M. Wisoff, J.H.,& Epstein, F.J. (1984). Pseudobulbar
A. Goodale, & R. J. W. Mansfield (Eds.), palsy after posterior fossa operation in chil-
Analysis of visual behavior (pp. 549586). dren. Neurosurgery, 15(5), 707709.
Cambridge, MA:MIT Press. Yakovlev, P.I.,& Locke, S. (1961). Limbic nuclei
Valenstein, E., Bowers, D., Verfaellie, M., of thalamus and connections of limbic cor-
Heilman, K. M., Day, A., & Watson, R. T. tex. III. Corticocortical connections of the
(1987). Retrosplenial amnesia. Brain, 110(Pt. anterior cingulate gyrus, the cingulum, and
6), 16311646. the subcallosal bundle in monkey. Archives of
van Harskamp, N. J., Rudge, P., & Cipolotti, Neurology, 5, 364400.
L. (2005). Cognitive and social impairments Yakovlev, P.I., Locke, S., Koskoff, D.Y.,& Patton,
in patients with superficial siderosis. Brain, R. A. (1960). Limbic nuclei of thalamus and
128(Pt. 5), 10821092. connections of limbic cortex. Archives of
Victor, M., Adams, R. D., & Collins, G. H. Neurology, 3, 620641.
(1971). The Wernicke-Korsakoff syndrome. Yeterian, E. H., & Pandya, D. N. (1985).
A clinical and pathological study of 245 Corticothalamic connections of the posterior
patients, 82 with post-mortem examinations. parietal cortex in the Rhesus monkey. Journal
Contemporary Neurology Series, 7, 1206. of Comparative Neurology, 237(3), 408426.
Vogt, B. A., Pandya, D. N., & Rosene, D. L. Yeterian, E. H., & Pandya, D. N. (1988).
(1987). Cingulate cortex of the Rhesus mon- Corticothalamic connections of paralim-
key: I. Cytoarchitecture and thalamic affer- bic regions in the Rhesus monkey. Journal of
ents. Journal of Comparative Neurology, 262(2), Comparative Neurology, 269(1), 130146.
256270. Yeterian, E.H.,& Pandya, D.N. (1989). Thalamic
von Cramon, D. Y., Hebel, N., & Schuri, U. connections of the cortex of the superior tem-
(1985). A contribution to the anatomical poral sulcus in the Rhesus monkey. Journal of
basis of thalamic amnesia. Brain, 108(Pt. 4), Comparative Neurology, 282(1), 8097.
9931008. Yeterian, E. H., & Pandya, D. N. (1991).
Voogd, J.,& Glickstein, M. (1998). The anatomy Corticothalamic connections of the supe-
of the cerebellum. Trends in Neuroscience, rior temporal sulcus in Rhesus monkeys.
21(9), 370375. Experimental Brain Research, 83(2), 268284.
Warren, J. D., & Thompson, P. D. (2000). Yeterian, E.H.,& Pandya, D.N. (1993). Striatal
Diencephalic amnesia and apraxia after connections of the parietal association corti-
left thalamic infarction. Journal of Neurology ces in Rhesus monkeys. Journal of Comparative
Neurosurgery and Psychiatry, 68(2), 248. Neurology, 332(2), 175197.
Weber, J.T.,& Yin, T.C. (1984). Subcortical pro- Yeterian, E. H., & Pandya, D. N. (1994).
jections of the inferior parietal cortex (area Laminar origin of striatal and thalamic pro-
7) in the stump-tailed monkey. Journal of jections of the prefrontal cortex in Rhesus
Comparative Neurology, 224(2), 206230. monkeys. Experimental Brain Research, 99(3),
Wedeen, V. J., Wang, R. P., Schmahmann, 383398.
J. D., Benner, T., Tseng, W. Y., Dai, G.,...de Yeterian, E. H., & Pandya, D. N. (1997).
Crespigny, A. J. (2008). Diffusion spectrum Corticothalamic connections of extrastriate
magnetic resonance imaging (DSI) tractog- visual areas in Rhesus monkeys. Journal of
raphy of crossing fibers. Neuroimage, 41(4), Comparative Neurology, 378(4), 562585.
12671277. Yeterian, E. H., & Pandya, D. N. (1998).
Weiller, C., Bormann, T., Saur, D., Musso, M.,& Corticostriatal connections of the superior
Rijntjes, M. (2011). How the ventral pathway temporal region in Rhesus monkeys. Journal
got lost:And what its recovery might mean. of Comparative Neurology, 399(3), 384402.
Brain and Language, 118(12), 2939. Ziegler, D. K., Kaufman, A., & Marshall, H. E.
Williams-Gray, C. H., Foltynie, T., Brayne, (1977). Abrupt memory loss associated with
C.E., Robbins, T.W.,& Barker, R.A. (2007). thalamic tumor. Archives of Neurology, 34(9),
Evolution of cognitive dysfunction in an 545548.
3
The executive control functions encompass a distinguishing the profiles associated with
wide range of high-level cognitive and behav- the behavioral variant of frontotemporal
ioral capacities that allow an individual to lobar degeneration (bvFTD) and Alzheimers
pursue goal-directed and context-appropriate disease (AD).
behavior. Some of the most disturbing neu-
rological disorders include those in which
executive functions have been compromised, Historical Perspective
perhaps because those affected have lost
capacities that we associated most with being The classic work on executive control func-
human. While the research literature on the tions initially emerged from observations of
executive control is vast and spans decades patients with neurological illness or brain
and many different experimental modali- injury. In his work in the late 19th and early
ties, there are still many questions regarding 20th centuries, John Hughlings Jackson
the discrete component functions implicated inferred that some abnormalities in behav-
in executive control, how these component ior resulted from the effects of pathology at
functions are organized, and what underly- the higher centers of the nervous systems,
ing neural structures support them. However, which led to a loss of influence over the lower
there is little disagreement that the executive centers (Jackson, 1932; Wozniak & Jackson,
control functions mediate vital human capac- 1999). He proposed that when lower cen-
ities, such as long-term planning, execution ters of the nervous system were liberated
of goals, and perspective taking. This chapter and no longer under control of the higher
will focus on elucidating principles and con- centers, due to disease, injury, or disruption
cepts associated with executive control func- from some other reason, this led to a reduc-
tions and their neuroanatomic substrates. We tion to a more automatic condition, or what
will then briefly illustrate several representa- would later be termed loss of inhibition.
tive patterns of executive dysfunction in the Leonardo Bianchi (1922) also observed that
dementias, with a particular emphasis on ablating areas in the frontal cortex in monkeys
71
72 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
paralimbic regions, including the dorsal Executive Control and Goal-Directed Behavior
anterior cingulate (dACC) and anterior
insular (AI) cortices comprise the salience As a heuristic, we have found it helpful to
network, while regions of the prefrontal break down the complex processes involved
heteromodal cortex, including dorsolateral in goal-directed behavior into different
frontal and superior parietal cortices, consti- classes of functions. At the center of this heu-
tute an executive control network (Seeley ristic model is the concept of a goal. Agoal
et al., 2007) (Fig. 3.3). The salience network can be defined as a cognitive representation
can be thought of as providing ongoing sur- of an objective that one is committed or moti-
veillance of internal (and external) events or vated to accomplish via directed behavioral
activity that is homeostatically relevant. In or mental activity. The complexity of goals
doing so, the salience network helps to allo- can vary along many dimensions. For exam-
cate, and may even compete for, resources ple, a goal can range from committing to fol-
with the executive control network, in low a concrete motor command (i.e., open
order to account for emotional factors that your eyes) to such complex and abstract
influence goal-directed processes (Seeley notions as devoting oneself to the eradication
et al., 2007). In addition to the salience and of homelessness. Goals can also be conceptu-
executive control networks, intrinsic net- alized as varying across several other facets,
works responsible for attentional control including temporal proximity (immediate to
(Corbetta & Shulman, 2002) and internally long term), how planful they are (proactive
focused operations, such as re-experiencing vs. reactive), and their level of abstractness or
ones past and imagining ones future meaningfulness.
(Buckner, Andrews-Hanna,& Schacter, 2008;
Gusnard, Raichle,& Raichle, 2001; Schacter,
Addis,& Buckner, 2007), also play important Execution of Goals
roles in goal-directed behavior. These net-
works will be discussed in more detail in the The ability to flexibly adapt ones behavior in
following sections. pursuit of a goal could not be accomplished
dACC
HT TP lateral
PAG parietal
FI FI
+4 +6 pre-SMA
DMPFC
+12
10 8
Salience Executive
Intrinsic connectivity
processing control
2 networks 2
Figure3.3 Salience and executive control networks revealed through intrinsic connectivity
mapping. Image adapted from Seeley etal., 2007. (See color plate section)
76 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
without executive control. Executive control aspects of working memory and the dorsal lat-
is not a unitary construct but instead refers to eral PFC facilitating the manipulation of infor-
a complex set of processes that allow for an mation (DEsposito, Postle, Ballard, & Lease,
organism to carry out goal-directed behavior. 1999; Petrides, 2000; Wagner, Maril, Bjork, &
We divide the process of executive control into Schacter, 2001). Still other work has suggested
three classes of operations:working memory, that the dorsal lateral PFC is more likely to
outcome/reward anticipation and monitor- be activated as the task demands increase,
ing, and response/behavioral selection. to provide the needed support and scaffold-
ing offered by executive control functions
(DEsposito etal., 1999; Petrides, 2000; Rypma,
Working Memory
Prabhakaran, Desmond, Glover, & Gabrieli,
Working memory is a theoretical construct 1999; Wagner et al., 2001). Clinical reports in
that describes a system of limited capac- humans and lesion studies in monkeys gener-
ity where information is temporarily stored ally confirm a central role of the PFC in work-
(or maintained) and manipulated, which is ing memory (for a review see Miller& Cohen,
critical for successful cognition (Baddeley, 2001). However, several lesion studies suggest
2003). Therefore, working memory sub- that working memory can be left relatively
sumes several executive control functions unimpaired following unilateral PFC damage
itself (referred to as the central executive (DEsposito& Postle, 1999), perhaps by means
by Baddeley), including attentional control, of compensatory activity in the intact hemi-
reasoning, planning, and ordering/organiz- sphere (Corbetta, Kincade, Lewis, Snyder, &
ing, which facilitate goal-directed behavior. Sapir, 2005; Voytek etal., 2010).
Information represented in working memory In addition to the PFC, data from func-
is subject to evaluation and manipulation tional imaging studies have also consis-
and serves as the basis for decisions and the tently revealed activity within the posterior
planning of complex behaviors (Genovesio, parietal cortex (PPC; BA 7) during working
Brasted,& Wise, 2006; Yoshida& Ishii, 2006). memory tasks (Curtis & DEsposito, 2006;
Neuroanatomically, the lateral PFC has long Owen et al., 2004; Wager & Smith, 2003).
been considered one of the most important Supporting their functional interactions,
brain regions involved in working memory lateral PFC and PPC tract-tracing studies
processes. Imaging studies, using delayed have confirmed reciprocal interconnections
match-to-sample tasks, have consistently doc- (Schwartz & Goldman-Rakic, 1984). More
umented prefrontal activation (see DEsposito recent neuroimaging research focused on
et al., 1998; Fletcher & Henson, 2001 for identifying large-scale intrinsic brain net-
reviews). However, the functional anatomic works has also revealed that lateral PFC
distinctions within the lateral PFC remain an interacts in a functionally cohesive manner
area of controversy. There is some evidence with lateral superior parietal regions (Seeley
to support the lateralization of function in the etal., 2007)to support working memory and
PFC, with the right PFC more engaged by spa- attention control. As introduced previously,
tial working memory tasks and the left PFC this network has been termed the executive
more engaged by verbal working memory control network (Seeley et al., 2007). Others
tasks (DEsposito et al., 1998; Schumacher have reported on an intrinsic network that
et al., 1996; Smith, Jonides, & Koeppe, 1996). also includes lateral prefrontal and parietal
Some studies support the specialization of regions, often called the fronto-parietal net-
function in the PFC that parallels the dorsal work (Niendam et al., 2012; Vincent et al.,
(where) versus the ventral (what) path- 2008). However, this network is more exten-
ways for visual processing in the posterior sive and includes regions that overlap with
cortex, such that dorsolateral PFC subserves the medial PFC and fronto-insular cortex,
spatial working memory and ventrolateral which Seeley and colleagues (2007) separate
PFC may preferentially subserve object work- into the salience network.
ing memory (Courtney, Ungerleider, Keil, &
Haxby, 1996; Wilson & OScalaidhe, 1993).
Task Setting
Other studies support a dissociation of PFC
according to processing demands, with the Task setting refers to the high-level coordina-
ventral PFC supporting the maintenance tion of several types of working memory and
CHAPTER 3. Executive Control, the Regulation of Goal-Directed Behaviors, and the Impact of Dementing Illness 77
executive control functions in order to estab- To elicit the process of task setting,
lish a goal-directed plan upon which motor researchers often employ paradigms that ask
or mental activity is enacted. At its simplest participants to act contrary to an overlearned
level, task setting describes the process of cre- tendency or prepotent response, as in the
ating mappings of a stimulus to a designated Stroop Interference (Egner & Hirsch, 2005),
response (Stuss& Alexander, 2007)or coding Simon (Peterson etal., 2002), and stop-signal
an action with a goal. As goals become more tasks (Aron & Poldrack, 2006). Other com-
complex, they require sequencing of multiple mon paradigms require participants to learn
responses or actions. Therefore, task setting and implement experimenter-provided rules
may occur several times during the execu- for mapping stimuli to responses, often
tion of a single goal, and/or multiple tasks under conditions that require flexible switch-
may be set simultaneously to facilitate a goal. ing between task rules or response strategies
Planning plays a critical role in the process of (Bunge, 2004). These tasks tend to emphasize
task setting and subsumes several executive experimental control of behavior, requir-
control functions, each with heavy working ing participants to pursue artificial goals or
memory demands. Planning occurs when respond according to rules dictated by the
a goal or planned event, held in working experimenter.
memory, triggers the generation of a new
order of mental representations. These men- Attentional Control and Processing Priorities
tal representations may consist of one or
more intermediate steps or tasks upon which Top-down attentional control, also referred
the goal is predicated. For example, if one to as goal-driven or endogenous attention, is
visualizes going on vacation, the anticipated responsible for selecting the information that
event (vacation) will not occur unless a series gains access to working memory (Knudsen,
of intermediate steps or tasks (e.g., choos- 2007). Given the amount of information and
ing a date, a place, a method of transporta- stimuli that confront humans, the process
tion) is first generated. Organization involves of selecting which information has access
the ordering or manipulation of tasks or to working memory is highly competitive
responses, such that the individual tasks are (Desimone& Duncan, 1995). This is generally
eventually arranged in a manner that, when thought to occur through one of two mecha-
viewed as a whole, conforms to some type of nisms:(1)by directing resources (sensory or
higher order logic or scheme. Organization motor) toward a target in the environment
also has a heavy working memory demand, (Andersen et al., 2004), and (2) by means of
as the higher order scheme must be held attentional biasing in order to improve the
in mind so that the individual parts can be signal-to-noise in all information process-
manipulated according to the scheme. For ing domains (sensory, motor, internal state,
example, it is impossible to organize a book- and memory) (Knudsen, 2007). The process
shelf without holding in mind a chosen orga- of directing resources to goal-appropriate
nizational scheme (e.g., arranging books stimuli or events via the top-down control
alphabetically, by size, by color, etc.). of spatial attention and eye movement has
Several groups have proposed that tasks been linked to the dorsal attention network,
or actions are organized in a gradient that which includes regions in the dorsolateral
extends from posterior to anterior lateral PFC, frontal eye fields, and superior parietal
PFC. That is, the more immediate/less cortex (Corbetta& Shulman, 2002; Fox etal.,
abstract tasks or actions are processed in 2005; Vincent etal., 2008)(Fig.3.4a).
posterior regions of the lateral PFC, closer Regions of this system overlap partially with
to premotor cortex, where they are more the executive control network, although there
immediately accessible by motor cortex. is evidence that they are two distinct networks
The more abstract, less temporally immedi- (Vincent etal., 2008). However, the functional
ate tasks or actions that do not require motor properties and organization of the posterior
responses are organized more anteriorly parietal cortex (PPC; which encompasses
toward the frontal pole (Badre, 2008; Badre& the superior parietal cortex) indicate that it
DEsposito, 2007, 2009; Barbalat, Chambon, is likely to be more involved in top-down
Franck, Koechlin,& Farrer, 2009; Kouneiher, modulation of spatial attention as opposed to
Charron,& Koechlin, 2009). working memory (Colby & Goldberg, 1999).
78 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
IPS/SPL FEF
AG SMG IFJ
V3A IFJ
IFG
STG
MT Ins
5 3 3 5
z-score functional connectivity
Figure3.4 Dorsal and ventral attention networks. Image adapted from Corbetta & Shulman (2011).
(See color plate section)
For example, the PPC appears to be more sus- Outcome/Reward Anticipation and Monitoring
ceptible to interruption by distracting stimuli
Selecting the best course of action in
(Powell& Goldberg, 2000), which results in a
goal-directed behavior describes a very
pattern of functional activity that is less per-
active mental state in which the brain is
sistent than the PFC (Fuster, 1995; Miller etal.,
dynamically making predictions and gener-
1996). Instead, activity in the PPC may repre-
ating expectations based on reinforcement
sent the integration of sensorimotor informa-
values of previous actions and experiences
tion in order to visually guide movements
(ODoherty, Kringelbach, Rolls, Hornak, &
(Buneo& Andersen, 2006).
Andrews, 2001; Ullsperger & von Cramon,
The second mechanism of top-down atten-
2004). Much of the work on decision-making
tional control, attentional biasing, is thought
and reward-maximizing behavior comes
to be facilitated by top-down modulation, which
from models of reinforcement learning
refers to neuronal enhancement or excita-
(Sutton & Barto, 1998), which suggest that
tion, inhibition, or possibly both. The role of
the flexibility of this process relies on ones
top-down modulation in cognitive control
ability to rapidly monitor and update pre-
and goal-directed behavior is explained in
diction values based on actual outcomes
more detail in Box 3.1.
and experience. Outcome and reward antici-
Although attention and working mem-
pation and monitoring are essential moti-
ory are generally thought of as two distinct
vators of goal-directed behavior. Regions
cognitive constructs, this notion has been
within the medial PFC, particularly the
challenged in favor of a model in which
orbitofrontal cortex (OFC) and anterior cin-
attention and working memory mutually
gulate cortex (ACC), play complementary
influence each other (Gazzaley & Nobre,
and reciprocal roles in this process (Berns,
2012; Kiyonaga, Egner, & Soto, 2012). First,
McClure, Pagnoni,& Montague, 2001; Elliott,
the contents of working memory have been
Friston,& Dolan, 2000).
conceptualized as active internal representa-
tions maintained within the focus of atten-
Anticipating Consequences/Outcomes
tion (Zanto& Gazzaley, 2009). Second, while
attentional control can determine what has The ability to anticipate consequences is a
access to working memory, it is perhaps also critical factor in making controlled decisions
true that representations held within work- among competing tasks or strategies. It may
ing memory can affect the allocation of atten- be the case that consequences and reward
tional resources. As such, working memory values associated with context-relevant infor-
may allow for the active maintenance of cur- mation, such as sensory signals, as well as
rent processing priorities (Lavie, Hirst, de knowledge of similar events and their asso-
Fockert,& Viding, 2004). Processing priorities ciated consequences, are gathered to inform
refer to important contextual information, us of our options. This process of anticipat-
such as rules, instructions, and intentions ing consequences can be thought of as a type
that are associated with a goal representation of internal monitoring, which involves keep-
(Cohen, Braver, & OReilly, 1996; Cohen & ing track of a designated set of external or
Servan-Schreiber, 1992). internal stimuli or responses and associated
CHAPTER 3. Executive Control, the Regulation of Goal-Directed Behaviors, and the Impact of Dementing Illness 79
reward value of a stimulus, while lateral OFC between predictive cues and outcomes dur-
has been shown to encode stimuli in terms ing discrimination learning (Rolls, Critchley,
of potential for punishment. In addition, an Mason, & Wakeman, 1996; Schoenbaum
anterior-posterior gradient has also been et al., 1999; Schoenbaum, Setlow, Nugent,
proposed, and it suggests that posterior OFC Saddoris, & Gallagher, 2003). Normal aging
encodes reward value for concrete primary is associated with a decline in cognitive flex-
reinforcers like taste and touch, while ante- ibility, and work from the animal literature
rior OFC encodes the value of more abstract, has shown that aged animals often have dif-
symbolic complex secondary reinforcing fac- ficulty modifying responses when contingen-
tors like money (Kringelbach & Rolls, 2004; cies change. Specifically, activity recorded
Rankin etal., 2006). in OFC reversal neurons of aged rats fails
The ability of the OFC to alter contingencies to show the same level of sensitivity or abil-
between stimuli and their expected reinforce- ity to flexibly encode stimulus-outcome
ment value is critical for flexible behavior associations relative to young control rats
(Schoenbaum& Roesch, 2005). In fact, a par- (Schoenbaum, Setlow, Saddoris,& Gallagher,
ticular class of neurons, called reversal neu- 2006).
rons (Thorpe, Rolls,& Maddison, 1983), has The ACC also plays a critical role in
been identified within the OFC that are asso- anticipating outcomes and consequences
ciated with flexibly coding representations of actions. The ACC is located in the neural
CHAPTER 3. Executive Control, the Regulation of Goal-Directed Behaviors, and the Impact of Dementing Illness 81
cross-road of motor, cognitive, and affec- within working memory to support the range
tive/arousal systems. It receives afferents of strategic possibilities that exist to achieve
from amygdala, fronto-insular cortex, OFC, a goal. In statistics, degrees of freedom
midline thalamus, and monoaminergic cen- refers to a number of values in an equation
ters of the brainstem. While OFC cells have that are free to vary. The term degrees of
been shown to encode the expected value of freedom, when applied metaphorically to
stimuli (Schoenbaum etal., 2006), cells within cognition, captures an important property
the ACC appear to encode the expected value of goal-directed behavior (Daffner & Searl,
of actions (Matsumoto, Matsumoto, Abe, & 2008). Task or plan management refers to the
Tanaka, 2007; Walton, Devlin,& Rushworth, process of holding multiple tasks or strategies
2004) and are perhaps more closely tied to (determined by the complexity of the goal),
the action-selection process (Rushworth & their expected or anticipated outcomes, and
Behrens, 2008). the relative value of these outcomes in work-
In addition, ACC activity in neuroimaging ing memory. The efficiency or quality of task
studies has also been associated with cod- management is influenced by an individuals
ing conflict between competing responses ability to inhibit prepotent responses and the
(Botvinick, Braver, Barch, Carter, & Cohen, capacity of working memory to maintain and
2001; Holroyd & Coles, 2002). The conflict manipulate a range of task/strategy options.
monitoring theory (Botvinick et al., 2001; Individuals with dysexecutive syndromes
Carter & van Veen, 2007) proposes that the typically follow the path of least resistance
ACC and more broadly regions within the because their limited capacity for work-
medial prefrontal cortex (MPFC) monitor ing memory, monitoring, inhibition, and
the level of conflict arising across potential initiation cannot provide the cognitive sup-
responses, including situations that require port necessary for the enactment of alterna-
the overriding of prepotent responses, situ- tive responses. Fewer cognitive degrees of
ations requiring selection among a set of freedom usually results in the generation of
equally permissible responses, and situa- behavioral responses that are most directly
tions involving errors. For example, in one tied to their sources of input, with few modu-
version of the Stroop Interference Task, the lating influences.
word red is printed in the color blue, and
the task is to name the color. Two divergent Performance/Reward Monitoring
responses compete to determine behavioral
output. The automatic tendency to read the Performance monitoring refers to the ability
word red must be countered in order to to track actions and their expected outcomes
correctly execute the task of naming the color, and utilize information signaling success or
which is blue. The ACC is recruited during failure in performance. In general, success-
this task. A signal from the ACC regarding ful monitoring necessitates intact working
the detection of conflict seems to call upon memory because the expected outcome must
other brain regions to exercise cognitive con- be kept in mind to serve as a comparison
trol. As discussed later, the ACC is also inte- point to the actual outcome. This informa-
grally involved in performance monitoring tion is then utilized to update reinforcement
and detecting prediction errors. associations of stimuli and actions. Without
Based on the information presented thus far performance monitoring, an individual
on anticipating consequences and outcomes, would have difficulty modifying behavior to
one might assume that action is therefore achieve a goal (Table3.1). Of note, the process
chosen simply based on the highest antici- of performance/reward monitoring is inex-
pated or most rewarded outcome. However, tricably linked to the process of anticipating
this would significantly constrain an indi- consequences/outcomes and is subserved
viduals behavioral repertoire, as a limited by similar neuroanatomical networks with
number of actions or behaviors would likely nodes within the ACC and OFC.
be repeated over and over (Rushworth & The ACC has been associated with hold-
Behrens, 2008). Therefore, there likely needs ing a central role in tracking ones perfor-
to be an incentive to explore other available mance, particularly when it deviates from
options, as well as a level of flexibility or expectations or from what is known to result
breadth (i.e., additional degrees of freedom) in reward. The ACC may index conflict at
82 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
the level of divergence from expectation, absence of input. They suggest that to opti-
response errors (Falkenstein, Hohnsbein, mize responding, particularly when activa-
Hoormann, & Blanke, 1991; Niki & tion becomes low (e.g., detecting occasional
Watanabe, 1979), and task difficulty/men- stimuli or performing occasional motor acts),
tal effort (Botvinick et al., 2001; Botvinick, lower level perceptual or motor representa-
Cohen, & Carter, 2004). According to the tions require energization or re-energization.
performance monitoring theory (Holroyd & Without such a process, performance over
Coles, 2008), medial PFC monitors actual a prolonged period will inevitably waiver
performances and detects both negative and (Table3.1).
positive prediction errors that subsequently Medial frontal structures, including the
engage cognitive control processes to enact anterior cingulate cortex (BA 24, 25, 32), the
behavioral adjustments (Holroyd & Coles, supplementary motor area (BA 6), and pre-
2002; Holroyd, Yeung, Coles,& Cohen, 2005). supplementary motor area (BA 6), are thought
While ACC activation is most often present to play an important role in the initiation
in neuroimaging studies during tasks where and maintenance of behavior (Passingham,
subjects have to evaluate the outcome of 1995; Paus, 2001; Ridderinkhof et al., 2004).
their chosen action and use this information As noted in the preceding sections, the ACC
to guide future behavior (Bush et al., 2002; is critical to the process of anticipating the
Knutson, Adams, Fong, & Hommer, 2001; potential reward value of various actions,
Ullsperger & von Cramon, 2003), the OFC which serves as a basis of motivating/ener-
is also likely involved in updating related gizing behavior. Paus (2001) has reviewed
stimulus-outcome associations (Schoenbaum how components of the ACC send efferents
etal., 2006). to skeletal muscle, oculomotor, and vocal-
ization systems. The ACC also has major
Response/Behavioral Selection connections with the lateral PFC, giving it
access to the extensive cognitive process-
Response or behavioral selection involves ing of this area. Patients with medial frontal
the parallel processes of initiating/sustaining damage often demonstrate impairments in
a task response and/or inhibiting responses the initiation of speech and motor move-
or activity in the service of carrying out ments or deficits in inhibiting reflexive motor
goal-directed behavior. responses (Paus, 2001) (e.g., grasp reflex) or
control of the contralateral limb (e.g., alien
Initiating and Sustaining Motor and hand syndrome) (Banks, 1989; Hashimoto,
MentalActivity 1998). Bilateral lesions of the anterior cingu-
late can cause akinetic mutism, a condition
Initiation is the purposeful, self-generated characterized by a failure to speak (mut-
commencement of an overt behavior or men- ism) or to begin volitional movements (aki-
tal activity. The process of initiating and sus- nesis) (Barris & Schuman, 1953; Nemeth,
taining any response is sometimes referred to Hegedus,& Molnar, 1988).
as energization (Stuss& Alexander, 2007).
Without guidance from working memory
Inhibiting or Stopping Motor and
and the process of task setting, initiation can-
MentalActivity
not occur and behaviors may be limited to
reflexive and automatic responses to environ- Inhibition involves the suppression of spe-
mental stimuli (Table3.1). cific behavioral output, mental activity, or an
Response maintenance, or sustaining a emotional response (usually an automatic or
response over time, is thought to reflect prepotent/overlearned response). Inhibition
the accumulation of activation sufficient is an important component of self-regulation,
to produce and sustain a response over which requires both inhibition of automatic
time (Alexander, Stuss, Shallice, Picton, & responses (suppression) and execution of dif-
Gillingham, 2005). Stuss and Alexander ferent, consciously chosen responses in their
(2007) argue that the response maintenance place. Behavioral inhibition also includes the
aspect of energization is responsible for coun- ability to cease a particular behavior at the
tering the neurophysiological tendency for appropriate time and is the basis of delayed
any neural activity to become inactive in the gratification, which involves denying oneself
CHAPTER 3. Executive Control, the Regulation of Goal-Directed Behaviors, and the Impact of Dementing Illness 83
something satisfying, presumably in order to by PFC (Davidson, 2000). OFC (and lateral
achieve a more important goal (Table3.1). PFC) show increased neural activity when
There is growing evidence that the lateral participants are actively regulating their emo-
PFC, especially in the right hemisphere, is tions and activity within the OFC, and lateral
activated during the inhibition of behavioral PFC has been shown to be inversely correlated
responses, for example, in motor go-no go with activity of amygdala (Ochsner, Bunge,
tasks, when a response must be withheld Gross,& Gabrieli, 2002). Patients with damage
(Liddle, Kiehl, & Smith, 2001). Functional to OFC or difficulty modulating OFC function
imaging studies have indicated that the often exhibit poor emotional regulation and
inferior lateral PFC (BA 44/45) is recruited strikingly disinhibited, inappropriate behavior
when a persons cognitive set needs to be (Box 3.2). In patients with neurodegenerative
shiftedfor example, during the Wisconsin diseases, emotional control has even been pre-
Card Sorting Task (Konishi et al., 1999) or dicted primarily by right OFC thickness, while
inhibiting memory processing of word asso- cognitive control was predicted by DLPFC
ciates (Anderson etal., 2004). Anderson and structures (Krueger etal., 2011).
colleagues (2004) provide evidence that the
lateral PFC (BA 45/46) is activated during a
task in which subjects are asked to control How Are Goals Selected?
(inhibit) memory processing of word associ-
ates. The increase in lateral prefrontal activ- In order for individuals to pursue goal-
ity is linked to a reduction in hippocampal directed behaviors, they need to be sufficiently
activation and an increased probability of motivated. According to the classic psycho-
not recalling a test item. As mentioned pre- logical theory of motivation proposed by Hull
viously, the lateral PFC is also involved in (1943), motivation describes a global modula-
top-down control of selective attention. tion or regulation factor that is based on the
Inhibitory activity also plays an important expected possible gains (rewards/meaning-
role in emotion regulation and social interactions fulness/punishment) of a range of behav-
(Box 3.2), and it is associated with activity in the ioral options. The expected gains of pursuing
orbitofrontal cortex. Specifically, the OFC has actions that lead to a particular goal are coded
been shown to mediate top-down regulation of or controlled by several factors, including,
the amygdala, critical for affective processing but likely not limited to, representations of
the self (information regarding personal val- attributes, such as abilities/skills, social
ues and beliefs that are carried across time), roles, psychological characteristics, and pref-
representations of the past and the future erences (DArgembeau & Salmon, 2012).
(information about past experiences and Humans also hold multiple representa-
expectation or the anticipation of a specific tions of their self-concept, including views
outcome), and representations of external and about themselves across different contexts
internal importance (how critical the behav- or relationships (Chen, Boucher, & Tapias,
ior is to an individuals external and internal 2006) and how they are seen by others.
homeostasis or survival). Input from systems Aside from personal traits, the self-concept
that generate homeostatic/survival value, is also thought to include knowledge about
representations of the self, and representa- personal goals, which plays a critical role in
tions of the past/future provide higher order guiding and motivating behavior (Higgins,
or top-down mechanisms that determine 1997; Markus& Nurius, 1986).
long-term and immediate goals. A prerequi- Imaging studies of the self-concept or
site for these systems to function is that the self-knowledge most frequently ask par-
brain be in an active state, which is facilitated ticipants to represent or reflect on their own
by the first system discussed here. psychological traits. Participants are asked to
judge whether different trait adjectives (e.g.,
Ascending Arousal System funny, loud, hard-working) describe their
own psychological traits or those of another
The ascending arousal system or the ascend- person, such as a famous person (Kelley etal.,
ing reticular activating system (ARAS) is a 2002)or a personally familiar person (e.g., a
bottom-up process that can be thought of as best friend) (Heatherton et al., 2006). These
acting as the brains furnace. It is respon- studies have strongly implicated the MPFC
sible for producing the heat or a global acti- as being most active when thinking about the
vating influence that provides the scaffolding self versus another. Other work has shown
for wakefulness and alertness. The ARAS is that the MPFC may also play an important
composed of two major pathways: (1) the role in thinking about how we are seen by
reticulothamalocortical pathway that pro- others. That is, the pattern of increased MPFC
motes cortical arousal, and (2) the extratha- activation is consistent when self-judgments
lamic pathway, which originates in the are made from ones own perspective and
brainstem and basal forebrain and sends when judgments are made while taking the
direct projections to the cortex (Kinomura, perspective of a personally familiar other
Larsson, Gulyas, & Roland, 1996). The (DArgembeau et al., 2007). These findings
Yerkes-Dodson law has provided the classic suggest that perhaps the neural architecture
framework for understanding the relation- that supports self-cognition is similar to that
ship between arousal and task performance, which supports social cognition (Amodio &
and it suggests that there is an optimal level Frith, 2006).
of arousal that follows an inverted u-shaped Studies investigating the neural corre-
curve. Either end of the spectrum (too little or lates of reflecting on personal goals have
too much arousal) can adversely affect task also implicated several regions in the MPFC,
performance (Yerkes& Dodson, 1908). While in addition to regions of the posterior cin-
the heat or activating influence produced gulate/precuneus (Johnson et al., 2006;
by this system is necessary for goal-directed Johnson, Nolen-Hoeksema, Mitchell, &
behavior, it is not sufficient. The heat then Levin, 2009; Mitchell etal., 2009). More spe-
needs to be channeled where it can be used cifically, Johnson and colleagues (2006) found
to fuel executive control functions. Mesulam that regions within the MPFC showed greater
(2000) has referred to the paralimbic PFC as activation when thinking about hopes and
the bridge that channels raw motivational aspirations, while non-PFC medial regions
energy toward context-appropriate objects. showed greater activation when thinking of
duties and obligations. The MPFC may also
play a role in processing the self-relatedness
Representations of the Self
or self-relevance of information, such that
The self-concept describes a uniquely human representations that elicit high activity in
ability to consciously represent personal the MPFC may be those that constitute the
CHAPTER 3. Executive Control, the Regulation of Goal-Directed Behaviors, and the Impact of Dementing Illness 85
network and the ventral attention network involved in monitoring the internal milieu
(which are partially overlapping), play criti- (Craig, 2009). A recent model suggests that
cal roles in deciding what information or the integration of information by the FI serves
stimuli are most urgent or task relevant to motivate goal-directed behavior to utilize
(Corbetta & Shulman, 2002; Seeley et al., attention and working memory resources
2007). They also facilitate an individuals (Menon& Uddin, 2010). The right FI has been
ability to disengage from ones way of think- referred to as a convergence zone that may
ing, current activity, or present circumstances represent a global emotional moment, built
and re-engage in a different way of thinking from the integration of interoceptive inputs,
or responding when the context or environ- with goals, hedonic conditions, and contex-
ment demands it. This ability, often referred tual information (Craig, 2009).
to as set shifting, allows a person to manage The ACC is also a critical node within
transitions, cope with unexpected changes the salience network and is also positioned
in plans, shift perspectives as relevant infor- where motor, cognitive, and affective/
mation becomes available, and think flex- arousal systems converge, similar to the FI.
ibly and creatively when solving problems. As such, the ACC is capable of integrating
Perseveration is the continued engagement in changes in motivational and arousal states,
a previous behavior despite the presence of with expected outcomes and potential rein-
cues in the environment that signal the need forcements to motivate behavior (Kerns etal.,
to shift or reorient (Table3.1). 2004; Menon etal., 2001; Ridderinkhof etal.,
2004).
The Salience Network
The Ventral Attention Network
The salience network likely plays two
important roles in goal-directed behavior. Similar to the salience network, the ventral
First, it is uniquely positioned to identify attention network plays a critical role in
the most homeostatically relevant stimuli keeping track of external events that may
through the rapid integration of sensory, impact our safety or survival. The ventral
visceral, autonomic, and hedonic signals attention network includes temporal-parietal
(Seeley et al., 2007). In this way, it is well junction (TPJ) and regions of the ventral
positioned to participate in the selection of frontal cortex (VFC) (inferior frontal gyrus,
an individuals current goal. However, the frontal opercular cortex, and anterior insula)
salience network is also thought to continu- and is lateralized to the right hemisphere
ously survey the internal (and external) (Corbetta & Shulman, 2002) (Fig. 3.4b). This
terrain to signal the occurrence of a salient system shows activity increases upon detec-
event that may require the rapid modifi- tion of salient targets, especially when they
cation of current processing priorities to appear in unexpected locations (Astafiev
ensure survival or homeostatic balance. et al., 2003; Astafiev, Stanley, Shulman, &
Thus, the salience network can disrupt Corbetta, 2004; Corbetta, Kincade, Ollinger,
executive control processing underlying McAvoy,& Shulman, 2000; Kincade, Abrams,
goal-directed behavior when a more imme- Astafiev, Shulman,& Corbetta, 2005).
diately relevant event requires attention/ The ventral attention network mediates
action. bottom-up, stimulus-driven reorienting of
Within the salience network, the anterior attention (Shulman et al., 2009) and acts
cingulate cortex (ACC), orbitofrontal cortex as a circuit breaker in response to novel,
(OFC), and the frontoinsular cortex (FI) have salient, or potentially significant stimuli
been identified as specialized nodes for sym- (Corbetta& Shulman, 2002). Astimulus may
pathetic efference and interoceptive feedback be salient based on hard-wired (e.g., loom-
(Craig, 2002; Critchley, 2005; Critchley, Elliott, ing stimuli) or learned (e.g., voice of a par-
Mathias,& Dolan, 2000; Critchley etal., 2004; ent) biological importance (Knudsen, 2007).
Saper, 2002) (Fig. 3.3). Specifically, the FI is The nervous system responds automatically
uniquely situated at the interface of the cog- to such salient stimuli with unusually strong
nitive, homeostatic, and affective systems of responses. Unexpected or highly salient stim-
the human brain, providing a link between uli can trigger the orienting response that
stimulus-driven processing and brain regions calls upon top-down control mechanisms
CHAPTER 3. Executive Control, the Regulation of Goal-Directed Behaviors, and the Impact of Dementing Illness 87
to evaluate whether the salient stimuli is of to frontal cortex. In rats, lesions to either
greater importance than the current contents midbrain VTA cell bodies or frontal cortical
of working memory (Miller & Cohen, 2001; areas result in very similar behavioral effects
Miller& DEsposito, 2005). (hyperactivity) (Pycock, Kerwin, & Carter,
Behaviorally, the function of the ventral 1980). In monkeys, destruction of dopamine
attention system manifests as the orient- terminals leads to impaired performance on
ing response, or the reorienting of attention the delayed alternation task in a manner sim-
toward a salient stimuli. A functional inter- ilar to that seen after destruction of the fron-
action between the dorsal and ventral atten- tal cortex itself (Brozoski, Brown, Rosvold,&
tion networks has been proposed such that Goldman, 1979).
task-relevant signals from the dorsal sys- Dopamine also plays an important role in
tem filter stimulus-driven signals in the anticipating outcomes and reward monitor-
ventral system, whereas stimulus-driven ing. It appears to do this by coding a predic-
circuit-braking signals from the ventral tion error, such that a reward that is better
system provide an interrupt to the dorsal than predicted elicits an activation (positive
system, reorienting it toward salient stimuli prediction error), a predicted reward that
(Corbetta & Shulman, 2002; Shulman et al., matches its outcome elicits no response, and a
2003). Pavlovs (1960) classic descriptions of reward that is worse than predicted induces a
the orienting response illustrate the impor- reduction in neural response (negative error)
tance of the ventral attention network in sup- (Bayer & Glimcher, 2005; Morris, Arkadir,
porting higher level cognitive functioning: Nevet, Vaadia, & Bergman, 2004; Nakahara,
Itoh, Kawagoe, Takikawa,& Hikosaka, 2004;
The biological significance [of the orienting Tobler, Fiorillo, & Schultz, 2005; Zaghloul
reflex] is obvious. If the animal were not et al., 2009). This reward-predicting signal
provided with such a reflex its life would specifies the value of future rewards, includ-
hang at every moment by a thread....In ing information regarding the probability of
man this reflex has been greatly developed encountering a stimulus or performing an
in its highest form by inquisitivenessthe action that will lead to a particular reward.
parent of that scientific method through This probability distribution of reward val-
which we hope one day to come to a true ues would ideally be normally distributed,
orientation in knowledge of the world such that extreme rewards occur less fre-
around us. (p.12) quently than intermediate rewards (Schultz,
2010).
Norepinephrine, released from neurons
Contributions of Neurotransmitter originating in the brainstems locus coe-
Function to Executive Control ruleus, serves as a central neurotransmit-
ter mediating arousal and vigilance, and
Dopamine is probably the best characterized helps to improve the ratio of signal-to-
neurotransmitter associated with the execu- noise (Arnsten & Li, 2005; Mesulam, 2000;
tive functions (Cohen & Servan-Schreiber, Nieuwenhuis, Aston-Jones, & Cohen, 2005;
1992). It contributes to the adequate func- Petersen & Posner, 2012; Usher, Cohen,
tion of working memory (Goldman-Rakic, Servan-Schreiber, Rajkowski,& Aston-Jones,
1996; Williams& Goldman-Rakic, 1995)and 1999). Specifically, norepinephrine stimula-
helps to regulate motivational states and tion of postsynaptic, alpha-2A adrenocep-
reward systems (Horvitz, Stewart,& Jacobs, tors on PFC pyramidal cell spines is critical
1997; Schultz, Dayan, & Montague, 1997; for strengthening appropriate PFC network
Wickelgren, 1997). Evidence in the animal connections (increasing or enchancing sig-
literature points to an optimal amount nals) (Arnsten & Li, 2005), whereas dopa-
of dopamine, which follows an inverted mine D1 stimulation on a separate set of
u-shaped curve. Too much or too little spines is important for reducing inappro-
dopamine is detrimental to working mem- priate network connections (decreasing or
ory performance (Arnsten, 1997; Arnsten & inhibiting noise) (Arnsten & Rubia, 2012).
Rubia, 2012). Dopamine originates from Alpha-2a noradrenergic receptors in the PFC
structures in the midbrain, including the are important in the modulation of focused
ventral tegmental area (VTA), that project attention (Wang et al., 2011). Disruption of
88 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
these receptors can lead to increased distract- cortex (Lin, Hou, & Jouvet, 1996; Scammell
ibility. Alpha-2a autoreceptors on neurons in et al., 2000). Orexins also activate a group of
the locus coeruleus also many modulate its DA neurons in the ventral tegmental area
discharge rates, leading to improved atten- that project to the PFC (Vittoz, Schmeichel,&
tion (Taylor& Russo, 2001). Berridge, 2008). NE and DA tend to be low dur-
Acetylcholine is released by neurons project- ing periods of drowsiness, moderate during
ing from basal forebrain to frontal cortex and conditions of alert interest, and high during
hippocampus in response to behaviorally sig- uncontrollable stress (Vijayraghavan, Wang,
nificant or novel events (Acquas, Wilson, & Birnbaum, Williams,& Arnsten, 2007). Under
Fibiger, 1996; Davidson & Marrocco, 2000). optimal conditions, NE and DA neurons tend
This neurotransmitter has been strongly impli- to produce relatively low levels of tonic firing,
cated in the modulation of selective attention but they fire to stimuli that are relevant and/
(Petersen & Posner, 2012). Positron emission or predict reward (Aston-Jones, Rajkowski,&
tomography (PET) studies in healthy volun- Cohen, 2000; Berridge & Waterhouse, 2003;
teers have suggested that inhibition of cholin- Schultz, 2002).
esterase activity (thus increasing cholinergic Consistent with these observations, phar-
tone) is associated with more efficient work- macological interventions that have been
ing memory (faster reaction times and more employed to improve arousal, motivation,
circumscribed activation of the right PFC) attention, and executive control functions
(Freo etal., 2005; Furey etal., 1997). include stimulant medications, catecholamine
Depletion of serotonin from OFC (but not boosters, alpha-2 agonists, dopaminergic
DLPFC) has been shown to markedly impair agents, modafinil, and cholinergic agents.
OFC regulation of emotion and inhibition Stimulant medications increase the avail-
(Clarke, Walker, Dalley, Robbins, & Roberts, ability of catecholamines (dopamine and
2007; Rubia etal., 2005). Less is known about norepinephrine). They may improve arousal
the role of serotonin in other aspects of execu- level, motivational tone, and attentional focus
tive control. Similar to dopamine, serotonin (Chiarello & Cole, 1987; Greenhill & Osman,
has been shown to affect working memory 2000; Marin, Fogel, Hawkins, Duffy,& Krupp,
function (Goldman-Rakic, 1999); however, 1995; Taylor& Russo, 2001; Wilens, Biederman,
serotonin may play a unique role in rever- Spencer, & Prince, 1995). Stimulants have
sal learning (Clarke, 2006; Clarke, Dalley, been studied most extensively in patients
Crofts, Robbins, & Roberts, 2004; Clarke with attention-deficit/hyperactivity disorders
etal., 2005). Deficits in reversal learning tend (ADHD) but also have been used with vari-
to result in marked perseveration to above able success for other disorders that lead to
rewarded stimuli. Disruption of a number dysexecutive syndromes (Challman& Lipsky,
of mechanisms may explain the pattern of 2000; Rahman etal., 2005; Siddall, 2005; Whyte
perseverative, inflexible behavior associated et al., 2004). Nonstimulant medications boost
with serotonin depletion in PFC, including norepinephrine (atomoxetine) or norepineph-
altered responsiveness to punishment, loss rine and dopamine (e.g., buproprion). As
of reward, or deficits in inhibitory control mentioned previously, modafinil promotes
(Robbins& Roberts, 2007). wakefulness and can treat narcolepsy and other
Orexin has key arousing effects needed sleep-related disorders. It seems to be an effec-
for the brain to enter a wakeful state (Saper, tive treatment for attention and executive dys-
Chou, & Scammell, 2001). Orexin-rich neu- function (Muller, Steffenhagen, Regenthal, &
rons directly project to the PFC and thalamus Bublak, 2004; Taylor & Russo, 2000; Turner,
(Moore, Abrahamson, & Van Den, 2001) but Clark, Dowson, Robbins, & Sahakian, 2004),
also to NE cell bodies in the locus coeru- but it does not tend to improve motivation.
leus (Horvath, Diano, & van den Pol, 1999). Dopaminergic agents (e.g., pramipexole,
Orexins excite the same synapses in the PFC bromocriptine, selegiline, L-dopa) are most
as nicotine and have been show to improve often prescribed in the context of treating
attentional function (Lambe, Olausson, Horst, Parkinsons disease. However, these medi-
Taylor,& Aghajanian, 2005). In fact, the antin- cations have also been used to help improve
arcolepsy medication, modafinil, is thought motivation, diminish apathy, and to aug-
to work via the orexin system (Turner et al., ment working memory and other executive
2003)to enhance excitatory projections to the functions (Luciana& Collins, 1997; Luciana,
CHAPTER 3. Executive Control, the Regulation of Goal-Directed Behaviors, and the Impact of Dementing Illness 89
Depue, Arbisi, & Leon, 1992; Marin et al., have been associated with lower synaptic
1995; McDowell, Whyte, & DEsposito, densities in older adults, as opposed to cell
1998; Muller, von Cramon,& Pollman, 1998; death (Terry, 2000). The PFC and medial tem-
Muller & von Cramon, 1994). In particu- poral structures have been shown to be par-
lar, activation of D1 receptors may be more ticularly affected by normal aging, as well as
important than activating D2 receptors when so-called pathological aging (Raz et al., 2003,
attempting to improve working memory 2004; Resnick, Pham, Kraut, Zonderman, &
performance in neurologically healthy indi- Davatzikos, 2003; West, 1996). In addition, to
viduals with low working memory capacity aging-related structural changes, evidence
(Kimber, Watson, & Mathias, 1997; Muller for white matter abnormalities (Decarli &
etal., 1998). However, the use of dopaminer- Scheltens, 2002; Pantoni & Garcia, 1997;
gic agents must be monitored closely because Pugh & Lipsitz, 2002), neurophysiologi-
they may increase behavioral and neuro- cal changes (Almaguer, Estupinan, Uwe, &
psychiatric symptoms, including impulse Bergado, 2002; Chao& Knight, 1997; Pelosi&
control difficulties, repetitive/stereotyped Blumhardt, 1999; Shankar, Teyler, & Robbins,
behaviors, agitation, and psychosis. 1998), and changes in neurotransmitters levels
Cholinesterase inhibitors (e.g., donepezil, (Gazzaley, Thakker, Hof, & Morrison, 1997;
rivastigimine, galantamine), which increase Volkow etal., 1996)have also been reported.
the availability of acetylcholine, were devel- The functional imaging literature com-
oped for the symptomatic treatment of prob- monly reports that older adults often exhibit
able AD. However, this class of medications overrecruitment of neural activity rela-
also appears to have a modest effect on aspects tive to their younger counterparts to carry
of executive functions, attention, and neuro- out episodic memory tasks (Cabeza, 2002),
psychiatric well-being associated with aging working memory tasks (Grady et al., 1998;
and other neurologic disorders (Furey et al., Reuter-Lorenz etal., 2000), and novelty pro-
1997; Furey, Pietrini, & Haxby, 2000; Khateb, cessing tasks (Daffner, Sun, et al., 2011; Riis
Ammann, Annoni,& Diserens, 2005; Yesavage etal., 2008). The functional significance of this
et al., 2008; Zhang, Plotkin, Wang, Sandel, & increased activation likely varies depend-
Lee, 2004). Cholinesterase inhibitors have ing on the perceptual, memory, verbal, spa-
been found to be effective in boosting cogni- tial, or executive functioning task; however,
tion in patients with AD, Parkinsons dis- there is evidence to suggest that age-related
ease, dementia with Lewy bodies, and mixed increases in neural activity when carrying
dementia, but not in patients with bvFTLD. out executive tasks may be compensatory.
Several hypotheses have been proposed to
explain these activation pattern changes
Executive Control and Cognitive Aging and their relationship to cognitive perfor-
mance. The compensation-related utiliza-
The gradual decline in cognitive abilities, tion of neural circuits hypothesis (CRUNCH)
particularly memory and executive function, (Reuter-Lorenz& Cappell, 2008)is based on
of many older adults is well documented imaging work in verbal and spatial working
(Craik & Salthouse, 2000; Greenwood, 2000). memory tasks that shows a discrepant pat-
Several major theories of cognitive aging sug- tern of prefrontal activation between younger
gest a salient role for changes in the functioning and older adults. Specifically, while younger
of frontal networks, including (1)the executive adults tend to show lateralized prefrontal
deficit (frontal aging) hypothesis, which proposes activation that is domain dependent, older
that executive abilities dependent on fron- adults demonstrate pattern bilateral prefron-
tal lobe integrity are affected earlier and to a tal activation that is not domain dependent
greater magnitude than other processes (West, (Reuter-Lorenz et al., 2000). CRUNCH is in
1996); (2)the inhibitory deficit hypothesis, which the tradition of cognitive resource theory,
suggests a reduction in the efficiency of inhibi- which suggests that while bilateral activa-
tory mechanisms (Hasher& Zacks, 1988); and tion may be compensatory, it comes at a com-
(3)the processing speed hypothesis, in which per- putational cost (Reuter-Lorenz & Cappell,
formance deficits are attributed to generalized 2008) and that the differences in PFC activ-
slowing of processing speed (Salthouse, 1996). ity patterns of old and young adults may be
Aging-related volume reductions, or atrophy, a function of age-associated differences in
90 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
processing capacity. As such, while recruiting (Mackenzie etal., 2009)that are associated with
more resources for tasks with relatively low atrophy in the frontal and temporal lobes. The
demands may help the older adult maintain most common clinical syndrome associated
task performance, at levels of higher demand with FTLD is behavioral variant frontotempo-
older adults may be limited by a resource ral dementia (bvFTD), which is characterized
ceiling (Daffner, Chong, etal., 2011). by a progressive deterioration of personality,
The posterior-anterior shift in aging social comportment, and cognition (Rascovsky
(PASA) hypothesis (Davis, Dennis, Daselaar, et al., 2011). In bvFTD, degeneration often
Fleck,& Cabeza, 2008)explains the pattern of begins in the paralimbic prefrontal regions,
increased frontal activation in aging by pro- including the pregenual anterior cingulate cor-
posing that there is a simultaneous reduction tex (pACC) and frontoinsular cortex (Boccardi
in occipital activity coupled with an increase etal., 2005; Broe etal., 2003; Schroeter, Raczka,
in frontal activity. The link between declines Neumann,& von Cramon, 2008; Seeley etal.,
in occipital function and sensory-perceptual 2008). As a result of the prominent impact
deficits is consistent with abundant evidence that the disease has on paralimbic prefrontal
that perceptual processing declines as a func- regions, initial symptoms of bvFTD include
tion of aging (for a review, see Schneider & changes in personality, impaired social interac-
Pichora-Fuller, 2000) and studies that show tion, disinhibition, deficits in impulse control,
age-related dedifferentiation in early sensory and loss of insight (Hodges & Miller, 2001).
processing (Gazzaley, Cooney, Rissman, & Disease progression often spreads to adjacent
DEsposito, 2005; Park et al., 2004). For orbital and dorsolateral frontal regions (Seeley,
example, Park and colleagues (2004) dem- Zhou, & Kim, 2012). Right-hemisphere struc-
onstrated an aging-related reduction in tures often show more pronounced involve-
category-specific activation within ventral ment than the left, although the pattern can be
visual cortex, including the fusiform face symmetrical. Intrigued by this atrophy pattern
area. Therefore, PASA is thought to indicate that preferentially affects paralimic prefron-
that the recruitment of higher order cognitive tal structures, Seeley, Menon, and colleagues
processes is in response to deficits in poste- (2007) studied healthy young adults in an
rior brain regions, although the exact func- attempt to clarify regions functionally corre-
tion of the compensatory frontal activity has lated with the right fronto-insular cortex. The
yet to be identified (Davis etal., 2008). resulting map revealed that the bilateral ACC,
An alternative theory regarding increased left FI, and subcortical, limbic, and brainstem
recruitment of frontal regions is that it reflects sites with known connections from primate
the process of dedifferentiation or loss of spe- and rodent axonal tracer studies (Mesulam&
cialized neural circuits. Age-related dedif- Mufson, 1982; Ongur & Price, 2000; Saper,
ferentiation of function refers to decreases 2002) all shared functional connectivity with
in signal-to-noise ratio in cortical process- the right FI. In addition, these network findings
ing that correlate with age and result in overlapped with the bvFTD atrophy pattern.
reduced regional process specificity and As described earlier, this circuit was referred to
increases in nonspecific cortical activation as the salience network in light of observa-
(Li, Lindenberger,& Sikstrom, 2001). Within tions that ACC and FI coactivate in response
this framework, age-related activity increases to emotionally significant ambient stimuli and
in frontal regions are thought to reflect gen- events, from pain, thirst, and hunger to social
eralized spreading of activity due to reduced rejection, embarrassment, collaboration, and
specialization of function. adoration (Craig, 2002; Critchley, 2005). Deficits
in executive control and social cognition are
core features of bvFTD (Kipps& Hodges, 2006;
Executive Control and the Dementias Rascovsky et al., 2007). Specifically, the neu-
ropsychological profile specified by the inter-
Behavioral Variant Frontotemporal Dementia national consensus criteria (Rascovsky et al.,
and Alzheimers Disease 2011)includes executive function deficits with
relative sparing of memory and visuospatial
Frontotemporal lobar degeneration (FTLD) functions. Early in the course of bvFTD, perfor-
describes a group of clinically, pathologi- mance on formal neuropsychological tests of
cally, and genetically heterogenous diseases executive functioning may be spared; however,
CHAPTER 3. Executive Control, the Regulation of Goal-Directed Behaviors, and the Impact of Dementing Illness 91
extensive and there are several comprehen- essential. Given the lack of insight that often
sive reviews (Caballol, Marti,& Tolosa, 2007; accompanies frontal systems dysfunction,
Levin & Katzen, 2005; Owen, 2004; Pillon, it can be helpful to obtain ratings of behav-
Boller, Levy, & Dubois, 2001; Zgaljardic, ior by family members, caregivers, or other
Borod, Foldi,& Mattis, 2003). Kudlicka etal. individuals who know the patient well.
(2011) conducted a meta-analysis of the stud- Several questionnaires have been specifi-
ies focusing on executive impairment in PD. cally designed to elicit information about a
In particular, they searched for studies of PD patients degree of executive dysfunction
patients without dementia or depression and (Table3.2).
a Hoehn and Yahr score of Ito III. Significant
difficulties were found in PD patients com-
pared with controls across measures of exec- Qualitative Observation
utive functioning, including verbal fluency,
digit span backward, Wisconsin Card Sorting Often a clinicians qualitative observations
Test, Stroop Test, and Trail Making Test of a patients behavior during the examina-
B.Impairments in some areas of functioning, tion can provide a wealth of information with
particularly executive functions, are evident regard to executive dysfunction. Symptoms
even at the early stages of the disease and may that are likely to be detectable by behavioral
predict the onset of dementia (Muslimovic, observation include disinhibition, impaired
Post, Speelman,& Schmand, 2005; Woods& context-appropriate behavior, disorganiza-
Troster, 2003). Of particular interest was the tion, poor initiation, affect dysregulation, and
finding that PD patients do not show deficits poor self-monitoring. Features of a patients
in all subcomponents of executive function- presentation likely to reveal dysexecutive
ing; instead, there is evidence for variable symptoms include dress and hygiene (dimin-
performance, with the strongest differences ished ability to organize or monitor oneself
between PD and controls groups found in or to adhere to social expectations), sponta-
working memory, problem solving, verbal neous speech (poor organization of thought
fluency, and inhibition (Marinus etal., 2003; processes, inappropriate content, failure to
Muslimovic et al., 2005; Uekermann et al., engage in reciprocal conversation), nonver-
2004; Weintraub& Stern, 2005). bal communication (lack of appreciation
of personal space, failure to perceive social
cues, poor eye contact), and inappropriate
Clinical Assessment of Executive Functions behavior.
History
Formal Neuropsychological Testing
Patients with significant executive and
behavioral dysfunction rarely initiate clini- In a previous chapter (Daffner & Searl,
cal evaluation. Obtaining a careful history 2008), we described several neuropsycho-
from reliable informants regarding changes logical batteries specifically developed to
in the patients personality and behavior is measure symptoms of frontal systems and
The Behavior Rating Inventory of Executive Function (BRIEF-A) (Gioia, Isquith, Guy, & Kenworthy, 2000)
Designed to assess the frequency and severity of dysexecutive symptoms (problems in inhibition,
shifting, emotional control, initiation, working memory, planning and organization, organization of
materials, and monitoring)
The Frontal Systems Behavior Scale (FrSBE) (Grace & Malloy, 2001)
A rating scale for adults age 1895 designed to measure changes in apathy, disinhibition, and
dysexecutive symptoms often associated with damage to frontal networks.
The Frontal Behavioral Inventory (FBI) (Blair etal., 2007; Kertesz, Davidson, & Fox, 1997)
Developed to track the evolution of symptoms, as well as record and monitor behavioral changes
over time, as it assesses both the presence of certain symptoms but also severity of disrupted
behaviors.
CHAPTER 3. Executive Control, the Regulation of Goal-Directed Behaviors, and the Impact of Dementing Illness 93
executive dysfunction, including the Frontal followed at a distance to code these errors
Assessment Battery (FAB; Dubois, Slachevsky, where needed.
Litvan, & Pillon, 2000), the Delis-Kaplan The Hotel Test (Manly etal., 2002)is made
Executive Function System (DKEFS; Delis& up of six activities that would be completed
Kaplan, 2001), the Behavioral Assessment in order to run a hotel. Apatient is provided
of Dysexecutive Syndromes (BADS; Wilson, with a list of tasks to be attempted over a
Alderman, Burgess, Emsile, & Evans, 1996), 15-minute period, with the goal that at the
and the Executive Control Battery (ECB; end of the time period the patient will make
Goldberg, Podel, Bilder, & Jaeger, 2000). an informed estimate of how long each task
However, classic tests of executive function would take to complete. Each task on its own
can fail to detect the dysexecutive changes may take longer than 15 minutes to complete,
in early frontally mediated neurodegen- and patients are informed that they will not
erative processes, such as bvFTD (Gregory complete each task. The Hotel Test is made
et al., 2002). Here we have chosen to focus up of six tasks, including compiling individ-
on alternative measures that can be added ual bills, sorting a collection of charity coins,
to traditional assessment batteries, includ- looking up telephone numbers, proofreading
ing ecologically valid neuropsychological the hotel leaflet, sorting conference labels,
tests and tests of social cognition, which and a prospective task requiring the patient
show promise in improving our ability to to remember to open and close the delivery
detect change in the earlier stages of frontal doors at specific times. The patient is pro-
dysfunction. vided with the materials needed to complete
the tasks and a clock. Scoring is based on sev-
Ecologically Valid Neuropsychological Tests eral categories, including (1)number of tasks
attempted; (2) number of tasks attempted
A growing number of studies are showing correctly; (3)time allocation; and (4)prospec-
that impairment in ecologically valid, or real tive memory performance. Similar to the
life, tests of complex decision making and MET, the patient is typically observed from a
planning have the potential to be more sensi- distance. Aversion of the Hotel Test is avail-
tive to the earliest stages of frontally medi- able commercially (with normative data) as
ated processes (Gregory etal., 2002; Torralva, part of the Behavioural Assessment of the
Roca, Gleichgerrcht, Bekinschtein,& Manes, Dysexecutive Syndrome (Wilson etal., 1996).
2007). Examples of these tasks include the While there is evidence for these tests to
Multiple Errands Test (Knight, Alderman,& be quite sensitive to early changes in PFC
Burgess, 2002) and the Hotel Test (Manly, function, they can be quite time intensive;
Hawkins, Evans, Woldt,& Robertson, 2002). in the case of the MET, it requires clinicians
Shallice and Burgess (1991) have shown and their patients to leave the safety of the
that patients with frontal lobe damage, who examination room. Although normative data
demonstrate normal performance on stan- do exist for these tests (Alderman, Burgess,
dard neuropsychological measures, tend Knight, & Henman, 2003; Dawson et al.,
to make more errors in everyday situations 2009; Knight etal., 2002; Manly etal., 2002),
that require planning and multitasking. The standardization of the procedures (particu-
MET and the abbreviated hospital version, larly on the MET) is difficult because no two
MET-HV, require individuals to perform a assessments will be exactly alike.
number of everyday tasks within four differ-
ent sets of categories:(1)attain specific goals,
Tests of Social Cognition
such as purchasing items, collecting an enve-
lope from a reception area, using the phone, Although tests of social cognition do not
and sending a letter; (2) obtain and write strictly tap executive functions, they have
down pieces of information; (3)call a number shown promise in improving diagnostic
20 minutes after the test has begun (prospec- accuracy of early frontally mediated neu-
tive memory); and (4) inform the examiner rodegenerative processes. Theory of mind
when every task has been completed. Errors tests have been proposed to assess social
are coded over five categories (inefficiencies, and emotional cognition, especially when
rule breaks, interpretation failures, task fail- classic executive tests show few abnor-
ures, and total fails). Patients are typically malities or normal performance (Adenzato,
94 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
Alexander, G.E., Newman, J.D.,& Symmes, D. Academy of Child and Adolescent Psychiatry, 51,
(1976). Convergence of prefrontal and acous- 356367.
tic inputs upon neurons in the superior tem- Aron, A. R., & Poldrack, R. A. (2006). Cortical
poral gyrus of the awake squirrel monkey. and subcortical contributions to stop signal
Brain Research, 116, 334338. response inhibition: Role of the subthalamic
Alexander, M.P.,& Stuss, D.T. (2000). Disorders nucleus. Journal of Neuroscience, 26, 24242433.
of frontal lobe functioning. Seminars in Astafiev, S. V., Shulman, G. L., Stanley, C. M.,
Neurology, 20, 427437. Snyder, A. Z., Van Essen, D. C., & Corbetta,
Alexander, M.P., Stuss, D.T., Shallice, T., Picton, M. (2003). Functional organization of human
T. W., & Gillingham, S. (2005). Impaired intraparietal and frontal cortex for attending,
concentration due to frontal lobe damage looking, and pointing. Journal of Neuroscience,
from two distinct lesion sites. Neurology, 65, 23, 46894699.
572579. Astafiev, S.V., Stanley, C.M., Shulman, G.L.,&
Almaguer, W., Estupinan, B., Uwe, F. J., & Corbetta, M. (2004). Extrastriate body area in
Bergado, J. A. (2002). Aging impairs human occipital cortex responds to the perfor-
amygdala-hippocampus interactions mance of motor actions. Nature Neuroscience,
involved in hippocampal LTP. Neurobiology of 7, 542548.
Aging, 23, 319324. Aston-Jones, G., Rajkowski, J., & Cohen, J.
Amodio, D.M.,& Frith, C.D. (2006). Meeting of (2000). Locus coeruleus and regulation of
minds: The medial frontal cortex and social behavioral flexibility and attention. Progress
cognition. Nature Reviews Neuroscience, 7, in Brain Research, 126, 165182.
268277. Baddeley, A. (2003). Working memory:Looking
Andersen, R., Meeker, D., Pesaran, B., Brezen, back and looking forward. Nature Reviews
B., Buneo, C., & Scherberger, H. (2004). Neuroscience, 4, 829839.
Sensorimotor transformations in the poste- Baddeley, A., Baddeley, H. A., Bucks, R. S., &
rior parietal portex. In M. S.Gazzaniga (Ed.), Wilcock, G. K. (2001). Attentional control in
The cognitive neurosciences III (pp. 463478). Alzheimers disease. Brain, 124, 14921508.
Cambridge, MA:MIT Press. Baddeley, A., Cocchini, G., Sala, S. D., Logie,
Anderson, M. C., Ochsner, K. N., Kuhl, R.H.,& Spinnler, H. (1999). Working memory
B., Cooper, J., Robertson, E., Gabrieli, and vigilance: Evidence from normal aging
S.W.,...Gabrieli, J.D. (2004). Neural systems and Alzheimers disease. Brain and Cognition,
underlying the suppression of unwanted 41, 87108.
memories. Science, 303, 232235. Baddeley, A.D.,& Hitch, G.J. (1974). Working
Anderson, P. J. (2008). Models of executive memory. In G. Bower (Ed.), The psychology of
function. In V. Anderson, R. Jacobs, & P. learning and motivation (pp. 4789). NewYork,
J.Anderson (Eds.), Executive functions and the NY:Academic Press.
frontal lobes: A lifespan perspective (pp. 321). Badre, D. (2008). Cognitive control, hierarchy,
NewYork, NY:Taylor& Francis. and the rostro-caudal organization of the
Andres, P. (2003). Frontal cortex as the central frontal lobes. Trends in Cognitive Science, 12,
executive of working memory:Time to revise 193200.
our view. Cortex, 39, 871895. Badre, D., & DEsposito, M. (2007). Functional
Arnold, S. F., Hyman, B. T., Flory, J., Damasio, magnetic resonance imaging evidence for a
A. R.,& Van Hoesen, G. W. (1991). The top- hierarchical organization of the prefrontal
ographical and neuroanatomical distribu- cortex. Journal of Cognitive Neuroscience, 19,
tion of neurofibrillary tangles and neuritic 20822099.
plaques in the cerebral cortex of patients Badre, D., & DEsposito, M. (2009). Is the
with Alzheimers disease. Cerebral Cortex, 1, rostro-caudal axis of the frontal lobe hier-
103116. archical? Nature Reviews Neuroscience, 10,
Arnsten, A. F. (1997). Catecholamine regu- 659669.
lation of the prefrontal cortex. Journal of Barbalat, G., Chambon, V., Franck, N., Koechlin,
Psychopharmacology, 11, 151162. E., & Farrer, C. (2009). Organization of cog-
Arnsten, A.F.,& Li, B.M. (2005). Neurobiology nitive control within the lateral prefrontal
of executive functions: Catecholamine cortex in schizophrenia. Archives of General
influences on prefrontal cortical functions. Psychiatry, 66, 377386.
Biological Psychiatry, 57, 13771384. Barbas, H., & Mesulam, M. M. (1985). Cortical
Arnsten, A. F., & Rubia, K. (2012). afferent input to the principalis region of the
Neurobiological circuits regulating atten- rhesus monkey. Neuroscience, 15, 619637.
tion, cognitive control, motivation, and emo- Bargh, J.A.,& Williams, E.L. (2006). The auto-
tion: Disruptions in neurodevelopmental maticity of social life. Current Directions in
psychiatric disorders. Journal of the American Psychological Science, 15, 14.
96 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
Barkley, R. A. (1997). Behavioral inhibition, Broe, M., Hodges, J.R., Schofield, E., Shepherd,
sustained attention, and executive func- C. E., Kril, J. J., & Halliday, G. M. (2003).
tions: Constructing a unifying theory of Staging disease severity in pathologically
ADHD. Psychological Bulletin, 121, 6594. confirmed cases of frontotemporal dementia.
Baron-Cohen, S., Wheelwright, S., Hill, J., Raste, Neurology, 60, 10051011.
Y.,& Plumb, I. (2001). The reading the mind Brozoski, T.J., Brown, R.M., Rosvold, H.E.,&
in the eyes test revised version:Astudy with Goldman, P. S. (1979). Cognitive deficit
normal adults, and adults with Asperger syn- caused by regional depletion of dopamine in
drome or high-functioning autism. Journal of prefrontal cortex of rhesus monkey. Science,
Child Psychology and Psychiatry, 42, 241251. 205, 929932.
Barris, R.W.,& Schuman, H.R. (1953). [Bilateral Buckner, R.L. (2012). The serendipitous discov-
anterior cingulate gyrus lesions; Syndrome ery of the brains default network. Neuroimage,
of the anterior cingulate gyri.]. Neurology, 3, 62, 11371145.
4452. Buckner, R. L., Andrews-Hanna, J. R., &
Bayer, H.M.,& Glimcher, P.W. (2005). Midbrain Schacter, D. L. (2008). The brains default
dopamine neurons encode a quantitative network: Anatomy, function, and relevance
reward prediction error signal. Neuron, 47, to disease. Annals of the NewYork Academy of
129141. Sciences, 1124, 138.
Berns, G. S., McClure, S. M., Pagnoni, G., & Buckner, R. L., & Carroll, D. C. (2007).
Montague, P.R. (2001). Predictability modu- Self-projection and the brain. Trends in
lates human brain response to reward. Journal Cognitive Sciences, 11, 4957.
of Neuroscience, 21, 27932798. Buneo, C.A.& Andersen, R.A. (2006). The pos-
Berridge, C. W., & Waterhouse, B. D. (2003). terior parietal cortex: Sensorimotor interface
The locus coeruleus-noradrenergic sys- for the planning and online control of visu-
tem: Modulation of behavioral state and ally guided movements. Neuropsychologia, 44,
state-dependent cognitive processes. Brain 25942606.
Research and Brain Research Reviews, 42, 3384. Bunge, S.A. (2004). How we use rules to select
Bianchi, L (1922). The mechanism of the brain and actions: A review of evidence from cogni-
the function of the frontal lobes. Edinburgh, tive neuroscience. Cognitive, Affective, and
UK:E& S Livingstone. Behavioral Neuroscience, 4, 564579.
Blair, M., Kertesz, A., Davis-Faroque, N., Hsiung, Bush, G., Vogt, B. A., Holmes, J., Dale, A. M.,
G.Y., Black, S.E., Bouchard, R.W.,...Feldman, Greve, D., Jenike, M.A.,& Rosen, B.R. (2002).
H. (2007). Behavioural measures in fronto- Dorsal anterior cingulate cortex: A role in
temporal lobar dementia and other demen- reward-based decision making. Proceedings
tias: The utility of the frontal behavioural of the National Academy of Science USA, 99,
inventory and the neuropsychiatric inven- 523528.
tory in a national cohort study. Dementia and Caballol, N., Marti, M. J., & Tolosa, E. (2007).
Geriatric Cognitive Disorders, 23, 406415. Cognitive dysfunction and dementia in
Boccardi, M., Sabattoli, F., Laakso, M. P., Testa, Parkinson disease. Movement Disorders,
C., Rossi, R., Beltramello, A.,...Frisoni, G. B. 22(Suppl 17), S358S366.
(2005). Frontotemporal dementia as a neural Cabeza, R. (2002). Hemispheric asymmetry
system disease. Neurobiology of Aging, 26, 3744. reduction in older adults: The HAROLD
Botvinick, M. M., Braver, T. S., Barch, model. Psychology of Aging, 17, 85100.
D. M., Carter, C. S., & Cohen, J. D. (2001). Calderon, J., Perry, R. J., Erzinclioglu, S. W.,
Conflict monitoring and cognitive control. Berrios, G.E., Dening, T.R.,& Hodges, J.R.
Psychological Review, 108, 624652. (2001). Perception, attention, and working
Botvinick, M. M., Cohen, J. D., & Carter, C. S. memory are disproportionately impaired in
(2004). Conflict monitoring and anterior cin- dementia with Lewy bodies compared with
gulate cortex:An update. Trends in Cognitive Alzheimers disease. Journal of Neurology,
Sciences, 8, 539546. Neurosurgery and Psychiatry, 70, 157164.
Bowler, J. (2003). Epidemiology: Identifying Carter, C. S., & van Veen, V. (2007). Anterior
vascular cognitive impairment. International cingulate cortex and conflict detection: An
Psychogeriatrics, 15(Suppl 1), 115122. update of theory and data. Cognitive, Affective,
Braak, H.,& Braak, E. (1991). Neuropathological and Behavioral Neuroscience, 7, 367379.
stageing of Alzheimer-related changes. Acta Challman, T. D., & Lipsky, J. J. (2000).
Neuropathologica, 82, 239259. Methylphenidate: Its pharmacology and
Bressler, S. L., & Menon, V. (2010). Large-scale uses. Mayo Clinic Proceedings, 75, 711721.
brain networks in cognition: Emerging Chao, L. L., & Knight, R. T. (1997). Prefrontal
methods and principles. Trends in Cognitive deficits in attention and inhibitory control
Sciences, 14, 277290. with aging. Cerebral Cortex, 7, 6369.
CHAPTER 3. Executive Control, the Regulation of Goal-Directed Behaviors, and the Impact of Dementing Illness 97
Chavis, D.A.,& Pandya, D.N. (1976). Further Corbetta, M.,& Shulman, G.L. (2002). Control
observations on corticofrontal connections of goal-directed and stimulus-driven atten-
in the rhesus monkey. Brain Research, 117, tion in the brain. Nature Reviews Neuroscience,
369386. 3, 201215.
Chen, S., Boucher, H.C.,& Tapias, M.P. (2006). Corbetta, M., & Shulman, G. L. (2011). Spatial
The relational self revealed: Integrative con- neglect and attention networks. Annual
ceptualization and implications for interper- Review of Neuroscience, 34, 569599.
sonal life. Psychological Bulletin, 132, 151179. Courtney, S. M., Ungerleider, L. G., Keil, K., &
Chiarello, R. J., & Cole, J. O. (1987). The use Haxby, J.V. (1996). Object and spatial visual
of psychostimulants in general psychia- working memory activate separate neural
try. A reconsideration. Archives of General systems in human cortex. Cerebral Cortex, 6,
Psychiatry, 44, 286295. 3949.
Christoff, K., Gordon, A. M., Smallwood, J., Craig, A. D. (2002). How do you feel?
Smith, R.,& Schooler, J.W. (2009). Experience Interoception: The sense of the physiologi-
sampling during fMRI reveals default net- cal condition of the body. Nature Reviews
work and executive system contributions to Neuroscience, 3, 655666.
mind wandering. Proceedings of the National Craig, A.D. (2009). How do you feelnow? The
Academy of Science USA, 106, 87198724. anterior insula and human awareness. Nature
Clarke, H.F., Dalley, J.W., Crofts, H.S., Robbins, Reviews Neuroscience, 10, 5970.
T. W., & Roberts, A. C. (2004). Cognitive Craik, F. I. M., & Salthouse, T. A. (2000). The
inflexibility after prefrontal serotonin deple- handbook of aging and cognition. Mahwah,
tion. Science, 304, 878880. NJ:Erlbaum.
Clarke, H.F., Walker, S.C., Crofts, H.S., Dalley, Critchley, H. D. (2005). Neural mechanisms of
J.W., Robbins, T.W.,& Roberts, A.C. (2005). autonomic, affective, and cognitive integra-
Prefrontal serotonin depletion affects rever- tion. Journal of Comparative Neurology, 493,
sal learning but not attentional set shifting. 154166.
Journal of Neuroscience, 25, 532538. Critchley, H. D., Elliott, R., Mathias, C. J., &
Clarke, H.F., Walker, S.C., Dalley, J.W., Robbins, Dolan, R. J. (2000). Neural activity relating
T. W., & Roberts, A. C. (2007). Cognitive to generation and representation of galvanic
inflexibility after prefrontal serotonin deple- skin conductance responses: A functional
tion is behaviorally and neurochemically spe- magnetic resonance imaging study. Journal of
cific. Cerebral Cortex, 17, 1827. Neuroscience, 20, 30333040.
Clarke, R. (2006). Vitamin B12, folic acid, and Critchley, H.D., Wiens, S., Rotshtein, P., Ohman,
the prevention of dementia. New England A., & Dolan, R. J. (2004). Neural systems
Journal of Medicine, 354, 28172819. supporting interoceptive awareness. Nature
Cohen, J. D., Braver, T. S., & OReilly, R. C. Neuroscience, 7, 189195.
(1996). A computational approach to pre- Crowell, T.A., Luis, C.A., Cox, D.E.,& Mullan,
frontal cortex, cognitive control and schizo- M. (2007). Neuropsychological comparison
phrenia: Recent developments and current of Alzheimers disease and dementia with
challenges. Philosophical Transactions of the lewy bodies. Dement Geriatr Cogn Disord, 23,
Royal Society of Londong B:Biological Sciences, 120125.
351, 15151527. Curtis, C.E.,& DEsposito, M. (2003). Persistent
Cohen, J. D., & Servan-Schreiber, D. (1992). activity in the prefrontal cortex during work-
Context, cortex, and dopamine: A connec- ing memory. Trends in Cognitive Sciences, 7,
tionist approach to behavior and biology in 415423.
schizophrenia. Psychological Review, 99, 4577. DArgembeau, A., Collette, F., Van der, L. M.,
Colby, C.L.,& Goldberg, M.E. (1999). Space and Laureys, S., Del Fiore, G., Degueldre,
attention in parietal cortex. Annual Review of C.,...Salmon, E. (2005). Self-referential
Neuroscience, 22, 319349. reflective activity and its relationship with
Conway, M. A. (2005). Memory and the self. rest:APET study. Neuroimage, 25, 616624.
Journal of Memory and Language, 53, 594628. DArgembeau, A., Ruby, P., Collette,
Corbetta, M., Kincade, J. M., Ollinger, J. M., F., Degueldre, C., Balteau, E., Luxen,
McAvoy, M. P., & Shulman, G. L. (2000). A.,...Salmon, E. (2007). Distinct regions of
Voluntary orienting is dissociated from target the medial prefrontal cortex are associated
detection in human posterior parietal cortex. with self-referential processing and perspec-
Nature Neuroscience, 3, 292297. tive taking. Journal of Cognitive Neuroscience,
Corbetta, M., Kincade, M.J., Lewis, C., Snyder, 19, 935944.
A. Z., & Sapir, A. (2005). Neural basis and DArgembeau, A., & Salmon, E. (2012). The
recovery of spatial attention deficits in spatial neural basis of semantic and episodic forms
neglect. Nature Neuroscience, 8, 16031610. of self-knowledge: Insights from functional
98 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
Friedman, N.P.,& Miyake, A. (2004). The rela- macaque monkeys. Neurobiology of Aging, 18,
tions among inhibition and interference 549553.
control functions: A latent-variable analysis. Genovesio, A., Brasted, P.J.,& Wise, S.P. (2006).
Journal of Experimental Psychology: General, Representation of future and previous spa-
133, 101135. tial goals by separate neural populations in
Funahashi, S., Bruce, C. J., & Goldman-Rakic, prefrontal cortex. Journal of Neuroscience, 26,
P. S. (1993). Dorsolateral prefrontal lesions 73057316.
and oculomotor delayed-response perfor- Gioia, G., Isquith, P., Guy, S., & Kenworthy,
mance: Evidence for mnemonic scotomas. L. (2000). Behavior rating inventory of execu-
Journal of Neuroscience, 13, 14791497. tive function. Odessa, FL: Psychological
Funkiewiez, A., Bertoux, M., de Souza, L. C., Assessment Resources.
Levy, R.,& Dubois, B. (2012). The SEA (Social Goldberg, E., Podel, K., Bilder, R., & Jaeger, J
cognition and Emotional Assessment):Aclin- (2000). The executive control battery. Melbourne,
ical neuropsychological tool for early diagno- Australia:PsychPress.
sis of frontal variant of frontotemporal lobar Goldman-Rakic, P. S. (1987). Circuitry of pri-
degeneration. Neuropsychology, 26, 8190. mate prefrontal cortex and regulation of
Furey, M. L., Pietrini, P., & Haxby, J. V. (2000). behavior by representational memory. In F.
Cholinergic enhancement and increased Plum, V. B.Mountcastle,& S. T.Geiger (Eds.),
selectivity of perceptual processing during The handbook of physiology, Section 1. The ner-
working memory. Science, 290, 23152319. vous system, Vol. 5.Higher functions of the brain
Furey, M.L., Pietrini, P., Haxby, J.V., Alexander, part1 (pp. 373417). Bethesda, MD:American
G. E., Lee, H. C., VanMeter, J.,...Freo, U. Physiological Society.
(1997). Cholinergic stimulation alters per- Goldman-Rakic, P. S. (1996). Regional and cel-
formance and task-specific regional cere- lular fractionation of working memory.
bral blood flow during working memory. Proceedings of the National Academy of Science
Proceedings of the National Academy of Science USA, 93, 1347313480.
USA, 94, 65126516. Goldman-Rakic, P. S. (1999). The psychic
Fuster, J.M. (1985). The prefrontal cortex, medi- neuron of the cerebral cortex. Annals of the
ator of cross-temporal contingencies. Human NewYork Academy of Sciences, 868, 1326.
Neurobiology, 4, 169179. Goldstein, K.,& Katz, E. (1937). The psychopa-
Fuster, J. M. (1995). Memory in the cerebral cor- thology of Pick's Disease. Archives of Neurology
tex: An empirical approach to neural networks and Psychiatry, 38(3), 473490.
in the human brain and nonhuman primate. Goldstein, K., & Scheerer, M. (1941). Abstract
Cambridge, MA:Dorsey Press. concrete behavior. Psychological Monographs,
Garrett, K.D., Browndyke, J.N., Whelihan, W., 53, 110130.
Paul, R. H., DiCarlo, M., Moser, D. J.,...Ott, Grace, J.,& Malloy, P. (2001). Frontal systems behav-
B. R. (2004). The neuropsychological pro- ior scale (FrSBe). Odessa, FL: Psychological
file of vascular cognitive impairmentno Assessment Resources.
dementia:Comparisons to patients at risk for Grady, C. L., McIntosh, A. R., Bookstein, F.,
cerebrovascular disease and vascular demen- Horwitz, B., Rapoport, S. I., & Haxby, J. V.
tia. Archives of Clinical Neuropsychology, 19, (1998). Age-related changes in regional cere-
745757. bral blood flow during working memory for
Gazzaley, A., Cooney, J. W., Rissman, J., & faces. NeuroImage, 8, 409425.
DEsposito, M. (2005). Top-down suppression Greenhill, L. L., & Osman, B. B. (2000).
deficit underlies working memory impair- Ritalin: Theory and practice. New York,
ment in normal aging. Nature Neuroscience, 8, NY:Mary Ann Liebert.
12981300. Greenwood, P. M. (2000). The frontal aging
Gazzaley, A.,& DEsposito, M. (2007). Unifying hypothesis evaluated. Journal of the
prefrontal cortex function:Executive control, International Neuropsychological Society, 6,
neural networks, and top-down modula- 705726.
tion. In B. Miller & J. Cummings (Eds.), The Gregory, C., Lough, S., Stone, V., Erzinclioglu,
human frontal lobes (pp. 187206). New York, S., Martin, L., Baron-Cohen, S., & Hodges,
NY:Guildford Press. J.R. (2002). Theory of mind in patients with
Gazzaley, A.,& Nobre, A.C. (2012). Top-down frontal variant frontotemporal dementia and
modulation:Bridging selective attention and Alzheimers disease: Theoretical and practi-
working memory. Trends in Cognitive Sciences, cal implications. Brain, 125, 752764.
16, 129135. Grinband, J., Hirsch, J., & Ferrera, V. P. (2006).
Gazzaley, A. H., Thakker, M. M., Hof, P. R., & A neural representation of categorization
Morrison, J. H. (1997). Preserved number of uncertainty in the human brain. Neuron, 49,
entorhinal cortex layer II neurons in aged 757763.
100 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
Gross, J.J. (1998). The emerging field of emotion Horvath, T.L., Diano, S.,& van den Pol, A.N.
regulation: An integrative review. Review of (1999). Synaptic interaction between hypo-
General Psychology, 2, 271299. cretin (orexin) and neuropeptide Y cells in the
Guidi, M., Paciaroni, L., Paolini, S., De Padova, rodent and primate hypothalamus: A novel
S.,& Scarpino, O. (2006). Differences and sim- circuit implicated in metabolic and endo-
ilarities in the neuropsychological profile of crine regulations. Journal of Neuroscience, 19,
dementia with Lewy bodies and Alzheimers 10721087.
disease in the early stage. Journal of the Horvitz, J.C., Stewart, T.,& Jacobs, B.L. (1997).
Neurological Sciences, 248, 120123. Burst activity of ventral tegmental dopamine
Gusnard, D.A., Akbudak, E., Shulman, G.L.,& neurons is elicited by sensory stimuli in the
Raichle, M.E. (2001). Medial prefrontal cortex awake cat. Brain Research, 759, 251258.
and self-referential mental activity:Relation to Hull, C. L. (1943). Principles of behavior.
a default mode of brain function. Proceedings NewYork, NY:Appleton-Century.
of the National Academy of Sciences USA, 98, Jackson, J. H. (1932). Selected writings of John
42594264. Hughlings Jackson. London, UK: Hodder and
Gusnard, D.A., Raichle, M.E.,& Raichle, M.E. Stoughton.
(2001). Searching for a baseline: Functional Johnson, M. K., Nolen-Hoeksema, S., Mitchell,
imaging and the resting human brain. Nature K.J.,& Levin, Y. (2009). Medial cortex activity,
Reviews Neuroscience, 2, 685694. self-reflection and depression. Social Cognitive
Hachinski, V.C.,& Bowler, J.V. (1993). Vascular and Affective Neuroscience, 4, 313327.
dementia. Neurology, 43, 21592160. Johnson, M. K., Raye, C. L., Mitchell,
Hasher, L.,& Zacks, R.T. (1988). Working mem- K. J., Touryan, S. R., Greene, E. J., &
ory, comprehension, and aging: A review Nolen-Hoeksema, S. (2006). Dissociating
and a new view. Psychology of Learning and medial frontal and posterior cingulate activ-
Motivation, 22, 193225. ity during self-reflection. Social Cognitive and
Heatherton, T.F. (2011). Neuroscience of self and Affective Neuroscience, 1, 5664.
self-regulation. Annual Review of Psychology, Kane, M.J.,& Engle, R.W. (2002). The role of pre-
62, 363390. frontal cortex in working-memory capacity,
Heatherton, T.F., Wyland, C.L., Macrae, C.N., executive attention, and general fluid intelli-
Demos, K. E., Denny, B. T., & Kelley, W. M. gence:An individual-differences perspective.
(2006). Medial prefrontal activity differenti- Psychonomic Bulletin Review, 9, 637671.
ates self from close others. Social Cognitve and Kelley, W. M., Macrae, C. N., Wyland, C. L.,
Affective Neuroscience, 1, 1825. Caglar, S., Inati, S.,& Heatherton, T.F. (2002).
Higgins, E.T. (1997). Beyond pleasure and pain. Finding the self? An event-related fMRI study.
American Psychologist, 52, 12801300. Journal of Cognitive Neuroscience, 14, 785794.
Hodges, J. R., & Miller, B. (2001). The clas- Kerns, J. G., Cohen, J. D., MacDonald, A. W.,
sification, genetics and neuropathology of III, Cho, R. Y., Stenger, V. A., & Carter, C. S.
frontotemporal dementia. Introduction to (2004). Anterior cingulate conflict monitor-
the special topic papers: Part I. Neurocase, 7, ing and adjustments in control. Science, 303,
3135. 10231026.
Holroyd, C. B., & Coles, M. G. (2002). The Kertesz, A., Davidson, W., & Fox, H. (1997).
neural basis of human error process- Frontal behavioral inventory: Diagnostic
ing: Reinforcement learning, dopamine, and criteria for frontal lobe dementia. Canadian
the error-related negativity. Psychological Journal of the Neurological Sciences, 24, 2936.
Review, 109, 679709. Kertesz, A., Hudson, L., Mackenzie, I.R. A.,&
Holroyd, C. B., & Coles, M. G. (2008). Dorsal Munoz, D. G. (1994). The pathology and
anterior cingulate cortex integrates reinforce- nosology of primary progressive aphasia.
ment history to guide voluntary behavior. Neurology, 44, 20652072.
Cortex, 44, 548559. Khateb, A., Ammann, J., Annoni, J. M., &
Holroyd, C. B., Yeung, N., Coles, M. G., & Diserens, K. (2005). Cognition-enhancing
Cohen, J. D. (2005). A mechanism for error effects of donepezil in traumatic brain injury.
detection in speeded response time tasks. European Neurology, 54, 3945.
Journal of Experimental Psychology: General, Kimber, J.R., Watson, L.,& Mathias, C.J. (1997).
134, 163191. Distinction of idiopathic Parkinsons disease
Hornak, J., ODoherty, J., Bramham, J., Rolls, from multiple-system atrophy by stimulation
E. T., Morris, R. G., Bullock, P. R., & Polkey, of growth-hormone release with clonidine.
C. E. (2004). Reward-related reversal learn- Lancet, 349, 18771881.
ing after surgical excisions in orbito-frontal Kimberg, D.Y.,& Farah, M.J. (1993). A unified
or dorsolateral prefrontal cortex in humans. account of cognitive impairments following
Journal of Cognitive Neuroscience, 16, 463478. frontal damage:The role of working memory
CHAPTER 3. Executive Control, the Regulation of Goal-Directed Behaviors, and the Impact of Dementing Illness 101
reasoning, emotion and empathy in fron- Menon, V., Adleman, N.E., White, C.D., Glover,
totemporal dementia. Neuropsychologia, 44, G. H., & Reiss, A. L. (2001). Error-related
950958. brain activation during a Go/NoGo response
Luciana, M.,& Collins, P.F. (1997). Dopaminergic inhibition task. Human Brain Mapping, 12,
modulation of working memory for spatial 131143.
but not object cues in normal humans. Journal Menon, V., & Uddin, L. Q. (2010). Saliency,
of Cognitive Neuroscience, 9, 330347. switching, attention and control: A network
Luciana, M., Depue, R. A., Arbisi, P., & Leon, model of insula function. Brain Structure and
A. (1992). Facilitation of working memory in Function, 214, 655667.
humans by a D2 dopamine receptor agonist. Mesulam, M. M. (1986). Frontal cortex and
Journal of Cognitive Neuroscience, 4, 5868. behavior. Annals of Neurology, 19, 320325.
Mackenzie, I. R., Neumann, M., Bigio, E. H., Mesulam, M. M. (2000). Principles of behavioral
Cairns, N. J., Alafuzoff, I., Kril, J.,...Mann, and cognitive neurology. Oxford, UK: Oxford
D. M. (2009). Nomenclature for neuropatho- University Press.
logic subtypes of frontotemporal lobar Mesulam, M.M.,& Mufson, E.J. (1982). Insula
degeneration: Consensus recommendations. of the old world monkey. I. Architectonics
Acta Neuropathologica, 117, 1518. in the insulo-orbito-temporal component of
Manly, T., Hawkins, K., Evans, J., Woldt, K.,& the paralimbic brain. Journal of Comparative
Robertson, I. H. (2002). Rehabilitation of Neurology, 212, 122.
executive function: Facilitation of effective Middleton, F. A., & Strick, P. L. (2002).
goal management on complex tasks using Basal-ganglia projections to the prefron-
periodic auditory alerts. Neuropsychologia, 40, tal cortex of the primate. Cerebral Cortex, 12,
271281. 926935.
Marin, R.S., Fogel, B.S., Hawkins, J., Duffy, J.,& Miller, B.T.,& DEsposito, M. (2005). Searching
Krupp, B. (1995). Apathy: A treatable syn- for the top in top-down control. Neuron, 48,
drome. Journal of Neuropsychiatry and Clinical 535538.
Neuroscience, 7, 2330. Miller, E.K.,& Cohen, J.D. (2001). An integra-
Marinus, J., Visser, M., Verwey, N. A., Verhey, tive theory of prefrontal cortex function.
F. R., Middelkoop, H. A., Stiggelbout, Annual Review of Neuroscience, 24, 167202.
A.M.,& van Hilten, J.J. (2003). Assessment of Miller, E. K., Erickson, C. A., & Desimone, R.
cognition in Parkinsons disease. Neurology, (1996). Neural mechanisms of visual working
61, 12221228. memory in prefrontal cortex of the macaque.
Markus, H.,& Nurius, P. (1986). Possible selves. Journal of Neuroscience, 16, 51545167.
American Psychologist, 41, 954969. Mitchell, K.J., Raye, C.L., Ebner, N.C., Tubridy,
Markus, H., & Wurf, E. (1987). The dynamic S. M., Frankel, H., & Johnson, M. K. (2009).
self-concept:Asocial psychological perspec- Age-group differences in medial cortex
tive. In Rosenweig, M.R.& Porter, L.W. (Eds.) activity associated with thinking about
Annual Review of Psychology (pp. 299337). self-relevant agendas. Psychology of Aging, 24,
Palo Alto, Ca:Annual Reviews. 438449.
Mason, M. F., Norton, M. I., Van Horn, J. D., Miyake, A., Friedman, N. P., Emerson, M. J.,
Wegner, D. M., Grafton, S. T., & Macrae, Witzki, A. H., Howerter, A., & Wager, T. D.
C. N. (2007). Wandering minds: The default (2000). The unity and diversity of executive
network and stimulus-independent thought. functions and their contributions to complex
Science, 315, 393395. frontal lobe tasks:Alatent variable analy-
Matsumoto, M., Matsumoto, K., Abe, H., & sis. Cognitive Psychology, 41, 49100.
Tanaka, K. (2007). Medial prefrontal cell activ- Moore, R. Y., Abrahamson, E. A., & Van Den,
ity signaling prediction errors of action val- P. A. (2001). [The hypocretin neuron sys-
ues. Nature Neuroscience, 10, 647656. tem:An arousal system in the human brain].
Mauss, I.B., Bunge, S.A.,& Gross, J.J. (2007). Archives Italiennes de Biologie, 139, 195205.
Automatic emotion regulation. Social and Morris, G., Arkadir, D., Nevet, A., Vaadia, E.,&
Personality Psychology Compass, 1, 146167. Bergman, H. (2004). Coincident but distinct
McDowell, S., Whyte, J., & DEsposito, M. messages of midbrain dopamine and striatal
(1998). Differential effect of a dopaminergic tonically active neurons. Neuron, 43, 133143.
agonist on prefrontal function in traumatic Muller, U., Steffenhagen, N., Regenthal, R., &
brain injury patients. Brain, 121, 11551164. Bublak, P. (2004). Effects of modafinil on
McKeith, I.G., Dickson, D.W., Lowe, J., Emre, working memory processes in humans.
M., OBrien, J.T., Feldman, H.,...Yamada, M. Psychopharmacology (Berlin), 177, 161169.
(2005). Diagnosis and management of demen- Muller, U., & von Cramon, D. Y. (1994). The
tia with Lewy bodies:Third report of the DLB therapeutic potential of bromocriptine in
Consortium. Neurology, 65, 18631872. neuropsychological rehabilitation of patients
CHAPTER 3. Executive Control, the Regulation of Goal-Directed Behaviors, and the Impact of Dementing Illness 103
with acquired brain damage. Progress in Pardini, M., Emberti, G.L., Mascolo, M., Benassi,
Neuropsychopharmacology and Biological F., Abate, L., Guida, S.,...Cocito L. (2012).
Psychiatry, 18, 11031120. Isolated theory of mind deficits and risk for
Muller, U., von Cramon, D. Y., & Pollman, S. frontotemporal dementia: A longitudinal
(1998). D1- versus D2-receptor modulation pilot study. Journal of Neurology, Neurosurgery
of visuospatial working memory in humans. and Psychiatry, 84(7), 818821.
Journal of Neuroscience, 18, 27202728. Park, D. C., Polk, T. A., Park, R., Minear, M.,
Muslimovic, D., Post, B., Speelman, J. D., & Savage, A., & Smith, M. R. (2004). Aging
Schmand, B. (2005). Cognitive profile of reduces neural specialization in ventral visual
patients with newly diagnosed Parkinson cortex. Proceedings of the National Academy of
disease. Neurology, 65, 12391245. Sciences USA, 101, 13091.
Nakahara, H., Itoh, H., Kawagoe, R., Takikawa, Passingham, D (1995). The frontal lobes and vol-
Y.,& Hikosaka, O. (2004). Dopamine neurons untary action. Oxford, UK:Oxford University
can represent context-dependent prediction Press.
error. Neuron, 41, 269280. Paus, T. (2001). Primate anterior cingulate cor-
Nemeth, G., Hegedus, K., & Molnar, L. (1988). tex: Where motor control, drive and cogni-
Akinetic mutism associated with bicingular tion interface. Nature Reviews Neuroscience, 2,
lesions: Clinicopathological and functional 417424.
anatomical correlates. European Archives Pavlov, I.P. (1960). Conditioned Reflexes. An inves-
of Psychiatry and Neurological Science, 237, tigation of the physiological activity of the cerebral
218222. cortex. NewYork, NY:Dover Publications, Inc.
Niendam, T. A., Laird, A. R., Ray, K. L., Dean, Pelosi, L.,& Blumhardt, L.D. (1999). Effects of
Y. M., Glahn, D. C., & Carter, C. S. (2012). age on working memory: An event-related
Meta-analytic evidence for a superordinate potential study. Brain Research Cognitive Brain
cognitive control network subserving diverse Research, 7, 321334.
executive functions. Cognitive, Affective, and Petersen, S.E.,& Posner, M.I. (2012). The atten-
Behavioral Neuroscience, 12, 241268. tion system of the human brain:20years after.
Nieuwenhuis, S., Aston-Jones, G., & Cohen, Annual Review of Neuroscience, 35, 7389.
J. D. (2005). Decision making, the P3, and Peterson, B. S., Kane, M. J., Alexander,
the locus coeruleus-norepinephrine system. G. M., Lacadie, C., Skudlarski, P., Leung,
Psychological Bulletin, 131, 510532. H. C.,...Gore JC. (2002). An event-related
Niki, H.,& Watanabe, M. (1979). Prefrontal and functional MRI study comparing interference
cingulate unit activity during timing behavior effects in the Simon and Stroop tasks. Brain
in the monkey. Brain Research, 171, 213224. Research Cognitive Brain Research, 13, 427440.
ODoherty, J., Kringelbach, M. L., Rolls, E. T., Petrides, M. (2000). Dissociable roles of
Hornak, J., & Andrews, C. (2001). Abstract mid-dorsolateral prefrontal and anterior
reward and punishment representations inferotemporal cortex in visual working
in the human orbitofrontal cortex. Nature memory. Journal of Neuroscience, 20, 74967503.
Neuroscience, 4, 95102. Peyron, R., Laurent, B., & Garcia-Larrea, L.
Ochsner, K. N., Bunge, S. A., Gross, J. J., & (2000). Functional imaging of brain responses
Gabrieli, J.D. (2002). Rethinking feelings:An to pain. A review and meta-analysis (2000).
FMRI study of the cognitive regulation of Neurophysiologie Clinique, 30, 263288.
emotion. Journal of Cognitive Neuroscience, 14, Pillon, B., Boller, F., Levy, R., & Dubois, B.
12151229. (2001). Cognitive deficits and dementia in
Okuda, J., Fujii, T., Ohtake, H., Tsukiura, T., Parkinsons disease. In F. Boller& S. F.Cappa
Tanji, K., Suzuki, K.,...Yamadori A. (2003). (Eds.), Handbook of neuropsychology (pp. 311
Thinking of the future and past: The roles 371). Elsevier, Amsterdam.
of the frontal pole and the medial temporal Posner, M.I.,& Petersen, S.E. (1990). The atten-
lobes. Neuroimage, 19, 13691380. tion system of the human brain. Annual
Ongur, D., & Price, J. L. (2000). The organi- Review of Neuroscience, 13, 2542.
zation of networks within the orbital and Posner, M.I.,& Snyder, C.R. R. (1975). Attention
medial prefrontal cortex of rats, monkeys and and cognitive control. In R. L. Solso (Ed.),
humans. Cerebral Cortex, 10, 206219. Information processing and cognition, the
Owen, A. M. (2004). Cognitive dysfunction in Loyola Symposium (pp. 5585). Hillsdale,
Parkinsons disease:The role of frontostriatal NJ:Erlbaum.
circuitry. Neuroscientist, 10, 525537. Powell, K. D., & Goldberg, M. E. (2000).
Pantoni, L., & Garcia, J. H. (1997). Cognitive Response of neurons in the lateral intrapa-
impairment and cellular/vascular changes rietal area to a distractor flashed during the
in the cerebral white matter. Annals of the delay period of a memory-guided saccade.
NewYork Academy of Sciences, 826, 92102. Journal of Neurophysiology, 84, 301310.
104 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
Pugh, K.G.,& Lipsitz, L.A. (2002). The micro- Koeppe, R. A. (2000). Age differences in the
vascular frontal-subcortical syndrome of frontal lateralization of verbal and spatial
aging. Neurobiology of Aging, 23, 421431. working memory revealed by PET. Journal of
Pycock, C. J., Kerwin, R. W., & Carter, C. J. Cognitive Neuroscience, 12, 174187.
(1980). Effect of lesion of cortical dopamine Ridderinkhof, K. R., Ullsperger, M., Crone,
terminals on subcortical dopamine receptors E. A., & Nieuwenhuis, S. (2004). The role of
in rats. Nature, 286, 7476. the medial frontal cortex in cognitive control.
Rahman, S., Robbins, T.W., Hodges, J.R., Mehta, Science, 306, 443447.
M.A., Nestor, P.J., Clark, L.,& Sahakian, B.J. Riis, J.L., Chong, H., Ryan, K.K., Wolk, D.A.,
(2005). Methylphenidate (Ritalin) can ame- Rentz, D.M., Holcomb, P.J.,& Daffner, K.R.
liorate abnormal risk-taking behavior in the (2008). Compensatory neural activity distin-
frontal variant of frontotemporal dementia. guishes different patterns of normal cognitive
Neuropsychopharmacology, 31(3), 651658. aging. NeuroImage, 39, 441454.
Rahman, S., Sahakian, B.J., Hodges, J.R., Rogers, Robbins, T. W., & Roberts, A. C. (2007),
R.D.,& Robbins, T.W. (1999). Specific cogni- Differential regulation of fronto-executive
tive deficits in mild frontal variant frontotem- function by the monoamines and acetylcho-
poral dementia. Brain, 122(Pt 8), 14691493. line. Cerebal Cortex, 17(1), 151160.
Rainer, G., Asaad, W. F., & Miller, E. K. (1998). Rolls, E. T., Critchley, H. D., Mason, R., &
Selective representation of relevant informa- Wakeman, E. A. (1996). Orbitofrontal cortex
tion by neurons in the primate prefrontal cor- neurons:Role in olfactory and visual associa-
tex. Nature, 393, 577579. tion learning. Journal of Neurophysiology, 75,
Rankin, K. P., Gorno-Tempini, M. L., Allison, 19701981.
S. C., Stanley, C. M., Glenn, S., Weiner, Rubia, K., Lee, F., Cleare, A.J., Tunstall, N., Fu,
M.W.,& Miller, B.L. (2006). Structural anat- C. H., Brammer, M., & McGuire, P. (2005).
omy of empathy in neurodegenerative dis- Tryptophan depletion reduces right infe-
ease. Brain, 129, 29452956. rior prefrontal activation during response
Rascovsky, K., Hodges, J. R., Kipps, C. M., inhibition in fast, event-related fMRI.
Johnson, J. K., Seeley, W. W., Mendez, Psychopharmacology (Berlin), 179, 791803.
M. F.,...Miller, B. M. (2007). Diagnostic cri- Rushworth, M.F.,& Behrens, T.E. (2008). Choice,
teria for the behavioral variant of frontotem- uncertainty and value in prefrontal and cingu-
poral dementia (bvFTD):Current limitations late cortex. Nature Neuroscience, 11, 389397.
and future directions. Alzheimer Disease and Rypma, B., Prabhakaran, V., Desmond, J. E.,
Associative Disorders, 21, S14S18. Glover, G. H., & Gabrieli, J. D. (1999).
Rascovsky, K., Hodges, J. R., Knopman, D., Load-dependent roles of frontal brain regions
Mendez, M. F., Kramer, J. H., Neuhaus, in the maintenance of working memory.
J.,...Miller, B. L. (2011). Sensitivity of revised Neuroimage, 9, 216226.
diagnostic criteria for the behavioural variant of Salthouse, T. A. (1996). The processing-speed
frontotemporal dementia. Brain, 134, 24562477. theory of adult age differences in cognition.
Raz, N., Gunning-Dixon, F., Head, D., Rodrigue, Psychological Review, 103, 403428.
K. M., Williamson, A., & Acker, J. D. (2004). Salthouse, T.A., Atkinson, T.M.,& Berish, D.E.
Aging, sexual dimorphism, and hemi- (2003). Executive functioning as a potential
spheric asymmetry of the cerebral cor- mediator of age-related cognitive decline
tex: Replicability of regional differences in in normal adults. Journal of Experimental
volume. Neurobiology of Aging, 25, 377396. Psychology:General, 132, 566594.
Raz, N., Rodrigue, K. M., Kennedy, K. M., Saper, C. B. (2002). The central autonomic ner-
Head, D., Gunning-Dixon, F., & Acker, J. D. vous system: Conscious visceral perception
(2003). Differential aging of the human stria- and autonomic pattern generation. Annual
tum:Longitudinal evidence. American Journal Review of Neuroscience, 25, 433469.
of Neuroradiology, 24, 18491856. Saper, C. B., Chou, T. C., & Scammell, T. E.
Resnick, S. M., Pham, D. L., Kraut, M. A., (2001). The sleep switch: Hypothalamic
Zonderman, A. B., & Davatzikos, C. (2003). control of sleep and wakefulness. Trends in
Longitudinal magnetic resonance imaging Neuroscience, 24, 726731.
studies of older adults: A shrinking brain. Scammell, T. E., Estabrooke, I. V., McCarthy,
Journal of Neuroscience, 23, 32953301. M.T., Chemelli, R.M., Yanagisawa, M., Miller,
Reuter-Lorenz, P. A., & Cappell, K. A. (2008). M. S., & Saper, C. B. (2000). Hypothalamic
Neurocognitive aging and the compensation arousal regions are activated during
hypothesis. Current Directions in Psychological modafinil-induced wakefulness. Journal of
Science, 17, 177182. Neuroscience, 20, 86208628.
Reuter-Lorenz, P. A., Jonides, J., Smith, E. E., Schacter, D. L., Addis, D. R., & Buckner, R. L.
Hartley, A., Miller, A., Marshuetz, C., & (2007). Remembering the past to imagine the
CHAPTER 3. Executive Control, the Regulation of Goal-Directed Behaviors, and the Impact of Dementing Illness 105
future:The prospective brain. Nature Reviews executive control. Journal of Neuroscience, 27,
Neuroscience, 8, 657661. 23492356.
Schneider, B.A.,& Pichora-Fuller, M.K. (2000). Seeley, W. W., Zhou, J., & Kim, E. J. (2012).
Age-related changes in temporal process- Frontotemporal dementia: What can the
ing: Implications for listening comprehen- behavioral variant teach us about human
sion. Seminars in Hearing, 22, 227239. brain organization? Neuroscientist, 18,
Schoenbaum, G., Chiba, A.A.,& Gallagher, M. 373385.
(1998). Orbitofrontal cortex and basolateral Shallice, T. (1982). Specific impairments of plan-
amygdala encode expected outcomes during ning. Philosophical Transactions of the Royral
learning. Nature Neuroscience, 1, 155159. Society of London B: Biological Sciences, 298,
Schoenbaum, G., Chiba, A. A., & Gallagher, 199209.
M. (1999). Neural encoding in orbitofron- Shallice, T., & Burgess, P. W. (1991). Deficits in
tal cortex and basolateral amygdala during strategy application following frontal lobe
olfactory discrimination learning. Journal of damage in man. Brain, 114, 727741.
Neuroscience, 19, 18761884. Shankar, S., Teyler, T. J., & Robbins, N. (1998).
Schoenbaum, G., & Roesch, M. (2005). Aging differentially alters forms of long-term
Orbitofrontal cortex, associative learning, potentiation in rat hippocampal area CA1.
and expectancies. Neuron, 47, 633636. Journal of Neurophysiology, 79, 334341.
Schoenbaum, G., Setlow, B., Nugent, S. L., Shulman, G. L., Astafiev, S. V., Franke,
Saddoris, M. P., & Gallagher, M. (2003). D., Pope, D. L., Snyder, A. Z., McAvoy,
Lesions of orbitofrontal cortex and basolat- M. P., & Corbetta, M. (2009). Interaction of
eral amygdala complex disrupt acquisition of stimulus-driven reorienting and expecta-
odor-guided discriminations and reversals. tion in ventral and dorsal frontoparietal and
Learning and Memory, 10, 129140. basal ganglia-cortical networks. Journal of
Schoenbaum, G., Setlow, B., Saddoris, M. P., & Neuroscience, 29, 43924407.
Gallagher, M. (2006). Encoding changes in Shulman, G.L., Fiez, J.A., Corbetta, M., Buckner,
orbitofrontal cortex in reversal-impaired aged R.L., Miezin, F.M., Raichle, M.E.,& Petersen,
rats. Journal of Neurophysiology, 95, 15091517. S. E. (1997). Common blood flow changes
Schroeter, M. L., Raczka, K., Neumann, J., & across visual tasks: II Decreases in cerebral
von Cramon, D.Y. (2008). Neural networks in cortex. Journal of Cognitive Neuroscience, 9,
frontotemporal dementiaa meta-analysis. 648663.
Neurobiology of Aging, 29, 418426. Shulman, G. L., McAvoy, M. P., Cowan, M. C.,
Schultz, W. (2002). Getting formal with dopa- Astafiev, S. V., Tansy, A. P., dAvossa, G., &
mine and reward. Neuron, 36, 241263. Corbetta, M. (2003). Quantitative analysis of
Schultz, W. (2010). Dopamine signals for reward attention and detection signals during visual
value and risk:Basic and recent data. Behavior search. Journal of Neurophysiology, 90, 33843397.
and Brain Function, 6, 24. Siddall, O. M. (2005). Use of methylpheni-
Schultz, W., Dayan, P., & Montague, P. (1997). date in traumatic brain injury. Annals of
A neural substrate of prediction and reward. Pharmacotherapy, 39, 13091313.
Science, 275, 15931599. Skinner, J. E., & Yingling, C. D. (1977). Central
Schumacher, E.H., Lauber, E., Awh, E., Jonides, gating mechanisms that regulate event-related
J., Smith, E. E., & Koeppe, R. A. (1996). PET potensials and behavior. Progress in Clinical
evidence for an amodal verbal working mem- Neurophysiology, 1, 3069.
ory system. Neuroimage, 3, 7988. Smith, E.E., Jonides, J.,& Koeppe, R.A. (1996).
Schwartz, M.L.,& Goldman-Rakic, P.S. (1984). Dissociating verbal and spatial working
Callosal and intrahemispheric connectivity memory using PET. Cerebral Cortex, 6, 1120.
of the prefrontal association cortex in rhesus Snowdon, D.A., Greiner, L.H., Mortimer, J.A.,
monkey: Relation between intraparietal and Riley, K. P., Greiner, P. A., & Markesbery,
principal sulcal cortex. Journal of Comparative W. R. (1997). Brain infarction and the clini-
Neurology, 226, 403420. cal expression of Alzheimer disease. The
Seeley, W. W., Crawford, R., Rascovsky, K., Nun Study. Journal of the American Medical
Kramer, J. H., Weiner, M., Miller, B. L., & Association, 277, 813817.
Gorno-Tempini, M.L. (2008). Frontal paralim- Spreng, R. N., Mar, R. A., & Kim, A. S. (2009).
bic network atrophy in very mild behavioral The common neural basis of autobiographi-
variant frontotemporal dementia. Archives of cal memory, prospection, navigation, theory
Neurology, 65, 249255. of mind, and the default mode: A quanti-
Seeley, W. W., Menon, V., Schatzberg, A. F., tative meta-analysis. Journal of Cognitive
Keller, J., Glover, G.H., Kenna, H.,...Greicius, Neuroscience, 21, 489510.
M.D. (2007). Dissociable intrinsic connectiv- Starkstein, S. E., Mayberg, H. S., Preziosi, T. J.,
ity networks for salience processing and Andrezejewski, P., Leiguarda, R.,& Robinson,
106 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
Dopamine transporters decrease with age. the dysexecutive syndrome. Suffolk, UK:Thames
Journal of Nuclear Medicine, 37, 554559. Valley Test Company.
Voytek, B., Davis, M., Yago, E., Barcelo, F., Vogel, Wilson, F. A. W., & OScalaidhe, S. P. (1993).
E.K.,& Knight, R.T. (2010). Dynamic neuro- Dissociation of object and spatial processing
plasticity after human prefrontal cortex dam- domains in primate prefrontal cortex. Science,
age. Neuron, 68, 401408. 260, 19551958.
Wager, T.D.& Smith, E.E. (2003). Neuroimaging Woods, S. P., & Troster, A. I. (2003). Prodromal
and working memory: A metaanalysis. frontal/executive dysfunction predicts incident
Cognitive, Affective, and Behavioral Neuroscience, dementia in Parkinsons disease. Journal of the
3, 255274. International Neuropsychology Society, 9, 1724.
Wagner, A.D., Maril, A., Bjork, R.A.,& Schacter, Wozniak, R.H.,& Jackson, J.H. (1999). Evolution
D.L. (2001). Prefrontal contributions to exec- and dissolution of the nervous system. Classics
utive control: fMRI evidence for functional in psychology, 1855-1941: Historical essays.
distinctions within lateral Prefrontal cortex. London, UK:Thoemes Continum.
NeuroImage, 14, 13371347. Yeo, B. T., Krienen, F. M., Sepulcre, J.,
Walker, M. P., Ayre, G. A., Cummings, J. L., Sabuncu, M. R., Lashkari, D., Hollinshead,
Wesnes, K., McKeith, I. G., OBrien, J. T., & M.,...Buckner, R. L. (2011). The organiza-
Ballard, C.G. (2000). Quantifying fluctuation tion of the human cerebral cortex estimated
in dementia with Lewy bodies, Alzheimers by intrinsic functional connectivity. Journal of
disease, and vascular dementia. Neurology, Neurophysiology, 106, 11251165.
54, 16161625. Yerkes, R. M., & Dodson, J. D. (1908). The
Walton, M.E., Devlin, J.T.,& Rushworth, M.F. relation of strength of stimulus to rapidly
(2004). Interactions between decision mak- of habit-formation. Journal of Comparative
ing and performance monitoring within Neurology and Psychology, 18, 459482.
prefrontal cortex. Nature neuroscience, 7(11), Yesavage, J. A., Friedman, L., Ashford, J. W.,
12591265. Kraemer, H. C., Mumenthaler, M. S., Noda,
Wang, M., Gamo, N.J., Yang, Y., Jin, L.E., Wang, A., & Hoblyn, J. (2008). Acetylcholinesterase
X. J., Laubach, M.,...Arnsten, A. F. (2011). inhibitor in combination with cognitive train-
Neuronal basis of age-related working mem- ing in older adults. Journal of Gerontology
ory decline. Nature, 476, 210213. B:Psychological Sciences and Social Sciences, 63,
Weintraub, D.,& Stern, M.B. (2005). Psychiatric 288294.
complications in Parkinson disease. American Yoshida, W., & Ishii, S. (2006). Resolution of
Journal of Geriatric Psychiatry, 13, 844851. uncertainty in prefrontal cortex. Neuron, 50,
West, R.L. (1996). An application of prefrontal 781789.
cortex function theory to cognitive aging. Zaghloul, K. A., Blanco, J. A., Weidemann,
Psychological Bulletin, 120, 272292. C.T., McGill, K., Jaggi, J.L., Baltuch, G.H.,&
Whyte, J., Hart, T., Vaccaro, M., Grieb-Neff, Kahana, M. J. (2009). Human substantia
P., Risser, A., Polansky, M., & Coslett, nigra neurons encode unexpected financial
H. B. (2004). Effects of methylphenidate rewards. Science, 323, 14961499.
on attention deficits after traumatic brain Zanto, T.P.,& Gazzaley, A. (2009). Neural sup-
injury: A multidimensional, randomized, pression of irrelevant information under-
controlled trial. American Journal of Physical lies optimal working memory performance.
Medicine and Rehabilitation, 83, 401420. Journal of Neuroscience, 29, 30593066.
Wickelgren, I. (1997). Getting the brains atten- Zgaljardic, D. J., Borod, J. C., Foldi, N. S., &
tion. Science, 278, 3537. Mattis, P. (2003). A review of the cogni-
Wilens, T. E., Biederman, J., Spencer, T. J., & tive and behavioral sequelae of Parkinsons
Prince, J. (1995). Pharmacotherapy of adult disease: Relationship to frontostriatal cir-
attention deficit/hyperactivity disorder: cuitry. Cognitive and Behavioral Neurology, 16,
Areview. Journal of Clinical Psychopharmacology, 193210.
15, 270279. Zhang, L., Plotkin, R. C., Wang, G., Sandel,
Williams, G.V.,& Goldman-Rakic, P.S. (1995). M.E.,& Lee, S. (2004). Cholinergic augmen-
Modulation of memory fields by dopamine tation with donepezil enhances recovery in
D1 receptors in prefrontal cortex. Nature, 376, short-term memory and sustained atten-
572575. tion after traumatic brain injury. Archives
Wilson, B., Alderman, N., Burgess, P., Emsile, of Physical Medicine and Rehabilitation, 85,
H.,& Evans, J. (1996). Behavioral assessment of 10501055.
4
Memory problems are the most common A greater understanding of these memory
issue that patients and families mention systems will aid clinicians in their diagno-
when coming to see a clinician for what turns sis and treatment of the memory disorders
out to be dementia. Memory dysfunction can of their patients. Accurate diagnosis will
be due to almost any type of neurodegenera- become more important as new therapeutic
tive disease, as well as by a diverse group of interventions for underlying causes of mem-
disorders, including strokes, tumors, head ory impairment or dementia are developed.
trauma, hypoxia, cardiac surgery, malnutri- A memory system can be thought of as a
tion, attention-deficit/hyperactivity disorder, mechanism by which the brain processes
depression, anxiety, and medication effects information so that it is available for use
(Budson & Solomon, 2011; Mesulam, 2000; at a later time (Schacter & Tulving, 1994).
Newman, Carpenter, Varma, & Just, 2003). Some systems are associated with conscious
Memory function can also be altered by nor- awareness (explicit) and can be recalled ver-
mal aging. Although once thought to be a bally (declarative), whereas others are typi-
simple concept, we now consider memory to cally unconscious (implicit) and are instead
be a collection of cognitive processes that are expressed by a change in behavior (nonde-
subserved by several major neural systems. clarative; Squire, 1992). Memory can also be
Memory research, which began with neuro- categorized in other ways, such as whether
psychological studies of patients with focal the material to be remembered is verbal
brain lesions using pencil and paper and now (Wagner et al., 1998) or visual (Ally, 2012;
relies on sophisticated neuroscientific meth- Brewer, Zhao, Desmond, Glover, & Gabrieli,
ods such as positron emission tomography, 1998).
functional magnetic resonance imaging, and
event-related potentials, has provided the
rationale for a more refined and improved Episodic Memory
classification system (Schacter, Wagner, &
Buckner, 2000). In this chapter a number of Episodic memory is the explicit and declara-
different types of memory will be reviewed, tive memory system used to remember a par-
including the important anatomical struc- ticular episode of life, such as sharing a meal
tures for each and the major neurological dis- with a friend on a specific date. This mem-
orders that disrupt them (Tables4.1 and 4.2). ory system is dependent upon the medial
108
TABLE4.1 Selected Memory Systems
Memory System Examples Awareness Length of Storage Major Anatomical Structures
Episodic memory Remembering a short story, what you had for Explicit Minutes to years Medial temporal lobe, anterior thalamic
dinner last night, and what you did on your Declarative nucleus, mamillary body, fornix,
last birthday prefrontal cortex
Semantic memory Knowing who was the first President of the Explicit Minutes to years Inferior lateral temporal lobes
United States, the color of a lion, and how a Declarative
fork and comb are different
Autonomic simple classical Pavlovs dog; a fear response Implicit Minutes to years Amygdala and basolateral limbic system
conditioning Nondeclarative
Motoric simple classical Eye-blink conditioning Implicit Minutes to months Cerebellum
conditioning Nondeclarative
Procedural memory Driving a standard transmission car, and Implicit Minutes to years Basal ganglia, cerebellum, supplementary
learning the sequence of numbers on a Nondeclarative motor area
touch-tone phone without trying
Perceptual priming Word-stem completion:octopusoct____ Implicit Minutes to days Cortical sensory association areas (e.g.,
Nondeclarative extrastriate visual cortex for visual
perceptual priming)
Conceptual priming Word-stem completion:sea creaturesoct____ Implicit Minutes to days Inferior prefrontal cortex
Nondeclarative
Working memory Phonological:keeping a phone number in your Explicit Seconds to minutes; Phonological:prefrontal cortex, Brocas area,
head before dialing Declarative information Wernikes area.
Spatial:mentally following a route, or rotating actively rehearsed Spatial:Prefrontal cortex, visual association
an object in your mind or manipulated areas
110 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
+++, Early and severe impairment; ++, moderate impairment; +, mild impairment; , occasional impairment or impair-
ment in some studies but not others;, no significant impairment; ?, unknown.
temporal lobes (including the hippocampus); pattern known as Ribots law. Starting with
episodic memory has been largely defined the onset of the injury to the brain, there is
by what patients with medial temporal lobe greatest disruption in the ability to learn new
lesions cannot remember relative to healthy information (anterograde amnesia), moder-
individuals. Other critical structures in the ate disruption in the ability to recall recently
episodic memory system (some of which are learned information (retrograde amnesia),
associated with a circuit described by Papez and the ability to recall remotely learned
in 1937)include the basal forebrain with the information is generally intact (Fig. 4.2;
medial septum and diagonal band of Brocas Ribot, 1881).
area, the retrosplenial cortex, the presubicu- The core of the episodic memory system
lum, the fornix, mammillary bodies, the is the hippocampus and other regions of the
mammillothalamic tract, and the anterior medial temporal lobe. It is worth examining
nucleus of the thalamus (Fig.4.1) (Mesulam, these structures more closely. The medial
2000). Alesion in any one of these structures temporal lobes are neuroanatomically com-
may cause dysfunction of the episodic mem- plex structures with multiple regions and
ory system. subregions. Figure4.3 shows the medial tem-
Memory loss due to dysfunction of the poral lobe structures, including the parahip-
episodic memory system generally follows a pocampal gyrus, presubiculum, subiculum,
Figure4.1 Episodic memory. The medial temporal lobes, including the hippocampus and
parahippocampus, form the core of the episodic memory system. Other brain regions are also
necessary for episodic memory to function correctly. In addition to being involved in episodic
memory, the amygdala is also important for the autonomic conditioning. (From Budson and Price,
2005; permission granted by the New England Journal of Medicine)
and hippocampus proper, including its Typically memories are retrieved when a
subregions. cue from the environment matches a part of
Although exactly how the medial tempo- the stored memory. Continuing our breakfast
ral lobes store and retrieve memories is still example, years later the individual might
an active area of research, our current under- now bite into a little cookie that tastes remark-
standing from cognitive neuroscience is as ably like the one that she had previously at
follows. An individual experiences an epi- lunch. This sensory cue is transferred from
sode of her life, such as having lunch that day. the cortex to the parahippocampal region
The cortically distributed patterns of neu- and to the hippocampus (Fig.4.4). After the
ral activity representing the sights, sounds, cue is transferred from the entorhinal cor-
smells, tastes, emotions, and thoughts during tex, it goes directly to the CA3 region, where
that episode are transferred first to the para- the original hippocampal index is retrieved
hippocampal region (including perirhinal (Fig. 4.6). The hippocampal index may be
and parahippocampal cortex), then to the used to retrieve much of the original pattern
entorhinal cortex, and then to the hippocam- of the neural activity representing the origi-
pus proper, specifically the dentate gyrus, nal episode stored in memory. This retrieved
where the disparate threads of experience are pattern of activity may then be transferred
bound together as a single memory (Fig.4.4) to the CA1 region, the subiculum, the ento-
(Wolosin, Zeithamova, & Preston, 2012). This rhinal cortex, and then back out to the cor-
bound information is then transferred to the texactively re-creating all of sights, sounds,
CA3 region, where it is further processed smells, tastes, emotions, and thoughts of the
(Fig. 4.5). It is in this CA3 region where the original memory episode (Fig.4.4).
critically important hippocampal index is The hippocampus remains critical for
assigned, allowing the memory to be stored memory retrieval until a process known
in a unique way so that it can later be recalled. as consolidation occurs. Much research still
112 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
CA2 E cf
CA3
S
V ML GL PL
CAI PrS
PaS
PHG
Cos
Figure4.3 Detailed anatomy of the medial temporal lobe. PHG, parahippocampal gyrus; Pr,
presubiculum; v, ventricle; S, subiculum. CA1, CA2, and CA3 are subregions of the hippocampus,
and ML, GL, and PL are different regions of the dentate gyrus of the hippocampus. (From
MartinJH. Neuroanatomy:Text and Atlas. NewYork, NY.:Elsevier, 1989, p.391; permission granted
by Elsevier)
Entorhinal cortex
Unique
index
Hippocampus assigned
Parahippocampal
region Dentate gyrus CA3
Cerebral
cortex
Hilus
Figure4.5 Schematic of encoding in the medial
temporal lobe.
Entorhinal cortex Subiculum first floor, and it was a happy day. From this
distributed pattern of neural activity a hip-
pocampal index can be formed that helps
one remember that the car was parked in
the green area, on the first floor, and halfway
down the aisle on the left (Fig.4.7A). On the
second day the car is parked in the yellow
area, on the second floor, and it was a sad
day. Nonetheless, this distinct pattern of
Dentate gyrus CA3 CA1 neural activity allows a unique hippocampal
Figure4.6 Schematic of retrieval in the medial index to form that enables one to remember
temporal lobe. that the car was parked in the yellow area,
on the second floor, and halfway down the
this imaginary parking garage there are two aisle on the right (Fig.4.7B). On the third day
areas, green and yellow, and two levels, first the car is also parked in the yellow area, on
and second. Two affective states, happy and the second floor, and it again was a sad day
sad, are also shown to represent not only (Fig. 4.7C). Although one might wish that
emotions but other contextual details that a hippocampal index will form to enable
may differ between days. On the first day one to remember that the car was parked in
the car is parked in the green area, on the the in the yellow area, on the second floor,
(A) Green Yellow 1 2 happy sad (B) Green Yellow 1 2 happy sad
way down, way down, All way down, way down, way down, right
on left on right on left on left OR All way down, left
Figure4.7 Aneural network model of episodic memory. (A)On the first day, a hippocampal index
helps one remember that the car is parked in the Green area, on the 1st floor, and it was a happy
day. (B)On the second day, a unique hippocampal index indicates that the car is parked in the
Yellow area, on the 2nd floor, and it was a sad day. (C)On the third day, the car is also parked in
the Yellow area, on the 2nd floor, and it again was a sad day. (D)There is a single hippocampal
index that forms for both days two and three. This hippocampal index is strengthened for the
common aspects of the two memories:parking in the Yellow area, on the 2nd floor. But this index
also contains divergent aspects of the memory:half-way down the aisle on the right and all the way
down the aisle on the left. Thus, on day three it is easy to remember that the car is parked in the
Yellow area on the 2nd floor, but it is difficult to remember if it is parked half-way down the aisle on
the right or all the way down the aisle on the left.
114 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
and all the way down the aisle on the left, TABLE4.3 AFiling Analogy of Episodic
there is a problem. When there are com- Memory
pletely overlapping patterns of neural activ-
Brain Structure Analogy
ity, a separate hippocampal index cannot
form. Instead, there is a single hippocam- Frontal lobes File clerk
pal index that forms for both days two and Medial temporal lobes Recent memory files
three (Fig.4.7D). This hippocampal index is Other cortical regions Remote memory files
strengthened for the common aspects of the
two memories:parking in the yellow area, on
the second floor. But this index also contains
divergent aspects of the memory: halfway remembering that someone broke into the
down the aisle on the right and all the way house and rearranged household items.
down the aisle on the left. Thus, on day three A useful analogy can help conceptualize
it is easy to remember that the car is parked the dysfunction in episodic memory that
in the yellow area on the second floor, but it occurs due to damage to the medial tempo-
is difficult to remember whether it is parked ral lobes (and Papezs circuit) versus dam-
halfway down the aisle on the right or all the age to the frontal lobes (Budson & Price,
way down the aisle on the left. 2002, 2005) (Table 4.3). The frontal lobes
In addition to the medial temporal lobes are the file clerk of the episodic memory
and Papezs circuit, the frontal lobes are system, the medial temporal lobes are the
also important for episodic memory (Ally, recent memory file cabinet, and other
McKeever, Waring, & Budson, 2009; Fletcher cortical regions are the remote memory
& Henson, 2001; Simons & Spiers, 2003). file cabinet (Fig. 4.8). Thus, if the frontal
Whereas the medial temporal lobes are lobes are impaired, it is difficultbut not
critical for the retention of information, the impossibleto get information in and out of
frontal lobes are important for the acquisi- storage. Placing new information into storage
tion, registration, or encoding of information may require stronger encoding, and retriev-
(Wagner et al., 1998); the retrieval of infor- ing information from storage may require
mation without contextual and other cues stronger cues from the environment. When
(Petrides, 2002); the recollection of the source the frontal lobes are impaired, the informa-
of information (Johnson, Kounios, & Nolde, tion stored in memory may also be distorted
1997); and the assessment of the temporal due to improper filing that leads to an
sequence and recency of events (Kopelman, inaccurate source, context, or sequence. If the
Stanhope, & Kingsley, 1997). It is also notable medial temporal lobes are impaired, on the
that the left medial temporal and left frontal other hand, it may be impossible for recent
lobes are most active when a person is learn- information to be stored. This will often lead
ing words (Wagner etal., 1998), and that the to the patient asking for the same informa-
right medial temporal and right frontal lobes tion again and againperhaps a dozen times
are most active when learning visual scenes in an hour. Older information that has been
(Brewer etal., 1998). consolidated over months to years is likely
In episodic memory the frontal lobes stored in other cortical regions and will there-
enable the individual to focus attention fore be available for retrieval even when the
on the information to be remembered medial temporal lobes or Papezs circuit are
and to engage the medial temporal lobes. damaged. To illustrate this analogy, we can
Dysfunction of the frontal lobes may cause a compare the episodic memory dysfunction
number of memory problems, including dis- attributable to depression versus Alzheimers
tortions of episodic memory and false mem- disease. Patients with depression have a dys-
ories, such as when information becomes functional file clerk, whereas patients with
associated with the wrong context (Johnson, Alzheimers disease have a dysfunctional
OConnor, & Cantor, 1997) or incorrect spe- recent memory file cabinet.
cific details (Budson et al., 2002). Extreme Recent evidence has suggested that the
memory distortions are often synonymous parietal lobes also play an important role in
with confabulations:Memories are created episodic memory (Dulas & Duarte, 2013). In
to be consistent with current information fact, in functional imaging studies the pari-
(Johnson, OConnor, & Cantor, 1997), such as etal lobes are more frequently associated
CHAPTER 4. MEMORY SYSTEMS IN DEMENTIA115
to be suffering from a memory distortion or that assist in retrieval, such as cued recall and
a false memory than a true hallucination. recognition, are used.
The same is true for the patient who claims Patients with frontotemporal dementia
that people are breaking into the house and often show no impairment in episodic mem-
moving around things. That these symptoms ory until late in the disease. If they do dem-
likely represent memory distortions rather onstrate early episodic memory impairment,
than true hallucinations or delusions has it is generally that of a frontal memory disor-
implications when it comes time for treat- der, similar to that of a patient with vascular
ment; that is, memory distortions are best dementia. Many other dementias also affect
treated with memory-enhancing medications the frontal lobes and thus may also lead to
(such as cholinesterase inhibitors) rather than a frontal episodic memory disorder. These
antipsychotic medications. dementias include progressive supranu-
Although not as impaired as medial tem- clear palsy, corticobasal degeneration, mul-
poral lobes, the frontal lobes are involved tiple system atrophy, and normal pressure
in both Alzheimers disease and mild cog- hydrocephalus.
nitive impairment (Dickerson et al., 2009;
Koivunen et al., 2012). Frontal lobe dys-
function may be one reason that patients Semantic Memory
with Alzheimers disease experience mem-
ory distortions and false memories. That Semantic memory refers to our store of con-
they show frontal lobe dysfunction also ceptual and factual knowledge that is not
means that, in addition to a major impair- related to any specific memory, such as the
ment with their file cabinet, patients color of broccoli or what a fork is used for.
with Alzheimers disease also show milder Like episodic memory, semantic memory is
but definite impairment with their file an explicit and declarative memory. Evidence
clerk as well. Additionally, patients with that semantic memory and episodic memory
Alzheimers disease have major pathology are separate memory systems has come from
in parietal cortex, and this pathology may both neuroimaging studies (Schacter et al.,
occur quite early in the disease (McKee 2000) and the fact that previously acquired
etal., 2006). Thus, although the medial tem- semantic memory is spared in patients who
poral lobe pathology is most relevant in the have severe impairment of the episodic
majority, patients with Alzheimers disease memory system, such as with disruption
have multiple components impaired in their of Papezs circuit or surgical removal of the
episodic memory system. medial temporal lobes (Corkin, 1984).
As vascular dementia is dementia due to In its broadest sense, semantic memory
multiple strokes, whether a patient experi- includes all our knowledge of the world not
ences episodic memory dysfunction and of related to any specific episodic memory. It
what quality depends upon the size, number, could therefore be argued that semantic mem-
and location of the cerebrovascular disease. ory resides in multiple cortical areas through-
However, the most common type of vascular out the brain. For example, there is evidence
dementia is that due to small vessel ischemic that visual images are stored in nearby visual
disease. Because small vessel ischemic disease association areas (Vaidya, Zhao, Desmond,
has a predilection for the subcortical white & Gabrieli, 2002). A more restrictive view
matter, and because most of the white matter of semantic memory justified in light of the
in the brain is carrying neural signals going to naming and categorization tasks by which it
or from the frontal lobes, patients with vascu- is usually tested, however, localizes seman-
lar dementia experience a frontal memory tic memory to the inferolateral temporal
disorder. In other words, because their fron- lobes (Fig. 4.9; Damasio, Grabowski, Tranel,
tal lobes are not working (or are not properly Hichwa, & Damasio, 1996; Perani etal., 1999).
connected to the rest of the brain), they show The most common clinical disorder disrupt-
impairment in the file clerk component of ing semantic memory is Alzheimers disease
episodic memory. Consequently encoding is (Gardini etal., 2013). This disruption may be
often impaired, as is free recall, whereas rela- due to pathology in the inferolateral temporal
tive preservation is typically seen when tasks lobes (Price & Morris, 1999) or to pathology
CHAPTER 4. MEMORY SYSTEMS IN DEMENTIA117
Supplementary
motor area
Basal ganglia
(putamen)
Prefrontal
cortex
Inferolateral
temporal lobe
Cerebellum
Semantic memory
Procedural memory
Working memory
Figure 4.9 Semantic, Procedural, and Working Memory. The inferolateral temporal lobes are
important in the naming and categorization tasks by which semantic memory is typically assessed.
However, in the broadest sense, semantic memory may reside in multiple and diverse cortical areas
that are related to various types of knowledge. The basal ganglia, cerebellum, and supplementary
motor area are critical for procedural memory. The prefrontal cortex is active in virtually all working
memory tasks; other cortical and subcortical brain regions will also be active, depending on the type
and complexity of the working memory task. In addition to being involved in procedural memory,
the cerebellum is also important for the motoric conditioning. (From Budson and Price, 2005;
permission granted by the New England Journal of Medicine.) (See color plate section)
in frontal cortex (Lidstrom etal., 1998), lead- older adults, naming difficulties may also
ing to poor activation and retrieval of seman- be a sign of a disorder of semantic memory.
tic information (Balota, Watson, Duchek, & When a disorder of semantic memory is
Ferraro, 1999). Supporting the idea that two suspected, the evaluation should include
separate memory systems are impaired in the same components as the workup for
Alzheimers disease, episodic and semantic episodic memory disorders. One of the first
memory decline independently of each other aspects of the history and cognitive exami-
in this disorder (Green & Hodges, 1996). nation that should be ascertained is whether
Almost any disorder that can disrupt the problem is solely one of difficulty in
the inferolateral temporal lobes may cause recalling peoples names and other proper
impairment of semantic memory, including nouns (common in healthy older adults)
traumatic brain injury, stroke, surgical lesions, or to a true loss of semantic information.
encephalitis, and tumors (Table4.2). Patients Patients with mild dysfunction of semantic
with semantic dementia (the temporal vari- memory may show only reduced generation
ant of frontotemporal dementia) exhibit defi- of words in a semantic category (e.g., the
cits in all functions of semantic memory, such number of grocery items that can be gener-
as naming, single-word comprehension, and ated in 1 minute), whereas patients with a
impaired general knowledge (such as the more severe impairment of semantic mem-
color of common items) (Hoffman, Meteyard, ory usually show a two-way naming defi-
& Patterson, 2012). Other aspects of cog- cit: They are unable to name an item when
nition, however, are relatively preserved, it is described, and they are also unable to
including components of speech, perceptual describe an item when it is named. General
and nonverbal problem-solving skills, and knowledge is also impoverished in these
episodic memory (Hodges, 2001). more severely affected patients. Treatment
Although naming difficulties (particularly will depend upon the specific disorder
with proper nouns) are common in healthy identified.
118 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
memory. Patients with major depression also regions involved in processing of sensory
show impairment in procedural memory information are important for perceptual
tasks, perhaps because depression involves priming. A patient with bilateral occipital
dysfunction of the basal ganglia (Sabe Jason, lobe lesions demonstrated normal episodic
Juejati, Leiguarda, & Starkstein, 1995). memory and conceptual priming while fail-
Disruption of procedural memory should ing to show perceptual priming (Keane,
be suspected when patients show evidence Gabrieli, Mapstone, Johnson, & Corkin,
of either substantial difficulties in learning 1995). Neuroimaging studies of visual
new skills (compared to their baseline) or the perceptual priming using positron emis-
loss of previously learned skills. For example, sion tomography and functional magnetic
patients may lose the ability to perform auto- resonance imaging show changes in activa-
matic, skilled movements, such as writing, tion of visual peristriate cortex (Schacter&
swinging a tennis racket, or playing a musi- Buckner, 1998). By contrast, neuroimaging
cal instrument. Although these patients may studies of conceptual priming typically
be able to relearn the fundamentals of these show changes in left prefrontal regions
skills, explicit thinking becomes required (Schacter & Buckner, 1998). Most studies
for their performance. As a result, patients have shown that patients with early degen-
with damage to the procedural memory erative diseases that do not affect the sensory
system lose the automatic, effortlessness of association cortices, such as Alzheimers,
simple motor tasks that healthy individuals Parkinsons, and Huntingtons diseases,
take for granted. The evaluation of disor- demonstrate normal perceptual priming
ders of procedural memory is similar to that (Koivisto, Portin, & Rinne, 1996). For con-
of disorders of episodic memory; treatment ceptual priming, however, many (but not
depends upon the specific disease process. all) studies have found these groups to be
Lastly, it is worth noting that patients whose impaired (Heindel et al., 1989; Millet, Le
episodic memory has been devastated by a Goff, Bouisson, Dartigues, & Amieva, 2010).
static disorder, such as encephalitis, have
had successful rehabilitation by using pro-
cedural memory (and other nondeclarative Working Memory
forms of memory) to learn new skills (Glisky
& Schacter, 1989). Bringing together the traditional fields of
attention, concentration, and short-term
memory, working memory refers to the
Priming ability to temporarily maintain and manip-
ulate information that one needs to keep in
Priming occurs when a prior encounter with mind. Requiring active and conscious par-
a particular item changes the response to the ticipation, working memory is an explicit
current item (Table 4.1). Because this phe- and declarative memory system. Working
nomenon occurs even if the individual does memory has traditionally been divided into
not consciously remember encountering the three components: one that processes pho-
prior item, priming is another example of an nologic information (e.g., keeping a phone
implicit and nondeclarative form of memory. number in your head), one that processes
Priming is often divided into perceptual prim- spatial information (e.g., mentally follow-
ing, which is modality specific (e.g., auditory, ing a route), and an executive system that
visual) and does not benefit from elaborate allocates attentional resources (Baddeley,
encoding at study, versus conceptual priming, 1998).
which is not modality specific and shows Studies have demonstrated that working
enhancement with increased encoding. memory involves a network of cortical and
Perceptual priming depends upon a per- subcortical areas, which differ depending
ceptual representation system, involved in on the particular task (Borst & Anderson,
processing information regarding the form 2013; Rowe, Toni, Josephs, Frackowiak, &
and structure of items but not their mean- Passingham, 2000). Participation of the pre-
ings (Tulving & Schacter, 1990). Converging frontal cortex, however, is involved in vir-
evidence suggests that posterior cortical tually all working memory tasks (Fig. 4.9;
120 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
Fletcher & Henson, 2001). The network Disorders of working memory may present
of cortical and subcortical areas typically in several different ways. Often the patient
includes posterior brain regions (e.g., visual will exhibit an inability to concentrate or pay
association areas) that are linked with pre- attention. Impairment in performing a new
frontal regions to form a circuit. Research task with multistep instructions is frequently
suggests that spatial working memory tends seen. Interestingly, a disorder of working
to involve more regions on the right side, memory may also present as a problem with
and phonologic working memory tends to episodic memory because information must
involve more regions on the left side of the first be kept in mind by working memory
brain. Bilateral brain activation is observed, in order for episodic memory to encode it
however, in more difficult working memory (Fletcher & Henson, 2001). Such cases will
tasks, regardless of the nature of the mate- therefore show a primary impairment in
rial being processed (Newman et al., 2003). encoding.
Additionally, an increase in the number of The evaluation of disorders of working
brain regions activated in prefrontal cortex memory is similar to that of disorders of epi-
is observed as the complexity of the task sodic memory. Treatment depends upon the
increases (Jaeggi etal., 2003). underlying cause. Stimulants, approved by
Because working memory depends upon the FDA for the treatment of attention-deficit/
networks which include frontal and pari- hyperactivity disorder (Mehta, Goodyer, &
etal cortical regions as well as subcortical Sahakian, 2004), are often helpful in disor-
structures, most neurodegenerative diseases ders of working memory.
impair working memory. Studies have
demonstrated that working memory may
be impaired in patients with Alzheimers Improving Memory in Dementia
disease, Parkinsons disease, Huntingtons
disease, and dementia with Lewy bodies Nonpharmacological treatments are invalu-
(Schneider et al., 2012), as well as less com- able and can often help improve and/or pre-
mon disorders such as progressive supra- serve daily function as much as medications.
nuclear palsy (Table 4.2; Calderon et al., Almost all of us use some type of external
2001; Gotham, Brown, & Marsden, 1988). system or device to enhance memory. Lists,
In fact, even prior to the onset of clinical calendars, date and address books, smart
symptoms, Alzheimers disease and vas- phones, and iPads can help patients with
cular pathology can lead to impairment in mild to moderate Alzheimers disease in
working memory (Bennett, Wilson, Boyle, addition to healthy individuals. Participating
Buchman, & Schneider, 2012). In addition in social activities has been shown to reduce
to these neurodegenerative diseases, almost apathy and improve mood, memory, and
any disease process that disrupts the frontal overall cognitive function. Other strategies
lobes or their connections to posterior corti- that have been shown to improve memory
cal regions and subcortical structures can include using habits, pictures, strategies, and
interfere with working memory. Such pro- participating in aerobic exercise.
cesses include tumors, strokes, multiple scle- Habit can compensate for poor memory.
rosis, head injury, and others (Kubat-Silman, Although patients with Alzheimers dis-
Dagenbach, & Absher, 2002; Sfagos et al., ease have great difficulty in remembering
2003). Because it involves the silent rehearsal verbal instructions such as Please remem-
of verbal information, almost any type of ber to put your keys on the hall table, they
aphasia may impair phonologic working can learn to place them there through habit
memory. Disorders that diminish attentional as well as anyone. Learning through habit,
resources, including attention-deficit/hyper- sometimes called muscle memory and
activity disorder, obsessive-compulsive dis- formally classified as procedural memory,
order, depression, and schizophrenia, can is learning through doing. Because the brain
also impair working memory (Egeland etal., regions involved in procedural memory,
2003; Klingberg, Forssberg, & Westerberg, basal ganglia and cerebellum, are relatively
2002; Purcell, Maruff, Kyrios, & Pantelis, spared by Alzheimers disease, patients can
1998). learn to do tasks such as put their keys on
CHAPTER 4. MEMORY SYSTEMS IN DEMENTIA121
the hall table by doing the action or activity knowledge will become increasingly impor-
repetitively. tant (Budson& Solomon, 2011).
It is said that a picture is worth a thousand
words. Some of our research has shown that,
although memory is enhanced by pictures Acknowledgments
relative to words for young adults, this effect
of pictures is even greater for healthy older This work was supported by National
adults, greater still for patients with mild Institute on Aging grant P30 AG13846. This
cognitive impairment, and is the greatest for material is also the result of work supported
patients with Alzheimers disease (Embree with resources and the use of facilities at the
etal., 2012). This enhancement of memory for Veterans Affairs Boston Healthcare System,
pictures versus words in Alzheimers disease Boston, MA.
is likely attributable to increased attention to
pictures (over words), as well as the distinc- References
tiveness of pictures that makes them easier
to remember. We also may process a picture Ally, B.A. (2012). Using pictures and words to
once as an image and once as its meaning. understand recognition memory deteriora-
tion in amnestic mild cognitive impairment
Bottom line:Let the family know that instead
and Alzheimers disease: A review. Current
of simply telling the patient that his grand- Neurology and Neuroscience Reports, 12(6),
daughter will be visiting today, show him 687694.
her picture, and he will be more likely to Ally, B. A., McKeever, J. D., Waring, J. D., &
remember. Budson, A.E. (2009). Preserved frontal memo-
Another study we conducted explored rial processing for pictures in patients with
patients memory for statements that they mild cognitive impairment. Neuropsychologia,
were told were true versus statements that 47(10), 20442055.
they were told were false. We found that Ally, B.A., Simons, J.S., McKeever, J.D., Peers,
patients with Alzheimers disease correctly P.V., & Budson, A.E. (2008a). Parietal contri-
butions to recollection: Electrophysiological
remembered that the true statements were
evidence from aging and patients with pari-
true 69% of the time, but they also incor- etal lesions. Neuropsychologia, 46(7), 18001812.
rectly remembered that the false statements Aly, M., & Moscovitch, M. (2010). The effects
were true 59% of the timemore than half of sleep on episodic memory in older and
(Mitchell, Sullivan, Schacter, & Budson, younger adults. Memory, 18(3), 327334.
2006). This result means that if you tell a Baddeley, A. D. (1998). Recent developments
patient with Alzheimers disease what not to in working memory. Current Opinion in
do, the patient will be more likely to think Neurobiology, 8:234238.
that he should do it than if you never said Balota, D. A., Watson, J. M., Duchek, J. M., &
anything at all. We therefore caution all of Ferraro, F. R. (1999). Cross-modal seman-
tic and homographic priming in healthy
our families to only tell their loved ones
young, healthy old, and in Alzheimers dis-
what they should do, not what they should ease individuals. Journal of the International
not do. It is one strategy that has been proven Neuropsychological Society, 5, 626640.
to work. Beaunieux, H., Eustache, F., Busson, P., de
la Sayette, V., Viader, F., & Desgranges, B.
(2012). Cognitive procedural learning in early
Conclusion Alzheimers disease: Impaired processes
and compensatory mechanisms. Journal of
When patients come to the clinic because of Neurophysiology, 6(1), 3142.
cognitive impairment, the complaint from Bechara, A., Tranel, D., Damasio, H., Adolphs,
patients and families is typically that of R., Rockland, C., & Damasio, A. R. (1995).
Double dissociation of conditioning and
memory loss. Understanding exactly which
declarative knowledge relative to the amyg-
memory system is impaired will lead to dala and hippocampus in humans. Science,
a more accurate diagnosis of the patients 269, 115118.
disorder. As more specific therapeutic strat- Bennett, D. A., Wilson, R. S., Boyle, P. A.,
egies are developed for the treatment of dis- Buchman, A. S., & Schneider, J. A. (2012).
eases that cause memory dysfunction, this Relation of neuropathology to cognition
122 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
in persons without cognitive impairment. Daselaar, S.M., Rombouts, S.A., Veltman, D.J.,
Annals of Neurology, 72(4), 599609. Raaijmakers, J.G., & Jonker, C. (2003). Similar
Berryhill, M. E., & Olson, I. R. (2008). Is the network activated by young and old adults
posterior parietal lobe involved in work- during the acquisition of a motor sequence.
ing memory retrieval? Evidence from Neurobiology of Aging, 24, 10131019.
patients with bilateral parietal lobe damage. Davidson, P.S., Anaki, D., Ciaramelli, E., Cohn,
Neuropsychologia, 46(7), 17751786. M., Kim, A. S., Murphy, K. J.,...Levine, B.
Borst, J. P., & Anderson, J. R. (2013). Using (2008). Does lateral parietal cortex support
model-based functional MRI to locate work- episodic memory? Evidence from focal lesion
ing memory updates and declarative mem- patients. Neuropsychologia, 46(7), 17431755.
ory retrievals in the fronto-parietal network. Dickerson, B.C., Bakkour, A., Salat, D.H., Feczko,
Proceedings of the National Academy of Science E., Pacheco, J., Greve, D.N.,...Buckner, R.L.
USA, 110(5), 16281633 (2009). The cortical signature of Alzheimers
Brewer, J. B., Zhao, Z., Desmond, J. E., Glover, disease: Regionally specific cortical thinning
G. H., & Gabrieli, J. D. (1998). Making relates to symptom severity in very mild
memories: Brain activity that predicts how to mild AD dementia and is detectable in
well visual experience will be remembered. asymptomatic amyloid-positive individuals.
Science, 281, 11851187. Cerebral Cortex, 19(3), 497510.
Budson, A. E., & Price, B. H. (2002). Dimitrova, A., Weber, J., Maschke, M., Elles,
Memory: Clinical disorders. In: Encyclopedia H. G., Kolb, F. P., Forsting, M.,...Timmann,
of life sciences. Vol. 11. London: Nature D. (2002). Eyeblink-related areas in human
Publishing Group, 529536. cerebellum as shown by fMRI. Human Brain
Budson, A. E., & Price, B. H. (2005). Memory Mapping, 17, 100115.
dysfunction. New England Journal Medicine, Dulas, M.R., & Duarte, A. (2013). The influence
352, 692699. of directed attention at encoding on source
Budson, A. E., Simons, J. S., Waring, J. D., memory retrieval in the young and old: An
Sullivan, A.L., Hussoin, T., & Schacter, D.L. ERP study. Brain Research, 1500, 5571.
(2007). Memory for the September 11, 2001, Egeland, J., Sundet, K., Rund, B.R., Asbjrnsen,
terrorist attacks one year later in patients with A., Hugdahl, K., Landr, N.I.,...Stordal, K.I.
Alzheimers disease, patients with mild cog- (2003). Sensitivity and specificity of memory
nitive impairment, and healthy older adults. dysfunction in schizophrenia:Acomparison
Cortex, 43(7), 875888. with major depression. Journal of Clinical and
Budson, A. E., & Solomon, P. R. (2011). Experimental Neuropsychology, 25, 7993.
Memory loss: A practical guide for clinicians. Eichenbaum, H. (1997). How does the brain orga-
Philadelphia, PA:Elsevier. nize memories? Science, 277(5324), 330332.
Budson, A. E., Sullivan, A. L., Mayer, E., Embree, L. M., Budson, A. E., & Ally, B. A.
Daffner, K.R., Black, P.M., & Schacter. D.L. (2012). Memorial familiarity remains intact
(2002). Suppression of false recognition in for pictures but not for words in patients
Alzheimers disease and in patients with with amnestic mild cognitive impairment.
frontal lobe lesions. Brain, 125, 27502765. Neuropsychologia, 50(9), 23332340.
Cabeza, R. (2008). Role of parietal regions in epi- Fletcher, P.C., & Henson, R.N. A. (2001). Frontal
sodic memory retrieval:The dual attentional lobes and human memory: Insights from
processes hypothesis. Neuropsychologia, 46(7), functional neuroimaging. Brain, 124, 849881.
18131827. Gardini, S., Cuetos, F., Fasano, F., Pellegrini, F.F.,
Calderon, J., Perry, R. J., Erzinclioglu, S. W., Marchi, M., Venneri, A., & Caffarra, P. (2013).
Berrios, G.E., Dening, T.R., & Hodges, J.R. Brain structural substrates of semantic mem-
(2001). Perception, attention, and working ory decline in mild cognitive impairment.
memory are disproportionately impaired in Current Alzheimer Research, 10(4), 373389.
dementia with Lewy bodies compared with Glisky, E.L., & Schacter, D.L. (1989). Extending
Alzheimers disease. Journal of Neurology, the limits of complex learning in organic
Neurosurgery and Psychiatry, 70, 157164. amnesia: Computer training in a vocation
Corkin, S. (1984). Lasting consequences of bilat- domain. Neuropsychologia, 27, 173178.
eral medial temporal lobectomy: Clinical Gotham, A. M., Brown, R. G., & Marsden,
course and experimental findings in H. M. C.D. (1988). Frontal cognitive functions in
Seminars in Neurology, 4,249259. patients with Parkinsons disease on and
Damasio, H., Grabowski, T. J., Tranel, D., off levodopa. Brain, 111, 299321.
Hichwa, R. D., & Damasio, A. R. (1996). A Green, J.D., & Hodges, J.R. (1996). Identification
neural basis for lexical retrieval. Nature, 380, of famous faces and famous names in
499505. early Alzheimers disease. Relationship to
CHAPTER 4. MEMORY SYSTEMS IN DEMENTIA123
anterograde episodic and general semantic Koivisto, M., Portin, R., & Rinne, J. O. (1996).
memory. Brain, 119, 111128. Perceptual priming in Alzheimers and
Heindel, W. C., Salmon, D. P., Shults, C. W., Parkinsons diseases. Neuropsychologia, 34,
Walicke, P. A., & Butters, N. (1989). 449457.
Neuropsychological evidence for multiple Koivunen, J., Karrasch, M., Scheinin, N. M.,
implicit memory systems: A comparison of Aalto, S., Vahlberg, T., Ngren, K.,...Rinne,
Alzheimers, Huntingtons, and Parkinsons J. O. (2012). Cognitive decline and amyloid
disease patients. Journal of Neuroscience, 9, accumulation in patients with mild cognitive
582587. impairment. Dementia and Geriatric Cognitive
Hodges, J. R. (2001). Frontotemporal dementia Disorders, 34(1), 3137.
(Picks disease):Clinical features and assess- Kopelman, M.D., Stanhope, N., & Kingsley, D.
ment. Neurology, 56, S6-S10 (1997). Temporal and spatial contex memory
Hoefer, M., Allison, S. C., Schauer, G. F., in patients with focal frontal, temporal lobe,
Neuhaus, J.M., Hall, J., Dang, J.N.,...Rosen, and diencephalic lesions. Neuropsychologia,
H. J. (2008). Fear conditioning in frontotem- 35, 15331545.
poral lobar degeneration and Alzheimers Kubat-Silman, A.K., Dagenbach, D., & Absher,
disease. Brain, 131(Pt 6), 16461657. J. R. (2002). Patterns of impaired verbal,
Hoffman, P., Meteyard, L., & Patterson, K. (2012). spatial, and object working memory after
Broadly speaking: Vocabulary in semantic thalamic lesions. Brain and Cognition, 50,
dementia shifts towards general, semanti- 178193.
cally diverse words. Cortex, doi: 10.1016/j. Lidstrom, A. M., Bogdanovic, N., Hesse, C.,
cortex.2012.11.004. Epub ahead of print. Volkman, I., Davidsson, P., & Blennow, K.
Holl, A.K., Wilkinson, L., Tabrizi, S.J., Painold, (1998). Clusterin (apolipoprotein J) protein
A., & Jahanshahi, M. (2012). Probabilistic clas- levels are increased in hippocampus and
sification learning with corrective feedback is in frontal cortex in Alzheimers disease.
selectively impaired in early Huntingtons Experimental Neurology, 154, 511521.
diseaseevidence for the role of the striatum Markowitsch, H. J. (1995). Anatomical basis of
in learning with feedback. Neuropsychologia, memory disorders. In M. S.Gazzaniga (Ed.).
50(9), 21762186. The cognitive neurosciences (pp. 765779).
Holz, J., Piosczyk, H., Landmann, N., Cambridge, MA:MIT Press.
Feige, B., Spiegelhalder, K., Riemann, McKee, A. C., Au, R., Cabral, H. J., Kowall,
D.,...Voderholzer, U. (2012). The timing of N. W., Seshadri, S., Kubilus, C. A.,...Wolf,
learning before night-time sleep differentially P. A. (2006). Visual association pathology
affects declarative and procedural long-term in preclinical Alzheimer disease. Journal of
memory consolidation in adolescents. PLoS Neuropathology and Experimental Neurology,
One, 7(7), e40963. 65(6), 621630.
Jaeggi, S.M., Seewer, R., Nirkko, A.C., Eckstein, Mehta, M. A., Goodyer, I. M., & Sahakian,
D., Schroth, G., Groner, R., & Gutbrod, K. B. J. (2004). Methylphenidate improves
(2003). Does excessive memory load attenu- working memory and set-shifting in AD/
ate activation in the prefrontal cortex? HD:Relationships to baseline memory capac-
Load-dependent processing in single and ity. Journal of Child Psychology and Psychiatry,
dual tasks: Functional magnetic resonance 45, 293305.
imaging study. Neuroimage, 19, 210225. Mesulam, M-M. (2000). Principles of behavioral
Johnson, M. K., Kounios, J., & Nolde, S. F. and cognitive neurology (2nd ed). New York,
(1997). Electrophysiological brain activity NY:Oxford University Press.
and memory source monitoring. NeuroReport, Millet, X., Le Goff, M., Bouisson, J., Dartigues,
8, 13171320. J.F., & Amieva, H. (2010). Encoding processes
Johnson, M.K., OConnor, M., & Cantor, J. (1997). influence word-stem completion priming in
Confabulation, memory deficits, and frontal Alzheimers disease:Ameta-analysis. Journal
dysfunction. Brain and Cognition, 34, 189206. of Clinical and Experimental Neuropsychology,
Keane, M.M., Gabrieli, J.D., Mapstone, H.C., 32(5), 494504.
Johnson, K. A., & Corkin, S. (1995). Double Mitchell, J.P., Sullivan, A.L., Schacter, D.L., &
dissociation of memory capacities after bilat- Budson, A.E. (2006). Mis-attribution errors in
eral occipital-lobe or medial temporal-lobe Alzheimers disease:The illusory truth effect.
lesions. Brain, 118(Pt 5), 11291148. Neuropsychology, 20(2), 185192.
Klingberg, T., Forssberg, H., & Westerberg, Newman, S. D., Carpenter, P. A., Varma, S., &
H. (2002). Training of working memory in Just, M. A. (2003). Frontal and parietal par-
children with ADHD. Journal of Clinical and ticipation in problem solving in the Tower of
Experimental Neuropsychology, 24, 781791. London: fMRI and computational modeling
124 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
of planning and high-level perception. Schacter, D. L., Wagner, A. D., & Buckner,
Neuropsychologia, 41, 16681682. R. L. (2000). Memory systems of 1999. In E.
Papez, J. W. (1937). A proposed mechanism of Tulving & F. I. M. Craik (Eds.), The Oxford
emotion. Archives of Neurology and Psychiatry, handbook of memory (pp. 627643). NewYork,
38, 725743. NY:Oxford University Press.
Pavlov, I.P. (1927). Conditioned reflexes:An inves- Schneider, J. A., Arvanitakis, Z., Yu, L., Boyle,
tigation of the physiological activity of the cerebral P.A., Leurgans, S.E., & Bennett, D.A. (2012).
cortex. London, UK:Oxford University Press. Cognitive impairment, decline and fluc-
Perani, D., Cappa, S.F., Schnur, T., Tettamanti, tuations in older community-dwelling sub-
M., Collina, S., Rosa, M.M., & Fazio, F. (1999). jects with Lewy bodies. Brain, 135(Pt 10),
The neural correlates of verb and noun 30053014.
processing. A PET study. Brain 122(Pt 12), Sfagos, C., Papageorgiou, C. C., Kosma,
23372344. K. K., Kodopadelis, E., Uzunoglu, N. K.,
Petrides, M. (2002). The mid-ventrolateral pre- Vassilopoulos, D., & Rabavilas, A. D. (2003).
frontal cortex and active mnemonic retrieval. Working memory deficits in multiple sclero-
Neurobiology of Learning and Memory, 78, sis: A controlled study with auditory P600
528538. correlates. Journal of Neurology, Neurosurgery
Potkin, K.T., & Bunney, W.E., Jr. (2012). Sleep and Psychiatry, 74, 12311235.
improves memory:The effect of sleep on long Simons, J. S., Peers, P. V., Hwang, D. Y., Ally,
term memory in early adolescence. PLoS One, B.A., Fletcher, P.C., & Budson, A.E. (2008). Is
7(8), e42191. the parietal lobe necessary for recollection in
Price, J. L., & Morris, J. C. (1999). Tangles and humans? Neuropsychologia, 46(4), 11851191.
plaques in nondemented aging and preclini- Simons, J.S., Peers, P.V., Mazuz, Y.S., Berryhill,
cal Alzheimers disease. Annals of Neurology, M. E., & Olson, I. R. (2010). Dissociation
45, 358368. between memory accuracy and memory con-
Purcell, R., Maruff, P., Kyrios, M., & fidence following bilateral parietal lesions.
Pantelis, C. (1998). Cognitive deficits in Cereb Cortex. 2010 Feb;20(2), 479485.
obsessive-compulsive disorder on tests of Simons, J. S., & Spiers, H. J. (2003). Prefrontal
frontal-striatal function. Biological Psychiatry and medial temporal lobe interactions
43, 348357. in long-term memory. Nature Reviews
Ribot, T. (1881). Les maladies de la mmoire. Paris, Neuroscience, 4, 637648.
France:Flix Alcan. Solomon, P. R., Stowe, G. T., & Pendlbeury,
Rowe, J. B., Toni, I., Josephs, O., Frackowiak, W. W. (1989). Disrupted eyelid conditioning
R. S., & Passingham, R. E. (2000). The pre- in a patient with damage to cerebellar affer-
frontal cortex: Response selection or main- ents. Behavioral Neuroscience, 103, 898902.
tenance within working memory? Science Squire, L. R. (1992). Memory and the hippo-
2000;288:16561660. campus:Asynthesis from findings with rats,
Ruch, S., Markes, O., Duss, S. B., Oppliger, D., monkeys, and humans. Psychological Review,
Reber, T. P., Koenig, T.,...Henke, K. (2012). 99, 195231.
Sleep stage II contributes to the consolidation Stickgold, R. (2005). Sleep-dependent memory
of declarative memories. Neuropsychologia, consolidation. Nature, 437, 12721278.
50(10), 23892396. Stickgold, R. (2006). Neuroscience: A memory
Sabe, L., Jason, L., Juejati, M., Leiguarda, R., & boost while you sleep. Nature, 444, 559560.
Starkstein, S.E. (1995). Dissociation between Tulving, E., & Schacter, D. L. (1990). Priming
declarative and procedural learning in and human memory systems. Science, 247,
dementia and depression. Journal of Clinical 301306.
and Experimental Neuropsychology, 17, 841848. Vaidya, C.J., Zhao, M., Desmond, J.E., & Gabrieli,
Salmon, D. P., Lineweaver, T. T., & Heindel, J.D. (2002). Evidence for cortical encoding spec-
W.C. (1998). Nondeclarative memory in neu- ificity in episodic memory: Memory-induced
rodegenerative disease. In A. I.Troster (Ed.), re-activation of picture processing areas.
Memory in neurodegenerative disease:Biological, Neuropsychologia, 40, 21362143.
cognitive, and clinical perspectives (pp. 210 Vilberg, K. L., & Rugg, M. D. (2008). Memory
225). Cambridge, UK:Cambridge University retrieval and the parietal cortex:Areview of
Press. evidence from a dual-process perspective.
Schacter, D.L., & Buckner, R.L. (1998). Priming Neuropsychologia, 46(7), 17871799.
and the brain. Neuron, 20, 185195. Vilberg, K.L., & Rugg, M.D. (2009). Functional
Schacter, D. L., & Tulving, E. (1994). What are significance of retrieval-related activity in
the memory systems of 1994? In D. L.Schacter lateral parietal cortex: Evidence from fMRI
& E. Tulving (Eds.), Memory systems 1994 and ERPs. Human Brain Mapping, 30(5),
(pp.138). Cambridge, MA:MIT Press. 14901501.
CHAPTER 4. MEMORY SYSTEMS IN DEMENTIA125
Wagner, A.D., Schacter, D.L., Rotte, M., Koutstaal, consolidation. Sleep Medicine Clinics, 6(1),
W., Maril, A., Dale, A. M.,...Buckner, R. L. 97108.
(1998). Building memories:Remembering and Wolosin, S. M., Zeithamova, D., & Preston,
forgetting of verbal experiences as predicted A. R. (2012). Reward modulation of hippo-
by brain activity. Science, 281, 11881191. campal subfield activation during successful
Wamsley, E. J., & Stickgold, R. (2011). associative encoding and retrieval. Journal of
Memory, sleep and dreaming: Experiencing Cognitive Neuroscience, 24(7), 15321547.
5
126
CHAPTER 5. Motor Programming Disorders in Dementia 127
inhibition. Often when patients act and there how to move ones joints to correctly accom-
is no action needed, their inappropriate plish the required action, how to direct ones
action is initiated by a stimulus. For example, hand and fingers to the object with which
Lhermitte (1983) noted that some patients, one wants to act upon, how fast to move
when in the presence of objects (e.g., a pen portions of ones forelimb, and how much
and paper), will utilize these objects (e.g., force to use. Aperson also needs to know the
write or draw) without an apparent goal. He mechanical advantage that tools and imple-
called this utilization behavior and sub- ment may afford, how to use these tools, and
sequently the environmental dependency how to sequence ones action to successfully
syndrome. Luria (1962) had previously complete ones goal-directed behavior. The
described an echopraxia task that may also diagnosis of apraxia may be important for
examine for environmental dependency. several reasons. First, it may help the clini-
In this echopraxia task the examiner asks cian understand the form of dementia from
the patient to put up two fingers when the which a patient is suffering. Second, all the
examiner puts up one finger and vice versa. limb-apraxic disorders discussed here can
Patients perform abnormally when they put cause a disability, and detecting the form of
the same number of fingers as does the exam- apraxia may help patients and caregivers to
iner. Crucian etal. (2007) reported that some understand the types of activities in which
patients who are tested with the crossed these patients should not engage because
response task, in which they are instructed to they may hurt themselves or other people.
close their eyes and move the hand opposite Third, knowledge of the disability may allow
that touched, will have a propensity to move patients and caregivers (ideally with the
the hand that has been stimulated. assistance of an occupational therapist) to
These when disorders, also called develop strategies that may limit the disabili-
action intentional disorders (Heilman, ties caused by these disorders.
2004), are most often observed in patients Whereas disorders of the brain that impair
who suffer with frontal-subcortical-basal the how networks that program pur-
ganglia dysfunction. The presence of these poseful actions of the forelimb are called
action-intentional disorders can be a major apraxia, this term in Greek literally means
cause of a decrement in a persons ability to without action. As mentioned previously,
successfully care for oneself or ones fam- we now call an absence of action, when an
ily, and to successfully interact with ones action is required, akinesia; however, this
environment. Thus, while not commonly term apraxia was a term originally used
assessed by clinicians who evaluate patients by Steinthal (1871) to describe impairment
for dementia, these disorders are a major of patients abilities to correctly carry out
cause of disability. Some of the most common how motor programs.
dementing diseases that may induce these
disorders are forms of vascular dementia,
multiple sclerosis, head trauma, Parkinsons Task Specific Versus General Forms
disease, and other degenerative movement ofLimb Apraxia
disorders, such as progressive supranuclear
palsy, corticobasal degeneration, and mul- In regard to the forelimbs, there are two
tiple systems atrophy. major forms of apraxia. One form is task
specific and the other form is general.
Task-specific apraxia includes disorders lim-
Apraxic Disorders ited primarily to one activity. For example,
dressing apraxia and constructional apraxia
Relevance are examples of task-specific apraxia. In
these two forms of specific apraxia there are
To successfully care for ourselves and our impairments of the how to dress or how
family as well as successfully interact with to draw, but these how deficits can be caused
our environment, people need to know how by disorders such as inattention or neglect so
to move or act. For example, a person has to that the person with dressing apraxia does
know how to posture ones forelimb to hold not dress ones left side, or deficits in ones
a tool or implement to work with an object, body image-schema, and most commonly
128 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
visuospatial deficits. Therefore, while dis- called conceptual apraxia (Heilman, Maher,
orders such as constructional apraxia are Greenwald, & Rothi, 1997; Ochipa, Rothi, &
commonly associated with dementia and Heilman, 1992)and that may also be associ-
are often assessed in neuropsychological ated with dementia. The diagnosis of these
batteries such as the Mini-Mental Status specific types of apraxia is dependent upon
Examination and the Montreal Cognitive the types of motor programming errors made
Assessment, these task-specific disorders by the patient. In this section we will describe
will not be discussed in this chapter. these four different forms of general forelimb
apraxia, including (1) the mean by which
Exclusionary Criteria patients may be tested for each of these forms
of apraxia, (2) the types of errors made by
In addition to apraxia, there are many dis- patients who exhibit these forms of apraxia,
orders that might impair a persons ability and (3) the pathophysiology that might
to perform purposeful skilled movements. account for these how program deficits. We
Therefore, in part, as noted by Geschwind will also briefly discuss the diseases that can
(1965), the diagnosis of apraxia is partly induce dementia and also may cause each of
dependent on the exclusion of other disor- these types of apraxia.
ders that may interfere with the performance
of goal-oriented actions. For example, if a
patient is impaired in performing purpose- Conceptual Apraxia
ful movements because the patient has
deficits such as weakness, abnormal move- Clinical
ments such as tremor, chorea, ballismus,
myoclonus, severe sensory-perceptual defi- Although there are animals that use tools, and
cits, attentional deficits such as neglect, or even some animals that fashion tools such
cognitive impairments such as an impaired as ravens, crows, and apes, it is primarily
comprehension, then the patients inability to humans who use tools to aid them in altering
perform purposeful goal-oriented actions is their environment. Humans have mechani-
not considered a form or apraxia. If a patient cal knowledge, and when the proper tool is
with dementia has one or more of these dis- not available, they are able to use alternative
orders and this disorder prevents the exam- tools or even develop new tools. Although
iner from fully investigating this patient, then often not assessed, there are patients who,
it may not be possible to learn whether this when presented with a problem that requires
patient has apraxia; however, if in the pres- an action, sometimes cannot recognize the
ence of some of these disorders some patients tool they need to fulfill the required action.
can be tested, the interpretation of these tests There are also patients who might not recall
must be considered in light of these patients the type of actions associated with specific
other disabilities. tools, utensils, or objects (tool-object action
associative knowledge). Unlike patients
with ideomotor apraxia who make spatial
Forms of Upper Limb Apraxia
and temporal errors, patients with concep-
The term apraxia was a term originally tual apraxia make content errors (Ochipa,
used by Steinthal (1871) to describe impair- Rothi, & Heilman, 1989). For example, when
ment of the human to correctly carry out shown a picture of a screwdriver and asked
how motor programs. Although the term to demonstrate by pantomiming the use of
apraxia was first used by Steinthal (1871), this tool, the patients with ideomotor apraxia
it was primarily Hugo Liepmann who made may move the incorrect joints, such as twist-
some of the first important contributions ing their wrist in circles; however, the patient
to the understanding of these how disor- with conceptual apraxia might pantomime
ders. Liepmann (1920) described three major a hammering motion by making pounding
forms of apraxia: (1) limb-kinetic apraxia; movements.
(2) ideomotor apraxia; and (3) ideational Patients with conceptual apraxia may have
apraxia. All three of these forms of apraxia another problem where they are unable to
can be seen with patients who have demen- recall which specific tool (e.g., hammer) is
tia. We described a fourth type that we associated with a specific object (e.g., nail)
CHAPTER 5. Motor Programming Disorders in Dementia 129
often use their hand and fingers as the tool. the incorrect joints or move these joins in
For example, when the patients with IMA are an incorrect fashion. For example, if asked
asked to demonstrate how they would use to pantomime using a hammer to hit a nail
a pair of scissors to cut a piece of paper in in a board that is placed horizontally, below
half, they will often extend their forefinger as eye level, patients with IMA may flex and
well as their middle finger and then abduct extend their arm at the elbow, but not flex
and adduct these fingers as if these fingers and extend (or ulnar and radial deviate) their
were the blades of the scissors. When making hand at their wrist. Thus, if they were hold-
this posture, these patients are not correctly ing an actual hammer, the head of this ham-
demonstrating the posture used for holding mer would not decent to hit the head of the
a pair of scissors but rather are making the nail.
emblem of scissors. Goodglass and Kaplan Whereas hammering can be performed
(1963) called these types of errors body-part with just movements of the wrist, some
as object errors, but when using the fingers actions with tools require the coordination of
as the blades of scissor, these patients are two or more joints. For example, if a person is
using their body part as the tool rather than asked to carve a slice of turkey with a knife,
the object upon which the tool works. Hence, normal people may fix their wrist and as they
we termed these errors body-part as tool bring their arm at the shoulder forward they
errors (BPTEs). extend their arm at the elbow. After they have
BPTEs are, however, not always indica- made this forward movement they have to
tor of the presence of IMA. When asked to reverse these movements, and as they move
pantomime the use of a tool, such as a pair their arm backward at their shoulder they
of scissors, even normal people will often have to flex their arm at the elbow; however,
make BPTEs. This failure to correctly carry with each stroke the elbow flexion is reduced
out this request may be related to the rarity to allow the knife to move downward. In
of occasions that people use transitive panto- contrast to normal people, patients with IMA
mimes versus emblems and using the finger will often just move one joint, either at the
as blades is an emblem of scissors rather than shoulder or elbow and thus rather than mak-
pantomime. However, when normal people ing a slicing movement, they will make stab-
are asked to not use their hand and fingers bing or chopping movements (Poizner, Mack,
or other body parts as the tools and instead Verfaellie, Rothi, & Heilman, 1990; Rothi,
to show the examiner how they would use Mack, Verfaellie, Brown, & Heilman, 1988).
the actual tool, most normal people will stop In addition to these egocentric postural and
making BPTEs. In contrast, many patients movement errors, patients with IMA can also
with IMA, unlike normal people, continue to make allocentric or target-oriented movement
make BPTEs even when the examiner repeat- errors. If a person is going to use a tool prop-
edly attempts to correct this abnormal behav- erly, the person must direct this tool to the
ior (Raymer, Maher, Foundas, Heilman, & object upon which the tool works. For exam-
Rothi, 1997). ple, when using a hammer to pound a nail,
Sometimes when patients with IMA do the hammer has to be directed to the head
stop making BPTEs and attempt to panto- of the nail. In addition to making egocentric
mime, they will incorrectly posture their fin- postural and movement errors, patients with
gers, hand, forearm, and arm. For example, IMA make allocentric errors by failing to
when attempting to hold a pair of scissors, direct their real or pretended actions toward
they may place their thumb below their the real or imaginary target of these actions
forefinger. (Poizner etal., 1990; Rothi etal., 1988).
In addition to positioning ones upper
limb in the correct posture, when correctly
pantomiming a transitive act a person needs Assessment for Ideomotor Apraxia
to correctly move the joints in ones upper
limb in order that the tool will be able to cor- Some patients or their families-caregivers
rectly move through space and be able to may be able to give a history of an impair-
perform its proper function. Independent of ment using tools and implements; however,
the position of the object on which this tool the construct of apraxia is not well known to
will act, patients with IMA often either move the general public, and thus it is uncommon
CHAPTER 5. Motor Programming Disorders in Dementia 131
skilled movement and vice versa. The fre- the area of the frontal lobe important in pro-
quent co-occurrence of these two disorders is viding the motor cortex with the movement
therefore probably related to two factors. One program.
factor is the cause of the cerebral dysfunction. This verbal-motor disconnection hypoth-
For example, strokes in the middle cerebral esis, however, cannot entirely explain why
artery distribution damage multiple cortical patients with IMA from a left parietal lesion
areas including those that mediate speech are also impaired when imitating. Geschwind
and those subserving purposeful skilled posited that to perform imitation the connec-
movements. It is also possible that certain tions between the visual association area, on
portions of the cerebral cortex have neuronal the left side, and premotor cortex, which is in
networks that perform more than one func- the white matter under the inferior parietal
tion; when these areas are damaged, there cortex, is also interrupted; Geschwind sug-
may be a loss of more than one function. gested that this left hemispheric white matter
pathway from the occipital cortex to the pre-
Parietal Lobe motor cortex was dominant for carrying this
information, but he did not explain why it
Liepmann (1920) noted that when a person was dominant. When patients with IMA are
with a left hemisphere injury demonstrated given a tool to hold in the hand (right or left)
signs of IMA, the person often had an injury and attempt to use this tool, they also make
to the inferior parietal lobe. Geschwind errors (Poizner etal., 1990)and Geschwinds
(1965) posited that lesions in this region left parietal white matter disconnection
caused apraxia because they disconnected hypotheses cannot also explain this observa-
Wernicke area (posterior portion of the left tion. As we will discuss in a subsequent sec-
superior temporal lobe), which is critical for tion, patients with degenerative diseases such
comprehension of speech, from the premotor as Alzheimers disease may also demonstrate
cortex, which is important in programming IMA, and many of these patient have degen-
the primary motor cortex. This disconnec- eration of their parietal lobe cortex; thus,
tion hypothesis is similar to that proposed white matter disconnection could not explain
by Wernicke (1874) and Lichtheim (1885) the IMA observed in these patients.
to account for conduction aphasia and that About three decades ago we put forth
conduction aphasia often accompanies IMA. an alternative movement representation
According to Geschwinds hypothesis, the hypothesis (Heilman et al., 1982; Rothi,
incoming verbal message that provides the Heilman, & Watson, 1985) that may account
patient with the knowledge of the panto- for the IMA associated with left inferior
mime that the examiner requested is decoded parietal lesions. We suggested that in right-
in Wernickes area, but this message must handed people these movement formula or
then be transmitted to the premotor cortex movement representations, which we also
in the left frontal lobe. When the pantomime have called praxicons, contain the spa-
is to be carried out with the right hand, then tial and temporal parameters of purposeful
the premotor cortex activates the corticospi- actions. The inferior parietal lobe of the left
nal neurons in the motor cortex, which acti- hemisphere receives visual information from
vate the appropriate motor neurons and then both the ventral what system important in
muscles. When the left hand is used, the left recognizing tool, implements, and the objects
premotor cortex transfers this information to upon which these tool interact and the dor-
the right premotor cortex, and the informa- sal where visual association system that
tion activates the motor neurons in the right provides information about the relationship
hemisphere. Thus, according to Geschwinds of the arm with an object in peripersonal
hypothesis, a lesion of the left supramarginal space. In addition, the inferior parietal lobe
gyrus could injure the white matter pathway also receives input from the superior parietal
(arcuate fasciculus) that connects Wernickes association areas that contain kinesthetic rep-
area, located in the posterior-superior tempo- resentations of upper limb movements. Based
ral lobe, with the left hemispheres convexity on this visuo-kinesthetic input, the left infe-
premotor cortex. This could, in turn, produce rior parietal lobe develops visuospatial kin-
an IMA because the area of the brain impor- esthetic representations of skilled movement.
tant in comprehension is disconnected from Thus, if there is an injury to these movement
CHAPTER 5. Motor Programming Disorders in Dementia 133
representations or praxicons, the patients Pramstaller and Marsden (1996) noted that
with this injury should demonstrate defi- subcortical lesions, which injure the supe-
cits of pantomiming to command, imitating rior longitudinal fasciculus, are associated
both meaningful and meaningless gestures with IMA and thus this form of apraxia can
and even using actual tools. In addition, if be induced by a disconnection syndrome.
these representations are degraded, patients However, this disconnection is not between
should not be able to comprehend other peo- the areas important for language comprehen-
ples pantomimes and these patients should sion and the motor cortex, but rather between
not be able to discriminate between correctly the movement representations stored in the
and incorrectly performed transitive panto- inferior parietal cortex and the premotor
mimes performed by the examiner. cortex.
In contrast, if these praxicons are intact, but
patients have injury to the premotor cortex or Supplementary Motor Area
the pathways that connect these movement
representations to premotor cortex, these As mentioned previously, the movement rep-
patients would also be expected to have per- resentations or praxicons that are stored in
formance deficits characteristic of IMA. In the left parietal lobe are probably stored in
contrast to patients with parietal lesions, the a three-dimensional visual and kinesthetic
patients with a premotor injury should be spatial-temporal code. In order for the motor
able to discriminate between incorrect and cortex to correctly activate the motor nerves
correct pantomimes performed by the exam- and the muscles to which these nerves are
iner. We (Heilman et al., 1982; Rothi et al., connected, and move a persons joints in
1985)tested patients with anterior and poste- the correct fashion, these visual-kinesthetic
rior left hemisphere cerebral cortical lesions spatial-temporal representations have to be
by assessing for IMA by having these patients translated into a motor program that selec-
produce transitive pantomimes as well as tively activates specific portions of the motor
assessing their pantomime discrimination. cortex in a specific temporal pattern.
We found that some patients with both left The medial portion of the premotor cortex
hemispheric anterior and posterior lesions (Brodmanns area 6), called the supplemen-
had the production deficits typical of IMA. tary motor area (SMA), receives projections
In contrast, we found that it was primarily from parietal neurons. The SMA projects to
the patients with posterior damage who had the convexity premotor cortex as well as to
both production and discrimination distur- primary motor cortex and also has direct
bances. More recently, Halsband and cowork- projections to the neurons of the spinal cord
ers (2001) replicated Heilman et al. (1982) that control upper limb movement. When
and Rothi etal.s (1985) results. These results the primary motor cortex in the hand area is
provided evidence against Geschwinds dis- stimulated, one or more fingers may twitch
connection hypothesis of IMA from parietal and if during functional imaging a person
lesions and instead support the postulate that moves just one finger in a repetitive motion,
injury of the left inferior parietal lobe induces the hand area in Brodmanns area 4, the pri-
IMA because injury to this area degrades the mary motor cortex on the contralateral side,
movement representations that are stored in will demonstrate activation. In contrast, if
this area. the SMA is stimulated, the person will per-
Haaland and her coinvestigators (2000) form complex arm, forearm, hand, and finger
were interested in attempting to more pre- movements; and during functional imag-
cisely localize the left hemispheric lesions ing when normal people perform transitive
that induce and do not induce IMA and pantomimes, there is activation of the SMA,
found that patients with IMA had injury to as well as primary motor cortex (Lauritzen,
the cortical regions adjacent to the intrapari- Henriksen, & Lassen, 1981; Rao et al., 1993).
etal sulcus, which is in part at the top of the Based on these reports, it appears that pre-
supramarginal gyrus. Functional imaging motor cortex and especially SMA is the area
has provided convergent evidence that the or areas of the brain that convert the poly-
left inferior parietal lobe stores movement modal (visual-kinesthetic) temporo-spatial
representations in right-handed subjects movement representation into a motor pro-
(Moll etal., 2000). gram, and it is this portion of the premotor
134 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
cortex that directs the activation of the motor however, subcortical structures have a great
neurons in primary motor cortex. Watson influence on cortical functions, and there
et al. (1986) reported several patients who have been several reports that subcorti-
sustained left-sided medial frontal lesions cal lesions can also induce IMA (Agostoni,
that included the supplementary motor area, Coletti, Orlando, & Tredici, 1983; Basso &
and these patients demonstrated an impair- Della Sala, 1986; Della Sala, Basso, Laiacona,
ment in performing transitive purposeful & Papagno, 1992; DeRenzi, Faglioni, Scarpa,
movements and these errors were consistent & Crisi, 1986; Kertesz & Ferro, 1984; Kleist,
with IMA; however, in contrast to the patients 1907; von Monakov, 1914). To learn the sub-
with left parietal lesions, these patients were cortical structures that may cause IMA when
able to discriminate between correctly and damaged, Pramstaller and Marsden (1996)
incorrectly performed pantomimes, and the performed a meta-analysis. In this analysis
reason for this dichotomy may be related to they reviewed the case reports of 82 patients
these patients preservation of their praxi- who had an IMA caused by a subcortical
cons (visuo-kinesthetic spatial temporal lesion. They concluded that lesions confined
movement representations). to the basal ganglia, including the putamen,
caudate, and the globus pallidus, rarely, if
Convexity Premotor Cortex ever, cause an IMA. Unfortunately, in most of
the studies reviewed by these investigators
The role of injury-degeneration of the con- the patients were only tested with imitation.
vexity premotor cortex in the development In addition, these patients performance was
of IMA is not well known. For example, only scored as either correct or incorrect. The
Faglioni and Basso (1985) wrote that they had most sensitive test for IMA is having patients
difficulty finding any well-documented cases pantomime to command, and Pramstaller
where patients had IMA as a result of injury and Marsdens (1996) results may have been
to convexity premotor region. Subsequently, related to the insensitivity of the testing pro-
Barrett etal. (1998) and Haaland etal. (2000) cedure used to assess these patients.
did report patients with frontal premotor Subsequently, Hanna-Pladdy et al. (2001)
injury who appeared to have an IMA. Barrett studied patients for IMA and compared
etals (1998) report described a study of one patients with cortical and subcortical strokes.
patient who could properly make a move- These investigators studied these patients
ment if it only required the movement of one using transitive and intransitive gestures,
joint of the upper limb, but it was impaired both to command and with imitation. They
when she was required to make movements found that both the group of patients with
that required the coordination between two cortical and subcortical lesions made the
or more joints. spatial and temporal error associated with
Haaland etal. (2000) studied a population IMA; however, they also found some dif-
of patients with stroke who had ideomotor ferences. Whereas the patients with cortical
apraxia, using the lesion overlap method for lesions were impaired in the production of
localization; in addition to finding parietal transitive and intransitive gestures-to-verbal
injury was associated with IMA, they found command and imitation, as well as impaired
that injury of a portion of the convexity pre- gesture discrimination, the participants who
motor cortex, the middle frontal gyrus, also had subcortical lesions only demonstrated
appeared to be a critical area. In contrast, mild production-execution deficits for transi-
however, Freund and Hummelsheim (1985) tive pantomimes to verbal command; consis-
studied a population of patients with con- tent with Pramstaller and Marsdens (1996)
vexity premotor lesions and also found that report, the patients with subcortical lesions
these patients were apraxic but instead of had normal imitation. In addition, unlike
having IMA they had limb-kinetic apraxia, a the patients with cortical lesions, the group
disorder that will be discussed later. of patients with the subcortical lesions were
unimpaired on a gesture (correct versus
Basal Ganglia and Thalamus incorrect) discrimination task. The subcor-
tical group, however, made more postural
In the prior sections the relationships between errors than the cortical group. Unlike the
IMA and cortical dysfunction was discussed; Pramsteller and Marsden study, this study
CHAPTER 5. Motor Programming Disorders in Dementia 135
by Hanna-Pladdy etal. does suggest that the common deficits observed in patients with
subcortical structures make an independent Alzheimers disease. In addition to making
contribution to the praxis processing system. postural, spatial, and temporal errors when
Unfortunately, we have not learned the role performing (pantomiming, imitating, or
of these subcortical structures in controlling using actual tools and implements) purpose-
the performance of purposeful skilled upper ful movements that are typical of ideomotor
limb movement. apraxia, patients with Alzheimers disease
Subcortical injury can also damage the also are impaired at pantomime recogni-
thalamus, and there have been several case tion and discrimination (Rousseaux, Rnier,
reports of patients who developed apraxia Anicet, Pasquier, & Mackowiak-Cordoliani,
from lesions of the left thalamus in the region 2012). Mozaz etal. (2006), using a posture rec-
of the pulvinar nucleus (Nadeau, Roeltgen, ognition test, also demonstrated that patients
Sevush, Ballinger, & Watson, 1994; Shuren, with Alzheimers disease are impaired.
Maher, & Heilman, 1994). This thalamic These comprehension discrimination stud-
nucleus has strong connections with the infe- ies suggest that patients with Alzheimers
rior parietal lobes, which, as discussed, play disease have a decrement in the movement
a critical role in storing movement represen- representations.
tations; thus, damage to this nucleus might An unusual form of dementia called
impair the activation of these movement posterior cortical atrophy that often
representations. starts with visuospatial disabilities and
visual agnosic disorders can also be asso-
ciated with ideomotor apraxia (Goethals &
Diseases That May Be Associated Santens, 2001)
With Cognitive Disorders and
Ideomotor Apraxia Parkinsons Disease
There have been several studies that have
Vascular
revealed that patients with Parkinsons
In the previous discussion of the patho- disease can have an ideomotor apraxia
physiology of IMA, most of the patients (Goldenberg, Wimmer, Auff, & Schnaberth,
studied had vascular disease, and thus 1986; Leiguarda et al., 1997). Goldenberg
patients with vascular dementia may reveal et al. (1986) found that the severity of
an IMA. The most common vascular lesion apraxia was not directly related to the sever-
to cause IMA is a thrombosis in the distri- ity of these patients Parkinsonian motor
bution of the left middle cerebral artery, signs but instead appeared to be related
which infarcts the parietal cortex; how- to their visuospatial and visuoperceptual
ever, injury to the left hemisphere premotor skills. Leiguarda et al. (1997) found that
cortex either medially with a left anterior there were no differences when patients
cerebral artery distribution infarction or lat- with Parkinsons disease were on versus
erally with an infarction in distribution of off their medication, suggesting that this
the anterior branches of the middle cerebral apraxic disorder was not related to a dopa-
artery can also cause IMA. mine deficit. The patients with Parkinsons
Studies of disability have revealed that disease who had ideomotor apraxia had
the presence of apraxia is one of the major normal pantomime comprehension and
reasons patients with strokes cannot per- were able to discriminate well-performed
form independently (Hanna-Pladdy et al., from improperly performed pantomimes,
2003)and often cannot return to work (Saeki suggesting that their impairment was not
& Hachisuka, 2004). related to degradation of their movement
representation, but rather an inability to
translate these representation into motor
Alzheimers Disease
programs. In addition, the apraxia appeared
Along with impairments of episodic mem- to be related to their performance on tests
ory, language (e.g., anomia), visuospatial of frontal-executive functions, such as the
skills and elements of the Gerstmanns syn- Tower of Hanoi, Trailmaking, and verbal
drome, ideomotor apraxia is one of the most fluency tests.
136 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
Heilman, Meador, and Loring (2000), as well Diseases That Can Cause
as Hanna-Pladdy and colleagues (2002), Limb-Kinetic Apraxia and May Be
have found that people with right-hand pref- Associated With Cognitive Disorders
erence are more likely to have an additional
ipsilateral loss of deftness (limb-kinetic Limb-kinetic apraxia can often be associated
apraxia) with left than right hemispheric with cerebrovascular disease. In addition,
injury. we have reported that many patients with
Parkinsons disease have this disorder, and
their loss of deftness does not appear to be
Pathophysiology related to their bradykinesia (Quencer etal.,
2007). Limb-kinetic apraxia can also be seen
Liepmann (1920) thought that the injury with the Parkinsons plus syndromes such as
of the primary sensorimotor cortex caused progressive supranuclear palsy (Leiguarda
limb-kinetic apraxia, and subsequently, et al., 1997) and corticobasal degeneration,
Lawrence and Kuypers (1968) demonstrated and, like the ideomotor apraxia, it may be
a loss of a precision pincher grasp in mon- asymmetrical. Gebhardt and coworkers
keys with lesions of the pyramid that inter- (2008) studied finger tapping, as a measure of
rupted the corticospinal tract. Freund and bradykinesia, and coin rotation, as a measure
Hummelsheim (1985) as well as Fogassi and of limb-kinetic apraxia, while both on and off
colleagues (2001) reported that damage to dopaminergic treatment and found that this
the premotor cortex (Brodmanns area 6)can treatment primarily improved bradykinesia
also induce limb-kinetic apraxia. Converging (finger tapping) and did not have a substan-
evidence for the role of premotor cortex in tial influence on coin rotation, suggesting
programming deft finger movements comes that in these patients it is not the dopaminer-
from the work of Nirkko and coworkers gic deficit that is causing this disorder.
(2001), who performed functional magnetic
resonance imaging while participants were
performing unilateral deft finger movements Ideational Apraxia
and found that performance of these move-
ments were associated with activation of the Clinical
convexity premotor cortex.
There also appears to be hemispheric Unfortunately the diagnostic term ide-
asymmetries in the development of limb- ational apraxia has been used to label many
kinetic apraxia in people who are right different disorders. This term has been used
handed, such that left hemisphere dysfunc- for patients with what we now call concep-
tion, such as stroke, can induce ipsilateral (as tual apraxia. De Renzi & Lucchelli (1968)
well as contralesional) limb-kinetic apraxia used this term for patients who had severe
(Heilman, Meador, & Loring, 2000; Hanna- ideomotor apraxia and were impaired when
Pladdy and colleagues, 2002); however, they attempted to use actual tools. I also
when right-handed patients have a right used this term for patients who could not
hemisphere stroke they may develop produce the correct transitive pantomime
limb-kinetic apraxia of their contralesional to verbal command but could perform nor-
left hand, but their right hand will often mally when seeing the tool or the object upon
perform normally. This lesion-induced which the tool normally works (Heilman,
hemispheric asymmetry suggests than in 1973). We now call this disorder dissocia-
right-handed people the left hemisphere has tion apraxia because it appears that in these
stronger ipsilateral control of spinal motor patients there is a dissociation of the systems
neurons than does the right hemisphere, important in comprehending speech and
and physiological studies in normal par- those important in programming movements
ticipants appear to support this postulate (Heilman & Watson, 2008). Liepmann (1920)
(Ghacibeh et al., 2007); however, it is not initially used this term for a disorder first
known whether this ipsilateral control is described by Marcuse (1904) and Pick (1905),
mediated by ipsilateral corticospinal path- where patients have an inability to correctly
ways or by means of the corpus callosum. sequence a series of acts, an ideational plan,
138 Part i Functional Neuroanatomy and Cognitive Neuroscience of Dementia
that are required to successfully complete as Alzheimers disease (Chainay, Louarn, &
a goal. Poeck (1983) noted that while some Humphreys, 2006). Giovannetti et al. (2006)
patients may have perseveration, this disor- demonstrated that patients with vascular
der is not solely caused by perseveration but dementia are more likely to have ideational
rather a disturbance in the conceptual orga- apraxia (deficits on the NAT) than patients
nization of actions. Some investigators now with Alzheimers disease. We assessed
call this disorder the action disorganiza- patients for Parkinsons disease for ide-
tion syndrome (Forde & Humphreys, 2002). ational apraxia and found that ideational
Thus, the most important test for making apraxia is associated with this condition.
the diagnosis of ideational apraxia is having These patients errors were predominantly
the patient perform a task that requires sev- in sequencing rather than repetition or omis-
eral sequential motor acts, such as making a sion, indicating that the poor performance
sandwich. Some clinicians test patients for was not caused by perseveration (Qureshi,
ideational apraxia by having them verbally Williamson, & Heilman, 2011). Leiguarda
describe the means by which they would etal. (1997) reported that some patients with
make something such as a sandwich. To Parkinsons plus syndromes such as progres-
assess for ideational apraxia, Qureshi et al. sive supranuclear palsy also have problems
(2011) assessed participants with sets of pic- with tasks involving multiple steps.
tures that showed the steps in completing a
task, but the steps were shown out of order.
The participants were required to point to the Summary
pictures in the correct sequence to complete
each task. In another test, the Natural Action This chapter describes the clinical character-
Test (NAT), subjects are presented with real istics that define the various forms of upper
objects and are required to perform multistep limb apraxia, including conceptual, ideomo-
tasks that lead to a completed goal (Schwartz tor, limb-kinetic, and ideational apraxia.
etal., 2002). When a person determines that some-
thing needs to be altered, he or she must
make some conceptual decisions, including
Pathophysiology whether a tool is needed and, if so, what tool
can best accomplish this goal. The person
Although some of the diseases that cause this must also know the action that this tool per-
disorder are reviewed later in the chapter, forms and the movements needed to operate
the pathophysiology is not well understood. this tool. If the correct tool is not available or
Liepmann (1920) thought that the lesion that a new tool is needed, the person also has to
induced this disorder was located in the left have the ability to understand the mechani-
occipital parietal region. A functional imag- cal advantage this tools affords and how this
ing study performed with normal subjects could be accomplished by an alternative tool
performing a sequential action task appeared or the development of a new tool. A loss of
to activate the parietal lobe, as suggested this mechanical knowledge is called con-
by Liepmann (1920); however, the critical ceptual apraxia. In right-handed people this
anatomic focus of dysfunction in ideational knowledge is stored in the left hemisphere,
apraxia remains unknown (Humphreys & but the exact locations of these representa-
Forde, 1998). The frontal lobes are thought tions are unknown.
to be important in sequencing and Niki etal. After a person selects a tool to work on an
(2009) reported several patients with frontal object, he or she also needs to have knowl-
lobe tumors who had evidence of the action edge of the posture required to hold this
disorganization syndrome or ideational tool as well as the egocentric and allocen-
apraxia. tric movements that permit this tool to be
properly moved through space. In people
who are right handed, these movement
Diseases Associated With Ideational Apraxia (temporo-spatial) representations appeared
to be stored in the left parietal lobe, and
Most often the patients with ideational degradation of these movement representa-
apraxia have some form of dementia such tions or damage to the premotor cortex that
CHAPTER 5. Motor Programming Disorders in Dementia 139
review of the literature. Clinical Neurology and Kertesz, A., & Ferro, J. M. (1984). Lesion size
Neurosurgery, 103(2), 115119. and location in ideomotor apraxia. Brain, 107,
Goldenberg, G., Wimmer, A., Auff, E., & 921933.
Schnaberth, G. (1986). Impairment of motor Kleist, K. (1907). Kortikale (innervatorische)
planning in patients with Parkinsons dis- Apraxie. Jahrbuch fur Psychiatrie und
ease: Evidence from ideomotor apraxia test- Neurologie, 28, 46112.
ing. Journal of Neurology, Neurosurgery and Lauritzen, M., Henriksen, L., & Lassen, N. A.
Psychiatry, 49(11), 12661272. (1981). Regional cerebral blood flow dur-
Goodglass, H., & Kaplan, E. (1963). Disturbance ing rest and skilled hand movements by
of gesture and pantomime in aphasia. Brain, Xenon-133 inhalation and emission comput-
86, 703720. erized tomography. Journal of Cerebral Blood
Haaland, K. Y., Harrington, D. L., & Knight, Flow and Metabolism, 1, 385389.
R.T. (2000). Neural representations of skilled Lawrence, D.G., & Kuypers, H.G. (1968). The
movement. Brain, 123(Pt 11), 23062313. functional organization of the motor system
Halsband, U., Schmitt, J., Weyers, M., Binkofski, in the monkey. II. The effects of lesions of
F., Grutzner, G., & Freund, H. J. (2001). the descending brain-stem pathways. Brain,
Recognition and imitation of pantomimed 91(1), 1536.
motor acts after unilateral parietal and pre- Leiguarda, R., Lees, A.J., Merello, M., Starkstein,
motor lesions: A perspective on apraxia. S., & Marsden, C. D. (1994). The nature of
Neuropsychologia, 39(2), 200216. apraxia in corticobasal degeneration. Journal
Hanna-Pladdy, B., Heilman, K.M., & Foundas, of Neurology, Neurosurgery and Psychiatry,
A. L. (2001). Cortical and subcortical contri- 57(4), 455459.
butions to ideomotor apraxia: Analysis of Leiguarda, R.C., Pramstaller, P.P., Merello, M.,
task demands and error types. Brain, 124, Starkstein, S., Lees, A. J., & Marsden, C. D.
25132527. (1997). Apraxia in Parkinsons disease, pro-
Hanna-Pladdy, B., Mendoza, J. E., Apostolos, gressive supranuclear palsy, multiple system
G. T., & Heilman, K. M. (2002). Lateralised atrophy and neuroleptic-induced parkinson-
motor control: Hemispheric damage and ism. Brain, 120(Pt 1), 7590.
the loss of deftness. Journal of Neurology, Lhermitte, F. (1983). Utilization behaviour
Neurosurgery and Psychiatry, 73, 574577. and its relation to lesions of the frontal lobes.
Hanna-Pladdy, B., Heilman, K.M., & Foundas, Brain, 106(Pt 2), 237255.
A.L. (2003). Ecological implications of ideo- Lichtheim, L. (1885). On aphasia. Brain, 7,
motor apraxia:Evidence from physical activi- 433484.
ties of daily living. Neurology, 60(3), 487490. Liepmann, H. (1920). Apraxia. Erbgn der ges
Heilman, K. M. (1973). Ideational apraxiaa Med, 1, 516543.
re-definition. Brain, 96, 861864. Liepmann, H., & Maas, O. (1907). Fall von
Heilman, K. M. (2004). Intentional neglect. linksseitiger Agraphie und Apraxie bei
Frontiers in Bioscience, 9, 694705. rechsseitiger Lahmung. Zeitschrift fur
Heilman, K.M., Maher, L.M., Greenwald, M.L., Psychologie und Neurologie, 10, 214227.
& Rothi, L. J. R. (1997). Conceptual apraxia Luria, A.R. (1962). Higher cortical functions in man.
from lateralized lesions. Neurology, 49, 457464. Moscow, Russia:Moscow University Press.
Heilman, K. M., Meador, K. J., & Loring, Marcuse, H. (1904). Apraktische Symptome bei
D. W. (2000). Hemispheric asymmetries einen Falle von seniler Demenz. Zentrlball fur
of limb-kinetic apraxia: A loss of deftness. Neurologie, 15, 737751.
Neurology, 55, 523526. Moll, J., de Oliveira-Souza, R., Passman, L. J.,
Heilman, K. M., Rothi, L. J. G., & Valenstein, Cunha, F. C., Souza-Lima, F., & Andreiuolo,
E. (1982). Two forms of ideomotor apraxia. P. A. (2000). Functional MRI correlates of
Neurology, 32, 415426. real and imagined tool-use pantomimes.
Heilman, K.M., & Watson, R.T. (2008). The dis- Neurology, 54, 13311336.
connection apraxias. Cortex, 44(8), 975982. Monza, D., Soliveri, P., Radice, D., Fetoni, V.,
Holl, A. K., Ille, R., Wilkinson, L., Otti, D. V., Testa, D., Caffarra, P., .
.
.
Girotti, F. (1998).
Hdl, E., Herranhof, B.,...Bonelli, R. M. Cognitive dysfunction and impaired orga-
(2011). Impaired ideomotor limb apraxia in nization of complex motility in degenera-
cortical and subcortical dementia:Acompari- tive Parkinsonian syndromes. Archives of
son of Alzheimers and Huntingtons disease. Neurology, 55(3), 372378.
Neurodegenerative Disorders, 8(4), 208215. Mozaz, M., Rothi, L.J., Anderson, J.M., Crucian,
Humphreys, G. W., & Forde, E. M. E. (1998). G.P., & Heilman, K.M. (2002). Postural knowl-
Disordered action schema and action disorga- edge of transitive pantomimes and intran-
nization syndrome. Cognitive Neuropsychology, sitive gestures. Journal of the International
15, 771811. Neuropsychology Society, 8(7), 958962.
CHAPTER 5. Motor Programming Disorders in Dementia 141
Mozaz, M., Garaigordobil, M., Gonzalez, A.,...Estkowski, L.D. (1993). Functional mag-
Rothi, L. J., Anderson, J., Crucian, G. P., & netic resonance imaging of complex human
Heilman, K. M. (2006). Posture recognition movements. Neurology, 43(11), 23112318.
in Alzheimers disease. Brain and Cognition, Raymer, A. M., Maher, L. M., Foundas, A. L.,
62(3), 241245. Heilman, K. M., & Rothi, L. J. G. (1997).
Nadeau, S. E., Roeltgen, D. P., Sevush, S., The significance of body part as tool errors
Ballinger, W.E., & Watson, R.T. (1994). Apraxia in limb apraxia. Brain and Cognition, 34,
due to a pathologically documented thalamic 287292.
infarction. Neurology, 44(11), 21332137. Rousseaux, M., Rnier, J., Anicet, L., Pasquier,
Niki, C., Maruyama, T., Muragaki, Y., & F., & Mackowiak-Cordoliani, M. A. (2012).
Kumada, T. (2009). Disinhibition of sequen- Gesture comprehension, knowledge and
tial actions following right frontal lobe dam- production in Alzheimers disease. European
age. Cognitive Neuropsychology, 26(3), 266285. Journal of Neurology,19(7), 10371044.
Nirkko, A. C., Ozdoba, C., Redmond, S. M., Rothi, L. J. G., Heilman, K. M., & Watson,
Brki, M., Schroth, G., Hess, C. W., & R. T. (1985). Pantomime comprehension
Wiesendanger, M. (2001). Different ipsilat- and ideomotor apraxia. Journal of Neurology,
eral representations for distal and proximal Neurosurgery and Psychiatry, 48, 207210.
movements in the sensorimotor cortex: acti- Rothi, L. J. G., Mack, L., Verfaellie, M., Brown,
vation and deactivation patterns. Neuroimage. P., & Heilman, K. M. (1988). Ideomotor
13(5), 825835. apraxia: Error pattern analysis. Aphasiology,
Ochipa, C., Rothi, L.J. G., & Heilman, K.M. (1989). 2, 381387.
Ideational apraxia: A deficit in tool selection Saeki, S., & Hachisuka, K. (2004). The associa-
and use. Annals of Neurology, 25, 190193. tion between stroke location and return to
Ochipa, C., Rothi, L. J. G., & Heilman, K. M. work after first stroke. Journal of Stroke and
(1992). Conceptual apraxia in Alzheimers dis- Cerebrovascular Disease, 13(4), 160163.
ease. Brain, 114, 25932603. Schwartz, M. F., Buxbaum, L. J., Ferraro, M.,
Pharr, V., Uttl, B., Stark, M., Litvan, I., Fantie, B., Veramonti, T., & Segal, M. (2002). Naturalistic
& Grafman, J. (2001). Comparison of apraxia action test. Suffolk, England: Thames Valley
in corticobasal degeneration and progressive Test Company.
supranuclear palsy. Neurology, 56(7), 957963. Shuren, J. E., Maher, L. M., & Heilman, K. M.
Pick, A. (1905). Sudien uber Motorische Apraxia (1994). Role of the pulvinar in ideomotor
und ihre Mahestenhende Erscheinungen. Leipzig, praxis. Journal of Neurology, Neurosurgery and
Germany:Deuticke. Psychiatry, 57(10), 12821283.
Poeck, K. (1983). Ideational apraxia. Journal of Silveri, M.C., & Ciccarelli, N. (2009). Semantic
Neurology, 230(1), 15. memory in object use. Neuropsychologia,
Poizner, H., Mack, L., Verfaellie, M., Rothi, L.J. 47(12), 26342641.
G., & Heilman, K. M. (1990). Three dimen- Steinthal, P. (1871). Abriss der Sprach wissenschaft.
sional computer graphic analysis of apraxia. Berlin.
Brain, 113, 85101. Uluduz, D., Ertrk, O., Kenangil, G., Ozekmeki,
Pramstaller, P.P., & Marsden, C.D. (1996). The S., Ertan, S., Apaydin, H., & Erginz, E. (2010).
basal ganglia and apraxia. Brain, 119(Pt 1), Apraxia in Parkinsons disease and multiple
319340. system atrophy. European Journal of Neurology,
Quencer, K., Okun, M.S., Crucian, G., Fernandez, 17(3), 413418.
H.H., Skidmore, F., & Heilman, K.M. (2007). Von Monakov, C. (1914). Die Lokalisation im
Limb-kinetic apraxia in Parkinson disease. Grosshirn und der Abbau der Function durch
Neurology, 68(2), 150151. Kortikale Herde. Wiesbaden, Germany:
Qureshi, M., Williamson, J.B., & Heilman, K.M. Bergmann.
(2011). Ideational apraxia in Parkinson dis- Watson, R.T., & Heilman, K.M. (1983). Callosal
ease. Cognitive and Behavioral Neurology, 24(3), apraxia. Brain, 106, 391403.
122127. Wernicke, C. (1874). Das Aphasiche Symptom
Rao, S. M., Binder, J. R., Bandettini, P. A., enkomplex. Breslau, Poland: Cohn and
Hammeke, T.A., Yetkin, F.Z., Jesmanowicz, Weigart.
Part II
145
146part iiThe Dementias: The Major Diseases and Clinical Syndromes
most likely consists of a subtle decline of evidence that the neuropathological disease
physical and mental performance without process of AD gradually takes place for many
definite physical changes detectable in the years prior to the manifestation of symp-
brain, probably as a result of physiologic toms. Many such investigators view this as an
changes in neurotransmitter and electro- opportunity for intervention (see Chapter18).
physiologic function. It has long been known, Briefly, on postmortem examination,
however, that many cognitively intact older the outstanding changes found in the
adults exhibit neuropathologic changes iden- brains of cognitively normal elderly indi-
tical to those of Alzheimers disease (AD) viduals include the following (Fig. 6.1).
dementia, but to a lesser extent (Knopman Macroscopically, atrophy is often present,
etal., 2003; Lace etal., 2009; Polvikoski etal., which is evidenced by weight loss (up to
2001; Price etal., 2009; Tomlinson, Blessed,& 200 grams [normal: women 1,260 g; men
Roth, 1968). Some authors have suggested 1,360 g]), narrowing of gyri and widen-
that a possible pathologic continuum exists ing of sulci, and ventricular dilatation.
between aging and AD. For example, as Microscopically, some neuronal loss is often
early as 1924, Simchowicz concluded that seen but with less decrease of the neuronal
senile dementia consists of both acceleration density than expected because of the shrink-
and increased intensity of the age-related age of the neuropil; occurrence of neurofi-
physiological involution of the brain brillary tangles of Alzheimer; immature and
(Simchowicz, 1924). Drachman formulated diffuse type plaques, and neuritic plaques;
Simchowiczs hypothesis 70 years later as granulovacuolar degeneration, and Hirano
follows:If we live long enough, will we all bodies especially within the hippocampus;
become demented? With our present lack of Marinesco bodies (pars compacta of the sub-
means to prevent the most common demen- stantia nigra); and vasculopathies (e.g., ath-
tia, AD, more and more of us will decline erosclerosis, arteriolosclerosis, hypertensive
cognitively, as life expectancy increases, evi- angiopathy, amyloid angiopathy, or cerebral
dently with an age-related acceleration of amyloid angiopathy [CAA]), and ferro-calcic
incidence (Drachman, 1994; p.1563). angiopathy, especially involving the len-
While the brain changes associated with ticular nucleus (globus pallidus > putamen).
normal age-related cognitive changes con- Microhemorrhages, criblures, lacunes, glial
tinue to be studied, many contemporary scars, or infarcts result from the vasculopa-
theorists view the occurrence of AD neuro- thies, which cause frequently mixed patho-
pathology in cognitively intact individuals as logical changes (Schneider, Arvanitakis,
Hirano body
Degenerative diseases
U Marinesco body
s
u Neurofibrillary changes
a
l Neuronal loss - Atrophy - Sclerotic/amyloid vasculopathies
a
g Neuritic plaques
i
n Granulovacuolar degeneration
g
Lewy body
degeneration, and Hirano body formation loss of the white matter with subsequent
(Lace et al., 2009). The stellate neurons of dementia may be caused by vasculopathies.
layer 2 of the entorhinal cortex are highly sus- Indeed, hypertensive vascular changes
ceptible to neurofibrillary tangle formation, (fibrosis of the walls of the vessels; i.e., arte-
most conspicuously in AD. The large and riolosclerosis) cause hypoperfusion of central
small pyramidal neurons of the hippocam- white matter. Agradual loss of oligodendro-
pus, and the granule neurons of the fascia cytes, myelin, and neuronal processes occurs
dentata, are susceptible to Pick bodies (Ball, with a reactive gliosis and widening of the
1979; Binetti, Growdon,& Vonsattel, 1998). perivascular spaces (criblures). Especially
Within the neocortex (Fig.6.2), the homo- involved is the subcortical white matter, as
typical cortex is usually more vulnerable in Binswanger disease. Nearly 30% of cohort
than the heterotypical cortex (motor cortex, of individuals with cerebral autosomal domi-
where the pyramidal neurons including Betz nant arteriopathy with subcortical infarcts
cells predominate, or visual cortex, where the and leukoencephalopathy (CADASIL) devel-
granular neurons prevail) (Kemper, 1994). oped dementia and a pathological pheno-
Neocortical neurons can be categorized as type similar to that of Binswanger disease
pyramidal and nonpyramidal cells. The pyra- (Davous& Bequet, 1995; Dichgans etal., 1998;
midal neurons have extensive intracortical Tournier-Lasserve etal., 1993). Dementing ill-
and extracortical connections; it is these neu- nesses with a predominantly myelinoclastic
rons that are most affected in neurodegenera- or demyelinating process include progres-
tive diseases associated with dementia. The sive multifocal leukoencephalopathy (PML),
unipolar pyramidal projection neurons of the the encephalopathy of the acquired immune
anterior insula and cingulate cortex known deficiency syndrome (AIDS), and multiple
as Von Economo neurons are particularly sclerosis (Brew, Rosenblum, Cronin,& Price,
vulnerable to FTLD (Seeley, etal., 2006). 1995; Fontaine etal., 1994).
The cerebral white matter harbors myelin- The amygdala is often severely involved in
ated and bare axons, fibrillary astrocytes, oli- neurodegenerative dementing diseases. In
godendrocytes, and blood vessels. Extensive AD, the amygdala often shows neuronal loss,
Figure6.2 Relative selective neocortical vulnerability of a 61-year-old patient who died of cardiac
arrest and who carried the clinical diagnosis of possible Alzheimers disease:The cuneus (left,
homotypic cortex) contains many neuropil threads that are labeled with AT8 antibodies directed
against phosphorylated tau, and scattered neuritic plaques. In contrast, the calcarine cortex (right,
heterotypic cortex) is relatively spared. (AT8 immunohistochemistry; original magnification, 25)
CHAPTER 6. The Neuropathology of Neurodegenerative Dementias 149
(A) (B)
(A) (B)
to, or within the cytoplasm of hippocampal directed against phosphorylated tau, anti-
pyramidal neurons, especially involved is the bodies directed against ubiquitinated pro-
Sommer sector (CA-1) (Hirano, 1994). They teins, but not with antibodies directed against
may appear as a result of age-related altera- -synuclein aggregates. They are found in
tions of the microfilamentous system. cortical and hippocampal, pyramidal neu-
Granulovacuolar degeneration consists rons; in neurons of the stratum granulosum
of the presence of one or more cytoplasmic of the dentate gyrus; and in the amygdala,
granules, 12 m across, surrounded by an and occasionally within the striatum and
optically empty rim, or vacuole measuring brainstem.
35 m in diameter. Especially involved are
the pyramidal neurons of the Sommer sector
(CA1) and subiculum of the hippocampus. Ballooned Neurons (Pick Cells)
Tomlinson et al. reported severe involve-
ment of the pyramidal cells of the Sommer Ballooned neurons, also referred to as Pick
sector in every demented patient and that cells are swollen neurons with convex con-
some degree of this change was found in tours, homogeneous glassy, pale, eosinophilic
70% of their control brains (Tomlinson etal., cytoplasm, and eccentric nuclei (Clark etal.,
1968). Both Hirano bodies and granulovacu- 1986). The cytoplasm is diffusely argyrophilic
olar degenerations are ubiquitinated and not with variable intensity. Ballooned neurons
labeled with AT8 antibodies directed against are found in a variety of neurodegenerative
phosphorylated tau. diseases including classic Picks disease, PSP,
corticobasal degeneration, and AD.
Pick Bodies
Status Spongiosus Versus
Pick bodies are neuronal, cytoplasmic, argyr- Spongiform Changes
ophilic, well outlined, and round, or oval
bodies measuring 1015m across (Fig.6.5). Status spongiosus consists of irregular cavita-
They are labeled with AT8 antibodies tion of the neuropil in the presence of a dense
152part iiThe Dementias: The Major Diseases and Clinical Syndromes
(A) (B)
Figure 6.5(A) Formalin fixed, lateral aspect of the left half brain of a 53-year-old patient with
frontotemporal lobar degeneration (classical Picks disease). Note the prominent circumscribed atrophy
involving the frontal lobe, rostral temporal lobe, and the inferior parietal lobule. Although atrophic,
the pre- and postcentral gyri, the caudal two thirds of the superior temporal gyrus, and occipital lobe
are relatively preserved. (B) Microphotographs of Pick bodies. Pick bodies are argyrophilic (bottom
left, Bielschowsky, 200), are labeled with AT8 antibodies directed against phosphorylated tau (bottom
right, AT8, 630), or with antibodies directed against ubiquitinated proteins. They are not labeled with
antibodies directed against -synuclein aggregates, which is in contrast to Lewy bodies. (Bielschowsky
silver stain; original magnification, 400) (See color plate section)
glial meshwork (Masters & Richardson, white matter in the areas mentioned previ-
1978). It is nonspecific and characteristically ously, often particularly prominently in the
is the manifestation of end-stage gliosis. medial temporal cortical regions, hippocam-
Spongiform changes consist of the presence pal formation, amygdaloid nucleus, and the
of small, round, or ovoid, optically empty anterior thalamus (Fig. 6.3). The ventricu-
vacuoles within the neuropil. Transcortical lar system is widened proportionally to the
or deep cortical spongiform changes asso- volume loss of the parenchyma. In most
ciated with gliosis are hallmarks of the instances, the nucleus coeruleus is paler than
spongiform encephalopathies, including normally expected, which is in contrast to the
Creutzfeldt-Jakob disease (CJD). However, to usually well-pigmented pars compacta of the
some extent, spongiform changes (with mild, substantia nigra.
or without reactive astrocytosis) are observed Microscopically, the characteristic lesions
in the Lewy body spectrum diseases, the FTD of AD are often widespread throughout the
spectrum diseases, and occasionally in AD brain, although their severity varies regionally
(Smith et al., 1987). In these instances, spon- (Braak, Alafuzoff, Arzberger, Kretzschmar,&
giform changes are usually confined to the Del Tredici, 2006; K. A. Jellinger & Bancher
superficial, cortical layers; but, at times, they 1998; Parvizi et al., 2001). Microscopic AD
are indistinguishable from those observed in neuropathology is usually most prominent in
spongiform encephalopathies, which must the entorhinal/perirhinal cortex, hippocam-
then be ruled out using Western blots. pal formation (Fig.6.6), amygdaloid nucleus,
basal forebrain including the substantia
innominata (nucleus of Meynert), hypothala-
Alzheimers Disease mus, thalamus, and the following regions of
the cerebral cortex:temporal, prefrontal, and
By the time a patient with AD typically dies, parietal. The motor and visual cortices are rel-
the gross appearance of the brain is dif- atively preserved, although not spared. The
fusely atrophic with a predilection for the characteristic lesions of AD include neuritic
prefrontal, parietal, and temporal lobes. In and diffuse amyloid plaques, neurofibrillary
10% of cases, however, the atrophy may be tangles of Alzheimer, with accompanying
circumscribed or minimal. On examination neuronal loss.
of the cut sections, the brunt of the atrophy Neuritic plaques tend to predominate
involves the cerebral cortex and adjacent in cortical layers II and III (Fig. 6.4A).
CHAPTER 6. The Neuropathology of Neurodegenerative Dementias 153
(A) (B)
involved in RNA regulation and transport. outstanding changes noticeable are pallor
There appear to be four distinct subtypes of of the pars compacta of the substantia nigra
FTLD-TDP pathology based on the morphol- (mesencephalon) and of the nucleus coeru-
ogy of the inclusions and their cellular local- leus (metencephalon) (Fig. 6.7). Usually the
ization (Mackenzie et al., 2011). Emerging DLB or PDD brain is not atrophic or is only
evidence indicates that each subtype may mildly atrophic.
be associated with characteristic clinical Microscopically, the hallmark of DLB/
and genetic features. To date, a number of PDD is intraneuronal cytoplasmic inclusions
genetic mutations in FTD and ALS patients referred to as the Lewy body (Fig. 6.8).
have been identified in conjunction with Lewy bodies are labeled with antibodies
TDP43 pathology, including mutations in directed against ubiquitinated proteins, and
GRN (the progranulin gene), the TDP gene specifically against -synuclein. In contrast
itself (TARDBP), VCP (the valosin contain- to Pick bodies, Lewy bodies are not argyro-
ing protein gene), and the recently identified philic. Their morphology varies, so two
C9ORF72 hexanucleotide repeat expansion. types of Lewy body can be distinguished:the
Another much less common neuropatho- brainstem or classical type involving mainly
logic subtype of FTLD, discovered in 2009, the pigmented neurons of the brainstem
is characterized by intranuclear inclusions of (Fig.6.8), and the cortical type, found mainly
the RNA-binding protein FUS (fused in sar- within cortical neurons.
coma). This protein is implicated in nuclear In PD, the outstanding findings are the
transcriptional activities. FUS inclusions are presence of Lewy bodycontaining neu-
seen in associated with mutations in the FUS rons and Lewy neurites, and loss of neurons
gene in a small proportion of familial ALS within both the peripheral and central ner-
cases and are seen in sporadic FTLD, often vous systems. Within the peripheral nervous
with a young age of onset. This is another system, the olfactory bulb, autonomic gan-
key finding that has generated tremendous glion, and myenteric plexus of the intestines
excitement in bringing together the FTLD (Kupsky, Grimes, Sweeting, Bertsch,& Cote,
and ALS research communities. 1987)are involved. In the brainstem, the fol-
See Chapter8 for discussion of the clinical lowing structures are commonly affected:the
aspects of FTD. dorsal motor nucleus of the vagus (choliner-
gic) and the reticular formation; the nucleus
coeruleus (noradrenergic) and neurons of the
Neuropathology of Dementias median raph (serotoninergic); the pars com-
Associated With Lewy Bodies pacta of the substantia nigra and tegmental
scattered pigmented neurons (dopaminer-
On gross examination of the brain of a gic), the Edinger-Westphal nucleus (cholin-
patient with PD dementia or DLB, the most ergic, preganglionic parasympathetic motor
(A) (B)
Figure 6.7 Transverse slices through the midbrain. (A) The normal adult pars compacta of the
substantia nigra is well pigmented. (B) In contrast to A, in Parkinson disease (B), or in dementia with
Lewy bodies, the normally expected pigment is decreased. This pigment, neuromelanin, is a by-product
of neuronal function. The cytoplasmic density of neuromelanin gradually increases with age.
CHAPTER 6. The Neuropathology of Neurodegenerative Dementias 155
Figure 6.8 Lewy body (brainstem type) is usually round, 830m in diameter, and consists of a
cytoplasmic, hyaline core with or without concentric lamellar bands, and with a peripheral, pale
halo. These two Lewy bodycontaining neurons are from the nucleus coeruleus. One of them has
two round Lewy bodies (lower left). The other has a somewhat bilobulated Lewy body with a
visible, basophilic, and dark core (upperright). (LHE stain; original magnification, 630) (See color
plate section)
neurons that control lens accommodation changes involve the deep cortical layers or
and pupillary constriction, which lie near the are transcortical, especially in the late stage
midline, dorsal to the oculomotor nucleus [III of the disease, and are associated with reac-
cranial nerve nucleus]). In the diencephalon, tive gliosis.
the structures involved include the thalamus, Some patients exhibit the neuropatho-
hypothalamus, and substantia innominata, logic hallmarks of both AD and DLB. This
including nucleus of Meynert (choliner- diagnosis, sometimes referred to as the AD
gic) (Braak et al., 2003; Halliday et al., 1990; Lewy body variant (ADLBV), is made when
Langston, 2006). the brain of a demented patient shows the
Neocortical neurons prone to contain changes of AD together with those of dif-
Lewy bodies are those located mainly fuse Lewy body disease. Perhaps patients
within layers V or VI with the following with ADLV have both AD and PD given the
temporospatial pattern in the majority of shared clinical and pathological characteris-
patients with protracted disease: parahip- tics (Brown etal., 1998; Perl, Olanow,& Calne,
pocampal gyrus, occipitotemporalis gyrus, 1998; Zaccai, Brayne, McKeith, Matthews,&
insular cortex, cingulate gyrus, homotypic Ince, 2008). In ADLBV, in addition to the
neocortex, and then heterotypic neocor- widespread presence of the Lewy bodycon-
tex (Braak etal., 2003; K.A. Jellinger, 2004, taining neurons, the density and distribu-
2008). When Lewy bodycontaining neu- tion of neuritic plaques and neurofibrillary
rons are widespread within the brain and tangles are such that the patient meets AD
brainstem, neuropathologists often refer to neuropathologic criteria as well.
the condition as diffuse Lewy body disease. See Chapter12 for discussion of the clinical
In DLB, Lewy bodycontaining neurons aspects of DLB.
occur in the same areas as those involved
in PD (see Fig. 6.8); in addition, they are
widespread within the cerebral cortex and Huntingtons Disease
amygdaloid nucleus. Furthermore, in DLB,
spongiform changes often occur and occa- HD is an autosomal dominant illness usu-
sionally can mimic prion diseases. However, ally with midlife onset of psychiatric, cog-
in contrast to CJD, the spongiform changes nitive, and motor symptoms. Death occurs
in DLBD tend to involve the superficial, cor- 1215 years from the time of symptomatic
tical layers, and are either without or with onset (Wexler et al., 2004). An unstable
mild reactive gliosis. In CJD, spongiform expansion of CAG (trinucleotide) repeats
156part iiThe Dementias: The Major Diseases and Clinical Syndromes
within the coding region of the gene IT15 paraventricular half of the caudate nucleus
(for Interesting Transcript. referred to as is more involved than the paracapsular half.
HD-IT15 CAG repeats) causes the disease. In summary, the dorsal third of the rostral
This gene, on chromosome 4 (4p16.3), encodes neostriatum is especially prone to degenerate
the 350-kDa-protein huntingtin whose func- in contrast to the relatively preserved ven-
tion is only partially known (Huntingtons tral third, including the nucleus accumbens.
Disease Collaborative Research Group, Features that HD shares with the other eight,
1993). An expanded polyglutamine residue currently known polyglutaminopathies are
(polyQ) distinguishes the mutated hunting- ubiquitinated, neuronal, nuclear inclusions
tin (with about 37 to 250 polyQ [mhtt]) from involving scattered neurons, and dystrophic
the wild type (with 8 to about 3436 polyQ neurites, and neuronal loss in regions more or
[whtt]). The disease manifests itself clini- less distinctive for each disease of this group.
cally when the critical threshold of about 37 The observation of these ubiquitinated aggre-
polyQ is exceeded (Hendricks et al., 2008). gates in HD human brains was made follow-
This phenomenon is observed in a group of ing the occurrence of widespread nuclear
nine inherited, neurodegenerative diseases inclusions seen in neurons, glial, and epen-
caused by polyQ extension, referred to as dymal cells of the first transgenic mice (R6/2)
polyglutaminopathies. harboring exon 1 of the human gene. This
The mhtt is expressed in all organs, yet the genetic insertion encodes htt with expanded
brunt of the changes of HD identified so far CAG-repeats, which translate into a series
occurs in the brain. The degeneration initially of consecutive glutamine residues or polyQ
involves the striatum (neuronal loss, gliosis), (Mangiarini etal., 1996).
then the cerebral cortex, and eventually is Among the theories for the selective, cel-
fairly diffusely throughout the brain (Hadzi lular damage in HD, the most compelling
et al., 2012; Halliday et al., 1998; Rb et al., involve impaired energy metabolism, excito-
2013; Vonsattel& DiFiglia, 1998). toxicity, and relative, selective endotoxicity.
Examination of coronal slices reveals bilat- The excitotoxicity theory proposes that
eral atrophy of the striatum in 95% of the HD subpopulations of striatal medium-sized
brains. The striatal atrophy is prominent in spiny projection neurons are hypersensitive
80%, mild in 15%, and subtle, if present at all, to corticostriatal and thalamostriatal gluta-
in 5% of the brains. Nonstriatal regions show mate, or excessive glutamate is released by
atrophy of variable severity or have normal these afferents, while striatal interneurons
appearance. As a rule, the postmortem HD are less affected. Mutated huntingtin causes
brain is diffusely smaller than normal in the neuronal dysfunction long before cell death.
late stage of the disease. The striatum is prob- Perhaps endotoxicity results from misfold-
ably the only site where neuronal loss and ing of mhtt. Wild-type huntintin is soluble.
active reactive, fibrillary astrocytosis coex- In contrast, mhtt is insoluble and forms
ist to be readily noticeable on postmortem aggregates. Despite the tremendous amount
examination using conventional methods of of recent important data obtained on whtt,
investigation. or mhtt, the relatively selective loss of stria-
The gradual atrophy of the striatum, tal neurons seen in HD continues to remain
which sequentially involves the neostria- mysterious.
tum, external segment, then the internal
segment of globus pallidus, typifies HD. References
In turn, the neostriatal loss has an ordered,
topographic distribution. The tail of the Attems, J., Jellinger, K., Thal, D. R., & Van
caudate nucleus shows more degeneration Nostrand, W. (2011). Review: Sporadic cere-
than the body, which is more involved than bral amyloid angiopathy. Neuropathology and
the head. Similarly, the caudal portion of Applied Neurobiology, 37, 7593.
Ball, M.J. (1979). Topography of Pick inclusion
the putamen is more degenerated than the
bodies in hippocampi of demented patients.
rostral portion. Aquantitative study. Journal of Neuropathology
Along the coronal (or dorsoventral) axis and Experimental Neurology, 38, 614620.
of the neostriatum, the dorsal, neostriatal Binetti, G., Growdon, J. H., & Vonsattel, J-P.G.
regions are more involved than the ven- (1998). Picks disease. Blue Books of Practical
tral ones. Along the medio-lateral axis, the Neurology. The Dementias, 19, 744.
CHAPTER 6. The Neuropathology of Neurodegenerative Dementias 157
Braak, H., Alafuzoff, I., Arzberger, T., Frigerio, R., Fujishiro, H., Maraganore, D. M.,
Kretzschmar, H., & Del Tredici, K. (2006). Klos, K. J., DelleDonne, A., Heckman,
Staging of Alzheimer disease-associated M.G.,...Ahlskog, J.E. (2009). Comparison of
neurofibrillary pathology using paraffin risk factor profiles in incidental Lewy body
sections and immunocytochemistry. Acta disease and Parkinson disease. Archives of
Neuropathologica, 112, 389404. Neurology, 66(9), 11141119.
Braak, H., Del Tredici, K., Rb, U., de Vos, Huntingtons Disease Collaborative Research
R.A., Jansen Steur, E.N.,& Braak, E. (2003). Group. (1993). A novel gene containing a tri-
Staging of brain pathology related to sporadic nucleotide repeat that is expanded and unsta-
Parkinsons disease. Neurobiology of Aging, 24, ble on Huntingtons disease chromosomes.
197211. Cell, 72, 971983.
Brew, B.J., Rosenblum, M., Cronin, K.,& Price, Grnthal, E. (1930). ber ein Brderpaar mit
R. W. (1995). AIDS dementia complex and Pickscher Krankheit. Eine vergleichende
HIV-1 brain infection: Clinical-virological Untersuchung, zugleich ein Beitrag zur
correlations. Annals of Neurology, 38, 563570. Kenntnis der Verursachung und des Verlaufs
Brown, D.F., Dababo, M.A., Bigio, E.H., Risser, der Erkrankung. Zeitschrift fr die gesa-
R. C., Eagan, K. P., Hladik, C. L., & White, mte Neurologie und Psychiatrie (Berlin), 129,
C. L., III. (1998). Neuropathologic evidence 350375.
that the Lewy body variant of Alzheimer dis- Hadzi, T. C., Hendricks, A. E., Latourelle,
ease represents coexistence of Alzheimer dis- J. C., Lunetta, K. L., Cupples, L. A., Gillis,
ease and idiopathic Parkinson disease. Journal T.,...Vonsattel, J. P. (2012). Assessment of
of Neuropathology and Experimental Neurology, cortical and striatal involvement in 523
57, 3946. Huntington disease brains. Neurology, 79(16),
Cairns, N.J., Neumann, M., Bigio, E.H., Holm, 17081715.
I.E., Troost, D., Hatanpaa, K.J.,...Mackenzie, Halliday, G.M., Li, Y.W., Blumbergs, P.C., Joh,
I.R. (2007b). TDP-43 in familial and sporadic T. H., Cotton, R. G., Howe, P. R.,...Geffen,
frontotemporal lobar degeneration with ubiq- L.B. (1990). Neuropathology of immunohis-
uitin inclusions. American Journal of Pathology, tochemically identified brainstem neurons in
171, 227240. Parkinsons disease. Annals of Neurology, 27,
Clark, A. W., Manz, H. J., White, C. L., III, 373385.
Lehmann, J., Miller, D., & Coyle, J. T. Halliday, G. M., McRitchie, D. A., Macdonald,
(1986). Cortical degeneration with swollen V., Double, K.L., Trent, R.J.,& McCusker, E.
chromatolytic neurons: Its relationship to (1998). Regional specificity of brain atrophy in
Picks disease. Journal of Neuropathology and Huntingtons disease. Experimental Neurology,
Experimental Neurology, 45, 268284. 154, 663672.
Davous, P.,& Bequet, D. (1995). CADASILun Hamilton, R.L. (2000). Lewy bodies in Alzheimers
nouveau modle de dmence sous-corticale. disease: A neuropathological review of 145
Revue Neurologique, 151, 634639. cases. Brain Pathology, 10(3), 378384.
Dichgans, M., Mayer, M., Uttner, I., Brning, Hendricks, A.E., Latourelle, J.C., Lunetta, K.L.,
R., Mller-Hcker, J., Rungger, G.,...Gasser, Cupples, L. A., Wheeler, V., MacDonald,
T. (1998). The phenotypic spectrum of M. E.,...Myers, R. H. (2008). Estimating the
CADASIL: Clinical findings in 102 cases. probability of de novo HD cases from trans-
Annals of Neurology, 44, 731739. mission of expanded penetrant CAG alleles
Drachman, D.A. (1994). If we live long enough, in the Huntington disease gene from male
will we all be demented?. Neurology, 44, carriers of hight normal alleles (2735 CAG).
15631565. American Journal of Medical Genetics Part A,
Ezekiel, F., Chao, L., Kornak, J., Du, A. T., 149A, 13751381.
Cardenas, V., Truran, D.,...Weiner, M. (2004). Hirano, A. (1994). Hirano bodies and related
Comparisons between global and focal brain neuronal inclusions. Neuropathology and
atrophy rates in normal aging and Alzheimer Applied Neurobiology, 20, 311.
disease. Alzheimer Disease and Associated Hulette, C. M., Welsh-Bohmer, K. A., Murray,
Disorders, 18, 196201. M. G., Saunders, A. M., Mash, D. C., &
Fontaine, B., Seilhean, D., Tourbah, A., McIntyre, L. M. (1998). Neuropathological
Daumas-Duport, C., Duyckaerts, C., Benoit, and neuropsychological changes in normal
N.,...Lyon-Caen, O. (1994). Dementia in two aging: Evidence for preclinical Alzheimer
histologically confirmed cases of multiple disease in cognitively normal individuals.
sclerosis: One case with isolated dementia Journal of Neuropathology and Experimental
and one case associated with psychiatric Neurology, 57(12), 11681174.
symptoms. Journal of Neurology, Neurosurgery, Jellinger, K. (2009). A critical evaluation of cur-
and Psychiatry, 57, 353359. rent staging of -synuclein pathology in
158part iiThe Dementias: The Major Diseases and Clinical Syndromes
Lewy body disorders. Biochimica et Biophysica dementia with VCP gene mutations. Journal
Acta, 1792, 730740. of Neuropathology and Experimental Neurology,
Jellinger, K. A. (2004). Lewy body-related 66, 152157.
-synucleinopathy in the aged human Neumann, M., Sampathu, D. M., Kwong,
brain. Journal of Neural Transmission, 111, L. K., Truax, A. C., Micsenyi, M. C., Chou,
12191235. T. T.,...Lee, V. M. (2006). Ubiquitinated
Jellinger, K. A. (2008). A critical reappraisal of TDP-43 in frontotemporal lobar degeneration
current staging of Lewy-related pathology in and amyotrophic lateral sclerosis. Science,
human brain. Acta Neuropathologica, 116, 116. 314, 130133.
Jellinger, K. A., & Bancher, C. (1998). Parvizi, J., Van Hoesen, G. W., & Damasio, A.
Neuropathology of Alzheimers dis- (2001). The selective vulnerability of brain-
ease: A critical update. Journal of Neural stem nuclei to Alzheimers disease. Annals of
Transmission, 54, 7795. Neurology, 49, 5366.
Kemper, T. L. (1994). Neuroanatomical and Perl, D. P., Olanow, C. W., & Calne, D. (1998).
meuropathological changes during aging Alzheimers disease and Parkinsons dis-
and dementia. In M. L.Albert& J. E.Knoefel ease: Dinstinct entities or extremes of a
(Eds.), Clinical neurology of aging (2nd ed., spectrum of neurodegeneration. Annals of
pp. 367). NewYork, NY:Oxford University Neurology, 44(Suppl 1), S19S31.
Press. Polvikoski, T., Sulkava, R., Myllykangas, L.,
Knopman, D. S., Parisi, J. E., Salviati, A., Notkola, I. L., Niinist, L., Verkkoniemi,
Floriach-Robert, M., Boeve, B. F., Ivnik, A.,...Haltia, M. (2001). Prevalence of
R.J.,...Petersen, R.C. (2003). Neuropathology Alzheimers disease in very elderly people.
of cognitively normal elderly. Journal of A prospective neuropathological study.
Neuropathology and Experimental Neurology, Neurology, 56, 16901996.
62, 10871095. Price, J.L., McKeel, D.W., Jr., Buckles, V.D., Roe,
Kupsky, W. J., Grimes, M. M., Sweeting, J., C. M., Xiong, C., Grundman, M.,...Morris,
Bertsch, R., & Cote, L. J. (1987). Parkinsons J.C. (2009). Neuropathology of nondemented
disease and megacolon: Concentric hyaline aging: Presumptive evidence for preclinical
inclusions (Lewy bodies) in enteric ganglion Alzheimer disease. Neurobiology of Aging, 30,
cells. Neurology, 37, 12531255. 10261036.
Lace, G., Savva, G. M., Forster, G., de Silva, Ross, G.W., Petrovitch, H., Abbott, R.D., Nelson,
R., Brayne, C., Matthews, F. E.,...Wharton, J., Markesbery, W., Davis, D.,...White, L. R.
S. B. (2009). Hippocampal tau pathology is (2004). Parkinsonian signs and substantia
related to neuroanatomical connections: An nigra neuron density in decendents elders
ageing population-based study. Brain, 132, without PD. Annals of Neurology, 56, 532539.
13241334. Rb, U., Hoche, F., Brunt, E. R., Heinsen, H.,
Langston, J. W. (2006). The Parkinsonss com- Seidel, K., Del Turco, D., .
.
.
den Dunnen,
plex: Parkinsonism is just the tip of the ice- W.F. (2013). Degeneration of the cerebellum
berg. Annals of Neurology, 59, 591596. in Huntingtons disease (HD): Possible rel-
Mackenzie, I.R. A., Neumann, M., Bigio, E.H., evance for the clinical picture and potential
Cairns, N. J., Alafuzoff, I., Kril, J.,...Mann, gateway to pathological mechanisms of the
D. M. (2010). Nomenclature and nosology disease process. Brain Pathology, 23, 165177.
for neuropathologic subtypes of frontotem- Savva, G.M., Wharton, S.B., Ince, P.G., Forster,
poral lobar degeneration: An update. Acta G., Matthews, F.E.,& Brayne, C. (2009). Age,
Neuropathologica, 119, 14. neuropathology, and dementia. New England
Mangiarini, L., Sathasivam, K., Seller, M., Journal of Medicine, 360(22), 23022309.
Cozens, B., Harper, A., Hetherington, Schmahmann, J.D. (2003). Vascular syndromes
C.,...Bates, G. P. (1996). Exon 1 of the HD of the thalamus. Stroke, 34, 22642278.
gene with an expanded CAG repeat is suffi- Schneider, J. A., Arvanitakis, Z., Bang, W., &
cient to cause a progressive neurological phe- Bennett, D. A. (2007). Mixed brain patholo-
notype in transgenic mice. Cell, 87, 493506. gies account for most dementia cases
Masters, C. L., & Richardson, E. P., Jr. (1978). in community-dwelling older persons.
Subacute spongiform encephalopathy Neurology, 69, 21972204.
(Creutzfeldt-Jakob disease). The nature and Seeley, W. W., Carlin, D. A., Allman, J. M.,
progression of spongiform change. Brain, 101, Macedo, M. N., Bush, C., Miller, B. L., &
333344. Dearmond, S.J. (2006). Early frontotemporal
Neumann, M., Mackenzie, I. R., Cairns, N. J., dementia targets neurons unique to apes and
Boyer, P. J., Markesbery, W. R., Smith, humans. Annals of Neurology, 60(6), 660667.
C. D.,...Forman, M. S. (2007). TDP-43 in Seeley, W. W., Crawford, R., Rascovsky, K.,
the ubiquitin pathology of frontotemporal Kramer, J. H., Weiner, M., Miller, B. L.,
CHAPTER 6. The Neuropathology of Neurodegenerative Dementias 159
Repetitive mild brain trauma is associated CTE, or punch drunk as it was originally
with the development of chronic traumatic known, was reported in 1928 by Harrison
encephalopathy (CTE), a progressive neu- Martland, a New Jersey pathologist, who
rodegenerative tauopathy with distinctive described the clinical symptom complex
clinical and pathological features. CTE is affecting boxers who stayed in the ring
associated with the play of contact athlet- long enough (p. 1103). Millspaugh (1937)
ics, especially boxing and American football, referred to the condition as dementia
but it has been linked to many other sports, pugilistica, while other terms such as the
including ice hockey, wrestling, rugby, and psychopathic deterioration of pugilists
soccer, and to other traumatic exposures, (Courville, 1962)and traumatic encephalop-
including physical abuse, poorly controlled athy (Parker, 1934)were also used. Critchley
epilepsy, head-banging behaviors, and introduced the term chronic progressive
trauma experienced during military service traumatic encephalopathy to highlight the
(Corsellis, Bruton,& Freeman-Browne, 1973; progressive nature of the condition (1957)
Geddes, Vowles, Nicoll, & Revesz, 1999; and noted that Once established it not only
Goldstein etal., 2012; Hof, Knabe, Bovier,& does not permit of reversibility, but it ordi-
Bouras, 1991; McKee etal., 2009, 2010, 2013; narily advances steadily...even though the
Omalu etal., 2005, 2006). CTE is not restricted boxer has retired from the ring. (p.360)
to professional athletes; early stages of CTE
have been also found in high school and col-
legiate athletes and in military veterans after Acute Mild Traumatic Brain Injury:
blast or concussive injury. Military service Subconcussion, Concussion, and
members are at risk for CTE due to hetero- Postconcussion
geneous traumatic exposures often involving
a combination of athletic participation, recre- Although all cases of neuropathologically
ational activities, training practices, as well as verified CTE have been associated with repet-
military combat (McKee etal., 2013). itive minor brain trauma, the pathophysio-
Historically, the concept of a neurodegen- logical mechanisms underlying how trauma
erative disease developing after repeated triggers a progressive neurodegeneration and
minor trauma to the brain was first recog- tauopathy remain inconclusive. Concussion
nized in boxing. The first medical study of and subconcussion are considered forms of
160
CHAPTER 7. Chronic Traumatic Encephalopathy 161
mild traumatic brain injury (mTBI). Mild TBI larger myelinated axons; it remains unclear
is classified by a Glasgow Coma Score of 13 whether this is due to intrinsic susceptibil-
to 15 with transient neurologic deficits fol- ity or because the myelin provides rela-
lowing an acute closed head injury. Although tive protection to axons (Reeves, Phillips, &
concussion and other forms of mTBI are usu- Povlishock, 2005). The microscopic changes
ally self-limited and symptoms resolve over in the brain that are a consequence of con-
a period of several weeks, prolonged symp- cussive injury, such as TAI, are not detect-
toms develop in 10%30% of individuals, a able with conventional structural imaging
condition referred to as postconcussive syn- studies, including computed tomography
drome (PCS) if the symptoms do not resolve (CT) scan and magnetic resonance imaging
in 3months (Dean& Sterr, 2013). Symptoms (MRI). Diffusion tensor imaging (DTI), how-
of concussion and postconcussion include ever, provides information about the white
headaches, dizziness, nausea, fatigue, anxiety, matter microstructure and fiber tract integ-
depression, irritability, sleep disturbances, rity that is useful in assessing the severity
sensitivity to noise and light, and changes in and predicting recovery in individuals with
coordination, balance, appetite, vision, and concussion and mTBI. The severity of symp-
hearing. In PCS, symptoms last for months to toms after mTBI correlates with reduction of
years following the injury and may produce white matter integrity on DTI, providing evi-
permanent disability. Neuropsychological dence that persistent microstructural brain
testing in PCS may reveal persistent, yet sub- injury underlies the persistent symptoms
tle, cognitive deficits, most often in the exec- of PCS (Johnson, Stewart, & Smith, 2012).
utive domain (Bohnen, Jolles, & Twijnstra, Furthermore, DTI is emerging as a valuable
1992). Percussive injuries less severe than tool in refining the diagnosis, prognosis, and
concussion that do not produce overt neu- management of mTBI (Bazarian, Zhu, Blyth,
rological symptoms, yet are associated with Borrino, & Zhong, 2012; Cubon, Putukian,
slight neuropsychiatric deficits or changes Boyer,& Dettwiler, 2011).
in functional magnetic resonance imaging, In addition to the traumatic stretch injury
are referred to as subconcussion (Talavage of axons and other cellular compartments
et al., 2010). Subconcussive injuries can be after mTBI, neurotransmitters, including
substantial in some sports; for instance, it glutamate, are abruptly released with mas-
has been reported that an offensive lineman sive increases in intracellular calcium, glu-
can experience over 1,000 subconcussive hits cose hypermetabolism, kinase activation,
over the level of 10 g in the course of a single and diminished cerebral blood flow (Giza&
season of college football (Crisco etal., 2012). Hovda, 2001). These metabolical distur-
Acceleration and deceleration forces on bances also improve with time and rest, but
the brain, either linear or rotational, produce lasting changes may occur.
concussion and subconcussion (Ommaya & Functional MRI (fMRI) studies have
Gennarelli, 1974). When the firmly gelatinous detected significant alterations in brain acti-
brain, which is suspended in cerebrospinal vation patterns in individuals with persis-
fluid inside a boney skull, is subjected to tent symptoms after mTBI (Chen, Johnston,
rapid acceleration, deceleration, and rota- Petrides, & Ptito, 2008; Chen et al., 2004;
tional forces, the brain elongates and deforms, Gosselin et al., 2011; McAllister et al., 2001;
stretching individual components such as Ptito, Chen,& Johnston, 2007). These abnor-
neurons, glial cells, and blood vessels. These mal brain activation patterns can remain for
traumatic stretch injuries affect neuronal cell months after injury, despite normal neuro-
bodies, axons, dendrites, blood vessels, and cognitive task performance (Chen etal., 2004;
glial cells; axons are especially vulnerable Lovell etal., 2007; McAllister etal., 1999). The
as they often extend long distances from discrepancy between fMRI and neurocogni-
the neuronal cell bodies and may be injured tive testing may be the result of functional
even without the death of the neuron of ori- reallocation of neurocognitive resources as
gin (Maxwell, Povlishock, & Graham, 1997; a compensatory mechanism, followed by a
Medana & Esiri, 2003). Traumatic axonal more prolonged period of microstructural
injury (TAI) does not uniformly affect all axo- recovery (Cubon et al., 2011). In a study of
nal populations. Smaller unmyelinated axons mTBI patients using fMRI to assess the neu-
are more damaged by concussive forces than ral correlate of working memory, patients
162part iiThe Dementias: The Major Diseases and Clinical Syndromes
with more severe postconcussive symptoms hours (Maxwell etal., 1995). The axolemma is
showed increased brain activity in the nor- one of the initial sites of injury; the increased
mal working memory network, as well as the permeability, uncontrolled influx of Ca2+,
recruitment of brain regions outside this net- swelling of mitochondria, disruption of
work (Smits etal., 2009). microtubules, and alterations in axonal trans-
Pathological studies of acute concussion port that follow mTBI produce axonal swell-
and PCS are rare and include subjects with ing and secondary axotomy (Giza& Hovda,
more severe traumatic injuries as well, but 2001; Maxwell etal., 1995). In addition, even
both demonstrate the presence of multifocal in the absence of additional traumatic or vas-
TAI, microhemorrhage, and microglial activa- cular injury, progressive axonal swelling and
tion (Blumbergs, 1944; Oppenheimer, 1968). disconnection can continue for years after
Oppenheimer reported that acute TBI, includ- TBI (Blumbergs, 1944), which contribute to
ing some cases of concussion, was associated the development of progressively greater
with microscopic petechial hemorrhages and disability in some individuals (Johnson etal.,
axonal injury associated with microglial clus- 2012). Determining the pathogenetic mecha-
ters that were often perivascular. Blumbergs nisms underlying continued axonal degen-
and colleagues examined five cases of human eration after TBI and the development of
concussive head injury and reported multifo- progressive late-life neurodegenerative dis-
cal axonal injury using beta-amyloid precur- ease is a critical focus of current research.
sor (-APP) immunohistochemistry in the
fornices, a major hippocampal projection
pathway thought to be important in memory Chronic Traumatic Encephalopathy
(Blumbergs, 1944). The authors suggested that
damage to the fornix might underlie some The symptoms of CTE are insidious, often
of the persisting memory deficits that occur first manifested as disturbances in atten-
in patients after concussion. In general, the tion or concentration or depression that are
amount and distribution of TAI is dependent occasionally associated with headaches.
on the severity of the TBI, with mild injury Short-term memory difficulties, aggres-
producing only microscopic axonal damage sive tendencies, executive dysfunction, and
and moderate and severe TBI producing more explosivity are also frequent symptoms.
severe axonal injury. Characteristically the first symptoms appear
around ages 3545years, although the range
is broad, from 26 years to 65 years (McKee
Axonal Injury in Mild Traumatic Brain Injury etal., 2013). There is characteristically a long
latent period (mean 8years, range 037years)
Severe TAI is also referred to as diffuse axonal between the last trauma and the develop-
injury (DAI) and is characterized by hallmark ment of symptoms (McKee et al., 2009). In
lesions in the corpus callosum and dorsolat- young individuals, it is unclear whether the
eral quadrants of the brainstem, first described symptoms represent prolonged postconcus-
by Strich (Maxwell, McCreath, Graham, & sive symptoms or the early manifestations
Gennarelli, 1995). DAI is only present after the of CTE. Unlike other neurodegenerative
most severe TBIs. Patients who sustain DAI disorders, headache is a persistent and early
are usually unconscious from the moment symptom in nearly half the individuals who
of impact and remain unconscious, vegeta- develop CTE. The headache may be migrain-
tive, or severely disabled until death. In DAI, ous or a constant dull pain. Other personality
axonal retraction balls and axonal swellings and behavioral changes that are common in
are found diffusely distributed in the corpus individuals with early (stage Ior II) CTE are
callosum, internal capsule, cerebral white irritability, explosivity, and erratic behaviors
matter, fornix, midbrain, pons, medulla, and (McKee etal., 2013). By stage III disease, most
cerebellum (Blumbergs, 1944). subjects are considered cognitively impaired
It is now appreciated that axons are not and by stage IV CTE, executive dysfunction
physically transected or sheared at the time and memory loss are usually severe and most
of injury, except in the most severe instances, are demented. Other symptoms often include
but instead they undergo a series of changes impulsivity, suicidality, language difficulties,
that results in a secondary axotomy within 24 paranoia, and visuospatial abnormalities;
CHAPTER 7. Chronic Traumatic Encephalopathy 163
approximately one third are suicidal at some II, the third ventricle may also be slightly
point in their course. Gait disturbances, dys- enlarged. Asmall cavum septum and pallor
arthria, and parkinsonism are found in about of the locus coeruleus and substantia nigra
10% of individuals with CTE in association are occasionally found in stage II. By stage
with late-stage disease. III, mild cerebral atrophy with dilation of the
In CTE, the severity of cognitive impair- lateral and third ventricles is characteristic.
ment is most likely associated with several Septal abnormalities, either cavum septum
pathologies, including neuroinflammation; or septal perforations; atrophy of the mam-
axonal, neuronal, and synapse loss; and the millary bodies, thalamus, and hypothalamus;
accumulation of toxic aggregates of tau and and thinning of the mid-portion of the corpus
TDP proteins. The severity of the tau pathol- callosum are found, and the locus coeruleus
ogy most likely contributes to cognitive and substantia nigra are depigmented. By
decline and behavioral changes, as has been stage IV CTE, there is marked atrophy of the
shown for Alzheimers disease (AD; McKee, medial temporal lobe and, less so, of the cere-
Kosik,& Kowall, 1991); however, there is also bral cortex, white matter, thalamus, hypo-
substantial axonal pathology in CTE, and axo- thalamus, and mammillary body. The brain
nal pathology likely accounts for some of the weight is often significantly diminished and
changes in personality and behavior, especially there is enlargement of the lateral and third
in early stages of disease when the accumula- ventricles, a sharply concave contour of the
tions of hyperphosphorylated-tau (p-tau) are third ventricle, and septal abnormalities.
minimal. Other contributors to clinical symp-
toms include toxic accumulations of TDP-43
Microscopic Pathology
and neuroinflammation. Although the clinical
symptoms of CTE often begin with behavior
Criteria for the Pathological Diagnosis
and personality changes in a persons thirties
or forties similar to those of frontotemporal ofChronic Traumatic Encephalopathy
dementia, the clinical course of CTE is con-
siderably slower and might span three or four In stage I CTE, there are focal epicenters of
decades. When symptoms of CTE begin later in perivascular p-tau neurofibrillary tangles
life, in persons in their fifties and sixties, mem- (NFTs) and astrocytic tangles (ATs), most
ory loss similar to AD is often the outstanding prominent in the sulcal depths and typically
symptom, usually associated with agitation, affecting superior and dorsolateral frontal cor-
aggression, and combative behaviors. tices (Box 7.1 and Table7.1; Figs. 7.1, 7.2, and
7.3). The cortex surrounding the epicenters is
unremarkable except for rare isolated NFTs in
Neuropathology of Chronic Traumatic superficial laminae of adjacent cortex. There
Encephalopathy are no NFTs in deep nuclei, including locus
coeruleus and nucleus basalis of Meynert,
In stage ICTE, there may be mild enlargement hypothalamus, thalamus, brainstem, or spi-
of the frontal horn of the lateral ventricle, but nal cord. In stage II CTE, p-tau pathology is
the brain is otherwise unremarkable. In stage found in multiple foci of the cerebral cortex,
Tau protein Six isoforms All six isoforms present All six isoforms present1
3 or 4 repeat tau 3 repeat and 4 repeat tau 3 repeat and 4 repeat tau present
present
Cell origin
Neuronal NFTs and pretangles NFTs and pretangles
Astrocytic Not present2 Prominent ATs
Neuronal
domain
Cell body Prominent Prominent
Dendrite Prominent Prominent
Axon Sparse Prominent
Cell origin
Perivascular Not present Prominent NFTs and ATs
Foci at depths of Not present Prominent NFTs and ATs
cerebral sulci
Irregular, patchy Not present Prominent
cortical distribution
Cortical laminae Predominantly laminae III Predominantly laminae I-III
and V
Subpial ATs Not present Prominent
Periventricular ATs Not present Present
Astrocytic plaques May be present Not present
Distribution
Mild pathology Braak stages IIII: CTE stages I-II:
NFTs in entorhinal NFTs in focal epicenters in cerebral
cortex, amygdala, and cortex, usually frontal lobe
hippocampus
Advanced pathology Braak stages IVVI: CTE stages III-IV:
High density of NFTs in High density of NFTs in
widespread cortical areas widespread cortical areas and
and medial temporal lobe, medial temporal lobe, patchy
uniform distribution irregular distribution
Low densities of NFTs High densities of NFTs in
in basal ganglia and thalamus, hypothalamus,
brainstem; none in mammillary bodies, brainstem.
mammillary bodies Moderate densities of NFTs in
White matter tracts relatively basal ganglia, especially nucleus
uninvolved. accumbens. Prominent p-tau
pathology in white matter tracts.
1
Schmidt etal. (2001).
2
Low densities of 4R immunoreactive thorn-shaped astrocytes are found in the temporal lobe of some older subjects
and older subjects with Alzheimers disease.
ATs, astrocytic tangles; NFTs, neurofibrillary tangles.
Source:Adapted from McKee etal. (2013).
ALZHEIMERS DISEASE
Figure7.3 How the p-tau pathology of chronic traumatic encephalopathy is distinctive from
Alzheimers disease. (Top row) Alzheimers disease:Double immunostained sections for A (red)
and PHF-1 (brown) show diffuse, relatively uniform cortical distribution of NFTs preferentially
involving laminae III and V, without accentuation at depths of sulci. Small blood vessels at sulcal
depths show no clustering of neurofibrillary pathology perivascularly. There is also no clustering
of neurofibrillary pathology in subpial or periventricular regions. (Bottom row) Chronic traumatic
encephalopathy:Sections immunostained for AT8 showing irregular cortical distribution of p-tau
pathology with prominent subpial clusters of p-tau astrocytic tangles, focal accentuation at depths
of sulci, and distribution of NFTs in superficial cortical laminae I-III. Small blood vessels at bottom
of cortical sulcus show prominent perivascular distribution of astrocytic tangles and NFTs (AT8).
Double immunostained section for A (red) and PHF-1 (brown) (center panel) shows dense NFTs
without A deposition. (See color plate section)
CHAPTER 7. Chronic Traumatic Encephalopathy 167
100 m 100 m
100 m
Figure7.4 The phosphorylated TDP43 pathology of chronic traumatic encephalopathy (CTE). (A, B,
D, and E) Dense pTDP-43 abnormalities are found in the cerebral cortex of stage IV CTE. (C) Dense
pTDP-43 pathology in substantia nigra pars compacta. (F) Pronounced pTDP-43 immunopositive
pathology in the periventricular region of the third ventricle. (All images:50m tissue sections; all
scale bars, 100m) (See color plate section)
AD and diffuse plaques predominate over distribution pattern that overlaps with that
neuritic plaques. found in the TDP pathologic subtype of
frontotemporal lobar degeneration (FTLD).
(A) (B)
*
(C) (D)
Figure7.5 The axonal pathology of chronic traumatic encephalopathy (CTE). (AC) Phosphorylated
neurofilament staining (SMI-34) in cerebral white matter of stage III CTE shows marked reduction
in axonal staining and numerous large, irregular axonal varicosities. Asmall arteriole shows marked
infiltration with hemosiderin-laden macrophages (asterisks). (D) Luxol fast hematoxylin blue-stained
section of white matter shows brisk astrocytosis, loss of myelinated fibers, and macrophages around
vessel (asterisk). (10m tissue sections; scale bars:100m) (See color plate section)
percentage of CTE subjects with A pathol- cases, in subjects who are significantly older
ogy is approximately the same that has been than those without LBs (McKee etal., 2013).
reported after severe acute TBI; diffuse corti- Approximately 16% of CTE cases meet crite-
cal A plaques have been reported in 30% to ria for the concomitant diagnosis of one of
38% of cases after severe acute TBI as early as the Lewy body spectrum disorders, half as
2 hours after injury (Ikonomovic etal., 2004). Parkinsons disease (PD) and half as demen-
In our recent series of 68 cases with CTE, tia with Lewy bodies (DLB). When CTE is
approximately 11% were diagnosed with coex- found in association with DLB-spectrum dis-
istent AD (McKee etal., 2013). In subjects with orders, symptoms of CTE usually appear first
comorbid CTE and AD, significant memory with the development of slowness of move-
loss generally begins in their forties or fifties, ment, gait disturbance, tremor, and, if DLB
occasionally together with behavioral and per- is present, visual hallucinations late in the
sonality changes, in the absence of a family disease course.
history of early-onset AD. In subjects with CTE
and AD, the p-tau pathology tends to be more
florid than found with either disease alone; Chronic Traumatic Encephalopathy and
there is extreme involvement of most regions Frontotemporal Lobar Degeneration
of cerebral cortex, diencephalon, basal ganglia,
brainstem, and spinal cord as well as marked Approximately 6% of subjects with CTE
A deposition. also develop FTLD either as FTLD-tau or
FTLD-TDP (McKee et al., 2013). The most
common FTLD, frontotemporal lobar degen-
Chronic Traumatic Encephalopathy eration with TDP-43-positive inclusions,
and Lewy Body Disease FTLD-TDP, is defined by TDP-43-positive
neuronal cytoplasmic and intranuclear inclu-
Alpha-synuclein-positive Lewy bodies (LBs) sions, dystrophic neurites, and glial cyto-
are found in approximately 22% of CTE plasmic inclusions in the superficial layers
CHAPTER 7. Chronic Traumatic Encephalopathy 169
of cerebral cortex and dentate gyrus (Cairns ganglia, diencephalon, brainstem, anterior
etal., 2007; Dickson, 2009; Litvan etal., 1996). horn cells, and white matter tracts of the spi-
In advanced CTE, the distribution of TDP-43 nal cord (Fig. 7.5; Box 7.2). In CTE + MND
is extremely widespread and in some areas there is also degeneration of lateral and ven-
overlaps with the pattern found in FTLD-TDP. tral corticospinal tracts of the spinal cord and
It is probable that p-tau aggregates promote marked loss of anterior horn cells from the
the aggregation and deposition of other spinal cord. The accumulation of abnormal
pathological proteins such as TDP-43, A, aggregates of p-tau and pTDP-43 is similar
and alpha-synuclein. Alternatively, repetitive to Guam Parkinsonism-dementia complex,
trauma itself might trigger the deposition of another example of an environmentally
multiple proteins (Uryu etal., 2002). acquired tauopathy and TDP-43 proteinopa-
thy (Hirano, 1992). The marked accumula-
tion of pathological pTDP-43 aggregates in
Chronic Traumatic Encephalopathy advanced stages of CTE, the partial immu-
With Motor Neuron Disease nohistochemical colocalization of ptau with
pTDP-43, and the development of MND and
Approximately 10% of individuals with FTLD in some individuals with CTE suggests
CTE develop a progressive motor neuron that CTE and FTLD share similar pathogenic
disease (CTE+MND), characterized by pro- mechanisms (Costanza et al., 2011; King
found weakness, atrophy, spasticity, and etal., 2010).
fasciculations (McKee et al., 2010, 2013).
Most individuals with CTE + MND pres-
ent with symptoms of MND and develop Pathogenetic Mechanisms of Chronic
mild cognitive and behavioral symptoms Traumatic Encephalopathy
several years after the onset of motor weak-
ness and fasciculations. One third of CTE + As a result of the percussive stretch injury to
MND subjects present with depression and neurons, the microtubule associated protein,
behavioral or cognitive changes prior to the tau, normally associated with microtubules in
development of symptoms of motor neuron axons, becomes abnormally phosphorylated,
disease. Individuals with motor neuron dis- misfolded, aggregated, and cleaved, all of
ease and CTE tend to die from respiratory which generate neurotoxicity (Amadoro etal.,
failure at younger ages and in earlier stages 2006; Chen, Wang,& Tseng, 2010; Khlistunova
of CTE (stage II-III) compared to subjects et al., 2006; McKee et al., 2013; Zilka et al.,
without MND. Independent of the stage of 2006). Although evidence suggests that tau
p-tau pathology, subjects with CTE+MND phosphorylation and misfolding is a revers-
show severe TDP-43 pathology as neuronal, ible process at least initially (Stieler etal., 2011;
glial, and neuritic inclusions involving wide- Van der Jeugd et al., 2012; Wolozin, 2012),
spread regions of the central nervous system, repeated traumatic injuries and progressively
including the cerebral hemispheres, basal greater accumulations of abnormal and toxic
BOX 7.2 Criteria for the Diagnosis of Chronic Traumatic Encephalopathy with Motor Neuron
Disease
1. Clinical diagnosis of definite amyotrophic lateral sclerosis using the revised El Escorial
criteria for the diagnosis of amyotrophic lateral sclerosis
2. The pathological diagnosis of chronic traumatic encephalopathy
3. Degeneration of lateral and ventral corticospinal tracts of the spinal cord
4. Marked loss of anterior horn cells from cervical, thoracic, and lumbar spinal cord with
gliosis
5. TDP-43 or pTDP-43 positive neuronal, glial, neuritic, or intranuclear inclusions in ante-
rior horn cells and white matter tracts of the spinal cord
p-tau appear to become self-perpetuating at the brain. In addition, the early and predomi-
some point. Individuals who evolve from nant involvement of the superior and dorso-
acute concussion and postconcussion states lateral frontal lobes in former football players
into a progressive tau-based neurodegenera- parallels the high frequency of impacts to
tion experience progressive clinical deteriora- the top of the head compared to those to the
tion, even though they have retired from their front, back, and side of the head in football
sport or ceased the activities associated with players (Guskiewicz etal., 2007; Mihalik, Bell,
brain trauma. How this progressive neurode- Marshall, & Guskiewicz, 2007), as well as
generation develops after episodes of acute fMRI data showing activation impairments in
minor neurotrauma in all probability involves dorsolateral prefrontal cortex that was asso-
spreading of tau pathology intercellularly and ciated with significantly higher numbers of
extracellularly throughout the brain. head collisions to the top-front of the head
Direct and indirect evidence for interneu- (Talavage etal., 2010).
ronal tau transmission in animal models One of the key features of CTE is that the
suggests that the transfer of toxic tau species disease continues to progress for decades after
between neurons might be due to interneuro- the activity that produced traumatic injury
nal spreading of tau mediated by a prion-like has stopped. It suggests that once the patho-
templated misfolding of tau (Clavaguera etal., logical cascades involved in CTE-related neu-
2009; de Calignon etal., 2012; Guo& Lee, 2011; rodegeneration are triggered, they continue to
Hall& Patuto, 2012; Kim etal., 2010; Liu etal., progress throughout the individuals lifetime.
2012). Other possible modes of transmission In our series of American football players,
involve oligomeric or toxic N-terminal tau in the number of years played (p <.0001), years
the receiving neuron with dysregulation of since retirement (p <.0001), and age at death
intracellular calcium (Frost, Jacks,& Diamond, (p <.0001) significantly correlated with patho-
2009; Park& Ferreira, 2005). Although spread- logical stage of CTE (McKee et al., 2013). In
ing of tau pathology is thought to occur from addition, the degree of aggregated p-tau and
one neuronal synapse to another, transmission TDP-43 protein deposition, neuronal and axo-
involving astrocytes or microglia or cerebro- nal loss, neuroinflammation, cerebral atrophy,
spinal fluid (CSF) pathways is also possible. and ventricular enlargement all increase with
CSF fluid enters the brain parenchyma along longer survival (McKee etal., 2013).
the VirchowRobin spaces surrounding pen-
etrating arteries, and brain interstitial fluid is
cleared along paravenous drainage pathways. Clinical Diagnosis of Chronic Traumatic
Transfer of tau pathology to astrocytes and Encephalopathy
neurons surrounding this clearance pathway
might be at least partially responsible for tau Presently, there are no available biomarkers for
propagation, as has been shown recently for the diagnosis of CTE; however, many promis-
A (Iliff etal., 2012). Clearance through para- ing biomarkers appear to be on the horizon,
venous flow and the CSF might also regulate including diffusion tensor imaging (DTI), func-
extracellular levels of p-tau and TDP-43 and tional connectivity (fMRI), or other advanced
explain the distinctive perivascular, subpial, imaging measures of axonal integrity, magnetic
and periventricular localization of both pro- resonance spectroscopy (MRS) to detect bio-
teins (Hall& Patuto, 2012). The striking sub- chemical metabolites, CSF and plasma protein
pial and periventricular location of abnormal markers (including p-tau and total tau), and
p-tau and p-TDP-43 deposits is a feature of new p-tau ligands to identify p-tau deposition
CTE that is unique from other tauopathies in the CSF and brain (Xia etal., 2013).
such as AD and FTLD-tau, suggesting that
CSF circulation of p-tau might be more severe
in CTE compared to other tauopathies. Genetic Risk for Chronic Traumatic
The patchy irregular location of the p-tau Encephalopathy and the Role of the
pathology suggests that the distribution is Apolipoprotein E Gene
related to direct mechanical injury from blows
to the top of the head; furthermore, the local- In acute TBI, there is evidence that the cogni-
ization to the perivascular region and sulcal tive and behavioral outcome of moderate and
depths corresponds to focal stress points of severe TBI is more severe in Apolipoprotein
CHAPTER 7. Chronic Traumatic Encephalopathy 171
Clavaguera, F., Bolmont, T., Crowther, Giza, C.C.,& Hovda, D.A. (2001). The neuro-
R. A., Abramowski, D., Frank, S., Probst, metabolic cascade of concussion. Journal of
A.,...Tolnay, M. (2009). Transmission and Athletic Training, 36(3), 228235.
spreading of tauopathy in transgenic mouse Goldstein, L. E., Fisher, A. M., Tagge,
brain. Nature Cell Biology, 11(7), 909913. C. A., Zhang, X. L., Velisek, L., Sullivan,
Corsellis, J.A., Bruton, C.J.,& Freeman-Browne, J. A.,...McKee, A. C. (2012). Chronic trau-
D. (1973). The aftermath of boxing. matic encephalopathy in blast-exposed mili-
Psychological Medicine, 3(3), 270303. tary veterans and a blast neurotrauma mouse
Costanza, A., Weber, K., Gandy, S., Bouras, C., model. Science Translational Medicine, 4(134),
Hof, P. R., Giannakopoulos, P., & Canuto, 134ra60.
A. (2011). Review: Contact sport-related Gosselin, N., Bottari, C., Chen, J. K., Petrides,
chronic traumatic encephalopathy in the M., Tinawi, S., de Guise, E.,& Ptito, A. (2011).
elderly: Clinical expression and struc- Electrophysiology and functional MRI in
tural substrates. Neuropathology and Applied post-acute mild traumatic brain injury. Journal
Neurobiology, 37(6), 570584. of Neurotrama, 28(3), 329341.
Courville, C.B. (1962). Punch drunk. Its patho- Guo, J.L.,& Lee, V.M. (2011). Seeding of normal
genesis and pathology on the basis of a veri- Tau by pathological Tau conformers drives
fied case. Bulletin of the Los Angeles Neurological pathogenesis of Alzheimer-like tangles. Journal
Society, 27, 160168. of Biological Chemistry, 286(17), 153171531.
Crisco, J. J., Wilcox, B. J., Machan, J. T., Guskiewicz, K. M., Mihalik, J. P., Shankar,
McAllister, T. W., Duhaime, A. C., Duma, V., Marshall, S. W., Crowell, D. H., Oliaro,
S.M.,...Greenwald, R.M. (2012). Magnitude S. M.,...Hooker, D. N. (2007). Measurement
of head impact exposures in individual col- of head impacts in collegiate football play-
legiate football players. Journal of Applied ers: Relationship between head impact bio-
Biomechanics, 28(2), 174183. mechanics and acute clinical outcome after
Critchley, M. (1957). Medical aspects of boxing, concussion. Neurosurgery, 61(6), 12441252;
particularly from a neurological standpoint. discussion 523.
British Medical Journal, 1(5015), 357362. Hall, G.F.,& Patuto, B.A. (2012). Is tau ready
Cubon, V. A., Putukian, M., Boyer, C., & for admission to the prion club? Prion, 6(3),
Dettwiler, A. (2011). A diffusion tensor imag- 223233.
ing study on the white matter skeleton in Harmon, K. G., Drezner, J. A., Gammons, M.,
individuals with sports-related concussion. Guskiewicz, K. M., Halstead, M., Herring,
Journal of Neurotrama, 28(2), 189201. S. A.,...Roberts, W. O. (2013). American
Dean, P.J.,& Sterr, A. (2013). Long-term effects Medical Society for Sports Medicine position
of mild traumatic brain injury on cognitive statement:concussion in sport. British Journal
performance. Frontiers in Human Neuroscience, of Sports Medicine, 47(1), 1526.
7, 30. Hirano, A. (1992). Amyotrophic lateral sclero-
de Calignon, A., Polydoro, M., Suarez-Calvet, sis and parkinsonism-dementia complex on
M., William, C., Adamowicz, D.H., Kopeikina, Guam: Immunohistochemical studies. Keio
K. J.,...Hyman, B. T. (2012). Propagation of Journal of Medicine, 41(1), 69.
tau pathology in a model of early Alzheimers Hof, P. R., Knabe, R., Bovier, P., & Bouras, C.
disease. Neuron, 73(4), 685697. (1991). Neuropathological observations in
Dickson, D. W. (2009). Neuropathology of a case of autism presenting with self-injury
non-Alzheimer degenerative disorders. behavior. Acta Neuropathologcia, 82(4), 321326.
International Journal of Clinical and Experimental Ikonomovic, M. D., Uryu, K., Abrahamson,
Pathology, 3(1), 123. E. E., Ciallella, J. R., Trojanowski, J. Q., Lee,
Friedman, G., Froom, P., Sazbon, L., Grinblatt, V. M.,...DeKosky, S. T. (2004). Alzheimers
I., Shochina, M., Tsenter, J.,...Groswasser, Z. pathology in human temporal cortex sur-
(1999). Apolipoprotein E-epsilon4 genotype gically excised after severe brain injury.
predicts a poor outcome in survivors of trau- Experimental Neurology, 190(1), 192203.
matic brain injury. Neurology, 52(2), 244248. Iliff, J.J., Wang, M., Liao, Y., Plogg, B.A., Peng,
Frost, B., Jacks, R.L.,& Diamond, M.I. (2009). W., Gundersen, G. A.,...Nedergaard, M.
Propagation of tau misfolding from the out- (2012). A paravascular pathway facilitates
side to the inside of a cell. Journal of Biological CSF flow through the brain parenchyma and
Chemistry, 284(19), 1284512852. the clearance of interstitial solutes, including
Geddes, J. F., Vowles, G. H., Nicoll, J. A., & amyloid beta. Science Translational Medicine,
Revesz, T. (1999). Neuronal cytoskeletal 4(147), 147ra11.
changes are an early consequence of repeti- Johnson, V. E., Stewart, W., & Smith, D. H.
tive head injury. Acta Neuropathologcia, 98(2), (2012). Axonal pathology in traumatic brain
171178. injury. Experimental Neurology, 246, 3543.
174part iiThe Dementias: The Major Diseases and Clinical Syndromes
Jordan, B. D., Relkin, N. R., Ravdin, L. D., traumatic brain injury: A functional MRI
Jacobs, A.R., Bennett, A.,& Gandy, S. (1997). study. Neurology, 53(6), 13001308.
Apolipoprotein E epsilon4 associated with McAllister, T. W., Sparling, M. B., Flashman,
chronic traumatic brain injury in boxing. L. A., Guerin, S. J., Mamourian, A. C., &
Journal of the American Medical Association, Saykin, A. J. (2001). Differential working
278(2), 136140. memory load effects after mild traumatic
Khlistunova, I., Biernat, J., Wang, Y., brain injury. Neuroimage, 14(5), 10041012.
Pickhardt, M., von Bergen, M., Gazova, McKee, A. C., Cantu, R. C., Nowinski, C. J.,
Z.,...Mandelkow, E. M. (2006). Inducible Hedley-Whyte, E. T., Gavett, B. E., Budson,
expression of Tau repeat domain in cell mod- A.E.,...Stern, R.A. (2009). Chronic traumatic
els of tauopathy:aggregation is toxic to cells encephalopathy in athletes: Progressive
but can be reversed by inhibitor drugs. Journal tauopathy after repetitive head injury. Journal
of Biological Chemistry, 281(2), 12051214. of Neuropathology and Experimental Neurology,
Kim, W., Lee, S., Jung, C., Ahmed, A., Lee, G.,& 68(7), 709735.
Hall, G. F. (2010). Interneuronal transfer of McKee, A.C., Gavett, B.E., Stern, R.A., Nowinski,
human tau between Lamprey central neurons C. J., Cantu, R. C., Kowall, N. W.,...Budson,
in situ. Journal of Alzheimers Disease, 19(2), A. E. (2010). TDP-43 proteinopathy and
647664. motor neuron disease in chronic traumatic
King, A., Sweeney, F., Bodi, I., Troakes, C., encephalopathy. Journal of Neuropathology and
Maekawa, S.,& Al-Sarraj, S. (2010). Abnormal Experimental Neurology, 69(9), 918929.
TDP-43 expression is identified in the neo- McKee, A. C., Kosik, K. S., & Kowall, N. W.
cortex in cases of dementia pugilistica, but is (1991). Neuritic pathology and dementia in
mainly confined to the limbic system when Alzheimers disease. Annals of Neurology,
identified in high and moderate stages of 30(2), 156165.
Alzheimers disease. Neuropathology, 30(4), McKee, A. C., Stein, T. D., Nowinski, C. J.,
408419. Stern, R. A., Daneshvar, D. H., Alvarez,
Litvan, I., Hauw, J.J., Bartko, J.J., Lantos, P.L., V.E.,...Cantu, R.C. (2013). The spectrum of
Daniel, S. E., Horoupian, D. S.,...Anderson, disease in chronic traumatic encephalopathy.
D. W. (1996). Validity and reliability of the Brain, 136(Pt 1), 4364.
preliminary NINDS neuropathologic crite- Medana, I. M., & Esiri, M. M. (2003). Axonal
ria for progressive supranuclear palsy and damage:Akey predictor of outcome in human
related disorders. Journal of Neuropathology CNS diseases. Brain, 126(Pt 3), 515530.
and Experimental Neurology, 55(1), 97105. Mihalik, J. P., Bell, D. R., Marshall, S. W., &
Liu, L., Drouet, V., Wu, J. W., Witter, M. P., Guskiewicz, K. M. (2007). Measurement of
Small, S. A., Clelland, C., & Duff, K. (2012). head impacts in collegiate football play-
Trans-synaptic spread of tau pathology in ers: An investigation of positional and
vivo. PLoS One, 7(2), e31302. event-type differences. Neurosurgery, 61(6),
Lovell, M.R., Pardini, J.E., Welling, J., Collins, 12291235; discussion 35.
M. W., Bakal, J., Lazar, N.,...Becker, J. T. Millspaugh, J. (1937). Dementia pugilistica. US
(2007). Functional brain abnormalities are Naval Medical Bulletin, 35, 297261.
related to clinical recovery and time to Omalu, B. I., DeKosky, S. T., Hamilton, R. L.,
return-to-play in athletes. Neurosurgery, 61(2), Minster, R.L., Kamboh, M.I., Shakir, A.M.,&
352359; discussion 960. Wecht, C. H. (2006). Chronic traumatic
Martland, H. (1928). Punch drunk. Journal of the encephalopathy in a national football league
American Medical Association, 91, 11031107. player:Part II. Neurosurgery, 59(5), 10861092;
Maxwell, W.L., McCreath, B.J., Graham, D.I.,& discussion 923.
Gennarelli, T. A. (1995). Cytochemical evi- Omalu, B. I., DeKosky, S. T., Minster, R. L.,
dence for redistribution of membrane pump Kamboh, M. I., Hamilton, R. L., & Wecht,
calcium-ATPase and ecto-Ca-ATPase activity, C. H. (2005). Chronic traumatic encephalop-
and calcium influx in myelinated nerve fibres athy in a National Football League player.
of the optic nerve after stretch injury. Journal Neurosurgery, 57(1), 128134; discussion -34.
of Neurocytology, 24(12), 925942. Ommaya, A. K., & Gennarelli, T. A. (1974).
Maxwell, W. L., Povlishock, J. T., & Graham, Cerebral concussion and traumatic uncon-
D. L. (1997). A mechanistic analysis of non- sciousness. Correlation of experimental and
disruptive axonal injury:Areview. Journal of clinical observations of blunt head injuries.
Neurotrama, 14(7), 419440. Brain, 97(4), 633654.
McAllister, T. W., Saykin, A. J., Flashman, Oppenheimer, D.R. (1968). Microscopic lesions
L.A., Sparling, M.B., Johnson, S.C., Guerin, in the brain following head injury. Journal of
S. J.,...Yanofsky, N. (1999). Brain activation Neurology, Neurosurgery and Psychiatry, 31(4),
during working memory 1month after mild 299306.
CHAPTER 7. Chronic Traumatic Encephalopathy 175
Park, S.Y.,& Ferreira, A. (2005). The generation Talavage, T. M., Nauman, E., Breedlove, E. L.,
of a 17 kDa neurotoxic fragment: An alter- Yoruk, U., Dye, A.E., Morigaki, K.,...Leverenz,
native mechanism by which tau mediates L. J. (2010). Functionally-detected cognitive
beta-amyloid-induced neurodegeneration. impairment in high school football players
Journal of Neuroscience, 25(22), 53655375. without clinically-diagnosed concussion.
Parker, H. L. (1934). Traumatic encephalopa- Journal of Neurotrauma, 31(4), 327328.
thy (`punch drunk) of professional pugi- Uryu, K., Laurer, H., McIntosh, T., Pratico, D.,
lists. Journal of Neurology and Psychopathology, Martinez, D., Leight, S.,...Trojanowski, J. Q.
15(57), 2028. (2002). Repetitive mild brain trauma acceler-
Ptito, A., Chen, J.K.,& Johnston, K.M. (2007). ates Abeta deposition, lipid peroxidation, and
Contributions of functional magnetic reso- cognitive impairment in a transgenic mouse
nance imaging (fMRI) to sport concus- model of Alzheimer amyloidosis. Journal of
sion evaluation. NeuroRehabilitation, 22(3), Neuroscience, 22(2), 446454.
217227. Van der Jeugd, A., Hochgrafe, K., Ahmed,
Reeves, T.M., Phillips, L.L.,& Povlishock, J.T. T., Decker, J. M., Sydow, A., Hofmann,
(2005). Myelinated and unmyelinated axons A.,...Mandelkow, E. M. (2012). Cognitive
of the corpus callosum differ in vulnerability defects are reversible in inducible mice
and functional recovery following traumatic expressing pro-aggregant full-length human
brain injury. Experimental Neurology, 196(1), Tau. Acta Neuropathologcia, 123(6), 787805.
126137. Wolozin, B. (2012). Regulated protein aggrega-
Stieler, J. T., Bullmann, T., Kohl, F., Toien, O., tion:Stress granules and neurodegeneration.
Bruckner, M. K., Hartig, W., .
.
.
Arendt, T. Molecular Neurodegeneration, 7, 56.
(2011). The physiological link between meta- Xia, C.F., Arteaga, J., Chen, G., Gangadharmath,
bolic rate depression and tau phosphoryla- U., Gomez, L.F., Kasi, D.,...Kolb, H.C. (2013).
tion in mammalian hibernation. PLoS One, [(18)F]T807, a novel tau positron emission
6(1), e14530. tomography imaging agent for Alzheimers
Smits, M., Dippel, D. W., Houston, G. C., disease. Alzheimers and Dementia, 9(6), 666676.
Wielopolski, P. A., Koudstaal, P. J., Zilka, N., Filipcik, P., Koson, P., Fialova,
Hunink, M. G., & van der Lugt, A. (2009). L., Skrabana, R., Zilkova, M.,...Novak,
Postconcussion syndrome after minor head M. (2006). Truncated tau from sporadic
injury: Brain activation of working memory Alzheimers disease suffices to drive neuro-
and attention. Human Brain Mapping, 30(9), fibrillary degeneration in vivo. FEBS Letters,
2789803. 580(15), 35823588.
8
Frontotemporal Dementia
Bradford C. Dickerson
The clinical and pathological investigation 1994). A few reports on these diseases were
of frontotemporal dementia (FTD) has a published through the middle of the 20th
complex history dating back over 100years, century, but it was not until the 1980s and
and in the 21st century its clinical and patho- 1990s that interest in these conditions was
logical classification continues to evolve with resurrected with advances in neuroimaging,
groundbreaking new discoveries. This chap- neuropathology, genetics, and related fields.
ter will provide a comprehensive review of Although terminology continues to be con-
FTD with an emphasis on behavioral variant fusing in this family of diseases, we now rec-
FTD; readers are referred to Chapter 9 for a ognize patients with several major forms of
detailed review of primary progressive apha- the clinical entity frontotemporal dementia
sia, the major language variant of FTD. (FTD), including behavioral variant FTD
In 1892, Arnold Pick described a 71-year-old (bvFTD), semantic dementia (SD) or the
patient with progressive cognitive decline, semantic variant of PPA, the nonfluent or
primarily manifesting as early loss of lan- agrammatic variant of PPA, and the logo-
guage (Pick, Girling, & Berrios, 1997). Pick penic variant of PPA. The neuropathological
noted the prominent anterior temporal lobe family of conditions is termed frontotem-
atrophy present in the brain of this patient, poral lobar degeneration (FTLD). FTLD is a
and he subsequently reported three further loosely knit group of neurodegenerative dis-
casesincluding very clear descriptions of eases that preferentially affect the frontal and
clinical and gross postmortem features. The anterior temporal lobes, with relative sparing
associated histologic abnormalities identi- of other cortical regions in many cases, and
fied microscopically were later described by often affects basal ganglia and in some cases
Alois Alzheimer, and in the 1920s the term basal forebrain and brainstem nuclei.
Picks disease was coined by Onari and For most of the 20th century, patients with
Spatz. As early as 1927, Schneider described progressive dementias presenting with prom-
the clinical course of the disease, highlighting inent early behavioral change were diagnosed
the insidious early changes in behavior and with Picks disease. In a series of studies
personality and, contrasted with Alzheimers starting in 1982, Mesulam reinvigorated the
disease (AD), the typical relative preserva- interest of the neurology and psychiatry com-
tion of memory and orientation into the mid- munities in progressive degenerative apha-
dle phases of the disease (Berrios& Girling, sias, which he termed primary progressive
176
CHAPTER 8. Frontotemporal Dementia 177
aphasia (PPA) (Mesulam, 1982). In the 1980s, (Harvey Skelton-Robinson, & Rossor, 2003;
the Lund (Gustafson, 1987) and Manchester Ratnavalli, Brayne, Dawson, & Hodges,
(Neary, Snowden, Northen, & Goulding, 2002) and one from Northern Italy (Borroni
1988)groups reported important early studies et al., 2010) to 35 per 100,000 cases from a
generating renewed interest in the behavioral recent door-to-door investigation in Southern
phenotype of FTD, soon thereafter proposing Italy (Bernardi et al., 2012). With regard to
clinical and pathological diagnostic criteria incidence, an American study revealed inci-
(Brun et al., 1994). In the late 1990s, formal dence rates in Rochester, Minnesota, of 2.2
international consensus research diagnostic per 100,000 between ages 40 and 49, 3.3 per
criteria (Neary et al., 1998) were developed 100,000 between ages 50 and 59, and 8.9 per
for three clinical subtypes of FTLD: fronto- 100,000 between ages 60 and 69 (Knopman
temporal dementia, progressive nonfluent etal., 2004).
aphasia, and semantic dementia. In 2001, One of the major challenges in this field is
McKhann and others proposed simpler cri- the large number of potential ways FTLD can
teria for the practicing clinician (McKhann be classified, yet this stems in part from many
et al., 2001), although some authors have exciting new developments in the field. For
criticized these criteria as being too vague. instance, there is an the increasing number of
Important advances were formalized in 2011 ways these diseases overlap with other neu-
when new consensus diagnostic criteria were rodegenerative diseases, including progres-
published for PPA (Gorno-Tempini et al., sive supranuclear palsy (PSP), corticobasal
2011) and bvFTD (Rascovsky et al., 2011). degeneration (CBD), and amyotrophic lateral
These criteria were then largely incorporated sclerosis (ALS).
with some simplification into the fifth edition
of the American Psychiatric Associations
Diagnostic and Statistical Manual of Mental Neuropathology of Frontotemporal
Disorders in 2013. Lobar Degeneration
(A) (D)
(B) (E)
(C) (F)
Figure 8.1 Tau pathology in a case of classical Picks disease prominently affects neuronal and
glial cells in gray matter (A, labeling with AT8 [phosphorylated tau] immunohistochemistry)
and also usually demonstrates prominent abnormalities in white matter (B, labeling with AT8
immunohistochemistry) of frontal and temporal cortices, including the dentate gyrus of the
hippocampus, with sparing of primary cortices particularly Heschls and calcarine cortex (C, absent
labeling with AT8 immunohistochemistry). The hippocampus (D, low-power hematoxylin and
eosin stain) also classically shows dense, smooth-contoured rounded cytoplasmic inclusions in
granule cells of the dentate gyrus (E, high-power hematoxylin and eosin stain), which are labeled
with AT8 immunohistochemistry (F). (See color plate section)
summarized as atrophy and substantial tau structures are variably affected, with some
pathology in prefrontal cortex, frontoinsula, patients showing minimal pathology and
anterior cingulate, and anterior temporal others exhibiting substantial pathology
cortex with relative sparing of the superior (Dickson, 2001). In recent years, Picks disease
temporal gyrus, especially its posterior third, has been conceptualized as part of a spectrum
as well as primary visual cortex (Hof, Bouras, of tauopathies that can present as bvFTD,
Perl,& Morrison, 1994; Yoshimura, 1989)(see including progressive supranuclear palsy
Fig.8.1). Prominent white matter tau pathol- and corticobasal degeneration and other less
ogy is commonly present (Zhukareva et al., common forms (Dickson, Kouri, Murray, &
2002). Some investigators have called atten- Josephs, 2011; Kertesz, Davidson,& Munoz,
tion to the heavy tau burden near the cortical 1999).
gray matterwhite matter junction, includ- Yet it eventually became clear that some
ing deep cortical layers and immediately patients with what otherwise appeared
subjacent white matter (Dickson, 2001). The clinically to have a frontal lobe-type demen-
basal ganglia, basal forebrain, and brainstem tia did not exhibit classical Picks disease.
CHAPTER 8. Frontotemporal Dementia 179
very early in the course of the C9ORF72 pathology of any given case of FTLD may
bvFTD phenotype (Boeve et al., 2012). PPA also involve these brain regions and systems.
phenotypes appear to be uncommon in Nevertheless, although the clinical syndrome
patients with this mutation. Thus, a growing may include extrapyramidal symptoms, for
research effort is being devoted to trying to example, the patient usually would not be mis-
understand genetic and other modifiers of taken for having Parkinsons disease because
these disease-associated mutations. of the presence of prominent language and/
With regard to clinical practice of genetic or behavioral symptoms. Furthermore, the
testing in patients with FTD, we and other patient may not in fact have a phenotype best
specialty groups follow an approach simi- described as parkinsonism because the
lar to that outlined in recent reviews (Fong, phenomenon is gait apraxia with axial rigid-
Karydas, & Goldman, 2012; Goldman et al., ity, which would probably best be described
2011; Quaid, 2011). First, we carefully obtain more specifically as PSP-like. These issues
a family history ideally encompassing three can be complicated, but it is important to rec-
generations, recording each blood relatives ognize the wide range of clinical phenomena
age of death, cause of death if known, and that can be caused by FTLD pathology.
general cognitive/behavioral/neuropsychi- For the purposes of diagnosis, it is essen-
atric status in later life. We acknowledge with tial to try to determine the earliest clinical
the family that FTD and related conditions symptoms that were initially present, which
were often not diagnosed or may have been may or may not be the symptoms most trou-
misdiagnosed in prior generations. Autopsy blesome to the patient and/or family at the
results from a family member provide criti- time of presentation. Since many of the early
cal information, but autopsies were not com- symptoms are related to changes in affect or
monly obtained. If there is a potential family personality, it is not surprising that patients
history of FTD or related disorders, we ask may first present to psychiatrists or other
the family to try to obtain additional infor- mental health professionals. In our initial
mation or records about the affected relatives visit with a new patient, we always interview
and to consider pursuing genetic testing and examine the patient independently from
after first meeting with our groups genetic our interview of the informant(s). Although
counselor. If there is clearly not a family his- time consuming, this approach facilitates an
tory of FTD or related disorders, and fam- open discussion of symptoms (informants
ily members lived past typical age of onset, may be uncomfortable discussing some
there is a low likelihood of the presence of a issues in front of the patient) and enables
genetic mutation. If family history informa- the clinician to evaluate insight and concern
tion is unavailable or blood relatives died at in the patient separately from influence by
a younger age, we suggest that the patient/ informants. Lack of awareness or concern is
family work with our genetic counselor often a core element of the clinical presenta-
to discuss the issues involved. In a patient tion in patients with bvFTD.
with an onset younger than 50, we and oth-
ers often recommend that the patient/family
consider genetic testing. Arecent study pres- Behavioral Variant Frontotemporal Dementia
ents a useful classification system for indicat-
ing the likelihood of a genetic mutation in a FTLD neuropathology is often associated
case of FTD (Wood etal., in press). with a clinical phenotype involving the insidi-
ous development of changes in interpersonal
and emotional behavior, commonly accom-
Clinical Characteristics of Frontotemporal panied by executive dysfunction. This clini-
Lobar Degeneration cal syndrome has traditionally been referred
to as Picks disease, starting with descrip-
The symptoms of these disorders are tions by Arnold Pick followed by Onari and
strongly related to the particular frontotem- Spatz, Schneider, Goldstein, and a series of
poral or frontostriatal brain regions that are other early- to mid-20th-century investiga-
affected. Symptoms referable to extrapyra- tors. Interest was resurrected by a number of
midal, brainstem, and upper/lower motor groups later in the 20th century, but formal
neuron systems may be present because the diagnostic criteria were not published until the
182part iiThe Dementias: The Major Diseases and Clinical Syndromes
Lund-Manchester criteria in 1994 (Brun etal., very active, jocular, and make rash decisions
1994), and then revised by an international or go on spending sprees can be mistak-
consensus group in 1998 (Neary etal., 1998). enly diagnosed with mania or hypomania.
Based on a variety of concerns regarding Disinhibition appears to be related particu-
prior criteria (Rascovsky et al., 2007), new larly to orbitofrontal and cingulo-opercular
international consensus diagnostic criteria abnormalities in FTD (OCallaghan, Hodges,
were published in 2011 (Rascovsky et al., & Hornberger, 2013).
2011)and are summarized in Table8.1. BvFTD Another very common early symptom is
appears to be the most common variant of apathy, including loss of interest in hobbies
FTLD. The specific symptoms of this variant or leisure activities and social withdrawal
depend on the particular regions of frontotem- (Chow et al., 2009; Massimo et al., 2009;
poral cortical and frontostriatal brain systems Shinagawa, Ikeda, Fukuhara, & Tanabe,
that are involved and their laterality. 2006); these behavioral changes are often
Disinhibition is a common early symptom, mistaken for depression. Yet patients with
and it can manifest as socially inappropriate bvFTD do not usually exhibit sadness or
behavior such as overly familiar interactions cry; do not talk about concerns, worries, or
with strangers; loss of manners or viola- thoughts of worthlessness or hopelessness;
tions of social normative behavior such as and do not usually exhibit the loss of appe-
public urination or changes in behavior dur- tite or sleep disturbance often seen in depres-
ing social meals; or impulsive actions such sion. Some investigators have suggested that
as unnecessary or excessive purchasing or bvFTD may present as a disinhibited or
shoplifting (Miller etal., 1991; Miller, Darby, inert (apathetic) subtype (Snowden et al.,
Benson, Cummings,& Miller, 1997; Snowden 2001), while many patients present with
et al., 2001). Sometimes patients who are intermixed symptoms of both types (Le Ber
CHAPTER 8. Frontotemporal Dementia 183
et al., 2006). Atrophy in the anterior cingu- cases becoming simpler. Simple repetitive
late cortex, dorsolateral prefrontal cortex behaviors include tapping or moving a limb,
(Massimo et al., 2009), and striatum (Rosen licking lips, picking skin, grunting, or moan-
etal., 2005)has been observed in association ing. These may appear similar to choreiform
with apathy in bvFTD. movements seen in dyskinetic movement
Loss of empathy or sympathy toward the disorders or tardive dyskinesia. Anatomic
spouse, other family members, and friends abnormalities associated with compulsive
is very common and can be subtle in some behaviors include striatal and anterior tempo-
cases, depending in part on premorbid per- ral atrophy (Josephs, Whitwell,& Jack, 2007;
sonality traits (Lough etal., 2006; Mendez& Perry etal., 2012; Rosso etal., 2001).
Perryman, 2003; Rankin, Kramer, & Miller, Changes in eating behavior are common
2005). These behavioral changes may con- and may include altered food preferences
cern family members for some time before it (such as an increased sweet tooth or a rigid ste-
becomes obvious that something is wrong, reotypy in the foods eaten from day to day) or
which often occurs when the patient exhib- gluttonous or binge-like eating (Bozeat etal.,
its a highly unusual response to an event 2000; Miller, Darby, Swartz, Yener, & Mena,
that almost universally provokes a vigorous, 1995). This maybut does not always
uniform emotion in most people, such as the result in substantial weight gain. Normative
death of a close friend or family member or social eating conventions are often violated,
the birth of a child. Even under these circum- including rapid eating or stuffing food in the
stances, the behavior is commonly attributed mouth, taking food from others plates, or
to depression or another psychiatric illness belching. Patients may exhibit changes in the
or to stress or a midlife crisis. Right anterior consumption of alcohol or cigarettes, some-
temporal cortex, anterior insula, and striatal times resulting in extreme intoxication or
abnormalities have been most consistently vomiting. Occasionally early, but more often
identified as related to loss of empathy (Perry later, in the course of the disease patients may
etal., 2001; Rankin etal., 2006). explore inedible objects by placing them in
Compulsive, ritualistic, or repetitive behav- their mouth, similar to the behavior seen in
iors are common in bvFTD, often early in the Kluver Bucy syndrome. The neurobiologic
illness, and can be very distressing to fam- basis of changes in eating behavior in FTD
ily members (Ames, Cummings, Wirshing, has received little investigation, but it appears
Quinn, & Mahler, 1994; Nyatsanza et al., to involve right lateralized ventral anterior
2003). In some cases, they may be the present- insula, striatum, and orbitofrontal cortex on
ing symptom (Mendez, Perryman, Miller, structural magnetic resonance imaging (MRI)
Swartz, & Cummings, 1997). Examples of voxel-based morphometry (Whitwell et al.,
these symptoms include repetitive projects 2007; Woolley etal., 2007), as well as hypothal-
(e.g., stereotyped writing of greeting cards), amus (Piguet, Petersen, etal., 2011).
chores (e.g., repeated emptying of trash), Executive dysfunction (problems with
or playing of card or computer games or organization, planning, sequencing, decision
repetitive watching of a particular television making, multitasking, or monitoring perfor-
show (Bozeat, Gregory, Ralph, & Hodges, mance) is very common in bvFTD (Bozeat
2000). Speech patterns may be stereotyped et al., 2000). Symptoms described by family
(e.g., catch phrases, telling of stories as if by members often include difficulty with finan-
a script). Some of these symptoms appear cial management, poor decision making,
similar to those of obsessive-compulsive dis- inability to complete tasks (particularly novel
order (OCD) but usually bvFTD patients do tasks), or not recognizing or correcting mis-
not describe obsessive thoughts or any relief takes. Despite the report of these symptoms
of such thoughts by a compulsive activity, as in daily life, patients may still perform within
is typically described in primary OCD. Some normal limits on neuropsychological tests of
patients have very rigid routines that must executive function (Gregory& Hodges, 1996).
be performed identically each day (often at a Progressive loss of executive abilities may
particular time, associated with clock watch- lead to job loss or disastrous mismanagement
ing); if these routines are disrupted, some of money. In many cases, it can be difficult to
patients become very upset. These symptoms determine which problems in daily life are
may change as the disease progresses, in some caused by executive dysfunction as opposed
184part iiThe Dementias: The Major Diseases and Clinical Syndromes
to apathy. This is not surprising given that behaviors, such as hoarding, and those
constructs of the executive functions usually involving changes in appetitive drives, such
include initiation or energization as a com- as sexual, eating, or drinking behaviors.
ponent process (see Chapter 3). Although Despite the inclusion in the new bvFTD diag-
executive dysfunction is typically thought nostic criteria of the relative preservation of
of as being caused by dorsolateral prefron- memory, memory impairment can be a prom-
tal cortical involvement, as also discussed inent early feature in some cases of bvFTD
in Chapters2 and 3, it can originate in ante- (Hornberger, Piguet, Graham, Nestor, &
rior cingulate, insular, parietal, or subcortical Hodges, 2010; Pennington, Hodges, &
nodes of large-scale executive systems. Hornberger, 2011), including those that are
Another important clinical feature of pathologically proven (Graham etal., 2005). In
bvFTD is lack of insight. This symptom some cases, memory symptoms are reported
was considered a core element of the Neary by the patient and/or family, but test perfor-
et al. (1998) diagnostic criteria but was mance is normal; this may reflect executive
not included in the new international con- contributions to memory encoding or retrieval
sensus diagnostic criteria because it was in daily life, which may be relatively controlled
thought to be too difficult to ascertain con- in the office setting (Pasquier, Grymonprez,
sistently. Nevertheless, it is well established Lebert,& Van der Linden, 2001). In other cases,
that many patients with bvFTD, and some day-to-day memory is preserved but psycho-
patients with semantic dementia, have a metric test performance is impaired due to the
striking lack of insight (Banks& Weintraub, magnitude of executive or semantic deficits,
2008; Eslinger et al., 2005; Williamson et al., thereby resulting in an overestimation of mem-
2009) even when confronted with obvious ory impairment. In our clinical practice, we do
impairments. Clinically, this can be particu- not avoid the clinical diagnosis of bvFTD in a
larly challenging when the patient refuses patient with well-documented amnesia if the
to make office follow-up visits because he or remainder of the clinical presentation is con-
she is convinced there is not a problem. Lack sistent with bvFTD, especially if supported by
of insight in FTD has been associated with neuroimaging test results.
right-lateralized ventromedial prefrontal Unlike the language-dominant types of
atrophy (Rosen etal., 2010). FTLD, language may be relatively intact early
Another core feature of bvFTD is person- in the course of bvFTD. This is particularly true
ality change. Alterations in personality can on basic neuropsychological tests of language
be prominent in bvFTD and also in semantic performance. Higher level language abilities
dementia (Rankin, Baldwin, Pace-Savitsky, at the level of discourse (Ash etal., 2006), as
Kramer, & Miller, 2005). Although well as emotionally laden forms of communi-
questionnaire-based instruments to assess cation, including prosody, irony, sarcasm, and
classical dimensional personality traits are humor, are often abnormal early in the course
readily available, changes in personality of bvFTD (Kipps, Nestor, Acosta-Cabronero,
might be best understood clinically by con- Arnold, & Hodges, 2009; Perry et al., 2001).
sidering more specific process-oriented func- As the disease progresses, semantic and other
tions contributing to personality traits. When impairments often become prominent.
faced with a family member who says, My Psychosis has been thought unusual in
spouse is not the person I married, his/her bvFTD, but the discovery of the C9ORF72
personality is completely different, it is expansion has highlighted the common pres-
incumbent upon the clinician to probe fur- ence of psychosis in patients as well as non-
ther to ascertain the specific changes being demented family members with this genetic
described. Some symptoms may include mutation (Boeve etal., 2012).
changes in the expression or comprehen-
sion of emotion, social withdrawal or disin-
hibition, or loss of empathy. In some cases Progressive Aphasic Subtypes of
a previously gruff or aggressive individual Frontotemporal Lobar Degeneration
becomes docile. The patients insight into
these changes is often poor. Other symp- The other major clinical phenotype of FTLD
toms that may also be described as person- involves a primary language disturbance. If
ality changes include obsessive-compulsive a patient presents with an isolated, gradually
CHAPTER 8. Frontotemporal Dementia 185
neuroimaging may be valuable for the inves- and functional neuroimaging may be normal
tigation of anatomic, metabolic, or perfusion early in the course of what ultimately declares
abnormalities in FTLD. See Chapter 22 for itself over time as FTD (Gregory etal., 1999).
more details about these techniques and data Electroencephalography is not commonly
interpretation. recommended in the diagnostic evaluation of
MRI is critical in the diagnostic workup suspected FTD, but it may demonstrate ante-
of suspected FTLD for both the exclusion of rior or focal slowing consistent with frontal
other potential causes of slowly progressive neurodegeneration.
frontal lobe syndromes, such as tumors, cere- Cerebrospinal fluid (CSF) biomarkers are
brovascular disease, or the newly identified being investigated in FTLD (Hu etal., 2011),
sagging brain syndrome (see Chapter 15) but they are not yet mature enough for use
and for the identification of abnormalities in clinical practice. In some cases, the exclu-
consistent with FTLD neurodegenerative sion of an atypical form of AD can be helpful
syndromes. Frontal and/or anterior tem- by analyzing CSF for amyloid- and tau (see
poral atrophy is the typical finding, and it Chapter22). General CSF investigation may
is often more prominent in the right hemi- be valuable to rule out other neurologic dis-
sphere in bvFTD and the left hemisphere orders if the patient has atypical features or a
in PPA (Fig. 8.3A). Metabolic or perfusion more rapid course (see Chapter15).
imaging can be useful in addition to MRI If clinical evidence of motor neuron disease
for the identification of abnormalities when is present, especially if it is subtle, electromy-
anatomic changes are subtle or undetectable ography can provide valuable information
(Fig. 8.3B). In some cases, both structural regarding the presence of upper or lower
(A) (B)
RH LH
RH - Lateral
Figure8.3 A58-year-old man presented with behavioral symptoms (including apathy, impulsive
eating) and executive dysfunction. (A) Magnetic resonance imaging (MRI) demonstrated bilateral
(right greater than left) frontal, temporal, and parietal atrophy, quantified with a map of cortical
thickness compared to controls. (B) Fludeoxyglucose positron emission tomography (FDG-PET)
showed prominent bilateral (right greater than left) frontal and temporal hypometabolism. This
man was found to have a Q300X (premature termination) mutation in GRN. He exhibited a 5-year
clinical course from first symptoms to death. Postmortem examination revealed the expected
TDP-43 pathology. (See color plate section)
188part iiThe Dementias: The Major Diseases and Clinical Syndromes
Left, Lateral
Figure8.4 A59-year-old man presented with behavioral symptoms (including loss of empathy,
aggression, lack of insight), executive dysfunction, and word-finding difficulties. Shortly thereafter
he developed dysarthria and dysphagia and was found to have clinical evidence of motor neuron
disease with bulbar predominance (tongue weakness, fasciculations, lip weakness, as well as mild
shoulder weakness and fasciculations with lower extremity hyperreflexia and extensor plantar
responses). Electromyography showed sharp waves, fibrillation potentials, and fasciculation
potentials in cervical, thoracic, and lumbar myotomes with long-duration, high-amplitude
polyphasic potentials with reduced recruitment and rapid firing. (A) Magnetic resonance
imaging (MRI) demonstrated bilateral (left greater than right) frontal atrophy, quantified with a
map of cortical thickness compared to controls. He exhibited a 3.5-year clinical course from first
symptoms to death. (B) Postmortem examination revealed the expected TDP-43 pathology (TDP-43
immunohistochemistry of dentate gyrus of hippocampus). (See color plate section)
motor neuron dysfunction, which may be AD cases, and eight controls. The FTLD
critical for prognosis (Fig.8.4). cases included five patients with behavioral
FTD, two with FTD/ALS, four with semantic
dementia, and one with progressive aphasia.
In Vivo Neuroimaging of The results indicated that all AD patients had
Neuropathologic Markers positive PiB PET scans, seven out of eight
controls had negative PiB scans, and eight
With the advent of neuroimaging tracers that of twelve FTLD cases had negative PiB PET
bind to specific pathologic molecules, such as scans.
Pittsburgh compound B (PiB) (Klunk et al., Although this initially seemed to be a high
2004)or the growing number of putative tau number of amyloid-positive FTLD cases, it
ligands (Chien et al., 2013; Fodero-Tavoletti may not be particularly surprising in light of
et al., 2011; Maruyama et al., 2013; Small several autopsy studies showing the presence
etal., 2006), it is possible to investigate clini- of AD pathology in 20%30% of FTLD cases,
copathologic relationships in vivo. Extensive with or without the presence of additional
efforts are under way to develop tracers spe- FTLD-type pathology (Davies et al., 2005;
cific for additional pathologic markers. This Forman et al., 2006; Kertesz, McMonagle,
will surely lead to a revolution in our under- Blair, Davidson, & Munoz, 2005; Knibb,
standing of the spectrum of frontotemporal Xuereb, Patterson,& Hodges, 2006). The dis-
dementias. In the first study of FTLD with tribution of PiB tracer uptake in these four
PiB, a comparison was made between PiB cases was similar to that typically seen in AD.
tracer uptake in twelve FTLD cases, seven Two of the cases carried clinical diagnoses
CHAPTER 8. Frontotemporal Dementia 189
of behavioral FTD, and the other two were Gustafson, 2003). A more recent study sug-
clinically diagnosed with semantic demen- gests a slightly better prognosis for bvFTD
tia. Of note, however, some elements of the patients, with a median survival of 4.2years
cognitive profiles and the fludeoxyglucose from diagnosis (Garcin et al., 2009). The
positron emission tomography (FDG-PET) development of early motor symptoms or
metabolic deficits of these four cases showed signs is a poor prognostic feature in all forms
features more often associated with AD than of FTD (Hu etal., 2009), as is early language
FTLD. Of the two FTLD patients who have impairment in bvFTD (Garcin et al., 2009).
come to autopsy in this series, one had a Recent data suggest that semantic dementia
tauopathy and one had a ubiquitinopathy; patients may commonly have a very slow
both were PiB negative. progression, with 50% of patients alive at
Subsequent to this initial study, Rabinovici 12.8years after diagnosis in a large cohort of
and colleagues have performed further inves- 100 patients (Hodges et al., 2010). The ulti-
tigation of the utility of amyloid imaging mate development of markers of the specific
in PPA and FTLD. A series of PPA patients form of neuropathology may be important
produced results that were consistent with for prognostication, with one autopsy study
expectations from pathologic series, with of 71 patients indicating that tau pathology
elevated cortical PiB binding in one out of six was associated with shorter (3 years) sur-
cases of agrammatic/nonfluent PPA, one out vival than non-tau forms of FTLD pathology
of five cases of semantic PPA, and four out of (8years) (Xie etal., 2008).
four cases of logopenic PPA (Rabinovici etal., In our practice, we always discuss the
2008). In a comparison of amyloid PET versus value of autopsy with family members and
FDG-PET imaging in the differential diagno- with patients if possible. Despite continued
sis of AD versus FTLD, PiB and FDG showed improvements in the use of clinical and bio-
similar overall accuracy in discriminating marker data for probabilistic prediction of
AD and FTLD, but PiB was more sensitive to FTLD or non-FTLD pathology, every special-
AD when interpreted qualitatively or quan- ized center continues to observe surprising
titatively. FDG was more specific, but only cases (Figs. 8.5 and 8.6). Not only is this infor-
when scans were classified quantitatively. mation important for providing family mem-
PiB slightly outperformed FDG in the small bers with the greatest detail possible about
subset of patients with known histopathol- the patients disease, it also contributes in
ogy (Rabinovici etal., 2012)(see Chapter22 extremely valuable ways to ongoing research
for further discussion). efforts.
(A) (D)
(B)
(E)
(C)
Figure8.5 A50-year-old man presented with unilateral dominant hand apraxia and depression
without rigidity, alien hand syndrome, or eye movement abnormalities, followed shortly by
executive dysfunction, word-finding difficulty, and memory loss. The initial neuroimaging
examination revealed markedly asymmetric dominant hemisphere fludeoxyglucose positron
emission tomography (FDG-PET) hypometabolism (A, B, C, left column) and atrophy (A, B, C,
right column) extending from perirolandic and dorsal parietal cortex (A) into perisylvian cortex
(B) and ventral temporal cortex (C) with relative preservation of frontal cortex and striatum. His
symptoms progressed to include marked upper extremity apraxia with the eventual development
of rigidity, aphasia, dysarthria, episodic and semantic memory impairment, compulsive behavior,
impulsive eating, and agitation. Along with the progression of symptoms, atrophy progressed from
(D) parietal and posterolateral temporal over a 4-year interval to include (E) ventral and anterior
temporal, insular, and posterior frontal cortex. (See color plate section)
(Cardarelli, Kertesz,& Knebl, 2010). Amulti- (Jicha& Nelson, 2011; Manoochehri& Huey,
disciplinary team of specialists is invaluable 2012; Piguet, Hornberger, Mioshi,& Hodges,
in caring for patients and families suffering 2011). For example, selective serotonin reup-
from FTD (Wylie, Shnall, Onyike, & Huey, take inhibitors or other antidepressants can
2013). Pharmacologic and nonpharmacologic modulate disinhibition or compulsive behav-
management depends on the identification ior, stimulants or pro-dopaminergic agents
and grading of severity of specific symptoms can sometimes reduce apathy or attentional
(including cognitive, behavioral, and motor impairment, and anticonvulsants/mood
symptoms), followed by their prioritiza- stabilizers or antipsychotic compounds can
tion and monitoring over time. Once this is ameliorate aggression or agitation. Yet side
done, judicious empiric use of medications effects of these medications may in some
can be tackled. At present, no medications cases outweigh benefits and always need
are approved for the symptomatic treatment close monitoring.
of FTD, but many medications have demon- Nonpharmacologic symptom management
strated utility in small studies or case series strategies generally require the expertise of
CHAPTER 8. Frontotemporal Dementia 191
(A) (B)
(C) (D)
Left Lateral
Figure8.6 The 50-year-old man described in Figure8.5 exhibited an 8-year clinical course from
first symptoms to death. Despite (A) the clear magnetic resonance imaging (MRI) evidence of initial
perirolandic and parietotemporal atrophy (left greater than right), quantified with a map of cortical
thickness compared to controls with (B) postmortem support for these gross findings, histological
examination revealed (C) Pick bodies and (D) tau immunoreactive pathology consistent with
pathological Picks disease. (See color plate section)
Ultimately, the quality of the partnership associated with the GGGGCC repeat expan-
between care providers experienced with sion in C9ORF72. Brain, 135, 765783.
FTD and patients/families with these dis- Borroni, B., Alberici, A., Grassi, M., Turla, M.,
eases is a critical factor that influences the Zanetti, O., Bianchetti, A.,...Padovani, A.
(2010). Is frontotemporal lobar degeneration
experience of living with FTD.
a rare disorder? Evidence from a prelimi-
nary study in Brescia county, Italy. Journal of
References Alzheimers Disease, 19, 111116.
Bozeat, S., Gregory, C. A., Ralph, M. A., &
Alzheimer, A. (1911). Uber eigenartige Hodges, J.R. (2000). Which neuropsychiatric
Krankheitsfalle der spateren Alters. Zeitschrift and behavioural features distinguish fron-
fr die gesamte Neurologie und Psychiatrie, 4, tal and temporal variants of frontotemporal
356385. dementia from Alzheimers disease? Journal
Ames, D., Cummings, J. L., Wirshing, W. C., of Neurology, Neurosurgery and Psychiatry, 69,
Quinn, B., & Mahler, M. (1994). Repetitive 178186.
and compulsive behavior in frontal lobe Brun, A., Englund, E., Gustafson, L., Passant,
degenerations. Journal of Neuropsychiatry and U., Mann, D., Neary, D., & Snowden, J. S.
Clinical Neuroscience, 6, 100113. (1994). Clinical and neuropathological crite-
Ash, S., Moore, P., Antani, S., McCawley, G., ria for frontotemporal dementia. The Lund
Work, M., & Grossman, M. (2006). Trying to and Manchester Groups. Journal of Neurology,
tell a tale:Discourse impairments in progres- Neurosurgery and Psychiatry, 57, 416418.
sive aphasia and frontotemporal dementia. Bugiani, O., Murrell, J. R., Giaccone, G.,
Neurology, 66, 14051413. Hasegawa, M., Ghigo, G., Tabaton,
Baker, M., Mackenzie, I. R., Pickering-Brown, M.,...Ghetti, B. (1999). Frontotemporal
S. M., Gass, J., Rademakers, R., Lindholm, dementia and corticobasal degeneration in a
C.,...Hutton, M. (2006). Mutations in pro- family with a P301S mutation in tau. Journal
granulin cause tau-negative frontotemporal of Neuropathology and Experimental Neurology,
dementia linked to chromosome 17. Nature, 58, 667677.
442, 916919. Cardarelli, R., Kertesz, A.,& Knebl, J.A. (2010).
Banks, S.,& Weintraub, S. (2008). Self-awareness Frontotemporal dementia: A review for
and self-monitoring of cognitive and behav- primary care physicians. American Family
ioral deficits in behavioral variant frontotem- Physician, 82, 13721377.
poral dementia, primary progressive aphasia Chien, D.T., Bahri, S., Szardenings, A.K., Walsh,
and probable Alzheimers disease. Brain and J. C., Mu, F., Su, M. Y.,...Kolb, H. C. (2013).
Cognition, 67, 5868. Early clinical PET imaging results with the
Bernardi, L., Frangipane, F., Smirne, N., Colao, novel PHF-tau radioligand [F-18]-T807.
R., Puccio, G., Curcio, S. A.,...Bruni, A. C. Journal of Alzheimers Disease, 34, 457468.
(2012). Epidemiology and genetics of fronto- Chow, T.W., Binns, M.A., Cummings, J.L., Lam,
temporal dementia:Adoor-to-door survey in I., Black, S.E., Miller, B.L.,...van Reekum, R.
southern Italy. Neurobiology of Aging, 33, 2948. (2009). Apathy symptom profile and behav-
e12948.e10. ioral associations in frontotemporal dementia
Berrios, G. E., & Girling, D. M. (1994). vs dementia of Alzheimer type. Archives of
Introduction: Picks disease and the fron- Neurology, 66, 888893.
tal lobe dementias. History of Psychiatry, 5, Clark, A. W., Manz, H. J., White, C. L., III,
539547. Lehmann, J., Miller, D., & Coyle, J. T.
Bickart, K. C., Brickhouse, M., Negreira, (1986). Cortical degeneration with swollen
A., Sapolsky, D., Feldman Barrett, L., & chromatolytic neurons: Its relationship to
Dickerson, B. C. (2014) Atrophy in distinct Picks disease. Journal of Neuropathology and
corticolimbic networks predicts social impair- Experimental Neurology, 45, 268284.
ments in frontotemporal dementia. Journal of Cruts, M., Gijselinck, I., van der Zee, J.,
Neurology, Neurosurgery, and Psychiatry, 85(4), Engelborghs, S., Wils, H., Pirici, D.,...Van
438448. Broeckhoven, C. (2006). Null mutations in
Binns, J.K.,& Robertson, E.E. (1962). Picks dis- progranulin cause ubiquitin-positive fron-
ease in old age. Journal of Mental Science, 108, totemporal dementia linked to chromosome
804810. 17q21. Nature, 442, 920924.
Boeve, B. F., Boylan, K. B., Graff-Radford, Cummings, J. L. (1997). The Neuropsychiatric
N. R., DeJesus-Hernandez, M., Knopman, Inventory: Assessing psychopathology in
D. S., Pedraza, O.,...Rademakers, R. (2012). dementia patients. Neurology, 48, S10S16.
Characterization of frontotemporal demen- Davies, R.R., Hodges, J.R., Kril, J.J., Patterson,
tia and/or amyotrophic lateral sclerosis K., Halliday, G. M., & Xuereb, J. H. (2005).
CHAPTER 8. Frontotemporal Dementia 193
The pathological basis of semantic dementia. variant frontotemporal dementia and the
Brain, 128, 19841995. frontal lobe syndrome in a population based
DeJesus-Hernandez, M., Mackenzie, I.R., Boeve, sample of 85 year olds. Journal of Neurology,
B. F., Boxer, A. L., Baker, M., Rutherford, Neurosurgery and Psychiatry, 74, 867871.
N. J.,...Rademakers, R. (2011). Expanded Gitlin, L. N., Kales, H. C., & Lyketsos, C. G.
GGGGCC hexanucleotide repeat in noncod- (2012). Nonpharmacologic management of
ing region of C9ORF72 causes chromosome behavioral symptoms in dementia. Journal
9p-linked FTD and ALS. Neuron, 72, 245256. of the American Medical Association, 308,
Dickson, D.W. (2001). Neuropathology of Picks 20202029.
disease. Neurology, 56, S16S20. Goldman, J. S., Rademakers, R., Huey, E. D.,
Dickson, D. W., Kouri, N., Murray, M. E., & Boxer, A. L., Mayeux, R., Miller, B. L., &
Josephs, K.A. (2011). Neuropathology of fron- Boeve, B. F. (2011). An algorithm for genetic
totemporal lobar degeneration-tau (FTLD-tau). testing of frontotemporal lobar degeneration.
Journal of Molecular Neuroscience, 45, 384389. Neurology, 76, 475483.
Dubois, B., Slachevsky, A., Litvan, I., & Pillon, Gorno-Tempini, M.L., Hillis, A.E., Weintraub,
B. (2000). The FAB: A Frontal Assessment S., Kertesz, A., Mendez, M., Cappa,
Battery at bedside. Neurology 55, 16211626. S.F.,...Grossman, M. (2011). Classification of
Eslinger, P. J., Dennis, K., Moore, P., Antani, primary progressive aphasia and its variants.
S., Hauck, R., & Grossman, M. (2005). Neurology, 76, 10061014.
Metacognitive deficits in frontotemporal Graham, A., Davies, R., Xuereb, J., Halliday,
dementia. Journal of Neurology, Neurosurgery G., Kril, J., Creasey, H.,...Hodges, J. (2005).
and Psychiatry, 76, 16301635. Pathologically proven frontotemporal
Evrard, H. C., Forro, T., & Logothetis, N. K. dementia presenting with severe amnesia.
(2012). Von Economo neurons in the anterior Brain, 128, 597605.
insula of the macaque monkey. Neuron, 74, Grasbeck, A., Englund, E., Horstmann, V.,
482489. Passant, U.,& Gustafson, L. (2003). Predictors
Fodero-Tavoletti, M. T., Okamura, N., of mortality in frontotemporal dementia:Aret-
Furumoto, S., Mulligan, R. S., Connor, A. R., rospective study of the prognostic influence of
McLean, C. A.,...Villemagne, V. L. (2011). pre-diagnostic features. International Journal of
18F-THK523: A novel in vivo tau imaging Geriatric Psychiatry, 18, 594601.
ligand for Alzheimers disease. Brain, 134, Gregory, C.A.,& Hodges, J.R. (1996). Clinical
10891100. features of frontal lobe dementia in compari-
Fong, J. C., Karydas, A. M., & Goldman, J. S. son to Alzheimers disease. Journal of Neural
(2012). Genetic counseling for FTD/ALS Transmission, Supplemntal 47, 103123.
caused by the C9ORF72 hexanucleotide Gregory, C.A., Serra-Mestres, J.,& Hodges, J.R.
expansion. Alzheimers Research Therapy, 4, 27. (1999). Early diagnosis of the frontal variant
Forman, M. S., Farmer, J., Johnson, J. K., of frontotemporal dementia: how sensitive
Clark, C. M., Arnold, S. E., Coslett, are standard neuroimaging and neuropsy-
H.B.,...Grossman, M. (2006). Frontotemporal chologic tests? Neuropsychiatry Neuropsychol
dementia: clinicopathological correlations. Behav Neurol 12, 128135.
Annals of Neurology, 59, 952962. Groen, J. J., & Endtz, L. J. (1982). Hereditary
Foster, N.L., Wilhelmsen, K., Sima, A.A., Jones, Picks disease: Second re-examination of
M. Z., DAmato, C. J., & Gilman, S. (1997). the large family and discussion of other
Frontotemporal dementia and parkinsonism hereditary cases, with particular reference
linked to chromosome 17: A consensus con- to electroencephalography, a computerized
ference. Conference Participants. Annals of tomography. Brain, 105(Pt 3), 443459.
Neurology, 41, 706715. Gustafson, L. (1987). Frontal lobe degenera-
Funkiewiez, A., Bertoux, M., de Souza, L. C., tion of non-Alzheimer type. II. Clinical pic-
Lvy, R.,& Dubois, B. (2012). The SEA (Social ture and differential diagnosis. Archives of
cognition and Emotional Assessment):a clini- Gerontology and Geriatrics, 6, 209223.
cal neuropsychological tool for early diagno- Harvey, R. J., Skelton-Robinson, M., & Rossor,
sis of frontal variant of frontotemporal lobar M. N. (2003). The prevalence and causes
degeneration. Neuropsychology, 26(1):8190. of dementia in people under the age of
Garcin, B., Lillo, P., Hornberger, M., Piguet, 65 years. Journal of Neurology, Neurosurgery
O., Dawson, K., Nestor, P.J.,& Hodges, J.R. and Psychiatry, 74, 12061209.
(2009). Determinants of survival in behavioral Heston, L. L. (1978). The clinical genetics of
variant frontotemporal dementia. Neurology, Picks disease. Acta Psychiatrica Scandinavica,
73, 16561661. 57, 202206.
Gislason, T. B., Sjogren, M., Larsson, L., & Hodges, J. R., Mitchell, J., Dawson, K.,
Skoog, I. (2003). The prevalence of frontal Spillantini, M.G., Xuereb, J.H., McMonagle,
194part iiThe Dementias: The Major Diseases and Clinical Syndromes
P.,...Patterson, K. (2010). Semantic demen- Kertesz, A., Davidson, W., & Fox, H. (1997).
tia: Demography, familial factors and sur- Frontal behavioral inventory: Diagnostic
vival in a consecutive series of 100 cases. criteria for frontal lobe dementia. Canadian
Brain, 133, 300306. Journal of Neurological Sciences, 24, 2936.
Hof, P. R., Bouras, C., Perl, D. P., & Morrison, Kertesz, A., Davidson, W., & Munoz, D. G.
J. H. (1994). Quantitative neuropathologic (1999). Clinical and pathological overlap
analysis of Picks disease cases:Cortical dis- between frontotemporal dementia, pri-
tribution of Pick bodies and coexistence with mary progressive aphasia and corticobasal
Alzheimers disease. Acta Neuropathologica, degeneration: the Pick complex. Dementia
87, 115124. and Geriatric Cognitive Disorders 10 Suppl 1,
Hornberger, M., Piguet, O., Graham, A. J., 4649.
Nestor, P.J.,& Hodges, J.R. (2010). How pre- Kertesz, A., McMonagle, P., Blair, M., Davidson,
served is episodic memory in behavioral vari- W.,& Munoz, D.G. (2005). The evolution and
ant frontotemporal dementia? Neurology, 74, pathology of frontotemporal dementia. Brain
472479. 128, 19962005.
Hu, W. T., Chen-Plotkin, A., Grossman, Kipps, C. M., Nestor, P. J., Acosta-Cabronero,
M., Arnold, S. E., Clark, C. M., Shaw, J., Arnold, R., & Hodges, J. R. (2009)
L.M.,...Trojanowski, J.Q. (2011). Novel CSF Understanding social dysfunction in the
biomarkers for frontotemporal lobar degen- behavioural variant of frontotemporal
erations. Neurology, 75, 20792086. dementia: the role of emotion and sarcasm
Hu, W.T., Seelaar, H., Josephs, K.A., Knopman, processing. Brain 132, 592603.
D.S., Boeve, B.F., Sorenson, E.J.,...Grossman, Klunk, W. E., Engler, H., Nordberg, A., Wang,
M. (2009). Survival profiles of patients with Y., Blomqvist, G., Holt, D.P.,...Lngstrm, B.
frontotemporal dementia and motor neuron (2004). Imaging brain amyloid in Alzheimers
disease. Archives of Neurology, 66, 13591364. disease with Pittsburgh Compound-B. Annals
Huey, E. D., Ferrari, R., Moreno, J. H., Jensen, of Neurology, 55, 306319.
C., Morris, C.M., Potocnik, F.,...Momeni, P. Knibb, J. A., Xuereb, J. H., Patterson, K., &
(2011). FUS and TDP43 genetic variability in Hodges, J. R. (2006). Clinical and pathologi-
FTD and CBS. Neurobiology of Aging, 33, 1016 cal characterization of progressive aphasia.
e10191017. Annals of Neurology 59, 156165.
Hutton, M., Lendon, C.L., Rizzu, P., Baker, M., Knopman, D. S., Mastri, A. R., Frey, W. H., II,
Froelich, S., Houlden, H.,...Heutink, P. (1998). Sung, J. H., & Rustan, T. (1990). Dementia
Association of missense and 5-splice-site lacking distinctive histologic features:Acom-
mutations in tau with the inherited dementia mon non-Alzheimer degenerative dementia.
FTDP-17. Nature, 393, 702705. Neurology, 40, 251256.
Ibach, B., Koch, H., Koller, M., Wolfersdorf, M., Knopman, D.S., Petersen, R.C., Edland, S.D.,
Workgroup for Geriatric Psychiatry of the Cha, R. H., & Rocca, W. A. (2004). The inci-
Psychiatric State Hospitals of G,& Workgroup dence of frontotemporal lobar degeneration
for Clinical Research of the Psychiatric State in Rochester, Minnesota, 1990 through 1994.
Hospitals of G. (2003). Hospital admission Neurology, 62, 506508.
circumstances and prevalence of fronto- Kwiatkowski, T. J., Jr., Bosco, D. A., Leclerc,
temporal lobar degeneration: A multicenter A.L., Tamrazian, E., Vanderburg, C.R., Russ,
psychiatric state hospital study in Germany. C.,...Brown, R. H., Jr. (2009) Mutations in
Dementia and Geriatric Cognitive Disorders, 16, the FUS/TLS gene on chromosome 16 cause
253264. familial amyotrophic lateral sclerosis. Science,
Janssen, J.C., Warrington, E.K., Morris, H.R., 323, 12051208.
Lantos, P., Brown, J., Revesz, T.,...Rossor, Le Ber, I., Guedj, E., Gabelle, A., Verpillat, P.,
M. N. (2002). Clinical features of frontotem- Volteau, M., Thomas-Anterion, C.,...Dubois,
poral dementia due to the intronic tau 10(+16) B. (2006). Demographic, neurological and
mutation. Neurology, 58, 11611168. behavioural characteristics and brain perfu-
Jicha, G.A.,& Nelson, P.T. (2011). Management sion SPECT in frontal variant of frontotempo-
of frontotemporal dementia:Targeting symp- ral dementia. Brain, 129, 30513065.
tom management in such a heterogeneous Leyton, C.E., Villemagne, V.L., Savage, S., Pike,
disease requires a wide range of thera- K. E., Ballard, K. J., Piguet, O.,...Hodges,
peutic options. Neurodegenerative Disease J. R. (2011). Subtypes of progressive apha-
Management, 1, 141156. sia: Application of the International
Josephs, K. A., Whitwell, J. L., & Jack, C. R., Consensus Criteria and validation using
Jr. (2007) Anatomic correlates of stereoty- beta-amyloid imaging. Brain, 134, 30303043.
pies in frontotemporal lobar degeneration. Lough, S., Kipps, C. M., Treise, C., Watson,
Neurobiology of Aging. P., Blair, J. R., & Hodges, J. R. (2006). Social
CHAPTER 8. Frontotemporal Dementia 195
reasoning, emotion and empathy in fron- Miller, B.L., Cummings, J.L., Villanueva-Meyer,
totemporal dementia. Neuropsychologia, 44, J., Boone, K., Mehringer, C.M., Lesser, I.M.,&
950958. Mena, I. (1991). Frontal lobe degenera-
Mackenzie, I.R., Rademakers, R.,& Neumann, tion:Clinical, neuropsychological, and SPECT
M. (2010). TDP-43 and FUS in amyotrophic characteristics. Neurology, 41, 13741382.
lateral sclerosis and frontotemporal demen- Modirrousta, M., Price, B.H.,& Dickerson, B.C.
tia. Lancet Neurology, 9, 9951007. (2013). Neuropsychiatric symptoms in pri-
Manoochehri, M.,& Huey, E.D. (2012). Diagnosis mary progressive aphasia: Phenomenology,
and management of behavioral issues in fron- pathophysiology, and approach to assess-
totemporal dementia. Current Neurology and ment and treatment. Neurodegenerative Disease
Neuroscience Reports, 12, 528536. Management, 3, 133146.
Maruyama, M., Shimada, H., Suhara, T., Munoz, D.G., Morris, H.R.,& Rosser, M. (2011).
Shinotoh, H., Ji, B., Maeda, J.,...Higuchi, M. Picks disease. In D. W.Dickson& R. O.Weller
(2013). Imaging of tau pathology in a tauopa- (Eds.), Neurodegeneration:The molecular pathol-
thy mouse model and in Alzheimer patients ogy of dementia and movement disorders (2nd
compared to normal controls. Neuron, 79, ed., pp. xxxx):Wiley-Blackwell.
10941108. Neary, D., Snowden, J., & Mann, D. (2005).
Massimo, L., Powers, C., Moore, P., Vesely, L., Frontotemporal dementia. Lancet Neurology 4,
Avants, B., Gee, J.,...Grossman, M. (2009). 771780.
Neuroanatomy of apathy and disinhibition in Neary, D., Snowden, J. S., Northen, B., &
frontotemporal lobar degeneration. Dementia Goulding, P. (1988). Dementia of frontal lobe
and Geriatric Cognitive Disorders, 27, 96104. type. Journal of Neurology, Neurosurgery and
Mathuranath, P. S., Nestor, P. J., Berrios, G. E., Psychiatry, 51, 353361.
Rakowicz, W., & Hodges, J. R. (2000). A Neary, D., Snowden, J. S., Gustafson, L.,
brief cognitive test battery to differentiate Passant, U., Stuss, D., Black, S.,..., Benson,
Alzheimers disease and frontotemporal D.F. (1998). Frontotemporal lobar degenera-
dementia. Neurology, 55, 16131620. tion:Aconsensus on clinical diagnostic crite-
McKhann, G. M., Albert, M. S., Grossman, M., ria. Neurology, 51, 15461554.
Miller, B., Dickson, D., & Trojanowski, J. Q. Neumann, M., Rademakers, R., Roeber, S.,
(2001). Clinical and pathological diagnosis Baker, M., Kretzschmar, H.A.,& Mackenzie,
of frontotemporal dementia: Report of the I. R. (2009). A new subtype of frontotempo-
Work Group on Frontotemporal Dementia ral lobar degeneration with FUS pathology.
and Picks Disease. Archives of Neurology, 58, Brain, 132, 29222931.
18031809. Neumann, M., Sampathu, D. M., Kwong,
Mendez, M. F., & Perryman, K. M. (2003). L. K., Truax, A. C., Micsenyi, M. C., Chou,
Disrupted facial empathy in drawings T. T.,...Lee, V. M. (2006). Ubiquitinated
from artists with frontotemporal dementia. TDP-43 in frontotemporal lobar degeneration
Neurocase, 9, 4450. and amyotrophic lateral sclerosis. Science,
Mendez, M. F., Perryman, K. M., Miller, B. L., 314, 130133.
Swartz, J. R., & Cummings, J. L. (1997). Neumann, M. A. (1949). Picks disease. Journal
Compulsive behaviors as presenting symp- of Neuropathology and Experimental Neurology,
toms of frontotemporal dementia. Journal of 8, 255282.
Geriatric Psychiatry and Neurology, 10, 154157. Nyatsanza, S., Shetty, T., Gregory, C., Lough, S.,
Mesulam, M., Wicklund, A., Johnson, N., Rogalski, Dawson, K.,& Hodges, J.R. (2003). A study
E., Leger, G. C., Rademaker, A.,...Bigio, E. H. of stereotypic behaviours in Alzheimers dis-
(2008). Alzheimer and frontotemporal pathol- ease and frontal and temporal variant fron-
ogy in subsets of primary progressive aphasia. totemporal dementia. Journal of Neurology,
Annals of Neurology, 63, 709719. Neurosurgery and Psychiatry, 74, 13981402.
Mesulam, M. M. (1982). Slowly progressive OCallaghan, C., Hodges, J. R., & Hornberger,
aphasia without generalized dementia. M. (2013). Inhibitory dysfunction in fron-
Annals of Neurology, 11, 592598. totemporal dementia: A review. Alzheimer
Miller, B. L., Darby, A. L., Swartz, J. R., Yener, Disease and Associated Disorders, 27, 102108.
G. G., & Mena, I. (1995). Dietary changes, Onari, K., & Spatz, H. (1926). Anatomische
compulsions and sexual behavior in fronto- Beitrage zur Lehre von der Pickschen
temporal degeneration. Dementia, 6, 195199. umschriebenen Grosshirnrinden-Atrophie
Miller, B.L., Darby, A., Benson, D.F., Cummings, (Picksche Krankheit). Z Neurol, 101, 470511.
J. L., & Miller, M. H. (1997). Aggressive, Pasquier, F., Grymonprez, L., Lebert, F., & Van
socially disruptive and antisocial behaviour der Linden, M. (2001). Memory impairment
associated with fronto-temporal dementia. differs in frontotemporal dementia and
British Journal of Psychiatry, 170, 150154. Alzheimers disease. Neurocase, 7, 161171.
196part iiThe Dementias: The Major Diseases and Clinical Syndromes
Pennington, C., Hodges, J.R.,& Hornberger, M. Rankin, K.P., Kramer, J.H.,& Miller, B.L. (2005).
(2011). Neural correlates of episodic memory Patterns of cognitive and emotional empa-
in behavioral variant frontotemporal demen- thy in frontotemporal lobar degeneration.
tia. Journal of Alzheimers Disease, 24, 261268. Cognitive and Behavioral Neurology, 18, 2836.
Perry, D. C., Whitwell, J. L., Boeve, Rankin, K. P., Baldwin, E., Pace-Savitsky, C.,
B. F., Pankratz, V. S., Knopman, D. S., Kramer, J. H., & Miller, B. L. (2005). Self
Petersen, R. C.,...Josephs, K. A. (2012). awareness and personality change in demen-
Voxel-based morphometry in patients with tia. Journal of Neurology, Neurosurgery and
obsessive-compulsive behaviors in behav- Psychiatry, 76, 632639.
ioral variant frontotemporal dementia. Rankin, K. P., Gorno-Tempini, M. L., Allison,
European Journal of Neurology, 19, 911917. S. C., Stanley, C. M., Glenn, S., Weiner,
Perry, R. J., Rosen, H. R., Kramer, J. H., Beer, M.W.,& Miller, B.L. (2006). Structural anat-
J. S., Levenson, R. L., & Miller, B. L. (2001). omy of empathy in neurodegenerative dis-
Hemispheric dominance for emotions, empa- ease. Brain, 129, 29452956.
thy and social behaviour:Evidence from right Rascovsky, K., Hodges, J. R., Kipps, C. M.,
and left handers with frontotemporal demen- Johnson, J. K., Seeley, W. W., Mendez,
tia. Neurocase, 7, 145160. M. F.,...Miller, B. M. (2007). Diagnostic cri-
Pick, A. (1892). ber die Beziehungen der teria for the behavioral variant of frontotem-
senilen Hirnatrophie zur Aphasie. Prager poral dementia (bvFTD):Current limitations
medicinische Wochenschrift, 17, 165167. and future directions. Alzheimer Disease and
Pick, A., Girling, D.M.,& Berrios, G.E. (1997). Associated Disorders, 21, S1418.
On the symptomatology of left-sided tem- Rascovsky, K., Hodges, J. R., Knopman, D.,
poral lobe atrophy. Classic Text No. 29. Mendez, M. F., Kramer, J. H., Neuhaus,
(Translated and annotated by D. M. Girling J.,...Miller, B.L. (2011). Sensitivity of revised
and G. E. Berrios.). History of Psychiatry, 8, diagnostic criteria for the behavioural vari-
149159. ant of frontotemporal dementia. Brain, 134,
Piguet, O., Hornberger, M., Mioshi, E., & 24562477.
Hodges, J. R. (2011) Behavioural-variant Ratnavalli, E., Brayne, C., Dawson, K., &
frontotemporal dementia: Diagnosis, clinical Hodges, J.R. (2002). The prevalence of fronto-
staging, and management. Lancet Neurology, temporal dementia. Neurology, 58, 16151621.
10, 162172. Renton, A. E., Majounie, E., Waite, A.,
Piguet, O., Petersen, A., Yin Ka Lam, B., Simn-Snchez, J., Rollinson, S., Gibbs,
Gabery, S., Murphy, K., Hodges, J. R., & J.R.,...Traynor, B.J. (2011). A hexanucleotide
Halliday, G.M. (2011) Eating and hypothala- repeat expansion in C9ORF72 is the cause of
mus changes in behavioral-variant fronto- chromosome 9p21-linked ALS-FTD. Neuron,
temporal dementia. Annals of Neurology 69, 72, 257268.
312319. Rosen, H. J., Alcantar, O., Rothlind, J., Sturm,
Poorkaj, P., Bird, T.D., Wijsman, E., Nemens, E., V., Kramer, J. H., Weiner, M., & Miller, B. L.
Garruto, R.M., Anderson, L.,...Schellenberg, (2010). Neuroanatomical correlates of cogni-
G.D. (1998). Tau is a candidate gene for chro- tive self-appraisal in neurodegenerative dis-
mosome 17 frontotemporal dementia. Annals ease. Neuroimage, 49, 33583364.
of Neurology, 43, 815825. Rosen, H. J., Allison, S. C., Schauer, G. F.,
Quaid, K.A. (2011). Genetic counseling for fron- Gorno-Tempini, M. L., Weiner, M. W., &
totemporal dementias. Journal of Molecular Miller, B. L. (2005). Neuroanatomical corre-
Neuroscience, 45, 706709. lates of behavioural disorders in dementia.
Rabinovici, G. D., Jagust, W. J., Furst, A. J., Brain, 128, 26122625.
Ogar, J. M., Racine, C. A., Mormino, Rosso, S.M., Roks, G., Stevens, M., de Koning,
E. C.,...Gorno-Tempini, M. L. (2008). Abeta I., Tanghe, H. L. J., Kamphorst, W.,...van
amyloid and glucose metabolism in three Swieten, J. C. (2001). Complex compulsive
variants of primary progressive aphasia. behaviour in the temporal variant of fronto-
Annals of Neurology, 64, 388401. temporal dementia. Journal of Neurology, 248,
Rabinovici, G. D., Rosen, H. J., Alkalay, A., 965970.
Kornak, J., Furst, A.J., Agarwal, N.,...Jagust, Rosso, S.M., Donker Kaat, L., Baks, T., Joosse, M.,
W. J. (2012). Amyloid vs FDG-PET in the de Koning, I., Pijnenburg, Y.,...van Swieten,
differential diagnosis of AD and FTLD. J.C. (2003). Frontotemporal dementia in The
Neurology, 77, 20342042. Netherlands:Patient characteristics and prev-
Rademakers, R., Cruts, M.,& van Broeckhoven, alence estimates from a population-based
C. (2004). The role of tau (MAPT) in fronto- study. Brain, 126, 20162022.
temporal dementia and related tauopathies. Sapolsky, D., Bakkour, A., Negreira, A.,
Human Mutation, 24, 277295. Nalipinski, P., Weintraub, S., Mesulam,
CHAPTER 8. Frontotemporal Dementia 197
Marsel Mesulam
Progressive aphasias have been recognized et al., 1990). PPA is a form of dementia since
for more than 100 years through case reports it causes gradual cognitive decline to the
by Pick, Srieux, Dejerine, Franceschi, and point where daily living functions become
Rosenfeld (Franceschi, 1908; Pick, 1892, 1904; compromised. It is also an unusual demen-
Rosenfeld, 1909; Srieux, 1893). The current tia since episodic memory functions remain
interest in this condition can be traced to largely preserved for many years. In con-
a 1982 report of six patients with a slowly trast to patients with amnestic dementias of
progressive language disorder and to the the Alzheimer-type (DAT), who tend to lose
subsequent delineation of the primary pro- interest in recreational and social activities,
gressive aphasia (PPA) syndrome (Mesulam, some patients with PPA maintain and even
1982, 2007). Primary progressive aphasia is intensify involvement in complex hobbies
diagnosed when language is the only area such as gardening, carpentry, sculpting, and
of major dysfunction early in the disease; painting.
when other mental faculties such as memory Primary progressive aphasia should be dif-
for daily events, visuospatial skills, face and ferentiated from states of pure progressive
object knowledge, and basic comportment dysarthria, speech apraxia, or phonological
remain relatively intact; and when struc- disintegration, where the formation, rather
tural brain imaging does not reveal a specific than usage, of words becomes disrupted
lesion, other than atrophy, that can account (Broussolle etal., 1996). It should also be dif-
for the language deficit (Mesulam, 2001, ferentiated from DAT and behavioral variant
2003; Mesulam & Weintraub, 1992). In some frontotemporal dementia (bvFTD), where
patients, the principal signs and symptoms word-finding disturbances or a paucity of
are confined to the area of language for as speech may arise, but on a background of
many as 1014 years. In others, impairments more salient impairments of memory (in
in other cognitive functions can emerge after DAT) and behavior (in bvFTD).
the initial few years, but the language dys- Age of onset has ranged from the 40s to the
function tends to remain the most salient 80s. However, the majority of patients have
feature and to deteriorate the most rapidly had onset before the age of 65 (Mesulam,
throughout the course of disease (Weintraub Wieneke, Thompson, Rogalski, & Weintraub,
198
CHAPTER 9. Primary Progressive Aphasia 199
h
Right Left
stg stg
psc
Figure9.1 (Top) Two coronal sections, showing the asymmetric atrophy of the left perisylvian
cortex in a patient with primary progressive aphasia. (Bottom) Two axial sections showing the
progression of atrophy.
low in PPA-G, may be normal in PPA-S, and for the classification of PPA into the PPA-G,
is highly variable in PPA-L. Repetition can PPA-L, and PPA-S subtypes (Gorno-Tempini
be impaired in both PPA-G and PPA-L, but et al., 2011). These guidelines have been
rarely in PPA-S. Some investigators consider implemented to select specific tests and
repetition impairments as key components of quantitative parameters for the subtyping of
PPA-L (Gorno-Tempini et al., 2008). In some patients at early and mild stages of disease
patients grammar and comprehension are (Mesulam etal., 2012). While the new system
jointly impaired early in the disease. These is rigorous, it is also burdensome. Table 9.1
patients can be said to have a mixed subtype offers a simpler descriptive set of guidelines
of PPA, designated PPA-M. The PPA-G and that should be adequate for use in most clini-
PPA-L variants collectively account for what cal settings.
is also known as progressive nonfluent apha-
sia (PNFA), while the PPA-S variant desig-
nates the predominantly aphasic form of Neuropsychological Profiles
semantic dementia (SD).
Specific guidelines have been introduced Standardized neuropsychological tests are
by an international group of investigators helpful for reaching an early diagnosis
CHAPTER 9. Primary Progressive Aphasia 201
(Weintraub& Mesulam, 1993, 1996; Weintraub word and sentence comprehension, nam-
etal., 1990). However, a strict reliance on neu- ing, reading, and writing (Kertesz, 2006). An
ropsychological tests, most of which depend Aphasia Quotient, derived from the WAB-R,
on verbal instructions, verbal responses, provides a measure of aphasia severity
or covert verbal reasoning, may occasion- that can be tracked over time. Based on a
ally lead to the erroneous conclusion that subtyping algorithm previously described
areas other than language are also impaired. (Mesulam etal., 2009, 2012), grammatical pro-
Scores on the Mini Mental State Examination duction can be tested with the Northwestern
(MMSE) (Folstein, Folstein, & McHugh, Anagram Test (NAT), a measure of sentence
1975), for example, can exaggerate the degree construction that does not place demands
of disability (Osher, Wicklund, Rademaker, on working memory or speech output
Johnson, & Weintraub, 2007). Although the (Weintraub et al., 2009). Single-word com-
language disorder in primary progressive prehension can be tested with items from the
aphasia may interfere with the ability to Peabody Picture Vocabulary Test (PPVT-IV),
memorize word lists or solve reasoning tasks, which provides a range of item difficulty
the patient typically has no difficulty recalling (Dunn & Dunn, 2006). The Boston Naming
daily events or behaving with sound judg- Test (BNT) provides a standardized mea-
ment, indicating that explicit memory, reason- sure of object naming (Kaplan, Goodglass,&
ing, and social skills remain relatively intact. Weintraub, 1983).
The neuropsychological examination of Nonverbal functions should be tested with
the patient with suspected PPA should dem- instruments that minimize interference from
onstrate the aphasia, characterize its sub- aphasia. Episodic memory can be tested with
type, and identify non-language cognitive the Three Words Three Shapes (3W3S) test,
domains that are relatively spared. Aphasia a measure we previously designed to dif-
can be tested with one of the several clini- ferentiate DAT from healthy cognitive aging
cal batteries designed for this purpose. The (Weintraub & Mesulam, 1985; Weintraub
Western Aphasia Battery (WAB-R) includes etal., 2000). The 3W3S test showed that PPA
subtests that measure spontaneous speech, patients have a selective retrieval impairment
202part iiThe Dementias: The Major Diseases and Clinical Syndromes
for words but not for shapes (Weintraub of the language network becomes disrupted
etal., 2012). PPA patients are therefore likely (Sonty etal., 2007). It appears, therefore, that
to forget words they hear or read but not disrupted language processing in PPA may
events they experience. This pattern is dif- initially reflect an impairment of information
ferent from the typical pattern of DAT where transfer within the language network rather
patients forget recent experiences. The rela- than a failure of activation at the network
tive preservation of reasoning skills in PPA nodes. In comparison to neurologically intact
can be documented with the Visual Verbal subjects, the PPA patients also display addi-
Test, a nonverbal test of cognitive flexibil- tional aberrant activations within regions
ity (Wicklund, Johnson,& Weintraub, 2004). of the brain outside of the classic language
Visuoperceptual functions can be tested network (Sonty etal., 2003). It is not yet clear
with Judgment of Line Orientation (Benton, whether these aberrant activations reflect
Hamsher, Varney,& Speen, 1998). Behavioral compensatory processes or abnormal disin-
changes, salient in early stages of bvFTD, but hibition. The latter possibility is supported
not typically apparent until later stages of ill- by the fact that the intensity of the aberrant
ness in PPA, can be assessed with the Frontal activations is inversely correlated with per-
Behavior Inventory (Kertesz, Nadkarni, formance on a naming test (Sonty etal., 2003).
Davidson,& Thomas, 2000).
Neuropathology
Functional and Structural
Neuroanatomy Postmortem examinations show that the vast
majority of PPA patients have the pathology
Quantitative morphometry shows that the of either frontotemporal lobar degenera-
PPA-G subtype is most closely associated with tion (FTLD) or of Alzheimers disease (AD).
atrophy in the posterior frontal lobe, including Both major types of FTLD, FTLD-TAU and
Brocas area; the PPA-S subtype with atrophy FTLD-TDP, have been reported (Mesulam
in the anterior temporal components of the lan- etal., 2008). In the majority of PPA-G the neu-
guage network, including the temporal pole; ropathology is of the FTLD type, mostly with
and the PPA-L subtype with atrophy in the tauopathy of the Pick or CBD/PSP types. In
temporo-parietal component of the language the majority of PPA-S, the neuropathology is
network (Gorno-Tempini etal., 2004; Mesulam also of the FTLD type but most frequently with
etal., 2009, 2012; Sapolsky etal., 2010). TDP-43 inclusions of type C. Approximately
Abnormalities of blood flow and metabo- 20%30% of patients in these two variants
lism may emerge prior to the detectable atro- show the neuropathology of AD (Knibb,
phy. Single-photon emission tomography Xuereb, Patterson,& Hodges, 2006; Mesulam
(SPECT) or positron emission tomography et al., 2008). In PPA-L, more than half of the
(PET) may therefore provide more sensi- cases have AD pathology and the rest FTLD
tive diagnostic information than structural (Leyton et al., 2011; Mesulam et al., 2008).
magnetic resonance imaging (MRI) or com- Quantitative analyses of postmortem cases
puted tomography (CT) scans. However, showed that PPA patients with AD pathol-
structural and metabolic imaging may be ogy had higher neocortical-to-entorhinal and
uninformative during the first several years left-to-right ratios of neurofibrillary tangles
of disease and the diagnosis may need to than patients who had the typical combina-
be based on the clinical examination alone tion of AD pathology with an amnestic (rather
(Mesulam et al., 2012). Functional imag- than aphasic) dementia (Gefen et al., 2012).
ing helps to explore the physiological bases This atypical distribution of neurofibrillary
of the language impairment. When asked degeneration is consistent with the anatomy
to identify homonyms or synonyms in the of the clinical phenotype in PPA.
course of functional MRI experiments, PPA Determining whether an individual PPA
patients and age-matched controls activate patient has AD versus FTLD pathology is
the same components of the language net- always challenging. APOE genotyping or
work, including Brocas and Wernickes areas F18-DG PET metabolic scans do not help
(Sonty et al., 2003). However, the functional in this differentiation. In fact, the 4 allele of
connectivity between these two major nodes APOE, which is a major risk factor for the
CHAPTER 9. Primary Progressive Aphasia 203
typical form of AD, is not a risk factor for the However, it is also well known that similar
type of AD that causes PPA (Gefen etal., 2012; mutations can cause entirely different phe-
Rogalski et al., 2011). Amyloid imaging with notypes in other families. Even within single
PET and cerebrospinal fluid evaluations for families with GRN mutations, some mem-
phosphotau and beta amyloid may be help- bers may have PPA and others, bvFTD. The
ful for the identification of patients with AD fact that identical neuropathological entities
pathology, but this remains to be proven in can cause PPA in some patients while caus-
neuropathologically verified cases (Rabinovici ing bvFTD or amnestic dementias in others
et al., 2008). A rapidly progressive language justifies the search for patient-specific sus-
disorder with all the initial characteristics ceptibility factors that interact with the neu-
of PPA has been described in conjunction rodegenerative disease by determining its
with Jacob-Creutzfeldt disease. However, the primary anatomical location.
course is much more rapid than in the usual No such susceptibility factor has yet been
cases (Mandell, Alexander,& Carpenter, 1989). identified in PPA or any of the other demen-
tia syndromes. The strongest lead thus far is
the high incidence of learning disabilities. We
Genetics and Risk Factors of Primary reported that learning disabilities, including
Progressive Aphasia dyslexia, were overrepresented in patients
with PPA and their first-degree relatives
The vast majority of PPA is sporadic. However, when compared to controls and AD patients
PPA has also been reported in dominantly (Mesulam & Weintraub, 1992; Rogalski,
inherited forms of FTLD caused by mutations Johnson, Weintraub, & Mesulam, 2008). In
in MAPT, GRN, or C9orf72 (Munoz, Ros, Fatas, some of these families, the concentration of
Bermejo, & Yebenes, 2007; Rademakers et al., dyslexia was striking, affecting the majority of
2007; Simn-Snchez et al., 2012). In the group children or siblings. Furthermore, two patients
of dominantly inherited FTLD kindreds, the with PPA onset in their 60s were found to
PPA phenotype has been described most fre- have left hemi-craniosynostosis, a mild devel-
quently in families with GRN mutations. In opmental abnormality that interferes with
two families, GRN mutations consistently the normal growth of the underlying cortex.
resulted in the PPA phenotype (Mesulam et al., In these two patients, the left hemisphere
2007). In the PPA1 family, three of four siblings hypoplasia was functionally compensated
had PPA. The mutation consisted of a single throughout most adulthood but appears to
nucleotide deletion in exon 9. In the PPA3 fam- have provided the neural background for
ily, two of three siblings had PPA. The muta- the emergence of PPA in the seventh decade
tion was a C>T transition in exon 11. Both of life (Alberca, Montes, Russell,& Mesulam,
mutations resulted in a premature termination 2004). These observations have led us to won-
codon and a haploinsufficiency of progranulin. der whether some cases of PPA could repre-
The neuropathological examination in affected sent the tardive manifestation of genetic or
members of both families showed FTLD acquired vulnerabilities of the language net-
pathology with inclusions containing TDP-43 work that remain functionally compensated
of type A. In one member of the PPA3 family during most of adulthood but that become the
unbiased stereology showed that the number locus of least resistance for the distribution of
of TDP-43 inclusions was higher in neocortex neurodegeneration. In other patients with a
than in memory-related mediotemporal limbic different set of prior vulnerabilities the same
areas, and higher in language-related neocorti- neurodegenerative process would be expected
ces of the left hemisphere than in contralateral to have a different distribution and therefore
areas on the right (Gliebus et al., 2010). The different clinical manifestations.
distribution of inclusions was thus concordant
with the PPA profile of impaired language
with relatively spared memory function. Contributions of Primary Progressive
The fit between the clinical picture and the Aphasia to Neurolinguistics
distribution of lesions may give the impres- andCognitive Neuroscience
sion that progranulin deficiency and the
resultant TDP-43 abnormalities selectively The contributions to classic aphasiology were
target components of the language network. based mostly on observations in patients
204part iiThe Dementias: The Major Diseases and Clinical Syndromes
with focal cerebrovascular lesions where an objective assessment of how the aphasia
the injury site, usually including cortical as interferes with verbal expression and lan-
well as subcortical areas, is abruptly and guage comprehension tends to help caregiv-
completely destroyed. In primary progres- ers cope with the patients impairments. We
sive aphasia, the gradual and selective loss find that psychosocial interventions, support
of cortical neurons in the language network groups, and targeted educational programs
leads to more specific and subtle perturba- are necessary components of a compre-
tions of language function. Research on PPA hensive approach to patients and families
has already led to several new insights con- (Weintraub& Morhardt, 2005).
cerning language function. One of the most In the absence of effective treatments that
consequential new insights has been the real- can prevent, reverse, or slow down the pro-
ization that the classic neurological account of gression of AD or FTLD, there is currently
language is incomplete and that the anterior no effective disease-modifying intervention
temporal lobe of the left hemisphere needs for PPA. Controlled trials with bromocriptine
to be inserted into the language network as and memantine have not yielded positive
a third major hub with a critical role in lan- results (Johnson et al., 2010; Reed, Johnson,
guage comprehension, especially of words Thompson, Weintraub, & Mesulam, 2004).
denoting concrete entities (Gitelman, Nobre, Although many patients with PPA may have
Sonty, Parrish, & Mesulam, 2005; Hodges, atypical AD, cholinesterase inhibitors have
Graham, & Patterson, 1995; Lambon Ralph, not been particularly useful. However, a new
Cipolotti, Manes,& Patterson, 2010; Mesulam trial of these agents, specifically in patients
et al., 2009). In fact, some of these observa- with the in vivo biomarkers of AD, would be
tions have cast serious doubts on existing useful to initiate. Anecdotal reports of suc-
characterizations of Wernickes area and its cess with omental transplants, intraspinal
role in language comprehension (Schwartz ethanercept, steroids, and transcranial mag-
et al., 2009). Another equally important netic stimulation have appeared but need to
insight has been the realization that gram- be confirmed. Avery special feature of PPA is
matical ability and fluency can be dissociated the relative sparing of the right hemisphere
neuropsychologically as well as anatomically for many years during the course of the dis-
(Rogalski etal., 2011; Thompson etal., 2011). ease. Stimulating the plasticity of the right
It is quite likely that future research in PPA hemisphere so that it can take over some of
will lead to additional insights into the func- the impaired language functions remains a
tional organization of the language network. major and futuristic goal for treatment.
The manifestations of PPA are distinctly This work was supported by grants DC008552
different from those of typical Alzheimers from the National Institute on Deafness
disease dementia. Different aspects of daily and other Communication Disorders and
living activities are impaired and require dif- AG13854 from the National Institute on
ferent sorts of intervention. Some patients Aging.
can learn sign language, others find it use-
ful to carry laminated cards with specific
References
messages, and still others benefit from voice
synthesizers or laptops containing digitally Alberca, R., Montes, E., Russell, E.,& Mesulam,
stored words and phrases. An evaluation M-M. (2004). Left hemicranial hypoplasia in
by a speech therapist is useful for explor- two patients with primary progressive apha-
ing alternative communication strategies. sia. Archives of Neurology, 61, 265268.
Benton, A., Hamsher, K., Varney, N., & Speen,
In contrast to DAT, where new information
O. (1998). Contributions to neuropsychological
cannot be retained in memory, the recall and assessment (2nd ed.). New York, NY: Oxford
evaluation of recent events remains intact, University Press.
although the patient may not be able to Broussolle, E., Bakchine, S., Tommasi, M.,
express this knowledge verbally. Explaining Laurent, B., Bazin, B., Cinotti, L.,...Chazot, G.
this phenomenon to the family and offering (1996). Slowly progressive anarthria with late
CHAPTER 9. Primary Progressive Aphasia 205
Mesulam, M-M., Rogalski, E., Wieneke, C., Rogalski, E.J.,& Mesulam, M-M. (2009). Clinical
Cobia, D., Rademaker, A., Thompson, C., & trajectories and biological features of primary
Weintraub, S. (2009). Neurology of anomia in progressive aphasia (PPA). Current Alzheimer
the semantic subtype of primary progressive Research, 6, 331336.
aphasia. Brain, 132, 25532565. Rosenfeld, M. (1909). Die partielle
Munoz, D. G., Ros, R., Fatas, M., Bermejo, Grosshirnatrophie. Journal of Psychology and
F., & Yebenes, J. G. (2007). Progressive non- Neurology, 14, 115130.
fluent aphasia associated with a new muta- Sapolsky, D., Bakkour, A., Negreira, A.,
tion V363I in tau gene. American Journal of Nalipinski, P., Weintraub, S., Mesulam,
Alzheimers Disease and Other Dementias, 22, M-M.,...Dickerson, B.C. (2010). Cortical neu-
294299. roanatomic correlates of symptom severity in
Osher, J., Wicklund, A., Rademaker, A., primary progressive aphasia. Neurology, 75,
Johnson, N., & Weintraub, S. (2007). The 358366.
Mini-Mental State Examination in behav- Schwartz, M.F., Kimberg, D.Y., Walker, G.M.,
ioral variant frontotemporal dementia and Faseyitan, O., Brecher, A., Dell, G.S.,& Coslett,
primary progressive aphasia. American H. B. (2009). Anterior temporal involvement
Journal of Alzheimers Disease and Other in semantic word retrieval: Voxel-based
Dementias, 22, 468473. lesion-symptom mapping evidence from
Pick, A. (1904). Zur Symptomatologie der aphasia. Brain, 132, 3411327.
linksseitigen Schlaffenlappenatrophie. Srieux, P. (1893). Sur un cas de surdit verbale
Monatsschrift fr Psychiatrie und Neurologie, pure. Revue de Medecine, 13, 733750.
16, 378388. Simn-Snchez, J., Dopper, E. G. P.,
Pick, A. (1982). Ueber die Beziehungen der Cohn-Hokke, P. E., Hukema, R. K., Nicolau,
senilen Hirnatrophie zur Aphasie. Prager N., Seelar, H.,...van Swieten, J. C. (2012).
Medizinische Wochenschrift, 17, 165167. The clinical and pathological phenotype of
Rabinovici, G. D., Jagust, W. J., Furst, A. J., C9ORF72 hexanucleotide repeat expansions.
Ogar, J. M., Racine, C. A., Mormino, Brain, 135, 723735.
E. C.,...Gorno-Tempini, M. L. (2008). A Sonty, S. P., Mesulam, M-M., Weintraub, S.,
amyloid and glucose metabolism in three Johnson, N. A., Parrish, T. P., & Gitelman,
variants of primary progressive aphasia. D. R. (2007). Altered effective connectivity
Annals of Neurology, 64, 388401. within the language network in primary pro-
Rademakers, R., Baker, M., Gass, J., Adamson, gressive aphasia. Journal of Neuroscience, 27,
J., Huey, E. D., Momeni, P.,...Hutton, M. 13341345.
(2007). Phenotypic variability associated with Sonty, S.P., Mesulam, M-M., Thompson, C.K.,
progranulin haploinsufficiency in patients Johnson, N.A., Weintraub, S., Parrish, T.B.,&
with the common 1477C-T (Arg493X) muta- Gitelman, D. R. (2003). Primary progressive
tion: An international initiative. Lancet aphasia: PPA and the language network.
Neurology, 6, 857868. Annals of Neurology, 53, 3549.
Reed, D. A., Johnson, N. A., Thompson, C., Thompson, C. K., Cho, S., Hsu, C-J.,
Weintraub, S., & Mesulam, M-M. (2004). A Wieneke, C., Rademaker, A., Weitner,
clinical trial of bromocriptine for tretment B. B.,...Weintraub, S. (2011). Dissociations
of primary progressive aphasia. Annals of between fluency and agrammatism in pri-
Neurology, 56, 750. mary progressive aphasia. Aphasiology, 26,
Rogalski, E., Johnson, N., Weintraub, S., & 2043.
Mesulam, M-M. (2008). Increased frequency Weintraub, S., & Mesulam, M-M. (1985).
of learning disability in patients with primary Mental state assessment of young and
progressive aphasia and their first degree rel- elderly adults in behavioral neurology. In
atives. Archives of Neurology, 65, 244248. M-M. Mesulam (Ed.), Principles of behavioral
Rogalski, E., Cobia, D., Harrison, T.M., Wieneke, neurology (pp. 71123). Philadelphia, PA:FA
C., Thompson, C., Weintraub, S.,& Mesulam, Davis.
M-M. (2011). Anatomy in language impair- Weintraub, S., & Mesulam, M-M. (1993). Four
ments in primary progressive aphasia. Journal neuropsychological profiles in dementia. In F.
of Neuroscience, 31, 33443350. Boller & J. Grafman (Eds.), Handbook of neu-
Rogalski, E., Rademaker, A., Helenewski, I., ropsychology (pp. 253281). Amsterdam, The
Johnson, N., Bigio, E., Mishra, M.,...Mesulam, Netherlands:Elsevier.
M. (2011). APOE e4 is a susceptibility fac- Weintraub, S., & Mesulam, M-M. (1996). From
tor in amnestic but not aphasic dementias. neuronal networks to dementia:Four clinical
American Journal of Alzheimers Disease and profiles. In F. Fret, Y. Christen, & F. Boller
Other Dementias, 25, 159163. (Eds.), La demence: Pourquoi? (pp. 7597).
CHAPTER 9. Primary Progressive Aphasia 207
Paris, France: Foundation Nationale de Weintraub, S., Rogalski, E., Shaw, E., Salwani,
Gerontologie. S., Rademaker, A., Wieneke, C.,& Mesulam,
Weintraub, S., Mesulam, M-M., Wieneke, C., M-M. (2012). Verbal and nonverbal mem-
Rademaker, A., Rogalski, E.J.,& Thompson, ory in primary progressive aphasia: The
C. K. (2009). The Northwestern Anagram Three Words-Three Shapes Test. Behavioral
Test: Measuring sentence production in pri- Neurology, 26, 6776.
mary progressive aphasia. American Journal Weintraub, S., Rubin, N. P., & Mesulam,
of Alzheimers Disease and Other Dementias, 24, M. M. (1990). Primary progressive aphasia.
408416. Longitudinal course, neuropsychological
Weintraub, S.,& Morhardt, D.J. (2005). Treatment, profile, and language features. Archives of
education and resources for non Alzheimer Neurology, 47(12), 13291335.
dementia: One size does not fit all. Alzheimer Wicklund, A., Johnson, N., & Weintraub, N.
Care Quarterly, 2005 (July/September), 201214. (2004). Preservation of reasoning in pri-
Weintraub, S., Peavy, G. M., OConnor, M., mary progressive aphasia: Further differ-
Johnson, N.A., Acar, D., Sweeney, J.,& Janssen, entiation from Alzheimers disease and the
I. (2000). Three wordsthree shapes:Aclini- behavioral presentation of frontotemporal
cal test of memory. Journal of Clinical and dementia. Journal of Clinical and Experimental
Experimental Neuropsychology, 22, 267278. Neuropsychology, 26, 347355.
10
208
TABLE10.1 Posterior Cortical Atrophy Review of the Literature From 1902 to 1988
Source No. of Onset Preserved Balints Gerstmanns Other Cortical Dysfunctions Longitudinal Pathology
Patients Before Early Syndrome (all or Syndrome (all or Follow-up
65years Insight partial) partial)
Source No. of Onset Preserved Balints Gerstmanns Other Cortical Dysfunctions Longitudinal Pathology
Patients Before Early Syndrome (all or Syndrome (all or Follow-up
65years Insight partial) partial)
Nonspecific complaints
I could see, but couldn't see
...vision dimmed and blurred and ...couldn't focus while reading
[I]get dizzy when [I see] objects [are] moved in certain ways
...when looking at letters, Icant see them togetherbetter if larger print
Complaints suggestive of simultanagnosia
...difficulty seeing things that are right in front of him
I can see it, but Ican't put it together
...when she looks out at the panorama of view, she does not see items that she should see
...having difficulty picking out one thing out of the many when she looked at a multitude of objects
I get dizzy when Iam in a store.
...cant tell where Isign on a cheque
Complaints suggestive of optic ataxia
....with an upright vacuum...with a cord rolled around the handle...she would get confused and
could not put the cord back [around the handle]
Complaints suggestive of visual tracking difficulties
Difficulty tracking reading material horizontally; used a ruler under each line to help
Complaints suggestive of prosopagnosia
Difficulty recognizing faces, geographical and landmark structures
disturbance, visual field cut, or symptoms is helpful in detecting this problem. One set
suggestive of simultanagnosia, that patients of diagnostic criteria has been established
are referred to a specialist. Even at this stage, to help with identification and diagnosis
diagnosis may still remain elusive because (Table10.3) (Tang-Wai etal., 2006).
memory may be relatively preserved and Often patients present with anxiety in the
simultanagnosia is difficult to demonstrate. absence of a prior psychiatric history (Crutch
Using a collage of items (e.g., animals) and et al., 2012). This anxiety appears to be
asking patients to pick out the different items related to their preserved insight that there is
Core features
Insidious onset and gradual progression
Presentation with visual complaints, in the absence of significant primary ocular disease to explain the
symptoms
Absence of stroke or tumour
Absence of early parkinsonism and hallucinations
Relative preservation of anterograde memory and insight (early in the disorder)
Plus any of the following symptoms
Simultanagnosia with or without optic ataxia or ocular apraxia
Constructional dyspraxia
Visual field defects
Environmental disorientation
Any of the elements of Gerstmanns syndrome
Supportive clinical features
Alexia
Presenile onset
Ideomotor or dressing apraxia
Prosopagnosia
Investigations
Neuropsychological deficits relating to parietal and/or occipital regions
Focal or asymmetric atrophy in parietal and/or occipital regions on structural imaging
Focal or asymmetric hypoperfusion or hypometabolism in parietal and/or occipital regions on
functional imaging
212part iiThe Dementias: The Major Diseases and Clinical Syndromes
a cognitive dysfunction, which the patient is demonstrates parietal and occipital atrophy
often unable to spontaneously describe. It is with some involvement of the temporal
often not until the patient is questioned about lobes when compared to persons with nor-
which circumstances cause the anxiety that mal cognition (Fig. 10.1) (Tang-Wai et al.,
symptoms of higher order visual processing 2004). Findings are often similar to typi-
are described, such as being visually over- cal Alzheimers disease (AD), with greater
whelmed in grocery stores, which is sugges- involvement of the parietal and occipital
tive of simultanagnosia. areas and relative preservation of the hip-
Some specific symptoms related to higher pocampi among patients with PCA (Crutch
order visual processing include the following: et al., 2012). Diffusion tensor imaging (DTI)
studies have demonstrated involvement
Reading difficulties are often reported, in the white matter tracts in the posterior
including letter-by-letter reading and regions of the brain, including the bilateral
using a ruler to help with tracking the line inferior longitudinal fasciculus, inferior
of print (without which the person may fronto-occipital fasciculus, and splenium of
lose track of the sentence on the page) the corpus callosum (Migliaccio et al., 2012;
Inability to fill out forms because the indi- Yoshida etal., 2004).
vidual elements on the form are difficult Functional neuroimaging with either
to process single-photon emission computed tomog-
Ability to a see small portion of a picture raphy (SPECT) or positron emission tomog-
but not the entire picture raphy (PET) mirrors the structural imaging
Inability to read the time on an analog findings with either hypoperfusion or hypo-
watch but not a digital watch metabolism, respectively, of the parietal
Inability to find static objects in front of and occipital areas (Nestor, Caine, Fryer,
the patient, such as a cluttered kitchen Clarke,& Hodges, 2003)(Fig.10.2). Bilateral
drawer, a refrigerator, or doorknobs or hypometabolism of the frontal eye fields has
light switches also been found on PET studies and may
Getting lost or disoriented in familiar areas
Misjudging distancesespecially while
driving or parking a car (resulting in some
cases in dents/scrapes or minor accidents)
11.97
CMRglc
1 2 3 4 8.98
5 6 7 8
5.99
9 10 11 12 2.99
13 14 0.00
Figure10.2 Positron emission tomography (PET) scan of a fourth patient with posterior cortical
atrophy demonstrating parietal and occipital hypometabolism. (See color plate section)
represent the cause of ocular apraxia in PCA Examination of the frequency of apolipo-
(Kas etal., 2011). protein E (APOE) genotype between PCA and
Individual case reports of patients with AD did not demonstrate any difference with
PCA undergoing amyloid-PET imaging typical AD or a significantly lower frequency
with the Pittsburg B compound (PiB) have than amnestic AD (Crutch etal., 2012). In our
shown increased PiB binding in the occipital original series of the 40 patients where we had
regions. However, when compared to typical genetic samples, we did not identify a muta-
AD, patients with PCA also showed similar tion in presenilin-1, presenilin-2, or amyloid
diffuse PiB binding in the frontal, temporal, precursor protein (unpublished data).
parietal, and occipital cortices despite the
typical findings of additional hypometabo-
lism posteriorly in the occipital regions on Biomarkers
FDG-PET (Rosenbloom etal., 2011).
Cerebrospinal fluid (CSF) biomarker analy-
sis measuring Abeta-42, total tau, and phos-
Genetics phorylated tau among patients with PCA
has shown that the profile is often consis-
There are two major findings thus far about tent with typical AD with high total and
the genetics of PCA. To date, there have not phosphorylated-tau and low Abeta-42 levels
been any published cases of more than one (Baumann et al., 2010). In addition to func-
person with PCA within a family with demen- tional neuroimaging, CSF biomarkers can
tia (Crutch etal., 2012). There is no difference help to discriminate AD from non-AD pro-
in the number of persons with a positive fam- cesses that cause PCA. In one study, three of
ily history of dementia in PCA and persons twenty PCA patients were considered to have
with typical AD (Mendez, Ghajarania, & corticobasal degeneration, two of whom had
Perryman, 2002; Tang-Wai etal., 2004). normal CSF biomarkers while the rest had
214part iiThe Dementias: The Major Diseases and Clinical Syndromes
CSF markers consistent with AD (Seguin initiation of levodopa can be useful to man-
etal., 2011). age the additional physical bradykinesia and
rigidity.
Pathology
Nonpharmacologic Therapy
Although PCA is a reasonably clinically
homogeneous syndrome, there is patho- One of the most valuable interventions that
logical heterogeneity. Corticobasal degen- can be done for patients with PCA is to help
eration, dementia with Lewy bodies, them adapt their surroundings and activities
subcortical gliosis, fatal familial insomnia, to maintain their independence, which can
and Creutzfeld-Jacob disease have all been result in clear improvement in quality of life,
described as causing PCA (Renner et al., at least anecdotally. Since the visuospatial
2004). However, the most common reported and visuoperceptual domains are predomi-
pathological cause is AD with increased den- nantly affected in PCA, resources that benefit
sity of neurofibrillary tangles and in some persons who have limited vision or who are
studies amyloid plaques in the primary and blind would also benefit patients with PCA.
association visual cortex compared to typi- General strategies include increasing the con-
cal AD (Crutch et al., 2012). Hippocampal trast of frequently used items from the back-
sparing is frequent pathological feature and ground, such as light switches or doorknobs,
accounts for the relatively preserved memory increasing light levels within the home/
and insight of these patients at the start of the environment, reducing clutter on floors and
disease (Murray etal., 2011). in drawers to allow easier identification of
items, using a colored rulers edge along a
line of text to help with visual scanning when
Management reading, and the use of talking books and
watches. This is most beneficial in the ear-
Pharmacotherapy lier stages of the disorder while memory and
insight are still relatively preserved. Ideally,
As most of the cases of PCA are attributable to referral to an occupational therapist aware of
AD and some cases due to DLB, it is reasonable the issues regarding PCA who can perform a
to prescribe cholinesterase inhibitors (done- tailored home assessment can help the per-
pezil, galantamine, or rivastigmine) and/or son and his or her family members. At the
an NMDA-receptor antagonist (memantine). University of Toronto, our occupational ther-
Although a few case studies have shown some apist has performed several individualized
benefit, however, the effectiveness of these home visits and has compiled a list of general
medications for use in PCA remains largely recommendations (Box 10.1) for patients with
unknown (Crutch etal., 2012). PCA. Given the relative rarity of PCA, these
For individuals who develop progressive recommendations have not been formally
and significant parkinsonism on examina- tested in studies but have appeared to help
tion, suggesting concomitant DLB or CBD, patients in our clinic.
General Environment (Resource Center; CNIB; Chiu, Oliver, Marshall,& Letts, 2001)
Simplify the environment
Remove clutter and objects no longer in use; keep pathways clear.
Remove unsafe furniture and accents (i.e., low-height stools, chairs, or tables).
Options to decrease the potential falls risk from scatter rugs and doormats:
- Remove all unsafe scatter rugs/mats
- Install nonslip underpadding
(continued)
CHAPTER 10. Posterior Cortical Atrophy 215
Bathroom
Reduce clutter on bathroom floor, countertop, in drawers and cabinets.
Use high-contrast nonslip bath mat or strips.
Safely install high-contrast grab bars in the shower or bathtub; use contrasting tactile
strip on existing grab bars to differentiate from the tub or towel bar.
Pick up bathmat when not in use and store appropriately to prevent falls.
If there is noted difficulty accurately locating the toilet, consider obtaining a toilet seat
in a contrasting bright color. Also consider obtaining a raised toilet seat with arms and
taping the arms with a bright color in contrast against the toilet seat.
Label important areas in the bathroom:toilet, sink, bathroom door (yellow paper with
black writing).
Tape handles (sink and toilet) with bright color contrasting tape to distinguish handles
from the rest of the sink or the toilet.
Use a contrasting colored tape or dot to indicate the hot water tap.
Keep soap in a bright container (i.e., red) with contrasting color soap (i.e., white).
Use signs as reminders to wash hands, flush toilet, brush teeth, etc.
Keep frequently used items (toothbrush, paste) in small shallow basket or on a mat to
contrast items against the counter.
Use toothpaste that contrasts in color to the toothbrush and bristles (i.e., red toothpaste
on white brush and bristles).
Cover mirrors if necessary:often people with vision problems may not be able to recog-
nize the item as a mirror.
Bedroom
Use bright, contrasting color fitted sheet, top sheet, pillowcases. Each should be a differ-
ent color to optimize identification and orientation to and within the bed.
It may be easier for some to use a duvet rather then numerous sheets and blankets.
Place a bright colored mat on nightstand to contrast against items placed on it.
Dressing
Label drawers and shelves with high-contrast wording or pictures.
Remove clothes that are no longer being used, including permanent removal of clothes
no longer worn and temporary storage of out-of-season clothing.
(continued)
216part iiThe Dementias: The Major Diseases and Clinical Syndromes
Simplify and organize arrangement of clothing; for example, group similar items
together, one drawer for shirts and another drawer for pants.
Lay out clothing for the day.
Minimize clothing requiring buttons and zippers and replace with elastic waists,
pull-over/on, and loose clothing.
Pin socks together when placing them in the laundry so they will stay matched.
Ensure appropriate choice of footwear:flat, nonslip sole, enclosed toe and heel, Velcro
fasteners.
Kitchen
Indicate frequently used settings on appliances with a contrasting color bumper dot,
tactile marker, bright tape, or nail polish (e.g., 350 degrees on the stove, normal cycle for
the dishwasher, and the 1-minute button on the microwave).
Dials at the front of the stove are more desirable than dials at the back of the stove in
order to avoid reaching over the elements.
Supervise the person while using the stove and, if necessary, disconnect the stove and
other appliances when the person is at home alone.
Consider using appliances with automatic shutoff (i.e., kettle).
Place cleaning supplies away from food supplies.
Dispose of hazardous substances that are no longer needed and store other potentially
hazardous substances in a secure place (i.e., locked cupboard).
Try to ensure that everything is put away in its routine place.
Plan an appropriate organizational structure to the kitchen. Consider having one desig-
nated area of counter space for preferred and usual foodsan area that is both accessible
and visible. Trial placing frequently used items on a contrasting mat or tray, located in
the same place every day. This is in an attempt to increase independence in finding fre-
quently used items and participating in meal preparation.
Keep counters clear and minimize clutter.
Other items to optimize safety, independence, and participation in the kitchen:
Elbow-length oven mitts to ensure maximum protection
Knife guard aid to enable safe use and pressure when cutting
Cutting board with a black side and a white side to enhance contrast while cutting
Gooseneck lamp above the cutting area may also assist with vision.
Large-print timer
Liquid measure tool to assist in pouring liquids and avoid spills
Relabel jars and canned goods using a thick black marker, white recipe card, single
words, and elastic bands.
Eating
Use brightly colored contrasting dishes and ensure they are all one solid color (no pat-
terns and no ridged edges).
Use a dark solid-colored placemat if using light-colored plates and use a light solid-colored
placemat if using dark plates.
Light-colored food will be easier to see on a solid dark-colored dish and dark food on a
light dish.
Avoid patterned table clothes.
Maintain a strict pattern for mealtime setup. For example, always place the same uten-
sils, drinking glass, and condiments in the same place for every meal.
Avoid cluttering the eating area and only have necessary items within reach.
Use verbal directions as reminders of where items are located (i.e., Your glass is on your
right, and Salt and pepper is on your left.)
Use plate guards if necessary during meal times.
(continued)
CHAPTER 10. Posterior Cortical Atrophy 217
Stairs
Ensure adequate lighting on the stairs; with switches at both the top and bottom.
Install secure railings on at least one if not both sides.
Install railing extensions that go further than the top and bottom of the stairs.
Remove or replace unsafe flooring with a plain, nonslip surface.
Contrasting color strips (paint or tape) on the edge of each individual step, as well as a
tactile cue at the tope and the bottom of the stairs (both inside and outside).
Progression
Install a lockable door or safety gate to prevent the use of stairs.
Arrange living area that can be maintained on one level.
Medication Routine
Supervision of medication routine is usually recommended.
Store medications in a secure place.
Remove and properly dispose of medications that are no longer needed or have expired.
Inquire whether the medication routine can be simplified (i.e., to once a day instead of
three times a day).
Other ways to simplify a meds routine:prefilled blister packs; medication organizers and
alarms; list of current medications; medication schedule.
not related to amyloid distribution. Neurology, Tang-Wai, D. F., Josephs, K. A., Boeve, B. F.,
76, 17891796. Dickson, D.W., Parisi, J.E.,& Petersen, R.C.
Rosenfeld, M. (1905). ber Herdsymptome bei (2003). Pathologically confirmed corticobasal
den zur Verbldung fhrenden Psychosen. degeneration presenting with visuospatial
Zeitschrift fr klinische Medicin, 56, 5968. dysfunction. Neurology, 61, 113435.
Seguin, J., Formaglio, M., Perret-Liaudet, Taylor, A., & Warrington, E. K. (1971). Visual
A., Quadrio, I., Tholance, Y., Rouaud, agnosia: A single case report. Cortex, 7,
O.,...Krolak-Salmon, P. (2011). CSF biomark- 152161.
ers in posterior cortical atrophy. Neurology, 76, von Hagen, K. O. (1941). Two clinical cases of
17821788. mind blindness (visual agnosia) one due to
Snowden, J. S., Stopford, C. L., Julien, C. L., carbon monoxide poisoning intoxication,
Thompson, J. C., Gibbon, L., Pritchard, one due to a diffuse degenerative process.
A.,...Mann, D. (2007). Cognitive pheno- Bulletin of the Los Angeles Neurological Society,
types in Alzheimers disease and genetic risk. 6, 191195.
Cortex. 43, 835845. Yoshida, T., Shiga, K., Yoshikawa, K., Yamada,
Tang-Wai, D. F., Graff-Radford, N. R., Boeve, K.,& Nakagawa, M. (2004). White matter loss
B. F., Dickson, D. W., Parisi, J. E., Crook, in the splenium of the corpus callosum in a
R.,...Petersen, R.C. (2004). Clinical, genetic, case of posterior cortical atrophy:Adiffusion
and neuropathologic characteristics of poste- tensor imaging study. European Neurology, 52,
rior cortical atrophy. Neurology, 63, 11681174. 7781.
11
220
CHAPTER 11. Progressive Supranuclear Palsy and Corticobasal Degeneration 221
basal ganglia and supranuclear oculomotor TABLE11.1 NINDS-SPSP Criteria for the
nuclei, with the most affected regions being Diagnosis of Progressive Supranuclear Palsy
the subthalamic nucleus and substantia PSP (PSP-RS)
nigra), though extension to the frontal cortex
Possible PSP (Clinical Probable)
can occur (Barsottini, Felicio, DeAquino, &
All three of these:
Pedoso, 2010; Dickson, Ahmed, Algom,
1. Gradually progressive disorder
Tsuboi,& Josephs, 2010). Pathological tau in 2. Onset at age 40 or later
PSP is composed of aggregates of 4 repeat 3. No evidence for competing diagnostic
(E10+) isoforms. Neurochemical studies possibilities
show degeneration of the dopaminergic, Plus either of these:
cholinergic, and GABAergic systems in the 4. Vertical gaze palsy
striatum and other basal ganglionic and Or
brainstem nuclei. 5. Slowing of vertical saccades and prominent
postural instability with falls or tendency to fall
in the first year
Clinical Features Probable PSP (Clinical Definite)
All five of these:
The mean age of onset of PSP is between 55 1. Gradually progressive disorder
2. Onset at age 40 or later
and 75 years (Litvan et al., 1996; OSullivan
3. No evidence for competing diagnostic
etal., 2008). The most commonly recognized
possibilities
criteria for the diagnosis of classical PSP 4. Vertical gaze palsy
phenotype is the NINDS-SPSP criteria (Litvan 5. Slowing of vertical saccades and prominent
et al., 1996, shown in Table 11.1). Using this postural instability with falls or tendency to fall
set of criteria the estimated prevalence of in the first year
PSP is 6.5 per 100,000 (Nath etal., 2001). The Criteria That Exclude PSP-RS From Consideration
inclusion clinical criteria emphasize promi- 1. Recent encephalitis
nent postural instability with falls/tendency 2. Alien limb syndrome, cortical sensory deficits,
to falls within the first year of symptom onset or temporoparietal atrophy
and vertical supranuclear gaze palsy or slow- 3. Psychosis unrelated to dopaminergic treatment
ing of vertical saccades (Litvan, 1998). These 4. Important cerebellar signs
criteria were developed for high specific- 5. Important unexplained dysautonomia
ity, aimed at excluding features suggestive 6. Severe, asymmetric parkinsonism
7. Relevant structural abnormality of basal ganglia
of other parkinsonian syndromes (Litvan,
on neuroimaging
Agid, Calne, et al., 1996). The probable
8. Whipples disease on CSF PCR, if indicated
NINDS-SPSP criteria emphasizes accuracy of
these criteria, when used by experienced cli-
nicians, is about 75% (Osaki etal., 2004), with PSP-RS (Richardsons Syndrome)
sensitivity of 75% and specficity of 98.5%
(Lopez etal., 1999), as this set of criteria iden- So-called Richardsons syndrome is the clas-
tifies the classical, also called Richardson sical form of PSP. These patients present with
PSP phenotype. early falls, axial rigidity, typically but rarely
The Neuroprotection and Natural History with retrocollis, and usually with the typical
in Parkinsons Plus Syndromes (NNIPPS) history of eye disturbances characterized by
Study Group adapted these criteria for use photophobia, blurred vision/diplopia, tearing,
in large-scale clinical trials. Their criteria and on examination slowed and hypometric
include an akinetic-rigid syndrome, pres- vertical saccades preceding the development
ent for 18 years, with an age of onset after of supranuclear vertical gaze palsy, as well as
age 30years, although none of their patients decreased convergence, square-wave jerks,
were younger than 50. They required a supra- and eyelid apraxia. Although vertical gaze
nuclear ophthalmoplegia and postural insta- palsy is the defining feature, it may occur
bility or falls within 3years of disease onset several years after symptom onset. PSP-RS
in the absence of other conditions, including patients also have early slow and slurred
idiopathic Parkinsons disease, history of speech, and dysphagia. Cognitive features,
stroke or head trauma, or severe tremor at including intellectual slowing and early exec-
rest (Benismon etal., 2009). utive function impairment, are characteristic
222part ii The Dementias: The Major Diseases and Clinical Syndromes
(see later discussion). Most patients become McMonagle, 2010). Initial descriptions of
dependent within 34 years of diagnosis cognitive impairment in PSP were charac-
(Gerstenecker etal., 2013). terized as a subcortical dementia (Albert,
Feldman, & Willis, 1974). This was defined
Motor Features by forgetfulness, slowness of mentation, per-
sonality or mood changes, and impaired abil-
The first motor symptom of PSP is usually ity to manipulate acquired knowledge, in the
postural instability and tendency to fall, absence of cortical features of aphasia, agno-
which is also a large source of morbidity and sia, or apraxia. This was noted to be similar to
mortality. Other common early or present- patients with frontal lobe lesions, and frontal
ing features include dysarthria, bradykinesia, dysfunction does appear early in classical PSP
and monotonous speech (Jankovic, Friedman, (Ghosh etal., 2012; Grafman, Litvan,& Stark,
Pirozzolo,& McCrary, 1990; Litvan etal. 1996). 1995; Pillon, Dubois, Ploska, & Agid, 1991).
Examination may show an akinetic-rigid syn- Complex tasks, including planning, attention
drome, with prominent axial rigidity and set shifting, abstraction, and reasononing,
symmetric bradykinesia. The neck may be are significantly impaired in PSP (Grafman
held in abnormal position (most typical but et al., 1995; Kertesz & Monagle, 2010). This
infrequently retrocollis) (Litvan, Agid, et al., includes decreased abilities on tests of verbal
1996). Gait may appear wide-based and fluency (Maher, Smith, & Lees, 1985; Pillon,
unsteady. In addition to early falls, dysarthria Dubois, Lhermitte,& Agid, 1986), attentional
and dysphagia may be prominent, which set shifting (Robbins etal., 1994), and initia-
increases the risk of aspiration pneumonia, tion and perseveration (Brown etal., 2010).
another source of morbidity and mortality in In addition, other studies point to notable
PSP. At times this phenotype is misdiagnosed deficits in visual attention, slowed informa-
initially as Parkinsons disease postural insta- tion processing, memory retrieval, parallel
bility gait disorder (PIGD) variant. processing, and executive functions (Brown
et al., 2010; Grafman et al., 1995; Kertesz &
Visual Symptoms Monagle, 2010; Soliveri etal., 2000; Vanvoorst
Symptoms of visual disturbance are an infre- etal., 2008).
quent presenting symptom and can include Visual attention difficulty has been iden-
diplopia, difficulties reading, and blurred fitied in several studies, when compared to
vision (Pelak & Hall, 2004). Characteristc eye controls or other parkinsonian disorders such
findings in PSP include supranuclear deficits a multiple systems atrophy (Esmonde, Giles,
in either downward or upward gaze preceded Gibson,& Jodges, 1996; Grafman etal., 1995;
by slowness of vertical saccades and decreased Soliveri et al., 2000). This includes tasks of
or absence of vertical optokinetic nystag- visual search and line orientation (Soliveri
mus, later affecting horizontal gaze. Vertical etal., 2000). Recent studies suggest this defi-
supranuclear gaze palsy may be a present- cit is a primary cognitive problem that cor-
ing symptom in less than 10% of the cases; it relates with the degree of disruption of eye
often develops within 34 years of symptom movement abnormalities (DiFabio, Zampieri,
onset but at times is never clinially manifested Tuite,& Konczak, 2006).
(Litvan et al., 1996). As upgaze abnormalities Slowed information processing has been
can occur in other neurodegenerative dis- described as taking increased time to respond
eases as well as in the course of normal aging, (up to several minutes to respond to a single
limitations in downward gaze are considered question). This feature can be marked (Albert
more specific for PSP (Litvan, Campbell, etal., et al., 1974). This slowing also appears to
1997); however, specificity increases when the be independent of motor slowing (Dubois,
upward gaze abnormalities are associated with Pillon, Legault,& Lhermitte, 1988).
absence of OKNs and slowing of saccades. Memory is usually preserved, although
retrieval is affected. Characteristically, in
PSP-RS short-term storage seems preserved
Cognitive Features
(Grafman et al., 1995), characterized by
Up to 70% of patients with PSP have been impaired free recall with preserved recog-
reported as having a frontal or classi- nition memory (Kertesz & Monagle, 2010).
cally subcortical dementia (Kertesz & Encoding is usually preserved in PSP-RS.
CHAPTER 11. Progressive Supranuclear Palsy and Corticobasal Degeneration 223
Behavioral changes are typically observed in gaze palsy that allows the diagnosis of PSP
patients with the PSP-RS phenotype. Usually, later in the disease course. Patients with this
they present with significant apathy, fre- phenotype have increased midbrain atrophy
quently confused with depression (Litvan compared to those with pure PNFA (without
et al., 1996), impulsivity and less frequently a gaze palsy) (Rohrer etal., 2010).
disinhibition. There are cases reported of
patients presenting with behavioral distur- PSP-CBS (Corticobasal Syndrome)
bance suggestive of frontotemporal dementia
as well (Hassan, Parisi, & Josephs, 2011). In Recent studies have shown that patients with
fact, frontotemporal dementia can also be a this phenotype may also have underlying PSP.
PSP phenotypic presentation. They usually present with a unilateral ideomo-
tor apraxia, alien limb phenomena, aphasia,
and cortical sensory deficit in addition to uni-
PSP-P (Parkinsonism)
lateral parkinsonism, myoclonus, and dysto-
This phenotype occurs in about one third of nia. The disease spreads contralaterally. Some
patients and is more indolent, with initial may develop eye movement abnormalities,
PD-like features that include asymmetric bra- usually increased latency of saccades affect-
dykinesia and rigidity, rest tremor, and clear ing horizontal and vertical gaze (Zadikoff &
but eventually limited levodopa response. Lang, 2005). Interestingly, review of the videos
Falls and cognitive impairment occur at later corresponding to the original cases described
stages than in PSP-RS. These patients have a by Steele-Richardson-Olsewski show that one
slower progression, though may look simi- of their cases had a clearly asymmetric pre-
lar to PSP-RS in about 6 years. Pathology is sentation. This phenotype is further discussed
greater in the basal ganglia and brainstem, later in this chapter.
with less observed in the cortex than that
seen with PSP-RS (Barsottini et al., 2010;
Dickson etal., 2010). Genetics
PSP-PAGF (Pure Akinesia With Gait Freezing) PSP is typically a sporadic disorder (Jankovic
et al., 1990), but familial aggregation has
Pure akinesia with gait freezing is a rare been recently reported by some investiga-
phenotypic presentation of PSP initially tors (Borroni, Agosti, Magnani, DiLuca, &
described by Imai (Imai, 1996). It is charac- Pakovani, 2011; Donker etal., 2009), although
terized by a gradual onset of pure gait freez- it remains controversial (Vidal, Vidailhet,
ing, in the absence of limb rigidity or eye Derkinderen, Tzourio, & Alprovitch, 2010).
movement abnormalities for several years. There are patients with mutations in the
Micrographia and hypophonia could also be gene responsible for tau protein production,
present. The majority of the patients with this microtubule associated protein tau (MAPT)
phenotype have postmortem PSP pathology. that may present with the PSP phenotype.
They also have a significantly slower pro- Approximately five mutations in MAPT are
gression than PSP-RS (Compta et al., 2007; responsible for a few autosomal dominant
Williams etal., 2007). Pathology is milder and familial cases (Borroni et al., 2011) with this
similar to that seen in PSP-P (Barsottini etal., phenotype. However, there has been a link in
2010; Dickson etal., 2010). polymorphisms in the MAPT gene associated
with PSP. In particular, eight polymorphisms
have been identified, defining two haplo-
PSP-PNFA (Progressive Nonfluent Aphasia)
types, H1 and H2. The H1 haplotype in par-
There are very few case reports of PSP patients ticular has been linked to an increased risk of
presenting with progressive nonfluent apha- PSP in the Caucasian population (Baker etal.,
sia (PSP-PNFA). However, most PSP patients 1999). More recently, using GWAS (Genome
have decreased spontaneous speech and ver- Wide Association Study), in addition to the
bal fluency, which as the retrieval deficits, H1 MAPT haplotype, several genes (STX6,
are characteristic features of their significant EIF2AK3, and MOB) have been identified
executive dysfunction. PSP-PNFA patients that are more prevalent in PSP patients
eventually develop vertical supranuclear (Hoglinger etal., 2011).
224part ii The Dementias: The Major Diseases and Clinical Syndromes
Figure11.1 A70-year-old woman with progressive supranuclear palsy, whose magnetic resonance
imaging (MRI) scan illustrates mild brain atrophy as seen from sagittal (left) and axial (right) views.
CHAPTER 11. Progressive Supranuclear Palsy and Corticobasal Degeneration 225
completed trials have failed to meet primary Wainer, & Watts, 2004), including ideomo-
outcome measures, but the infrastructure for tor, ideational, and limb-kinetic apraxia (see
conducting multicenter clinical trials con- Chapter 5). Ideomotor apraxia is defined as
tinues to mature as a result of these initial impaired motor acts despite intact motor,
attempts, facilitating next-generation trials. sensory, and language function. Since
patients with the CBS frequently show motor
deficits, it is recommended to explore praxis
Corticobasilar Degeneration in the most spared limb. Patients commit
temporal and spatial errors, affecting tim-
The least common atypical parkinso- ing, sequencing, amplitude, orientation, and
nian disorder, corticobasilar degeneration limb position in space (Gross & Grossman,
(CBD), was first described in 1968 (Rebeiz, 2008). This is usually demonstrated by the
Kolodny,& Richardson, 1968). This was ini- inability to mimic activities such as brush-
tially described as asymmetric akinesia and ing teeth or waving goodbye. Ideational
rigidity, dystonia of the upper limb, apraxia, apraxia is defined as the inability to carry out
and myoclonus, now termed the corticobasal a complex, multistep task, such as making a
syndrome (CBS). Understanding of this com- cup of tea. Limb-kinetic apraxia causes gross
plex disorder has included recognition of difficulties with dexterity and fine motions
various clinical phenotypes and standard- of the affected limb, such as using scissors
ization of neuropathological criteria, and (Leiguarda etal., 2002).
recently the standardization of clinical crite- Eye movement abnormalities can also
ria (Armstrong etal., 2013). The various phe- be present, including increased latency
notypes include the corticobasal syndrome, of saccades and jerky smooth pursuit eye
primary progressive aphasia, and behavioral movements. Unlike PSP, however, range of
variant of frontotemporal dementia. movements is generally full. Blepharospasm
CBD typically occurs in the sixth and and eyelid apraxia can also occur.
seventh decade, with a life expectancy of While CBS was traditionally thought
79 years from symptom onset (Wenning, to predict underlying CBD pathology, in
Litvan,& Tolosa, 2011). recent years it has been increasingly recog-
nized that CBD is just one of a broader set
of underlying pathologies. In addition to
PSP, posterior forms of Alzheimers disease,
Clinical Features
Creutzfeld-Jakob disease, and frontotempo-
ral lobar degeneration (usually tauopathy)
Corticobasal Syndrome
can present with this phenotype.
The classic features of CBS include asymmet- In one series, over half of CBD cases had
ric levodopa-nonresponsive parkinsonism cognitive impairment and 70% during the
(akinesia and rigidity) accompanied by corti- disease course (Armstrong etal., 2013). This
cal and basal ganglia dysfunction, including has included deficits in memory retrieval as
limb and oculomotor apraxia (loss of ability well as other aspects of cognition. One study
to perform these movements, despite lack demonstrated patients with CBD had diffi-
of primary motor or sensory disturbances), culties with word fluency, verbal comprehen-
cortical sensory deficits (extinction to double sion, perceptual organization, and cognitive
simultaneous stimulation, agraphesthesia, flexibility (Vanvoorst et al., 2008). Another
astereognosia), dystonic posturing of the study showed executive, language, and
limb, myoclonus (brief jerks), and alien limb visuospatial deficits with relative preserva-
phenomena (inability to recognize owner- tion of episodic memory (Murray etal., 2007).
ship of a limb) (Kouri et al., 2011). Of these Several series have also demonstrated preva-
symptoms, limb rigidity is observed most lent memory loss, where patients with a clini-
frequently (Armstrong et al., 2013). A large cal diagnosis of Alzheimers disease proved
percentage of patients also develop cognitive to have CBD (Grimes, Lang, & Bergeron,
dysfunction or frank dementia during the 1999; Ling et al., 2010; Murray et al., 2007).
course of their illness. See Table11.2 for a list of clinical CBS pheno-
Apraxia is a characteristic feature. Different types and Table11.3 for current CBS diagnos-
types of apraxia are observed in CBS (Stover, tic criteria.
226part ii The Dementias: The Major Diseases and Clinical Syndromes
CBS, corticobasal syndrome; FBS, frontal behavioral-spatial syndrome; NAV, nonfluent/agrammatic variant of primary
progressive aphasia; PSPS, progressive supranuclear palsy syndrome.
Litvan, I., Agid, Y., Calne, D., Campbell, G., OSullivan, S.S., Massey, L.A., Williams, D.R.,
Dubois, B., Duvoisin, R. C.,...Zee, D. S. Silveira-Moriyama, L., Kempster, P. A.,
(1996). Clinical research criteria for the Holton, J. L.,...Lees, A. J. (2008). Clinical
diagnosis of progressive supranuclear outcomes of progressive supranuclear palsy
palsy (Steele-Richardson-Olszewski syn- and multiple systems atrophy. Brain, 131(5),
drome): Report of the NINDS-SPSP interna- 13621372.
tional workshop. Neurology, 47, 19. Pelak, V. S., & Hall, D. A. (2004).
Llado, A., Sanchez-Valle, R., Rey, M.J., Ezquerra, Neuro-ophthalmic manifestations of neuro-
M., Tolosa, E., Ferrer, I., & Molinuevo, J. L. degenerative disease. Ophthalmology Clinics of
(2008). Clinicopathological and genetic cor- North America, 17(3), 311320.
relates of frontotemporal lobar degenera- Pillon, B., Dubois, B., Ploska, A., & Agid, Y.
tion and corticobasal degeneration. Journal of (1991). Severity and specificity of cognitive
Neurology, 255, 488494. impairment in Alzheimers, Huntingtons,
Lopez, O. L., Litvan, I., Catt, K. E., Stowe, R., Parkinsons diseases and progressive supra-
Klunk, W., Kaufer, D. I.,...DeKosky, S. T. nuclear palsy. Neurology, 41, 634643.
(1999). Accuracy of four clinical diagnostic Pillon, B., Dubois, B., Lhermitte, F., & Agid, Y.
criteria for the diagnosis of neurodegenera- (1986). Heterogeneity of cognitive impair-
tive dementias. Neurology, 53(6), 12921299. ment in progressive supranuclear palsy,
Maher, E. R., Smith, E. M., & Lees, Parkinsons disease, and Alzheimers dis-
A. J. (1985). Cognitive deficits in the ease. Neurology, 36, 11791185.
Steele-Richardson-Olszewski syndrome Rebeiz, J. J., Kolodny, E. H., & Richardson,
(progressive supranuclear palsy). Journal of E. P. (1968). Corticodentatonigral degenera-
Neurology, Neurosurgery and Psychiatry, 48, tion with neuronal achromasia. Archives of
12341239. Neurology, 18, 2033.
Massey, L. A., Micallef, C., Paviour, D. C., Robbins, T.W., James, M., Owen, A.M., Lange,
O'Sullivan, S. S., Ling, H., Williams, K. W., Lees, A. J., Leigh, P. N.,...Summers
D. R.,...Jger, H. R. (2012). Conventional B. A. (1994). Cognitive deficits in progres-
magnetic resonance imaging in confirmed sive supranuclear palsy, Parkinsons dis-
progressive supranuclear palsy and multiple ease, and multiple system atrophy in tests
systems atrophy. Movement Disorders, 27(14), sensitive to frontal lobe dysfunction. Journal
17541762. of Neurology, Neurosurgergy and Psychiatry,
Matsuo, H., Takashima, H., Kishikawa, M., 57, 7988.
Kinoshita, I., Mori, M., Tsujihata, M., & Rohrer, J. D., Paviour, D., Bronstein, A. M.,
Nagataki, S. (1991). Pure akinesia:An atypi- OSullivan, S. S., Lees, A., & Warren, J. D.
cal manifestation of progressive supranuclear (2010). Progressive supranuclear palsy syn-
palsy. Journal of Neurology, Neurosurgery and drome presenting as progressive nonfluent
Psych, 54(5), 397400. aphasia: A neuropsychological and neuro-
McMonagle, P., Blair, M., & Kertesz, A. (2006). imaging analysis. Movement Disorders, 25(2),
Corticobasal degeneration and progressive 179188.
aphasia. Neurology, 67, 14441451. Soliveri, P., Monza, D., Paridi, D., Carella, F.,
Murray, R., Neumann, M., Forman, M. S., Genitrini, S., Testa, D., & Girotti, F. (2000).
Farmer, J., Massimo, L., Rice, A.,...Grossman, Neuropsychological follow up in patients
M. (2007). Cognitive and motor assessment in with Parkinsons disease, striatonigral
autopsy-proven corticobasal degeneration. degeneration-type multiple systems atrophy,
Neurology, 68, 12741283. and progressive supranuclear palsy. Journal
Nath, U., Ben-Shlomo, Y., Thomson, of Neurology, Neurosurgery and Psychiatry, 69,
R. G., Morris, H. R., Wood, N. W., Lees, 313318.
A. J., & Burn, D. J. (2001). The preva- Steele, J. C., Richardson, J. C., & Olszewski,
lence of progressive supranuclear palsy J. (1964). Progressive supranuclear palsy.
(Steele-Richardson-Olswekski syndrome) in Archives of Neurology, 10, 333359.
the UK. Brain, 124(7), 14381449. Stover, N. P., Wainer, B. H., & Watts, R. L.
Nieforth, K. A., & Golbe, L. I. (1993). (2004). Corticobasal degeneration. In R.
Retrospective study of drug response in 87 L. Watts & W. C. Koller (Eds.), Movement
patients with progressive supranuclear palsy. disorders: Neurologic principles and prac-
Clinical Neuropharmacology, 16(4), 338346. tice (2nd ed., pp. 763778). San Francisco,
Osaki, Y., Ben-Shlomo, Y., Lees, A. J., Daniel, CA:McGraw-Hill
S. E., Colosimo, C., Wenning, G., & Quinn, Vanvoorst, W. A., Greenaway, M. C.,
N. (2004). Accuracy of clinical diagnosis of Boeve, B. F., Ivnik, R. J., Parisi, J. E., Eric
progressive supranuclear palsy. Movement Ahlskog, J.,...Josephs, K. A. (2008).
Disorders, 19(2), 181189. Neuropsychological findings in clinically
230part ii The Dementias: The Major Diseases and Clinical Syndromes
atypical autopsy confirmed corticobasal Wenning, G., Litvan, I., & Tolosa, E. (2011).
degeneration and progressive supranuclear Milestones in atypical and secondary Park
palsy. Parkinsonism and Related Disorders, 14, insonisms. Movement Disorders, 26, 10831095.
376378. Williams, D.R., Holton, J.L., Strand, K., Revesz,
Vidal, J. S., Vidailhet, M., Derkinderen, P., T., & Lees, A. J. (2007). Pure akinesia with
Tzourio, C., & Alprovitch, A. (2010). gait freezing: A third clinical phenotype of
Familial aggregation in atypical Parkinsons progressive supranuclear palsy. Movement
disease: A case control study in multiple Disorders, 2007:22(15), 22352241.
system atrophy and progressive supra- Zadikoff, C., & Lang, A. E. (2005). Apraxia
nuclear palsy. Journal of Neurology, 257(8), in movement disorders. Brain, 128(7),
13881393. 14801497.
12
Dementia with Lewy bodies (DLB) and on Dementia With Lewy Bodies (McKeith,
Parkinsons disease dementia (PD-D) are neu- Perry, & Perry, 1999; McKeith et al., 2005).
rodegenerative disorders that affect cognition, Subsequently diagnostic criteria for PD-D
behavior, movement, and autonomic function. were also published (Emre et al., 2007). DLB
Both DLB and PD-D are members of the class and PD-D have grossly overlapping clinical
of neurodegenerative diseases collectively features except for the chronology and tem-
referred to as synucleinopathies; they are poral course of symptoms. In the consensus
believed to represent two entities on the same guidelines, an arbitrary cut point was pro-
disease spectrum with overlapping clinical, posed with regard to chronology of symp-
neurochemical, and pathological findings. toms to distinguish these two disorders. Thus,
patients who develop dementia after 1 year
Dementia With Lewy Bodies following the onset of parkinsonian symptoms
should be diagnosed as PD-D, whereas those
Several other terms have been used to who develop dementia and parkinsonism
describe DLB in the past, including diffuse concomitantly or within 1year of each other
Lewy body disease, Lewy body dementia, should be diagnosed as DLB. This so-called
the Lewy-body variant of Alzheimers dis- 1-year rule is largely meant for research pur-
ease, senile dementia of Lewy-body type, poses. In practice, patients who are diagnosed
and dementia associated with cortical Lewy with Parkinsons disease (PD) first and sub-
bodies. The term DLB was proposed at a sequently develop dementia should be given
consensus meeting (the First International the diagnosis of PD-D, whereas those who
Workshop of the Consortium on dementia develop dementia first followed by parkin-
with Lewy bodies) in 1996 (I. G. McKeith, sonism should be designated as DLB.
2006)and is now widely used.
Although the term itself presumes the pres- Epidemiology of Dementia With Lewy Bodies
ence of a particular pathology (i.e., Lewy bod-
ies), clinical diagnostic criteria with reasonable The first pathological description of the
predictive accuracy for the pathological entity entity now known as DLB was made by
have been developed by the Consortium Okazaki et al. in 1961. It is the second
231
232part ii The Dementias: The Major Diseases and Clinical Syndromes
Behavioral Features
Clinical Features of Dementia With
Lewy Bodies Persistent visual hallucinations are the most
common psychiatric symptom and at least two
Clinical features of DLB include cognitive, thirds of patients report visual hallucinations
psychiatric, neurological, sleep, and auto- (McKeith etal., 2005). Hallucinations are usu-
nomic symptoms. ally present early in the course of illness; they
are often recurrent, well formed, detailed,
and consist of mute images (Mosimann etal.,
Cognitive Features 2006). They may be nondisturbing to patients,
but they are usually stressful for the family
The central clinical feature required for the and caregivers. Patients may have preserved
diagnosis of DLB is progressive cognitive insight into hallucinations. Loss of vision and
decline that interferes with normal social a decreased level of consciousness can exac-
and occupational function (McKeith et al., erbate visual hallucinations. Visual illusions
2005). The cognitive profile of DLB is char- are also common where patients perceive
acterized by significant deficits in executive objects differently from their true identity.
and visuospatial functions as well as atten- Auditory, olfactory, and tactile hallucinations
tion (Calderon et al., 2001; Walker, Allen, appear less common, and they usually occur
Shergill, & Katona, 1997). Prominent mem- together with concomitant visual halluci-
ory impairments may be absent in the early nations. Delusions are less prevalent; they
stages of DLB, but they usually appear as the constitute a supportive feature for diagnosis
disease progresses. On the other hand, DLB of DLB (McKeith etal., 2004). They are com-
patients with concurrent Alzheimer-type tau monly in the form of belief of strangers living
pathology may show prominent memory in the home (phantom boarder) or delusions
deficits, more characteristic of AD, even in of persecution; delusions of theft and infi-
the early stage. delity may also occur. Three classes of psy-
A core feature of DLB is the fluctuation chotic symptoms were found to be associated
in cognitive function, which is an early and with dissociable perfusion abnormalities on
prominent symptom, occurring in 50% to single-photon emission computed tomogra-
75% of patients during the course of the dis- phy (SPECT) imaging: visual hallucinations
ease (McKeith et al., 2005). Fluctuation has with dysfunction of the parietal and ventral
been defined as pronounced variations in occipital cortices, misidentifications with
attention and alertness that may vary from dysfunction of the limbic-paralimbic struc-
hour to hour or day to day and has been tures, and delusions with dysfunction of the
found to occur regardless of the severity of frontal cortices (Nagahama, Okina, Suzuki,&
cognitive disturbances (Ferman et al., 2004). Matsuda, 2010). Depression and anxiety may
There is no consistent fluctuation pattern for appear years before the onset of dementia
the same patient. Fluctuations in cognition and up to 40% of DLB patients experience
and attention interfere with neuropsycholog- a major depressive episode in the course of
ical evaluation and lead to high variability of their illness (Auning etal., 2011).
cognitive performance. Fluctuations in cogni-
tion are reported to be associated with cholin-
ergic deficits (Ferman etal., 2004); they can be Motor, Autonomic, and Other
identified in the electroencephalogram and Associated Features
can be measured with neuropsychological
evaluations using timed or paced computer- Another core feature of DLB is the presence
ized tests such as choice reaction time or digit of spontaneous (i.e., non-drug-induced)
vigilance, or using fluctuation rating scales parkinsonism and has a prevalence ranging
234part ii The Dementias: The Major Diseases and Clinical Syndromes
from 70% to 100% (McKeith et al., 2005). incontinence, or constipation. Urinary incon-
Some pathological series indicate that 25% tinence is the most frequent autonomic symp-
of DLB cases may have no parkinsonism. In tom and constipation is the second (McKeith
a prospective clinicopathological study, the etal., 2005). These symptoms are thought to
absence of parkinsonism was found to be be due to the presence of Lewy body pathol-
the most common reason for misdiagnosis of ogy and neuronal loss in the central and
DLB (McKeith etal., 2000). Parkinsonism var- likely also peripheral autonomic nervous
ies in severity; patients usually have rigidity system (McKeith etal., 2005).
and bradykinesia, shuffling gait, stooped Other supporting features of DLB include
posture, and masked faces while resting repeated falls, syncope, and transient loss
tremor is infrequent. Postural instability can of consciousness. DLB patients often report
be profound early in the illness. McKeith frequent unexplained falls; these may be
et al. reported that more than 50% of DLB related to postural instability or autonomic
patients have severe sensitivity to neurolep- dysfunction. Transient and otherwise unex-
tics (Keith etal., 1992). Neuroleptic sensitiv- plained lapses of consciousness, with or
ity is not dose related; it may may appear as without falls, may represent orthostatic
rapid and irreversible worsening of parkin- syncope.
sonism, cognitive decline, drowsiness, and
occasionally with a neuroleptic malignant
syndromelike presentation with autonomic Neuropathological and Biochemical
instability. Severe sensitivity to neuroleptics Correlates of Dementia With Lewy Bodies
increases morbidity and mortality in DLB
patients. The pathologic diagnosis of DLB mandates
the presence of Lewy bodies (LBs) in neu-
ronal cytoplasma; Lewy neurites are also
Other Clinical Features common. They can be seen in the brainstem
nuclei, amygdala, limbic-paralimbic cortices,
Other features suggestive or supportive of basal ganglia, and cerebral cortex (Hansen
diagnosis include sleep or sleep-wake cycle et al., 1990). Gliosis and neuronal loss are
disturbances. REM sleep behavior disorder also present in these regions. LBs are usually
is a parasomnia characterized by loss of nor- found in the deeper layers of the neocortex
mal skeletal muscle atonia during REM sleep, and tend to be widespread; they also involve
with associated motor activity, resulting in medulla and peripheral autonomic nervous
vivid dreams with simple or complex motor system. Alpha-synuclein is the major pro-
behavior (Postuma, Gagnon, & Montplaisir, tein component of LBs and Lewy neurites
2012). It predominately occurs in males and (Spillantini, Crowther, Jakes, Hasegawa, &
has an onset after the age of 5060. It is pres- Goedert, 1998); neurofilaments, ubiquitin,
ent in nearly 70% of DLB patients and may torsin A, and parkin appear to be minor struc-
occur many years before the onset of demen- tural components (Beyer, Domingo-Sbat,&
tia or parkinsonism. It may be the first symp- Ariza, 2009). Morphologically, LBs may be
tom of DLB or other synucleinopathies such divided into brainstem and cortical types
as Parkinsons disease or multiple system (Hansen et al., 1990). Brainstem type LBs
atrophy (Postuma etal., 2012). As the disease are easily seen using standard histological
progresses, it may become less frequent or less methods: They are spherical intraneuronal
symptomatic (Postuma, Gagnon, Vendette,& cytoplasmic inclusions characterized by a
Montplaisir, 2009). The inclusion of RBD as a hyaline eosinophilic core, concentric lamellar
core clinical feature improves the diagnostic band, and a narrow pale halo. Hematoxylin
accuracy of autopsy-confirmed DLB patients and eosin staining is usually sufficient to
(Ferman etal., 2011). Excessive daytime som- detect brainstem-type LBs. Cortical LBs
nolence, a disturbance of sleep-wake cycle, is may occur in limbic and neocortical regions,
also common. mainly in the small neurons of the cortex.
Autonomic abnormalities are frequent Due to their small size and lack of halo,
in DLB patients (Horimoto et al., 2003). they are not readily identifiable with classi-
Autonomic dysfunction may include ortho- cal histological stains; immunohistochem-
static hypotension, impotence, urinary istry with anti-alpha-synuclein antibodies
CHAPTER 12. Dementia With Lewy Bodies and Parkinsons Disease Dementia 235
is required to detect them. The last revision hallucinations (Harding, Broe, & Halliday,
of the DLB Consortium criteria proposed 2002). Cholinergic deficits are greater in
a revised pathologic classification using temporal cortex of those with visual hal-
alpha-synuclein immunohistochemistry with lucinations as compared to those without
semiquantitative grading of Lewy-related (Gmez-Isla et al., 1999). Muscarinic M1
pathology (mild, moderate, severe, very postsynaptic receptor binding in the tempo-
severe) in brainstem, limbic, and diffuse neo- ral lobe may be increased in patients with
cortical areas rather than counting LBs in delusional thinking (Ballard etal., 2000).
various brain regions (McKeith et al., 2005). A dopaminergic deficit is the other impor-
However, the validation of this pathologic tant neurochemical feature of DLB. The
classification is as yet limited (Nelson et al., reduction in postsynaptic D2 receptor den-
2010). sity in the striatum is greater in DLB than in
In addition to Lewy body pathology, 75% PD or healthy controls, which may contrib-
to 90% of DLB patients have concomitant ute to the weak response to dopaminergic
amyloid plaques and many patients meet drugs or neuroleptic sensitivity seen in DLB
the pathological criteria for Alzheimers dis- patients (Piggott et al., 1999). Deficits in the
ease according to Consortium to establish serotoninergic and noradrenergic systems
a registry for Alzheimers disease (CERAD) may also be related to cognitive-behavioral
criteria (Consensus recommendations for impairment. LBs occur in the dorsal raphe
the postmortem diagnosis of Alzheimers nucleus, and marked reduction of serotonin
disease, 1997; Lopez etal., 2002; Mirra etal., levels have been reported in the basal ganglia
1991). Concomitant amyloid plaques are and cerebral cortices of patients with DLB
common, whereas neurofibrillary tangles (Perry etal., 1990).
are rare. In addition, vascular pathology
can be found in up to 30% of DLB patients
(Jellinger, 2003). Concomitant AD-type or Neuroimaging Features of Dementia
vascular pathology may have an impact on With Lewy Bodies
the clinical presentation (Merdes etal., 2003).
The presence of concomitant AD pathology Relative preservation of the hippocampus
may be associated with more severe memory and medial temporal lobes compared with
impairment and atrophy in the medial tem- AD patients has been described in pathologi-
poral lobe compared to pure DLB patients, cally confirmed DLB patients (Burton et al.,
whereas LB pathology may be associated 2009). Sabattoli et al. found that there was
with more severe executive and visuospatial mild hippocampal atrophy (10%20%) in
dysfunction. It was suggested that the pres- DLB patients compared to a control group,
ence or absence of AD pathology may deter- but it was less than that seen in AD (Sabattoli
mine the premortem DLB diagnosis, rather etal., 2008). There is, however, considerable
than the distribution of LBs (Nelson et al., overlap between AD and DLB, and the util-
2009). ity of magnetic resonance imaging (MRI) for
Biochemically DLB is associated with pro- differential diagnosis is limited. In patho-
found cholinergic and dopaminergic deficits logically verified DLB cases, LBs but not
(Perry, Irving, Blessed, Fairbairn, & Perry, AD pathology was associated with reduced
1990). A cholinergic deficit is more promi- amygdala volume, while neither LB nor AD
nent in DLB than in AD and tends to occur pathology was associated with volume loss
early in the disease course (Samuel, Alford, in hippocampus or entorhinal cortex, sug-
Hofstetter, & Hansen, 1997). There is loss gesting that other neuropathological fac-
of cholinergic neurons in the nucleus basa- tors account for atrophy in these structures
lis of Meynert (Perry etal., 1994), deficits in (Burton etal., 2012). Others have found that
choline acetyltransferase levels are found in hippocampal atrophy on MRI may be associ-
temporal and parietal cortex, and reduction ated with neurofibrillary tangle pathology in
of choline acetyltransferase activity in tem- patients with LB pathology (Kantarci et al.,
poral lobe is correlated with the degree of 2012). Atrophy in other cortical and subcorti-
the cognitive impairment (Lippa, Smith, & cal structures has also been reported in DLB,
Perry, 1999). Ahigher LB density in the limbic including the striatum, substantia innomi-
system (amygdala) is associated with visual nata, hypothalamus, and dorsal midbrain
236part ii The Dementias: The Major Diseases and Clinical Syndromes
(Kantarci et al., 2012). The rate of overall occipital hypometabolism is not always pres-
cerebral atrophy in longitudinal MRI studies ent and FDG-PET changes may be similar
has been reported to be 1.4% per year, three to that seen in AD. Reduced uptake of 18
times more than that seen in controls, but less F-fluorodopa in the striatum may distinguish
than that seen in AD (2% per year) (OBrien DLB from AD with high sensitivity and spec-
etal., 2001). ificity (Hu etal., 2000). Several studies, using
In an MR spectroscopy (MRS) study, Molina 123I-beta-CIT SPECT, demonstrated reduced
et al. found no changes in the gray matter dopamine transporter binding in the caudate
N-asetyl aspartat/Creatinin (NAA/Cr) levels and posterior putamen in DLB compared to
in DLB patients compared to healthy controls AD patients (McKeith et al., 2007; OBrien
(Molina et al., 2002). In another MRS study et al., 2009), but no difference between DLB
using a single voxel spanning the right and and PD patients. Similarly, thoracic SPECT
left posterior cingulate gyri and inferior pre- imaging using 123-I metaiodobenzylguani-
cunei, Kantarci et al. reported that NAA/ dine (MIBG), a marker of postganglionic car-
Cr levels were reduced in subjects with AD, diac sympathetic innervation, shows reduced
vascular dementia, and frontotemporal lobar cardiac MIBG uptake in DLB and PD patients
degeneration compared with healthy con- as opposed to normal findings in AD (Yoshita
trols but were not reduced in DLB (Kantarci et al., 2001). It was suggested that combin-
et al., 2004). In a diffusion tensor imaging ing SPECT and MIBG scintigraphy could
study, changes (increased diffusivity [D]and increase the diagnostic accuracy for DLB
decreased fractional anisotropy [FA] values) (Tateno etal., 2011). In studies using amyloid
in corpus callosum and pericallosal areas PET imaging, 80% of DLB cases were found
were found in DLB patients as compared to to have increased amyloid load, whereas
normal controls (Bozzali et al., 2005). White only 20% of patients with PD-D have this
matter was also affected in the frontal, pari- finding (Edison etal., 2008; Foster etal., 2010;
etal, and occipital areas with less involvement Gomperts etal., 2008).
of the temporal lobe. The authors suggested Standard electroencephalography (EEG)
that these white matter changes may reflect may show early slowing of background activ-
the pathophysiological process that eventu- ity in DLB patients compared with AD as well
ally affects neurons in the association corti- as epoch-by-epoch fluctuations. Frontal inter-
ces. In another DTI study, the DLB group had mittent delta activity and transient temporal
reduced FA in the precuneus area compared slow waves are other changes that are more
to controls and AD patients (Firbank, Colloby, common in DLB than in AD (Bonanni etal.,
Burn, McKeith, & OBrien, 2003). Areas of 2008; Roks, Korf, van der Flier, Scheltens, &
reduced FA in DLB versus controls were also Stam, 2008).
found primarily in parietooccipital white
matter tracts where the changes were more
diffuse in AD; compared to AD, DLB was Cerebrospinal Fluid Biomarkers
also associated with reduced FA in pons and inDementia With Lewy Bodies
left thalamus (Watson etal., 2012). This study
suggests that patterns of DTI changes in AD Currently, there are no blood or cerebrospinal
and DLB are significantly different and DTI fluid (CSF) markers that can be used for diag-
may be a useful technique to investigate early nosis, to follow disease progression, or as
changes in DLB. Finally, resting-state func- an outcome parameter for therapeutic inter-
tional magnetic resonance imaging (fMRI) ventions in DLB. Alpha-synuclein has been
studies have reported increased functional studied as a potential biomarker for DLB, but
connectivity between the right posterior cin- results have been controversial (Mollenhauer
gulate and other brain areas (Galvin, Price, et al., 2008; Ohrfelt et al., 2009). Amyloid
J. L., Yan, Morris, & Sheline, 2011; Kenny, beta 40-42 in CSF, a biomarker for AD, has
Blamire, Firbank,& OBrien, 2012). been found to be lower in DLB compared
SPECT and positron emission tomography to controls and PD-D cases (Bibl etal., 2006;
(PET) studies have demonstrated decreased Parnetti et al., 2008). In addition, Mulugeta
glucose metabolism and perfusion deficits et al. suggested CSF amyloid 38 as a diag-
in parietal and occipital areas in DLB (Albin nostic biomarker for DLB (Mulugeta et al.,
etal., 1996; Lobotesis etal., 2001). However, 2011); the A42/A38 ratio discriminated
CHAPTER 12. Dementia With Lewy Bodies and Parkinsons Disease Dementia 237
AD from DLB with a sensitivity of 78% and a social and occupational functioning of the
specificity of 67%. patient (i.e., dementia). Core features include
fluctuation in cognition with pronounced
variation in attention and alertness, recur-
Diagnosis of Dementia With Lewy Bodies rent and persistent visual hallucinations,
and spontaneous parkinsonism. Consensus
The revised consensus criteria for clinical guidelines recommend that two of the core
diagnosis of DLB are shown in Table 12.1 clinical features have to be present for a diag-
(McKeith et al., 2005). The central feature nosis of probable and one for a diagnosis of
required for the diagnosis of DLB is progres- possible DLB. Suggestive and supportive
sive cognitive decline that interferes with the features may increase diagnostic accuracy.
TABLE12.1 Revised Criteria for the Clinical Diagnosis of Dementia With Lewy Bodies (DLB)
CT, computerized tomography; EEG, electroencephalography; MIBG, metaiodobenzylguanidine; MRI, magnetic reso-
nance imaging; PET, positron emission tomography; SPECT, single-photon emission computerized tomography.
not require drug treatment, however, if they cases (OC) analysis. More than twice as many
are not frightening or otherwise distressing patients on rivastigmine (63.4%) than on pla-
to the patient. Antipsychotics are used to cebo (30.0%) showed at least a 30% improve-
treat psychotic symptoms, but neuroleptics ment from baseline in their NPI-4 scores
should be used with great caution in DLB, (p .001), with psychotic features resolving
as some patients may show severe neuro- almost completely in over half of the treated
leptic sensitivity, which is not predictable in patients. Apathy, anxiety, delusions, and hal-
an individual patient (McKeith et al., 1992). lucinations were the symptoms to show the
In addition, antipsychotics may increase the best response. There was also a significant
risk of cerebrovascular events and death improvement in a computerized test of atten-
in elderly patients with dementia (Raedler, tion, choice reaction time. During a 3-week
2010). As reductions in cholinergic activity washout period, improvements seen with
correlate with hallucinations, cholinesterase rivastigmine returned to baseline. Nausea
inhibitors may be considered for manage- (37%), vomiting (25%), anorexia (19%), and
ment of hallucinations and delusions, if they somnolence (9%) were the most common
are not severe, before using a neuroleptic side effects. Worsening of parkinsonism was
(McKeith etal., 2000; Mori, Ikeda,& Kosaka, not reported, although emergent tremor was
2012). If the symptoms are refractory, cause noted in four rivastigmine-treated patients.
significant impairment or severe burden for In another large randomized, placebo-
caregivers, quetiapine and clozapine can be controlled study, the effect of donepezil (3, 5,
considered. Initial doses should be low and 10 mg/day) was assessed in 140 DLB patients
the dose should be titrated slowly while mon- for 12 weeks (Mori etal., 2012). Patients given
itoring for functional decline. Neuroleptics 5 mg or 10 mg donepezil showed greater
can cause orthostatic hypotension, and blood improvement in the majority of the cognitive
pressure monitoring may be necessary in and behavioral scales, including the MMSE
some patients. and NPI. Donepezil treatment also led to
Since patients with DLB have severe cho- improved global function, as measured by
linergic deficits, several studies have been CIBIC-plus and reduced caregiver burden
performed with cholinesterase inhibitors. at the highest dose. Patients taking donepe-
Results from randomized controlled trials zil were less apathetic, less anxious, had less
with rivastigmine and donepezil indicated cognitive fluctuation, and had fewer delu-
improvements in cognitive function and sions and hallucinations compared to pla-
behavioral symptoms (McKeith et al., 2000; cebo patients. Approximately 8% of the study
Mori et al., 2012). McKeith et al. reported a population withdrew due to adverse events,
multicenter, randomized, controlled study and the prevalence of withdrawal or adverse
of 120 patients with DLB using rivastig- events, including typical cholinergic side
mine or placebo for 20 weeks (McKeith effects, did not differ among treatment groups.
et al., 2000). Patients with a diagnosis of Changes in glutamatergic activity have
probable DLB and a Mini Mental State been reported in patients with DLB (Dalf,
Examination (MMSE) score of greater than Albasanz, Martin, & Ferrer, 2004). The
10 were treated with 612 mg/day of riv- N-methyl-D-aspartate antagonist meman-
astigmine or placebo. Although there was a tine was tested in two randomized, placebo-
slight improvement in mean MMSE score in controlled studies including DLB patients; how-
the rivastigmine group at week 20, this was ever, the results were not consistent (Aarsland
not statistically significant compared to pla- etal., 2009; Emre etal., 2010). The larger study
cebo. Clinician-assessed global status was in patients with Lewy-body-related demen-
also not significantly different between the tias included 199 patients, of which 121 had
two treatment groups. Change from base- PD-D and 78 had DLB (Emre etal., 2010). At
line in mean Neuropsychiatric Inventory week 24, patients treated with memantine
(NPI, 10 items) score was also not signifi- had greater improvements in global status
cantly different between the two groups in (as measured by the Alzheimers Disease
the intention-to-treat (ITT, last observation Cooperative Study [ADCS] clinical global
carried forward) analysis at week 20; the impression of change [CGIC] score) than
difference was, however, statistically signifi- did patients who received placebo; improve-
cant in favor of rivastigmine in the observed ments were predominantly in the DLB group.
240part ii The Dementias: The Major Diseases and Clinical Syndromes
Another study with a mean follow-up of to early-onset familial PD, sometimes associ-
3.6 2.2 years found a two-fold increase in ated with dementia. There is, however, a more
the risk of dementia in PD patients with a his- robust relationship with cognitive decline and
tory of smoking. In the same study there was multiplication of alpha-synuclein gene such as
no significant association with head injury, its duplication, and more so with its triplica-
diabetes mellitus, and incident dementia tion (Farrer etal., 2004; Sironi etal., 2010).
(Levy, Tang, et al., 2002). Estrogen replace- Mutations in parkin, PINK1, and DJ-1
ment therapy was found to be protective in genes cause autosomal recessive PD.
one study (Marder etal., 1998). Dementia rates seem to be lower in patients
with PINK1 and DJ-1 mutations, whereas the
rate in parkin mutations may be more simi-
Genetics of Parkinsons Disease lar to idiopathic PD patients. There are case
Dementia reports of cognitive impairment associated
with the G2019S LRRK2 mutations where
In a community-based study, siblings of the inheritance pattern is autosomal domi-
PD-D patients were found to have three-fold nant (Wider, Dickson,& Wszolek, 2010). The
increased risk of history of AD (Marder etal., frequency of dementia in monogenic forms
1999). The data on the association of the apo- of PD does not appear to be higher, and
lipoprotein E 4 (ApoE 4)allele with PD-D indeed it may be lower than in sporadic PD.
have been inconsistent (Huang, Chen, & Relatively younger age of patients, especially
Poole, 2004). in recessive forms, may be one reason for this
Variations in the tau (MAPT) gene seem to observation (Kasten etal., 2010).
be a genetic risk factor: MAPT H1/H1 hap-
lotype has been associated with a greater
rate of cognitive decline and dementia in PD Clinical Features of Parkinsons
patients (Goris etal., 2007; Healy etal., 2004), Disease Dementia
being a strong predictor of dementia with an
odd ratio of 12.1 in the CamPaIGN cohort. Clinical features of PD-D include cognitive,
In a Spanish case-control study consisting of behavioral, or autonomic symptoms as well
PD, PD-D, DLB, and AD patients and control as disturbances of the sleep-wake cycle. In
subjects, the H1 haplotype was found to be typical cases, the profile of dementia can be
strongly associated with PD and has a strong best described as a dysexecutive syndrome
influence on the risk of dementia in PD with prominent impairment of attention,
patients but not in other neurodegenerative executive and visuospatial functions, mod-
diseases such as DLB and AD (Set-Salvia erately impaired memory, and neuropsy-
etal., 2011). chiatric symptoms, including apathy and
A significantly higher frequency of hetero- psychosis (Table12.3).
zygote mutations in the glucocerebrosidase
gene (GBA) has been reported in PD and
dementia with Lewy bodies (DLB) compared Cognitive Features
with control subjects. GBA mutations may
exert a large effect on susceptibility for Lewy Some degree of cognitive impairment is fre-
body disorders at the individual level, but quently seen already in nondemented PD
they are associated with a modest (approxi- patients, even at the onset of the disease.
mately 3%) population-attributable risk in The most common deficits are in executive
individuals of European ancestry (Mata etal., functions, visuospatial functions, memory,
2008). Up to half of the PD patients hetero- and attention (Table12.4). Cognitive impair-
zygous for GBA mutations developed cogni- ment without dementia can be designated as
tive impairment later in their disease in one mild cognitive impairment of PD, or PD-MCI
series (Goker-Alpan etal., 2008). Recently PD where the activities of daily living are largely
patients with GBA mutations were found to preserved. Transition from MCI to dementia
be at higher risk of dementia with an odds is gradual, both in terms of symptom sever-
ratio of 5.8 (Set-Salvia etal., 2012). ity as well as temporal course. The profile of
Altered expression of or missense mutations cognitive deficits in PD-MCI is variable, but
in the alpha-synuclein gene have been linked the most frequent subtype is single-domain
CHAPTER 12. Dementia With Lewy Bodies and Parkinsons Disease Dementia 243
I. Core features
1. Diagnosis of Parkinsons disease according to Queen Square Brain Bank criteria
2. Adementia syndrome with insidious onset and slow progression, developing within the context of
established Parkinsons disease and diagnosed by history, clinical, and mental examination, defined
as follows:
Impairment in more than one cognitive domain
Representing a decline from premorbid level
Deficits severe enough to impair daily life (social, occupational, or personal care), independent of
the impairment ascribable to motor or autonomic symptoms
II. Associated clinical features
1. Cognitive features:
Attention:Impaired. Impairment in spontaneous and focused attention, poor performance in
attentional tasks; performance may fluctuate during the day and from day to day
Executive functions:Impaired. Impairment in tasks requiring initiation, planning, concept
formation, rule finding, set shifting, or set maintenance; impaired mental speed (bradyphrenia)
Visuospatial functions:Impaired. Impairment in tasks requiring visuospatial orientation,
perception, or construction
Memory:Impaired. Impairment in free recall of recent events or in tasks requiring learning new
material, memory usually improves with cueing, recognition is usually better than free recall
Language:Core functions largely preserved. Word-finding difficulties and impaired
comprehension of complex sentences may be present.
2. Behavioral features
Apathy:Decreased spontaneity; loss of motivation, interest, and effortful behavior
Changes in personality and mood, including depressive features and anxiety
Hallucinations:Mostly visual, usually complex, formed visions of people, animals, or objects
Delusions:Usually paranoid, such as infidelity or phantom boarder (unwelcome guests living in
the home) delusions
Excessive daytime sleepiness
III. Features that do not exclude PD-D but make the diagnosis uncertain
Coexistence of any other abnormality that may by itself cause cognitive impairment, but judged
not to be the cause of dementia, e.g., presence of relevant vascular disease in imaging
Time interval between the development of motor and cognitive symptoms not known
IV. Features suggesting other conditions or diseases as cause of mental impairment, which, when
present, make it impossible to reliably diagnose PD-D
Cognitive and behavioral symptoms appearing solely in the context of other conditions such as:
Acute confusion due to
a) Systemic diseases or abnormalities
b) Drug intoxication
Major depression according to DSM-IV
Features compatible with probable vascular dementia criteria according to NINDS-AIREN
(dementia in the context of cerebrovascular disease as indicated by focal signs in neurological
exam such as hemiparesis, sensory deficits, and evidence of relevant cerebrovascular disease by
brain imaging and a relationship between the two as indicated by the presence of one or more of
the following:onset of dementia within 3months after a recognized stroke, abrupt deterioration
in cognitive functions, and fluctuating, stepwise progression of cognitive deficits)
nonamnestic MCI with a slightly higher fre- DLB. PD-D patients tend to be more apathetic
quency than single-domain amnestic MCI, compared to AD patients. Impaired attention
both of which are more common than multi- is an important determinant of activities of
domain MCI (Aarsland etal., 2010). daily living (ADLs) in PD-D; in one study a
Impairment of attentional functions and measure of vigilance and focused attention
working memory is an early and prominent was the single strongest cognitive predictor
feature of patients with PD-D. Reaction time of ADL status, matching the strength of the
and vigilance are impaired; fluctuating atten- effect of motor function on ADLs (Bronnick
tion is similar to those seen in patients with etal., 2006).
244part ii The Dementias: The Major Diseases and Clinical Syndromes
Probable PD-D
A. Core features:Both must be present
B. Associated clinical features:
Typical profile of cognitive deficits including impairment in at least two of the four core cognitive
domains (impaired attention which may fluctuate, impaired executive functions, impairment in
visuospatial functions, and impaired free recall memory, which usually improves with cueing)
The presence of at least one behavioral symptom (apathy, depressed or anxious mood, hallucinations,
delusions, excessive daytime sleepiness) supports the diagnosis of Probable PD-D; lack of behavioral
symptoms, however, does not exclude the diagnosis.
C. None of the group III features present
D. None of the group IV features present
Possible PD-D
A. Core features:Both must be present
B. Associated clinical features:
Atypical profile of cognitive impairment in one or more domains, such as prominent or receptive-type
(fluent) aphasia, or pure storage-failure type amnesia (memory does not improve with cueing or in
recognition tasks) with preserved attention
Behavioral symptoms may or may not be present
OR
C. One or more of the group III features present
Test, whereas there were no significant dif- population. The ADL scale, caregiver burden
ferences on ADL and behavioral scales. scale, and a number of cognitive tests did not
There was no worsening of motor symptoms. show significant differences between active
In another open-label study, the effects of and placebo in either population (Emre etal.,
donepezil on central processing speed and 2010). These results suggest that memantine
other attentional measures were tested over may have mild beneficial effects in patients
20 weeks. Power of attention, continuity of with DLB but not clearly in PD-D.
attention, and reaction time variability were Another NMDA antagonist, amantadine,
found to be improved as compared to base- was reported to delay the onset of dementia
line (Rowan etal., 2007). in PD and to attenuate its severity in a ret-
In a few open-label studies galantamine rospective analysis (Inzelberg et al., 2006).
was suggested to have beneficial effects in These results should be interpreted with cau-
patients with PD-D (Aarsland, Mosimann,& tion, however, until they are replicated in
McKeith, 2004). In a placebo-controlled, prospective, randomized, controlled trials.
randomized, double-blind 16-week trial of Behavioral symptoms may improve with
galantamine, 1624 mg in 69 nondemented ChE-Is; therefore, patients with behavioral
PD patients, there were no beneficial effects symptoms such as hallucinations should be
on any of the cognitive functions assessed; first treated with these agents before con-
dropouts due to gastrointestinal side effects sidering neuroleptics (Emre et al., 2004).
and self-reported worsening of PD symp- Neuroleptic treatment, however, may
toms were greater in the galantamine group become necessary, especially in patients
(Grace, Amick,& Friedman, 2009). with severe psychosis or agitation. Classical
In a Cochrane meta-analysis evaluating the neuroleptics are contraindicated as they
efficacy of ChE-Is in PD-D, 5.3% of patients worsen motor function and may result in
were concluded to have benefits on outcome life-threatening neuroleptic hypersensitiv-
scales, whereas 10.1% patients on placebo ity. Studies with new generation (atypical)
demonstrated worsening, suggesting that neuroleptics in PD-D patients are few; most
the effect size is close to 15% (Maidment, studies were performed in PD patients with
Fox, & Boustani, 2006). In another, more hallucinations or psychosis, without indicat-
recent Cochrane meta-analysis the authors ing the presence or absence of dementia. In
concluded that the use of cholinesterase a systematic review of atypical neuroleptics
inhibitors in PD-D is associated with a posi- for the treatment of psychosis in PD, clozap-
tive impact on global assessment, cognitive ine was concluded to be the only drug with
function, behavioral disturbance, and activi- proven efficacy and acceptable tolerability
ties of daily living rating scales (Rolinski, provided that appropriate safety monitoring
Fox, Maidment,& McShane, 2012). Based on is performed (Goetz, Koller,& Poewe, 2002).
two large randomized controlled trials and Other atypical neuroleptics such as olanzap-
the results of meta-analysis, treatment with ine and risperidone can worsen motor func-
a ChEI such as rivastigmine or donepezil tion; the efficacy of quetiapine is not well
should be considered in patients with PD-D, demonstrated, although it may be considered
taking into account expected benefits and under careful monitoring for side effects.
risks. There are no randomized, controlled stud-
In a randomized, placebo-controlled trial ies of antidepressants in patients with PD-D.
including patients either with DLB or PD-D, Tricyclic antidepressants such as amitrip-
summarized previously in detail, there was a tyline and nortriptiline may be effective in
significant difference in favor of memantine PD depression; they should, however, not
in the global outcome scale, whereas there be administered in patients with PD-D, as
were no significant differences on MMSE and they may worsen cognition due to their anti-
NPI. Patients with PD-D had more benefits cholinergic effects. The dopamine agonist
as compared to those with DLB (Aarsland pramipexole was shown to be effective in PD
etal., 2009). In the largest ever randomized, depression (Barone etal., 2010), but it has the
placebo-controlled trial, however, which potential to worsen hallucinations and con-
included 199 patients either with DLB or fusion in PD-D patients and should not be
PD-D, there were no significant differences considered in this population. Selective sero-
between memantine and placebo in the PD-D tonin reuptake inhibitors such as paroxetine,
CHAPTER 12. Dementia With Lewy Bodies and Parkinsons Disease Dementia 251
or mixed serotonin and noradrenalin reup- with progressive supranuclear palsy and
take inhibitors such as venlafaxine, have Alzheimers disease. Journal of Neurology,
been shown to be effective in PD depression Neurosurgery and Psychiatry, 74, 12151220.
(Richard et al., 2012) and they are preferred Aarsland, D., Mosimann, U.P.,& McKeith, I.G.
(2004). Role of cholinesterase inhibitors in
in patients with PD-D, taking into account
Parkinsons disease and dementia with Lewy
their adverse effects and potential interaction
bodies. Journal of Geriatric Psychiatry and
with other medication such as monamine Neurology, 17, 164171.
oxidase B inhibitors. Antidepressants with Aarsland, D., Zaccai, J., & Brayne, C. (2005). A
sedating properties such as trazodone can be systematic review of prevalence studies of
considered to treat sleep disturbances. If RBD dementia in Parkinsons disease. Movement
causes significant distress and is thought to Disorders, 20, 12551263.
warrant treatment, melatonin or very low Adler, C.H., Caviness, J.N., Hentz, J.G., Lind,
doses of clonazepam may be used; daytime M., & Tiede, J. (2003). Randomized trial of
somnolence and confusion, however, should modafinil for treating subjective daytime
sleepiness in patients with Parkinsons dis-
be monitored. Excessive daytime sleepiness
ease. Movement Disorders, 18, 287293.
may occur in PD-D patients, more frequently
Albin, R. L., Minoshima, S., DAmato, C. J.,
than in nondemented PD patients. Modafinil, Frey, K.A., Kuhl, D.A.,& Sima, A.A. (1996).
a well-tolerated agent that promotes wakeful- Fluoro-deoxyglucose positron emission
ness, was tested in nondemented PD patients tomography in diffuse Lewy body disease.
(Adler, Caviness, Hentz, Lind, & Tiede, Neurology, 47, 462466.
2003)but not in PD-D; it may be considered Allan, L. M., Ballard, C. G., Allen, J., Murray,
empirically. Atomoxetine, a highly selective A., Davidson, A.W., McKeith, I.G.,& Kenny,
noradrenaline reuptake inhibitor, may also R. A. (2007). Autonomic dysfunction in
be effective in the treatment of excessive day- dementia. Journal of Neurology, Neurosurgery
and Psychiatry, 78, 671677.
time somnolence (Weintraub etal., 2010).
Alves, G., Larsen, J.P., Emre, M., Wentzel-Larsen,
T., & Aarsland, D. (2006). Changes in motor
References subtype and risk for incident dementia in
Parkinsons disease. Movement Disorders, 21,
Aarsland, D., Andersen, K., Larsen, J. P., Lolk, 11231130.
A., & Kragh-Srensen, P. (2003). Prevalence Apostolova, L.G., Beyer, M., Green, A.E., Hwang,
and characteristics of dementia in Parkinson K. S., Morra, J. H., Chou, Y-Y.,...Thompson,
disease:an 8-year prospective study. Archives P.M. (2010). Hippocampal, caudate, and ven-
of Neurology, 60, 387392. tricular changes in Parkinsons disease with
Aarsland, D., Ballard, C., Walker, Z., Bostrom, and without dementia. Movement Disorders,
F., Alves, G., Kossakowski, K.,...Londos, 25, 687688.
E. (2009). Memantine in patients with Auning, E., Rongve, A., Fladby, T., Booij, J.,
Parkinsons disease dementia or demen- Hortobgyi, T., Siepel, F. J.,...Aarsland, D.
tia with Lewy bodies: A double-blind, (2011). Early and presenting symptoms of
placebo-controlled, multicentre trial. Lancet dementia with Lewy bodies. Dementia and
Neurology, 8, 613618. Geriatric Cognitive Disorders, 32, 202208.
Aarsland, D., Brnnick, K., Ehrt, U., De Deyn, Ballard, C., Piggott, M., Johnson, M., Cairns,
P. P., Tekin, S., Emre, M., & Cummings, N., Perry, R., McKeith, I.,...Perry, E. (2000).
J. L. (2007). Neuropsychiatric symptoms in Delusions associated with elevated musca-
patients with Parkinsons disease and demen- rinic binding in dementia with Lewy bodies.
tia: Frequency, profile and associated care Annals of Neurology, 48, 868876.
giver stress. Journal of Neurology, Neurosurgery Ballard, C., Ziabreva, I., Perry, R., Larsen, J. P.,
and Psychiatry, 78, 3642. OBrien, J., McKeith, I.,... Aarsland, D. (2006).
Aarsland, D., Bronnick, K., Williams-Gray, Differences in neuropathologic characteristics
C., Weintraub, D., Marder, K., Kulisevsky, across the Lewy body dementia spectrum.
J.,...Emre, M. (2010). Mild cognitive impair- Neurology, 67, 19311934.
ment in Parkinson disease: A multicenter Barker, W.W., Luis, C.A., Kashuba, A., Luis, M.,
pooled analysis. Neurology, 75, 10621069. Harwood, D. G., Loewenstein, D.,...Duara,
Aarsland, D., Litvan, I., Salmon, D., Galasko, R. (2002). Relative frequencies of Alzheimer
D., Wentzel-Larsen, T.,& Larsen, J.P. (2003). disease, Lewy body, vascular and frontotem-
Performance on the dementia rating scale poral dementia, and hippocampal sclerosis
in Parkinsons disease with dementia and in the State of Florida Brain Bank. Alzheimer
dementia with Lewy bodies: Comparison Disease and Associated Disorders, 16, 203212.
252part ii The Dementias: The Major Diseases and Clinical Syndromes
Barone, P., Poewe, W., Albrecht, S., Debieuvre, effect on disease risk. American Journal of
C., Massey, D., Rascol, O.,...Weintraub, Geriatric Psychiatry, 14, 10221031.
D. (2010). Pramipexole for the treat- Bozzali, M., Falini, A., Cercignani, M., Baglio, F.,
ment of depressive symptoms in patients Farina, E., Alberoni, M.,... Nemni, R. (2005).
with Parkinsons disease: A randomised, Brain tissue damage in dementia with Lewy
double-blind, placebo-controlled trial. Lancet bodies: An in vivo diffusion tensor MRI
Neurology, 9, 573580. study. Brain, 128, 15951604.
Beyer, K., Domingo-Sbat, M., & Ariza, A. Braak, H., Del Tredici, K., Rb, U., de Vos, R.A.
(2009). Molecular pathology of Lewy body I., Jansen Steur, E.N. H.,& Braak, E. (2003).
diseases. International Journal of Molecular Staging of brain pathology related to sporadic
Science, 10, 724745. Parkinsons disease. Neurobiology of Aging, 24,
Bibl, M., Mollenhauer, B., Esselmann, H., Lewczuk, 197211.
P., Klafki, H-W., Sparbier, K.,...Wiffang, Bronnick, K., Ehrt, U., Emre, M., De Deyn,
J. (2006). CSF amyloid-beta-peptides in P. P., Wesnes, K., Tekin, S., & Aarsland, D.
Alzheimers disease, dementia with Lewy (2006). Attentional deficits affect activities
bodies and Parkinsons disease dementia. of daily living in dementia-associated with
Brain, 129, 11771187. Parkinsons disease. Journal of Neurology,
Bissessur, S., Tissingh, G., Wolters, E. C., & Neurosurgery and Psychiatry, 77, 11361142.
Scheltens, P. (1997). rCBF SPECT in Brnnick, K., Alves, G., Aarsland, D., Tysnes,
Parkinsons disease patients with mental O-B., & Larsen, J. P. (2011). Verbal memory
dysfunction. Journal of Neural Transmission in drug-naive, newly diagnosed Parkinsons
Supplemental, 50, 2530. disease. The retrieval deficit hypothesis revis-
Bogaerts, V., Engelborghs, S., Kumar-Singh, ited. Neuropsychology, 25, 114124.
S., Goossens, D., Pickut, B., van der Zee, Burn, D., Emre, M., McKeith, I., De Deyn, P.P.,
J.,...Van Broeckhoven, C. (2007). A novel Aarsland, D., Hsu, C., & Lane, R. (2006).
locus for dementia with Lewy bodies:Aclini- Effects of rivastigmine in patients with and
cally and genetically heterogeneous disorder. without visual hallucinations in demen-
Brain, 130, 22772291. tia associated with Parkinsons disease.
Bohnen, N. I., Kaufer, D. I., Hendrickson, R., Movement Disorders, 21, 18991907.
Ivanco, L. S., Lopresti, B. J., Constantine, Burn, D. J., Rowan, E. N., Minett, T., Sanders,
G. M.,...Dekosky, S. T. (2006). Cognitive J., Myint, P., Richardson, J.,...McKeith,
correlates of cortical cholinergic denervation I. G. (2003). Extrapyramidal features in
in Parkinsons disease and Parkinsonian Parkinsons disease with and without
dementia. Journal of Neurology, 253, dementia and dementia with Lewy bod-
242247. ies: A cross-sectional comparative study.
Bohnen, N.I., Kaufer, D.I., Ivanco, L.S., Lopresti, Movement Disorders, 18, 884889.
B., Koeppe, R.A., Davis, J.G.,...Dekosky, S.T. Burton, E. J., Barber, R., Mukaetova-Ladinska,
(2003). Cortical cholinergic function is more E. B., Robson, J., Perry, R. H., Jaros,
severely affected in parkinsonian dementia E.,...OBrien, J. T. (2009). Medial tem-
than in Alzheimer disease: An in vivo posi- poral lobe atrophy on MRI differentiates
tron emission tomographic study. Archives of Alzheimers disease from dementia with
Neurology, 60, 17451748. Lewy bodies and vascular cognitive impair-
Bonanni, L., Thomas, A., Tiraboschi, P., Perfetti, ment:Aprospective study with pathological
B., Varanese, S., & Onofrj, M. (2008). EEG verification of diagnosis. Brain, 132, 195203.
comparisons in early Alzheimers disease, Burton, E.J., Mukaetova-Ladinska, E.B., Perry,
dementia with Lewy bodies and Parkinsons R. H., Jaros, E., Barber, R., & OBrien, J. T.
disease with dementia patients with a 2-year (2012). Neuropathological correlates of vol-
follow-up. Brain, 131, 690705. umetric MRI in autopsy-confirmed Lewy
Boot, B.P., Boeve, B.F., Roberts, R.O., Ferman, body dementia. Neurobiology of Aging, 33,
T. J., Geda, Y. E., Pankratz, V. S.,...Petersen, 12281236.
R. C. (2012). Probable rapid eye movement Buter, T.C., van den Hout, A., Matthews, F.E.,
sleep behavior disorder increases risk for Larsen, J.P., Brayne, C.,& Aarsland, D. (2008).
mild cognitive impairment and Parkinson Dementia and survival in Parkinson dis-
disease:Apopulation-based study. Annals of ease: A 12-year population study. Neurology,
Neurology, 71, 4956. 70, 10171022.
Borroni, B., Grassi, M., Costanzi, C., Archetti, Calderon, J., Perry, R. J., Erzinclioglu, S. W.,
S., Caimi, L., & Padovani, A. (2006). Berrios, G.E., Dening, T.R.,& Hodges, J.R.
APOE genotype and cholesterol levels in (2001). Perception, attention, and working
Lewy body dementia and Alzheimer dis- memory are disproportionately impaired in
ease: Investigating genotype-phenotype dementia with Lewy bodies compared with
CHAPTER 12. Dementia With Lewy Bodies and Parkinsons Disease Dementia 253
Alzheimers disease. Journal of Neurology, Edison, P., Rowe, C. C., Rinne, J. O., Ng, S.,
Neurosurgery and Psychiatry, 70, 157164. Ahmed, I., Kemppainen, N.,...Brooks, D. J.
Chan, S.S. M., Chiu, H.F. K., Lam, L.C. W.,& (2008). Amyloid load in Parkinsons disease
Leung, V. P. Y. (2002). Prevalence of demen- dementia and Lewy body dementia measured
tia with Lewy bodies in an inpatient psycho- with [11C]PIB positron emission tomogra-
geriatric population in Hong Kong Chinese. phy. Journal of Neurology, Neurosurgery and
International Journal of Geriatric Psychiatry, 17, Psychiatry, 79, 13311338.
847850. Emre, M., Aarsland, D., Albanese, A., Byrne,
Chartier-Harlin, M-C., Kachergus, J., Roumier, E. J., Deuschl, G., De Deyn, P. P.,...Lane, R.
C., Mouroux, V., Douay, X., Lincoln, (2004). Rivastigmine for dementia associated
S.,...Deste, A. (2004). Alpha-synuclein locus with Parkinsons disease. New England Journal
duplication as a cause of familial Parkinsons of Medicine, 351, 25092518.
disease. Lancet, 364, 11671169. Emre, M., Aarsland, D., Brown, R., Burn, D.J.,
Clark, L. N., Kartsaklis, L. A., Wolf, G. R., Duyckaerts, C., Mizuno, Y.,...Dubois, B.
Dorado, B., Ross, B.M., Kisselev, S.,...Marder, (2007). Clinical diagnostic criteria for demen-
K. (2009). Association of glucocerebrosidase tia associated with Parkinsons disease.
mutations with dementia with Lewy bodies. Movement Disorders, 22, 16891707; quiz 1837.
Archives of Neurology, 66, 578583. Emre, M., Tsolaki, M., Bonuccelli, U., Deste, A.,
Compta, Y., Parkkinen, L., OSullivan, S. S., Tolosa, E., Kutzelnigg, A.,...Jones, R. (2010).
Vandrovcova, J., Holton, J. L., Collins, Memantine for patients with Parkinsons
C.,...Revesz, T. (2011). Lewy- and disease dementia or dementia with Lewy
Alzheimer-type pathologies in Parkinsons bodies: A randomised, double-blind,
disease dementia:Which is more important? placebo-controlled trial. Lancet Neurology, 9,
Brain, 134, 14931505. 969977.
Consensus recommendations for the post- Emre M. (2003). What causes mental dys-
mortem diagnosis of Alzheimers dis- function in Parkinsons disease? Movement
ease. The National Institute on Aging, Disorders, 18(Suppl 6), S63S71.
and Reagan Institute Working Group on Engelborghs, S., Dermaut, B., Goeman, J.,
Diagnostic Criteria for the Neuropathological Saerens, J., Marin, P., Pickut, B. A., (2003).
Assessment of Alzheimers Disease. (1997). Prospective Belgian study of neurodegenera-
Neurobiology of Aging, 18, S1S2. tive and vascular dementia:APOE genotype
Dalf, E., Albasanz, J. L., Martin, M., & Ferrer, effects. Journal of Neurology, Neurosurgery and
I. (2004). Abnormal metabotropic glutamate Psychiatry, 74, 11481151.
receptor expression and signaling in the cere- Farrer, M., Kachergus, J., Forno, L., Lincoln,
bral cortex in diffuse Lewy body disease is S., Wang, D-S., Hulihan, M.,... De Deyn,
associated with irregular alpha-synuclein/ P. P. (2004). Comparison of kindreds with
phospholipase C (PLCbeta1) interactions. Parkinsonism and alpha-synuclein genomic
Brain Pathology, 14, 388398. multiplications. Annals of Neurology, 55,
Dalrymple-Alford, J. C., MacAskill, M. R., 174179.
Nakas, C. T., Livingston, L., Graham, C., Fnelon, G., Mahieux, F., Huon, R., & Zigler,
Crucian, G. P.,...Anderson, T. J. (2010). The M. (2000). Hallucinations in Parkinsons dis-
MoCA: Well-suited screen for cognitive ease: Prevalence, phenomenology and risk
impairment in Parkinson disease. Neurology, factors. Brain, 123(Pt 4), 733745.
75, 17171725. Ferman, T.J., Boeve, B.F., Smith, G.E., Lin, S-C.,
Dubois, B., Tolosa, E., & Kulisevsky, J. (2007). Silber, M. H., Pedraza, O.,...Dickson, D. W.
Efficacy and safety of donepezil in the treat- (2011). Inclusion of RBD improves the diag-
ment of Parkinsons disease patients with nostic classification of dementia with Lewy
dementia. bodies. Neurology, 77, 875882.
Dubois, B., Burn, D., Goetz, C., Aarsland, D., Ferman, T. J., Smith, G. E., Boeve, B. F., Ivnik,
Brown, R. G., Broe Gerald, A.,...Emre, M. R.J., Petersen, R.C., Knopman, D.,...Dickson,
(2007). Diagnostic procedures for Parkinsons D. W. (2004). DLB fluctuations: Specific fea-
disease dementia: Recommendations from tures that reliably differentiate DLB from AD
the movement disorder society task force. and normal aging. Neurology, 62, 181187.
Movement Disorders, 22, 23142324. Firbank, M.J., Colloby, S.J., Burn, D.J., McKeith,
Ebmeier, K. P., Calder, S. A., Crawford, J. R., I.G.,& OBrien, J.T. (2003). Regional cerebral
Stewart, L., Besson, J. A., Mutch, W. J. blood flow in Parkinsons disease with and
(1990). Mortality and causes of death in idio- without dementia. Neuroimage, 20, 13091319.
pathic Parkinsons disease: Results from the Foster, E. R., Campbell, M. C., Burack,
Aberdeen whole population study. Scottish M. A., Hartlein, J., Flores, H. P., Cairns,
Medical Journal, 35, 173175. N. J.,...Perimutter, J. S. (2010). Amyloid
254part ii The Dementias: The Major Diseases and Clinical Syndromes
imaging of Lewy body-associated disorders. Hansen, L., Salmon, D., Galasko, D., Masliah,
Movement Disorders, 25, 25162523. E., Katzman, R., DeTeresa, R.,...Klauber, M.
Gaig, C., Valldeoriola, F., Gelpi, E., Ezquerra, (1990). The Lewy body variant of Alzheimers
M., Llufriu, S., Buongiorno, M.,...Tolosa, disease: A clinical and pathologic entity.
E. (2011). Rapidly progressive diffuse Lewy Neurology, 40, 18.
body disease. Movement Disorders, 26, Hanyu, H., Sato, T., Hirao, K., Kanetaka, H.,
13161323. Sakurai, H.,& Iwamoto, T. (2009). Differences
Galasko, D., Hansen, L. A., Katzman, R., in clinical course between dementia with
Wiederholt, W., Masliah, E., Terry, R.,...Thal, Lewy bodies and Alzheimers disease.
L. J. (1994). Clinical-neuropathological cor- European Journal of Neurology, 16, 212217.
relations in Alzheimers disease and related Harding, A. J., Broe, G. A., & Halliday, G. M.
dementias. Archives of Neurology, 51, 888895. (2002). Visual hallucinations in Lewy body
Galvin, J.E., Price, J.L., Yan, Z., Morris, J.C.,& disease relate to Lewy bodies in the temporal
Sheline, Y. I. (2011). Resting bold fMRI dif- lobe. Brain, 125, 391403.
ferentiates dementia with Lewy bodies vs Healy, D. G., Abou-Sleiman, P. M., Lees, A. J.,
Alzheimer disease. Neurology, 76, 17971803. Casas, J. P., Quinn, N., Bhatia, K.,...Wood,
Galvin, J. E., Pollack, J., & Morris, J. C. (2006). N. W. (2004). Tau gene and Parkinsons dis-
Clinical phenotype of Parkinson disease ease:Acase-control study and meta-analysis.
dementia. Neurology, 67, 16051611. Journal of Neurology, Neurosurgery and
Goetz, C. G., Koller, W. C., & Poewe, W. Psychiatry, 75, 962965.
(2002). Drugs to treat dementia and psy- Hely, M. A., Morris, J. G. L., Reid, W. G. J., &
chosis: Management of Parkinsons disease. Trafficante, R. (2005). Sydney Multicenter
Movement Disorders, 17(Suppl 4), S120S127. Study of Parkinsons disease: Non-L-
Goker-Alpan, O., Lopez, G., Vithayathil, J., dopa-responsive problems dominate at
Davis, J., Hallett, M., & Sidransky, E. (2008). 15years. Movement Disorders, 20, 190199.
The spectrum of Parkinsonian manifestations Hely, M. A., Reid, W. G. J., Adena, M. A.,
associated with glucocerebrosidase muta- Halliday, G.M.,& Morris, J.G. L. (2008). The
tions. Archives of Neurology, 65, 13531357. Sydney multicenter study of Parkinsons dis-
Gmez-Isla, T., Growdon, W. B., McNamara, ease:The inevitability of dementia at 20years.
M., Newell, K., Gmez-Tortosa, E., Movement Disorders, 23, 837844.
Hedley-Whyte, E. T.,...Hyman, B. T. (1999). Hilker, R., Thomas, A. V., Klein, J. C.,
Clinicopathologic correlates in temporal cor- Weisenbach, S., Kalbe, E., Burghaus,
tex in dementia with Lewy bodies. Neurology, L.,...Heiss, W. D. (2005). Dementia in
53, 20032009. Parkinson disease: Functional imaging of
Gomperts, S. N., Rentz, D. M., Moran, cholinergic and dopaminergic pathways.
E., Becker, J. A., Locascio, J. J., Klunk, Neurology, 65, 17161722.
W. E.,...Johnson, K. A. (2008). Imaging Horimoto, Y., Matsumoto, M., Akatsu, H., Ikari,
amyloid deposition in Lewy body diseases. H., Kojima, K., Yamamoto, T.,...Kosaka, K.
Neurology, 71, 903910. (2003). Autonomic dysfunctions in dementia
Goris, A., Williams-Gray, C. H., Clark, G. R., with Lewy bodies. Journal of Neurology, 250,
Foltynie, T., Lewis, S.J. G., Brown, J.,...Sawcer, 530533.
S. J. (2007). Tau and alpha-synuclein in sus- Hu, X. S., Okamura, N., Arai, H., Higuchi, M.,
ceptibility to, and dementia in, Parkinsons Matsui, T., Tashiro, M.,...Sasaki, H. (2000).
disease. Annals of Neurology, 62, 145153. 18F-fluorodopa PET study of striatal dopa-
Grace, J., Amick, M.M.,& Friedman, J.H. (2009). mine uptake in the diagnosis of dementia
A double-blind comparison of galantamine with Lewy bodies. Neurology, 55, 15751577.
hydrobromide ER and placebo in Parkinson Huang, X., Chen, P. C., & Poole, C. (2004).
disease. Journal of Neurology, Neurosurgery and APOE-[epsilon]2 allele associated with
Psychiatry, 80, 1823. higher prevalence of sporadic Parkinson dis-
Hall, S., Ohrfelt, A., Constantinescu, R., ease. Neurology, 62, 21982202.
Andreasson, U., Surova, Y., Bostrom, Hulette, C., Mirra, S., Wilkinson, W., Heyman,
F.,...Hansson, O. (2012). Accuracy of a panel A., Fillenbaum, G., & Clark, C. (1995). The
of 5 cerebrospinal fluid biomarkers in the dif- Consortium to Establish a Registry for
ferential diagnosis of patients with dementia Alzheimers Disease (CERAD). Part IX.
and/or Parkinsonian disorders. Archives of A prospective cliniconeuropathologic study
Neurology, 69(11), 14451452. of Parkinsons features in Alzheimers dis-
Halliday, G., Hely, M., Reid, W., & Morris, J. ease. Neurology, 45, 19911995.
(2008). The progression of pathology in longi- Inzelberg, R., Bonuccelli, U., Schechtman, E.,
tudinally followed patients with Parkinsons Miniowich, A., Strugatsky, R., Ceravolo,
disease. Acta Neuropathologica, 115, 409415. R.,...Rabey, J.M. (2006). Association between
CHAPTER 12. Dementia With Lewy Bodies and Parkinsons Disease Dementia 255
amantadine and the onset of dementia in Levy, G., Schupf, N., Tang, M-X., Cote, L. J.,
Parkinsons disease. Movement Disorders, 21, Louis, E. D., Mejia, H.,...Marder, K. (2002).
13751379. Combined effect of age and severity on the
Jellinger, K.A. (1991). Pathology of Parkinsons risk of dementia in Parkinsons disease.
disease. Changes other than the nigros- Annals of Neurology, 51, 722729.
triatal pathway. Molecular Chemistry and Levy, G., Tang, M-X., Cote, L. J., Louis, E. D.,
Neuropathology, 14, 153197. Alfaro, B., Mejia, H.,...Marder, K. (2002). Do
Jellinger, K.A. (2000). Morphological substrates risk factors for Alzheimers disease predict
of mental dysfunction in Lewy body dis- dementia in Parkinsons disease? An explor-
ease:an update. Journal of Neural Transmission atory study. Movement Disorders, 17, 250257.
Supplemental, 59, 185212. Lim, A., Tsuang, D., Kukull, W., Nochlin, D.,
Jellinger, K. A. (2003). Prevalence of vascular Leverenz, J., McCormick, W.,...Larson, E.B.
lesions in dementia with Lewy bodies. Apost- (1999). Clinico-neuropathological correlation
mortem study. Journal of Neural Transmission, of Alzheimers disease in a community-based
110, 771778. case series. Journal of the American Geriatric
Kantarci, K., Petersen, R. C., Boeve, B. F., Society, 47, 564569.
Knopman, D. S., Tang-Wai, D. F., OBrien, Lippa, C. F., Smith, T. W., & Perry, E. (1999).
P.C.,...Jack, C.R., Jr. (2004). 1H MR spectros- Dementia with Lewy bodies:Choline acetyl-
copy in common dementias. Neurology, 63, transferase parallels nucleus basalis pathol-
13931398. ogy. Journal of Neural Transmission, 106,
Kantarci, K., Ferman, T.J., Boeve, B.F., Weigand, 525535.
S. D., Przybelski, S., Vemuri, P.,...Dickson, Litvan, I., Goldman, J.G., Trster, A.I., Schmand,
D.W. (2012). Focal atrophy on MRI and neu- B.A., Weintraub, D., Petersen, R.C.,...Emre,
ropathologic classification of dementia with M. (2012). Diagnostic criteria for mild
Lewy bodies. Neurology, 79, 553560. cognitive impairment in Parkinsons dis-
Kasten, M., Kertelge, L., Brggemann, N., van ease:Movement Disorder Society Task Force
der Vegt, J., Schmidt, A., Tadic, V.,...Klein, guidelines. Movement Disorders, 27, 349356.
C. (2010). Nonmotor symptoms in genetic Lobotesis, K., Fenwick, J.D., Phipps, A., Ryman,
Parkinson disease. Archives of Neurology, 67, A., Swann, A., Ballard, C.,...OBrien, J. T.
670676. (2001). Occipital hypoperfusion on SPECT
Kenny, E. R., Blamire, A. M., Firbank, M. J., & in dementia with Lewy bodies but not AD.
OBrien, J.T. (2012). Functional connectivity in Neurology, 56, 643649.
cortical regions in dementia with Lewy bodies Lopez, O.L., Becker, J.T., Kaufer, D.I., Hamilton,
and Alzheimers disease. Brain, 135, 569581. R. L., Sweet, R. A., Klunk, W., & DeKosky,
Kobayashi, S., Tateno, M., Park, T. W., Utsumi, S.T. (2002). Research evaluation and prospec-
K., Sohma, H., Ito, Y. M., .
.
.
Saito, T. (2011). tive diagnosis of dementia with Lewy bodies.
Apolipoprotein E4 frequencies in a Japanese Archives of Neurology, 59, 4346.
population with Alzheimers disease and Lucetti, C., Logi, C., Del Dotto, P., Berti, C.,
dementia with Lewy bodies. PLoS One, 6, e18569. Ceravolo, R., Baldacci, F., .
.
.Bonuccelli, U.
Kuhl, D. E., Minoshima, S., Fessler, J. A., Frey, (2010). Levodopa response in dementia with
K. A., Foster, N. L., Ficaro, E. P.,...Koeppe, Lewy bodies: A 1-year follow-up study.
R. A. (1996). In vivo mapping of choliner- Parkinsonism and Related Disorders, 16, 522526.
gic terminals in normal aging, Alzheimers Maetzler, W., Reimold, M., Liepelt, I., Solbach,
disease, and Parkinsons disease. Annals of C., Leyhe, T., Schweitzer, K., .
..
Berg, D.
Neurology, 40, 399410. (2008). [11C]PIB binding in Parkinsons dis-
Kulisevsky, J., & Pagonabarraga, J. (2009). ease dementia. Neuroimage, 39, 10271033.
Cognitive impairment in Parkinsons dis- Maidment, I., Fox, C., & Boustani, M. (2006).
ease: Tools for diagnosis and assessment. Cholinesterase inhibitors for Parkinsons dis-
Movement Disorders, 24, 11031110. ease dementia. Cochrane Database of Systematic
de Lau, L. M. L., Schipper, C. M. A., Hofman, Reviews, CD004747.
A., Koudstaal, P. J., & Breteler, M. M. B. Marder, K., Tang, M. X., Alfaro, B., Mejia,
(2005). Prognosis of Parkinson disease: Risk H., Cote, L., Jacobs, D., .
.
.
Mayeux, R.
of dementia and mortality: the Rotterdam (1998). Postmenopausal estrogen use and
Study. Archives of Neurology, 62, 12651269. Parkinsons disease with and without demen-
Lee, S-J., Kim, J-S., Yoo, J-Y., Song, I-U., Kim, tia. Neurology, 50, 11411143.
B-S., Jung, S-L.,... Lee, K.S. (2010). Influence Marder, K., Tang, M. X., Alfaro, B., Mejia, H.,
of white matter hyperintensities on the cog- Cote, L., Louis, E., .
..
Mayeux, R. (1999).
nition of patients with Parkinson disease. Risk of Alzheimers disease in relatives of
Alzheimer Disease and Associated Disorders, 24, Parkinsons disease patients with and with-
227233. out dementia. Neurology, 52, 719724.
256part ii The Dementias: The Major Diseases and Clinical Syndromes
Marder, K., Tang, M. X., Cote, L., Stern, Y., & treatment. Consortium on Dementia with
Mayeux, R. (1995). The frequency and associ- Lewy Bodies. Neurology, 53, 902905.
ated risk factors for dementia in patients with Meeus, B., Nuytemans, K., Crosiers, D.,
Parkinsons disease. Archives of Neurology, 52, Engelborghs, S., Peeters, K., Mattheijssens,
695701. M.,...Theuns, J. (2010). Comprehensive genetic
Marion, M-H., Qurashi, M., Marshall, G., & and mutation analysis of familial dementia
Foster, O. (2008). Is REM sleep behaviour with Lewy bodies linked to 2q35-q36. Journal
disorder (RBD) a risk factor of dementia in of Alzheimers Disease, 20, 197205.
idiopathic Parkinsons disease? Journal of Meeus, B., Verstraeten, A., Crosiers, D.,
Neurology, 255, 192196. Engelborghs, S., Van den Broeck, M.,
Mata, I. F., Samii, A., Schneer, S. H., Roberts, Mattheijssens, M.,...Theuns, J. (2012). DLB
J. W., Griffith, A., Leis, B. C.,...Zabetian, and PDD: A role for mutations in dementia
C. P. (2008). Glucocerebrosidase gene muta- and Parkinson disease genes? Neurobiology of
tions:Arisk factor for Lewy body disorders. Aging, 33, 629.e5629.e18.
Archives of Neurology, 65, 379382. Merdes, A. R., Hansen, L. A., Jeste, D. V.,
Matsui, H., Nishinaka, K., Oda, M., Niikawa, Galasko, D., Hofstetter, C. R., Ho, G. J.,...
H., Kubori, T.,& Udaka, F. (2007). Dementia Corey-Bloom, J. (2003). Influence of
in Parkinsons disease: Diffusion tensor Alzheimer pathology on clinical diagnostic
imaging. Acta Neurologica Scandinavica, 116, accuracy in dementia with Lewy bodies.
177181. Neurology, 60, 15861590.
McKeith, I., Fairbairn, A., Perry, R., Thompson, Miech, R. A., Breitner, J. C. S., Zandi, P. P.,
P., & Perry, E. (1992). Neuroleptic sensi- Khachaturian, A.S., Anthony, J.C.,& Mayer,
tivity in patients with senile dementia of L. (2002). Incidence of AD may decline in the
Lewy body type. British Medical Journal, 305, early 90s for men, later for women:The Cache
673678. County study. Neurology, 58, 209218.
McKeith, I., Del Ser, T., Spano, P., Emre, M., Mirra, S. S., Heyman, A., McKeel, D., Sumi,
Wesnes, K., Anand, R.,...Spiegel, R. (2000). S. M., Crain, B. J., Brownlee, L. M.,...Berg,
Efficacy of rivastigmine in dementia with L. (1991). The Consortium to Establish a
Lewy bodies: A randomised, double-blind, Registry for Alzheimers Disease (CERAD).
placebo-controlled international study. Part II. Standardization of the neuropatho-
Lancet, 356, 20312036. logic assessment of Alzheimers disease.
McKeith, I., Mintzer, J., Aarsland, D., Burn, D., Neurology, 41, 479486.
Chiu, H., Cohen-Mansfield, J.,...Reid, W. Molina, J.A., Garca-Segura, J.M., Benito-Len,
(2004). Dementia with Lewy bodies. Lancet J., Gmez-Escalonilla, C., del Ser, T., Martnez,
Neurology, 3, 1928. V., & Viao, J. (2002). Proton magnetic reso-
McKeith I., OBrien, J., Walker, Z., Tatsch, K., nance spectroscopy in dementia with Lewy
Booij, J., Darcourt, J., .
.
.
Meyer, I. (2007). bodies. European Neurology, 48, 158163.
Sensitivity and specificity of dopamine trans- Mollenhauer, B., Cullen, V., Kahn, I., Krastins, B.,
porter imaging with 123I-FP-CIT SPECT in Outeiro, T. F., Pepivani, I.,...Schlossmacher,
dementia with Lewy bodies:Aphase III, mul- M. G. (2008). Direct quantification of
ticentre study. Lancet Neurology, 6, 305313. CSF alpha-synuclein by ELISA and first
McKeith, I. G. (2006). Consensus guidelines cross-sectional study in patients with neu-
for the clinical and pathologic diagnosis of rodegeneration. Experimental Neurology, 213,
dementia with Lewy bodies (DLB): Report 315325.
of the Consortium on DLB International Molloy, S., McKeith, I. G., OBrien, J. T., &
Workshop. Journal of Alzheimers Disease, 9, Burn, D.J. (2005). The role of levodopa in the
417423. management of dementia with Lewy bod-
McKeith, I.G., Ballard, C.G., Perry, R.H., Ince, ies. Journal of Neurology, Neurosurgery and
P. G., OBrien, J. T., Neill, D.,...Perry, E. K. Psychiatry, 76, 12001203.
(2000). Prospective validation of consensus Mori, E., Ikeda, M., & Kosaka, K. (2012).
criteria for the diagnosis of dementia with Donepezil for dementia with Lewy bod-
Lewy bodies. Neurology, 54, 10501058. ies: A randomized, placebo-controlled trial.
McKeith, I.G., Dickson, D.W., Lowe, J., Emre, Annals of Neurology, 72, 4152.
M., OBrien, J.T., Feldman, H.,...Yamada, M. Mosimann, U. P., Rowan, E. N., Partington,
(2005). Diagnosis and management of demen- C. E., Collerton, D., Littlewood, E., OBrien,
tia with Lewy bodies:Third report of the DLB J. T.,...McKeith, I. G. (2006). Characteristics
Consortium. Neurology, 65, 18631872. of visual hallucinations in Parkinson disease
McKeith, I.G., Perry, E.K.,& Perry, R.H. (1999). dementia and dementia with Lewy bodies.
Report of the second dementia with Lewy American Journal of Geriatric Psychiatry, 14,
body international workshop:Diagnosis and 153160.
CHAPTER 12. Dementia With Lewy Bodies and Parkinsons Disease Dementia 257
Mulugeta, E., Londos, E., Ballard, C., Alves, Pagonabarraga, J., Llebaria, G., Garca-Snchez,
G., Zetterberg, H., Blennow, K.,...Aarsland, C., Pascual-Sedano, B., Gironell, A., &
D. (2011). CSF amyloid 38 as a novel diag- Kulisevsky, J. (2008). A prospective study of
nostic marker for dementia with Lewy bod- delusional misidentification syndromes in
ies. Journal of Neurology, Neurosurgery and Parkinsons disease with dementia. Movement
Psychiatry, 82, 160164. Disorders, 23, 443448.
Muslimovic, D., Post, B., Speelman, J. D., & Papapetropoulos, S., Lieberman, A., Gonzalez, J.,
Schmand, B. (2005). Cognitive profile of Singer, C., Laufer, D.Z.,& Mash, D.C. (2006).
patients with newly diagnosed Parkinson Family history of dementia: Dementia with
disease. Neurology, 65, 12391245. Lewy bodies and dementia in Parkinsons
Nagahama, Y., Okina, T., Suzuki, N.,& Matsuda, disease. Journal of Neuropsychiatry and Clinical
M. (2010). Neural correlates of psychotic Neuroscience, 18, 113116.
symptoms in dementia with Lewy bodies. Parkkinen, L., Pirttil, T.,& Alafuzoff, I. (2008).
Brain, 133, 557567. Applicability of current staging/categoriza-
Nelson, P.T., Kryscio, R.J., Jicha, G.A., Abner, tion of alpha-synuclein pathology and their
E.L., Schmitt, F.A., Xu, L.O.,...Markesbery, clinical relevance. Acta Neuropathologica, 115,
W.R. (2009). Relative preservation of MMSE 399407.
scores in autopsy-proven dementia with Parnetti, L., Tiraboschi, P., Lanari, A., Peducci,
Lewy bodies. Neurology, 73, 11271133. M., Padiglioni, C., DAmore, C.,... Calabresi,
Nelson, P.T., Jicha, G.A., Kryscio, R.J., Abner, P. (2008). Cerebrospinal fluid biomark-
E.L., Schmitt, F.A., Cooper, G.,...Markesbery, ers in Parkinsons disease with dementia
W.R. (2010). Low sensitivity in clinical diag- and dementia with Lewy bodies. Biological
noses of dementia with Lewy bodies. Journal Psychiatry, 64, 850855.
of Neurology, 257, 359366. Perry, E.K., Haroutunian, V., Davis, K.L., Levy,
Nervi, A., Reitz, C., Tang, M-X., Santana, V., R., Lantos, P., Eagger, S.,... McKeith, I. G.
Piriz, A., Reyes, D.,...Mayeux, R. (2011). (1994). Neocortical cholinergic activities dif-
Familial aggregation of dementia with Lewy ferentiate Lewy body dementia from classical
bodies. Archives of Neurology, 68, 9093. Alzheimers disease. Neuroreport, 5, 747749.
Nishioka, K., Ross, O. A., Vilario-Gell, C., Perry, E.K., Marshall, E., Kerwin, J., Smith, C.J.,
Cobb, S. A., Kachergus, J. M., Mann, D. M. Jabeen, S., Cheng, A.V.,& Perry, R.H. (1990).
A.,...Farrer, M.J. (2011). Glucocerebrosidase Evidence of a monoaminergic-cholinergic
mutations in diffuse Lewy body disease. imbalance related to visual hallucina-
Parkinsonism and Related Disorders, 17, 5557. tions in Lewy body dementia. Journal of
OBrien, J. T., Paling, S., Barber, R., Williams, Neurochemistry, 55, 14541456.
E.D., Ballard, C., McKeith, I.G.,...Fox, N.C. Perry, R. H., Irving, D., Blessed, G., Fairbairn,
(2001). Progressive brain atrophy on serial A., & Perry, E. K. (1990). Senile dementia of
MRI in dementia with Lewy bodies, AD, and Lewy body type. A clinically and neuro-
vascular dementia. Neurology, 56, 13861388. pathologically distinct form of Lewy body
OBrien, J. T., McKeith I. G, Walker, Z., Tatsch, dementia in the elderly. Journal of Neurological
K., Booij, J., Darcourt, J.,...Reininger, C. Sciences, 95, 119139.
(2009). Diagnostic accuracy of 123I-FP-CIT Piggott, M. A., Marshall, E. F., Thomas, N.,
SPECT in possible dementia with Lewy bod- Lloyd, S., Court, J.A., Jaros, E., (1999). Striatal
ies. British Journal of Psychiatry, 194, 3439. dopaminergic markers in dementia with
Ohrfelt, A., Grognet, P., Andreasen, N., Lewy bodies, Alzheimers and Parkinsons
Wallin, A., Vanmechelen, E., Blennow, diseases: Rostrocaudal distribution. Brain,
K., & Zetterberg, H. (2009). Cerebrospinal 122(Pt 8), 14491468.
fluid alpha-synuclein in neurodegenera- Pletnikova, O., West, N., Lee, M.K., Rudow, G.L.,
tive disorders-a marker of synapse loss? Skolasky, R. L., Dawson, T. M.,...Troncoso,
Neuroscience Letters, 450, 332335. J. C. (2005). Abeta deposition is associated
Okazaki, H., Lipkin, L. E., & Aronson, S. M. with enhanced cortical alpha-synuclein
(1961). Diffuse intracytoplasmic ganglionic lesions in Lewy body diseases. Neurobiology of
inclusions (Lewy type) associated with pro- Aging, 26, 11831192.
gressive dementia and quadriparesis in flex- Poewe, W., Wolters, E., Emre, M., Onofrj,
ion. J. Neuropathol. Experimental Neurology M., Hsu, C., Tekin, S., & Lane, R. (2006).
1961; 20:237244. Long-term benefits of rivastigmine in demen-
Olichney, J. M., Galasko, D., Salmon, D. P., tia associated with Parkinsons disease: An
Hofstetter, C. R., Hansen, L. A., Katzman, active treatment extension study. Movement
R., & Thal, L. J. (1998). Cognitive decline Disorders, 21, 456461.
is faster in Lewy body variant than in Postuma, R.B., Gagnon, J-F.,& Montplaisir, J.Y.
Alzheimers disease. Neurology, 51, 351357. (2012). REM sleep behavior disorder: From
258part ii The Dementias: The Major Diseases and Clinical Syndromes
in a movement disorder clinic. Parkinsonism Wider, C., Dickson, D.W.,& Wszolek, Z.K. (2010).
and Related Disorders, 17, 395397. Leucine-rich repeat kinase 2 gene-associated
Vendette, M., Gagnon, J-F., Dcary, A., disease:Redefining genotype-phenotype cor-
Massicotte-Marquez, J., Postuma, R. B., relation. Neurodegenerative Diseases, 7, 175179.
Doyon, J.,...Montplaisir, J. (2007). REM sleep Williams, M. M., Xiong, C., Morris, J. C., &
behavior disorder predicts cognitive impair- Galvin, J. E. (2006). Survival and mortality
ment in Parkinson disease without dementia. differences between dementia with Lewy
Neurology, 69, 18431849. bodies vs Alzheimer disease. Neurology, 67,
Walker, M. P., Ayre, G. A., Cummings, J. L., 19351941.
Wesnes, K., McKeith, I. G., OBrien, J. T., & Williams-Gray, C.H., Foltynie, T., Brayne, C.E.
Ballard, C.G. (2000a). Quantifying fluctuation G., Robbins, T. W., & Barker, R. A. (2007).
in dementia with Lewy bodies, Alzheimers Evolution of cognitive dysfunction in an inci-
disease, and vascular dementia. Neurology, dent Parkinsons disease cohort. Brain, 130,
54, 16161625. 17871798.
Walker, M. P., Ayre, G. A., Cummings, Williams-Gray, C. H., Evans, J. R., Goris,
J. L., Wesnes, K., McKeith, I. G., OBrien, A., Foltynie, T., Ban, M., Robbins,
J. T.,...Ballard, C. G. (2000b). The Clinician T. W.,...Barker, R. A. (2009). The distinct
Assessment of Fluctuation and the One Day cognitive syndromes of Parkinsons dis-
Fluctuation Assessment Scale. Two methods ease: 5 year follow-up of the CamPaIGN
to assess fluctuating confusion in dementia. cohort. Brain, 132, 29582969.
British Journal of Psychiatry, 177, 252256. Wiltshire, K., Concha, L., Gee, M., Bouchard,
Walker, Z., Allen, R. L., Shergill, S., & Katona, T., Beaulieu, C., & Camicioli, R. (2010).
C.L. (1997). Neuropsychological performance Corpus callosum and cingulum tractogra-
in Lewy body dementia and Alzheimers dis- phy in Parkinsons disease. Canadian Journal
ease. British Journal of Psychiatry, 170, 156158. Neurological Sciences, 37, 595600.
Walker, Z., Allen, R.L., Shergill, S., Mullan, E.,& Woodruff, B.K., Graff-Radford, N.R., Ferman,
Katona, C.L. (2000). Three years survival in T.J., Dickson, D.W., DeLucia, M.W., Crook,
patients with a clinical diagnosis of demen- J. E.,...Duara, R. (2006). Family history of
tia with Lewy bodies. International Journal of dementia is a risk factor for Lewy body dis-
Geriatric Psychiatry, 15, 267273. ease. Neurology, 66, 19491950.
Watson, R., Blamire, A.M., Colloby, S.J, Wood, Woods, S. P., & Trster, A. I. (2003). Prodromal
J.S., Barber, R., He, J.,& OBrien, J.T. (2012). frontal/executive dysfunction predicts incident
Characterizing dementia with Lewy bod- dementia in Parkinsons disease. Journal of the
ies by means of diffusion tensor imaging. International Neuropsychology Society, 9, 1724.
Neurology, 79, 906914. Yamada, T., Hattori, H., Miura, A., Tanabe,
Weintraub, D., Mavandadi, S., Mamikonyan, M., & Yamori, Y. (2001). Prevalence of
E., Siderowf, A. D., Duda, J. E., Hurtig, Alzheimers disease, vascular demen-
H. I.,...Stern, M. B. (2010). Atomoxetine for tia and dementia with Lewy bodies in a
depression and other neuropsychiatric symp- Japanese population. Psychiatry and Clinical
toms in Parkinson disease. Neurology, 75, Neuroscience, 55, 2125.
448455. Yoshita, M., Taki, J.,& Yamada, M. (2001). A clin-
Weintraub, D., Moberg, P.J., Culbertson, W.C., ical role for [(123)I]MIBG myocardial scintig-
Duda, J. E., & Stern, M. B. (2004). Evidence raphy in the distinction between dementia
for impaired encoding and retrieval memory of the Alzheimers-type and dementia
profiles in Parkinson disease. Cognitive and with Lewy bodies. Journal of Neurology,
Behavioral Neurology, 17, 195200. Neurosurgery and Psychiatry, 71, 583588.
Wesnes, K. A., McKeith, I., Edgar, C., Emre, Zaccai, J., McCracken, C., & Brayne, C. (2005).
M.,& Lane, R. (2005). Benefits of rivastigmine A systematic review of prevalence and inci-
on attention in dementia associated with dence studies of dementia with Lewy bodies.
Parkinson disease. Neurology, 65, 16541656. Age and Ageing, 34, 561566.
13
While Alzheimers disease (AD) is the most reader is encouraged to review both for fur-
common cause of dementia among older ther details. Evolving consensus, however,
individuals (Evans et al., 1989; Sayetta, has moved toward defining vascular cogni-
1986), the lifetime risk for stroke equals and tive impairment (VCI) as encompassing all
may exceed the risk of AD in some circum- forms of cognitive impairment associated
stances (Seshadri et al., 2006). In addition, with CVD, ranging from subtle impairments
magnetic resonance imaging (MRI) evidence in otherwise cognitively normal individu-
of asymptomatic cerebrovascular disease als through mild cognitive impairment to
(CVD) occurs in one third of older individu- dementia (OBrien et al., 2003). In fact, the
als (Decarli et al., 2005). It is, therefore, not most recent consensus specifically states that
surprising that concurrent CVD is often seen the term VCI characterizes all forms of cog-
in older dementia patients, even though they nitive deficits from VaD to MCI of vascular
may have a slowly progressive dementing origin (Gorelick etal., 2011, p.2673) and vas-
illness most consistent with AD (Mungas, cular dementia (VaD) is considered to be the
Reed, Ellis, & Jagust, 2001). This chapter extreme end of the spectrum of VCI (Gorelick
reviews the definition of vascular cognitive etal., 2011; Hachinski etal., 2006), where vas-
impairment as it relates to dementia after cular disease is felt to be the sole cause for the
stroke, slowly progressive dementia, and the cognitive impairment (Fig.13.1).
interaction of clinically silent CVD with AD. VCI also encompasses dementias where
both CVD and AD processes are thought
to co-occur (Gorelick et al., 2011; Hachinski
Vascular Cognitive Impairment Defined etal., 2006). As noted by Gorelick etal.:VCI
encompasses all the cognitive disorders asso-
As our understanding of the relationship ciated with cerebrovascular disease, from
between vascular disease and cognition con- frank dementia to mild cognitive deficits.
tinues to evolve, so does our terminology. Simply put, VCI is a syndrome with evidence
In fact, over the last 5 years, two separate of clinical stroke or subclinical vascular brain
consensus conference statements have been injury and cognitive impairment affecting at
published (Hachinski et al., 2006; Gorelick least one cognitive domain. The most severe
et al., 2011), although the aim of the two form of VCI is VaD (Gorelick et al., 2011,
statements differed slightly. The interested p.2673).
260
CHAPTER 13. Vascular Cognitive Impairment 261
VaD AD
Dementia
1. The diagnosis of dementia should be based on a decline in cognitive function from a prior baseline
and a deficit in performance in cognitive domains that are of sufficient severity to affect the subjects
activities of daily living.
2. The diagnosis of dementia must be based on cognitive testing, and a minimum of four cognitive
domains should be assessed:executive/attention, memory, language, and visuospatial functions.
3. The deficits in activities of daily living are independent of the motor/sensory sequelae of the vascular
event.
suggests the presence of systemic vascular cognitive syndrome generally follows imme-
disease that may require medical treatment. diately from the stroke, thereby assuring a
The diagnosis of VaD is based on two causal relationship. All symptoms months
factors: demonstration of the presence of a to years after a stroke should cause the clini-
cognitive disorder (dementia or MCI) by neu- cian to suspect a secondary cause unless new,
ropsychological testing and presence of vas- clinically silent brain infarction (e.g., frontal
cular disease by neuroimaging. The second lobe infarct) involving cortex or subcortical
critical clinical feature of VaD is determining white matter can be identified with imaging.
the relationship of the CVD to the cognitive It is important that the clinician recognize
symptoms. To appropriately diagnose VaD, it that the occasional strategic infarct can
is critical to identify the presence of cortical cause an abrupt dementia syndrome (Roman,
or subcortical infarcts or other stroke lesions, 2003). Examples include thalamic infarction,
and these should be associated with clinical which can cause a dense amnesia and execu-
symptomatology. Although some authors tive function impairments, or infarction of the
propose that the symptoms should appear angular gyrus, which can cause Gertsmanns
within 3months after a stroke, this is an arbi- syndrome (agraphia, acalculia, finger agno-
trary time and symptoms may develop after sia, and right-left confusion).
this time frame. Studies of the sensitivity of
this diagnostic approach note that it is quite
specific (Gold et al., 2002), but not sensitive Probable Vascular Dementia
to the presence of CVD in combination with With Extensive Subcortical
AD pathology, which will be discussed later. Cerebrovascular Disease
FLAIR
T1 T2* SWI
Figure13.2 Magnetic resonance imaging (MRI) in cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy (CADASIL).
cognitive decline, and behavioral changes. etal., 1998). Individuals with CADASIL pre-
Clinical diagnostic studies that support the senting with psychiatric problems also have
diagnosis of CADASIL include MRI white been described.
matter changes in the anterior aspect of the CADASIL, however, is a unique disease
temporal poles bilaterally and white matter that often begins before 30years of age with
changes in the external capsule (Fig. 13.2). dementia onset by age 55, on average. As a
Additionally, subcortical lacunar infarcts consequence, contamination by AD is rela-
and microhemorrhages are often common. tively rare. In the common clinical setting of
Recent publications note that anterior tempo- dementia, individuals are often mistakenly
ral white matter changes may occur as early diagnosed as mixed dementia or subcorti-
as age 20years (Lesnik Oberstein etal., 2003; cal ischemic vascular dementia when find-
van den Boom et al., 2003). Cerebral micro- ings of modest white matter disease in the
bleeds, located in the thalamus, can also absence of subcortical infarcts. In these set-
occur (Lesnik Oberstein etal., 2003). tings, AD pathology is generally the leading
The pattern of cognitive dysfunction is cause of the dementia (Chui et al., 2006). It,
characterized by deficits in executive func- therefore, is difficult to assess the extent of
tion (timed measures and measures of error subcortical vascular injury necessary to be
monitoring), verbal fluency, and memory sufficient for dementia. Criteria have been
with benefit from cues. In most cases, cog- developed that attempt to codify the extent
nitive decline is slowly progressive with of subcortical pathology necessary to cause
additional stepwise deterioration and is asso- dementia in SIVD (Roman et al., 1993) but
ciated with repeated lacunar infarcts noted by have generally failed (van der Flier, van
MRI (Liem etal., 2007). Some have observed Straaten, Barkhof, & Scheltens, 2005). The
deterioration of working memory and execu- strongest pathological evidence for subcorti-
tive function in individuals with NOTCH3 cal vascular injury sufficient to contribute to
mutations in the prestroke phase, and infer dementia (Knopman etal., 2003)suggests that
that cognitive decline may start insidiously more than four lacunas are necessary with or
before the onset of symptomatic ischemic without extensive white matter pathology,
episodes. Importantly, about thirty percent of particularly if these lacunas occur in strate-
individuals with CADASIL experience psy- gic areas such as the thalamus (Van der Werf
chiatric disturbances, varying from personal- et al., 2003). Neuroimaging, therefore, is an
ity changes to severe depression (Dichgans important tool in the assessment of VCI.
264part ii The Dementias: The Major Diseases and Clinical Syndromes
Imaging of Vascular Cognitive Impairment group were significant for CN, WMH, and
MTA with CN and WMH being significantly
Early attempts to compare MRI measures worse in the VaD group, whereas MTA was
among clinically diagnosed AD and VaD significantly worse for the AD group. While
subjects were relatively small and incon- AD subjects generally had worse MTA rat-
clusive. More recent reports of the qualita- ings and CN had low ratings, the VaD group
tive assessment of MRI differences between showed a substantial proportion of subjects
AD and VaD patients with larger samples at each MTA rating level except0.
have suggested that medial-temporal atro- As expected, VaD had a substantially
phy (MTA), particularly hippocampal atro- higher prevalence of large infarcts (39%) com-
phy, is uniquely associated with clinical pared to AD (5%) and CN (2%). Significant
AD as opposed to VaD (Du et al., 2002). In differences in the prevalence of both large
fact, hippocampal atrophy is considered and small infarcts between VaD and AD sub-
the imaging hallmark of clinical AD and is jects were also noted.
strongly associated with AD pathology (Jack Regression models comparing the patho-
et al., 1997, 1999, 2002). Bastos-Leite et al., logical processes underlying these two sam-
however, reported a high rate of MTA in a ples found both similarities and differences.
well-characterized sample of VaD patients For example, among VaD patients, age, sex,
and an association of MTA with cognitive infarcts, WMH, and MTA were significantly
functioning in the same group (Bastos-Leite related to cerebral atrophy. Conversely, only
et al., 2007); similarly other MRI studies age, WMH, and MTA were significantly asso-
have found extensive hippocampal atro- ciated with cerebral atrophy in the AD group.
phy in patients with suspected VaD (Fein In addition, the regression model accounted
et al., 2000), and hippocampal sclerosis has for more variance of cerebral atrophy in
been associated with severe hippocampal VaD patients (R2=0.36) than for AD patients
atrophy on MRI (Jagust etal., 2008). Global (R2=0.27).
cerebral atrophy also has been associated The authors next explored the relationship
with cognitive performance in both AD and between MTA and vascular markers (WMH
VaD patients (Scheltens et al., 1992). While and stroke [yes/no]). Among VaD patients,
VaD characteristically has been associated both presence of stroke and WMH contrib-
with white matter hyperintensities (WMH) uted significantly to MTA, but in opposing
in addition to infarction, WMH have been directions with increasing WMH associated
negatively correlated with cognitive func- with worsening MTA scores, but the presence
tioning in persons with normal cognition of stroke associated with improved MTA
(Au et al., 2006), VaD (Gootjes et al., 2004), scores. Conversely, among AD patients, only
MCI (Nordahl etal., 2005), and AD (Yoshita age and WMH contributed significantly to
etal., 2006), suggesting that the effect of this the model predicting MTA.
pathology transcends clinical diagnosis. Finally, the authors investigated the rela-
Recently, Logue et al. (2011) performed a tionship between MRI measures and cogni-
semiquantitative assessment of MRI mea- tive ability (MMSE) to test the hypothesis
sures from a clinical trial of donepezil in VaD that various MRI measures would show dif-
and a genetic study of AD. A total of 2,237 ferent associations with cognition due to the
individual MRI datasets were assessed with different etiologies of dementia. Surprisingly,
nearly equal distribution between cognitively MMSE scores were related to MTA in both
normal older individuals (CN), VaD, and AD. VaD (R2=0.131) and AD (R2=0.123) with a
Measures of cerebral atrophy, medial tempo- similar magnitude. Examining vascular fac-
ral atrophy, extent of WMH and the presence, tors in relation to MMSE scores, associations
size, and location of cerebral infarcts were were found between MMSE and WMH in the
obtained for each individual scan. VaD group, but this association explained
For all MRI ratings, the CN group was only a limited amount of additional variance
lowest with the VaD group showing the (R2=0.039) in MMSE. There was no associa-
highest scores on cerebral atrophy, white tion between WMH and MMSE for the AD
matter hyperintensities, and number of group.
infarcts. The AD group showed the greatest In summary, this study finds that vascu-
MTA. Differences between the VaD and AD lar injury is apparent in patients believed to
CHAPTER 13. Vascular Cognitive Impairment 265
have VaD with significantly greater WMH 2001; Gorelick etal., 2011; Lopez etal., 2003;
and multiple infarcts. In VaD the vascular Nordahl et al., 2005). This is the vascular
injury also leads to both cerebral and hip- equivalent of MCI commonly used to iden-
pocampal atrophy. However, the cognitive tify subjects in the transition from normalcy
aspects of the dementia syndrome appear to AD (Winblad etal., 2004).
most strongly correlated with the atrophy According to the recent consensus state-
measures. Because of this, the authors con- ment by Gorelick et al. (2011), the same
clude that MRI data from two dementia diagnostic criteria applied to VaD should
cohorts with differing etiologies find that be applied for the diagnosis of VaMCI with
dementia symptoms are most strongly the exception that instrumental activities
associated with cerebral atrophy suggest- of daily living should be unaffected or only
ing that tissue loss is the major substrate mildly affected. Most authors interpret this to
of the dementia syndrome. Therefore, we imply that the clinical dementia rating scale
are left to conclude that there is no specific (CDR) (Morris, 1993) should be no greater
MRI measure to date that reliably predicts than 0.5. This new diagnostic criteria also
VaD, and we can only conclude that MRI includes the condition of unstable VaMCI.
is sensitive to vascular brain injury, but it This term is used to designate individuals
cannot predict the impact on cognition. initially diagnosed with VaMCI who subse-
Further studies on this topic are in progress, quently improve to normal cognitive ability.
and recently published standards for these Reversibility may result from multiple causes
investigations should hopefully improve such as treatment of concurrent medical ill-
the harmonization of methods and report- nesses, treatment of depression, or post-
ing of results across laboratories. stroke recovery. Importantly, this diagnostic
Positron emission tomography (PET) will approach brings VCI into a taxonomy similar
likely prove to be a valuable tool for gener- to the AD community, emphasizing only dif-
ating new insights into the dissociable and ferences in disease etiology.
synergistic aspects of CVD and AD. For The prevalence of VaMCI is likely to be
example, a recent fluorodeoxyglucose PET substantial. For example, multiple studies
investigation in individuals with mild cog- find an increased prevalence of men in MCI
nitive impairment (MCI) who converted to studies (Petersen et al., 2005). Older men
dementia demonstrated that frontal hypo- have substantially greater brain vascular
metabolism was associated with WMH burden (Wolf etal., 1991)and are at a greater
but temporoparietal hypometabolism was lifetime risk for stroke as compared to AD
associated with cerebrospinal fluid amy- (Seshadri & Wolf, 2007). Finally, nearly 40%
loid levels. The advent of cerebral amyloid of all patients diagnosed with amnestic MCI
PET imaging, however, may prove helpful fail to show evidence of amyloid retention
to more precisely understanding the role of when using amyloid imaging (Pike et al.,
cerebrovascular disease in VCI. Preliminary 2007). While many other non-AD dementias
studies suggest that cerebral amyloid reten- have prodromal states, most are not memory
tion is associated with vascular risk factors specific with the exception of vascular dis-
(Reed etal., 2011), but not WMH or cognition ease, suggesting that this may be the second
among older individuals (Marchant et al., most common form of MCI, although this
2011). Although preliminary, the combined remains to be studied.
use of MRI measures of vascular brain injury Given the high prevalence of CVD in
and amyloid PET may offer new insights into the elderly and evidence suggesting that
the pathophysiology of VCI. CVD may strongly contribute to prevalent
dementia, a number of studies have begun to
explore the possible impact of CVD on cogni-
Vascular Mild Cognitive Impairment tive impairment among the elderly (DeCarli
et al., 2001; Lopez et al., 2003; Luchsinger
Cerebrovascular disease can also cause et al., 2009; Rockwood et al., 1999, 2000). In
mild cognitive deficits that can affect mul- these studies, evidence of vascular brain
tiple cognitive functions, and some authors injury, primarily identified by risk factors or
have proposed the term vascular mild cog- the presence of WMH on MRI, is increased
nitive impairment (VaMCI) (DeCarli et al., in prevalence among individuals with MCI,
266part ii The Dementias: The Major Diseases and Clinical Syndromes
including amnestic MCI (aMCI). In fact, at 1998; van Dijk, Prins, Vermeer, Koudstaal,&
least one study has suggested that aMCI may Breteler, 2002; Vermeer, Koudstaal, Oudkerk,
result strictly from vascular disease alone Hofman, & Breteler, 2002; Vermeer,
(Nordahl et al., 2005). In addition, a more Longstreth, & Koudstaal, 2007). Moreover,
recent study found evidence that both WMH reports from the Framingham Heart Study
and silent brain infarcts are associated with support the notion that WMH, silent cere-
incident MCI (Debette et al., 2010). Another bral infarcts, and cerebral atrophy increase
intriguing finding of this study was that these substantially in prevalence with increasing
same vascular markers were associated with age and are all related to vascular risk fac-
increased mortality. Competitive mortality, tors within a community population (Decarli
therefore, may explain why fewer individu- et al., 2005; Jeerakathil et al., 2004; Seshadri
als with severe CVD progress onto dementia. etal., 2004).
Although episodic memory has histori- These studies have also explored the rela-
cally been linked to the hippocampus and tionship between CVD and cognition. Much
surrounding cortices, evidence from neuro- of the results from these studies can be sum-
psychological and neuroimaging studies sug- marized by noting that frontal lobemediated
gests that the prefrontal cortex plays a critical cognitive domains of attention, concentration,
role in implementing executive control pro- and psychomotor speed are most affected
cesses that contribute to normal episodic (Au et al., 2006; Elias et al., 2004; Seshadri
memory functioning (Ranganath, Johnson,& etal., 2004; Swan etal., 1998, 2000). Evidence
DEsposito, 2003). Episodic memory failure of frontal lobe dysfunction, particularly by
in VaMCI, therefore, may be secondary to a WMH, is supported by PET imaging, which
more general impairment in executive con- finds reduced frontal metabolism in associa-
trol processes. tion with vascular-related brain injury, par-
ticularly WMH (DeCarli etal., 1995; Tullberg
etal., 2004)as well as significant associations
Impact of Cerebrovascular Disease between frontal lobe metabolism, memory
onCognition in Normal Individuals impairment, and future cognitive decline in
patients with dementia and WMH (Reed,
Finally, to understand the full spectrum of Eberling, Mungas, Weiner, & Jagust, 2000,
VCI, it is important to understand how vas- 2001).
cular brain injury can affect individuals who In summary, community-based studies of
appear cognitively normal. predominately healthy individuals find a sig-
A number of epidemiological studies show nificant inverse relationship between vascu-
strong associations between elevations in lar brain injury and cognitive performance.
middle life blood pressure and the preva- It is important to remember, however, that
lence of later life cognitive impairment and while these differences are significant at the
dementia (Elias, 1993; Elias, DAgostino, population level, they are generally asymp-
Elias,& Wolf, 1995; Elias etal., 2004; Launer, tomatic to the individual, although one study
1995). While the exact mechanism by which (de Groot et al., 2001) found that individu-
CVD leads to cognitive impairment remains als with WMH complain more frequently of
unclear, a number of cross-sectional as well as memory loss.
longitudinal prospective studies suggest that
CVD-related brain changes are associated
with these cognitive changes (Longstreth Interaction of Cerebrovascular
et al., 1996, 1998; Swan et al., 1998, 2000; andAlzheimers Disease
Vermeer etal., 2003).
In older individuals (Decarli et al., 2005; The relative impact of CVD on dementia
Longstreth et al., 1998) who have normal occurrence has a long and debatable his-
cognition, evidence of cerebrovascular injury tory (Brust, 1988; OBrien, 1988). While
is common. Epidemiological studies of cog- there is a well-developed literature with
nitively normal older individuals find sig- regard to dementia after stroke (Henon
nificant increases in WMH burden and silent et al., 2001; Moroney et al., 1996, 1997a,
cerebral infarcts detected by MRI with increas- 1997b; Tatemichi, 1990; Tatemichi etal., 1990,
ing age (Decarli etal., 2005; Longstreth etal., 1992; Tatemichi, Desmond, & Prohovnik,
CHAPTER 13. Vascular Cognitive Impairment 267
1995; Tatemichi, Desmond, Prohovnik, & cardiovascular risk score was created using
Eidelberg, 1995), it remains quite common to all four risk factors and was associated
identify individuals who have a slowly pro- with dementia in a dose-dependent fashion.
gressive dementing illness, multiple vascular Compared with participants having no risk
risk factors, and extensive WMH or lacunar factors, the risk for dementia increased from
infarction detected by brain imaging. The 1.27 for having one risk factor to 2.37 for hav-
impact of this cerebrovascular brain injury in ing all four risk factors. Not only did this
asymptomatic individuals on dementia inci- study identify that the presence of multiple
dence remains unclear, but accumulating evi- cardiovascular risk factors found at midlife
dence suggests that CVD-related brain injury substantially increases risk of late-life demen-
may significantly increase the likelihood of tia but showed that this relationship occurred
developing dementia, possibly through an in a dose-dependent manner with increasing
additive interaction with AD (Esiri, Nagy, exposure.
Smith, Barnetson,& Smith, 1999; Jagust, 2001;
Schneider et al., 2003, 2004; Snowdon et al.,
1997), although individuals for whom their Magnetic Resonance Imaging
vascular disease is limited to WMH generally Measures of Cerebrovascular Disease
have substantial AD pathology at autopsy and Incident Dementia
(Chui etal., 2006).
A number of studies have recently examined
the role of vascular disease identified by MRI
Vascular Risk Factors and Incident Dementia on progression to dementia. For example,
Debette and colleagues (Debette etal., 2010),
In a seminal work, Launer and colleagues studied the relationship between WMH and
studied the relationship between middle-life SBI and risk of future stroke, dementia, and
blood pressure measures and late-life cog- death. In their study, they noted that exten-
nition in a group of Asian Americans living sive WMH and SBI were significantly asso-
in Hawaii (Launer, 1995). This study found ciated with future stroke, dementia, and
an inverse relationship between the pattern death. A prior study by Vermeer colleagues
of middle-life systolic blood pressure and a (Vermeer et al., 2003) found that baseline
measure of general cognition (CASI scores) at thalamic infarcts were associated with mem-
later life. Unfortunately, this study could not ory deficits, whereas infarcts in other brain
determine dementia incidence nor did it iden- regions were most strongly associated with
tify prevalent dementia types at follow-up psychomotor speed. Importantly, in this non-
examination. Since this initial observation, demented group, future cognitive decline
however, a number of studies have exam- was only significantly associated with new
ined these relationships further. For exam- infarction seen on repeat MRI, suggesting
ple, Whitmer and colleagues (Whitmer, that repeated or multiple vascular events
2007 Whitmer, Gunderson, Barrett-Connor, were necessary for cognitive decline. Our
Quesenberry,& Yaffe, 2005; Whitmer, Sidney, laboratory has also studied the impact of
Selby, Johnston,& Yaffe, 2005; Whitmer etal., WMH and SBI on trajectories of cognitive
2008)conducted a retrospective cohort study decline. While we did not find a relation-
of 8,845 participants of a health maintenance ship between SBI and cognitive decline, we
organization who underwent health evalu- found that extensive WMH were associated
ations from 1964 to 1973 when they were with about a 4% drop in yearly cognitive
between the ages of 40 and 44. Midlife car- ability (Carmichael et al., 2010). Moreover,
diovascular risk factors included total choles- similar measures in the Alzheimers Disease
terol, diabetes, hypertension, and smoking. Neuroimaging Initiative cohort (Carmichael
Diagnoses of dementia were then ascertained et al., 2010) concluded that the presence of
by medical records review between 1994 and extensive WMH was associated with sig-
2003. The authors identified 721 participants nificant increases in MMSE and ADAS-Cog,
(8.2%) with incident dementia. Smoking, measures commonly used to test medication
hypertension, high cholesterol, and diabetes effects on AD treatment.
at midlife were each associated with a 20% to In summary, these data suggest that both
40% increase in risk of dementia. Acomposite vascular risk factors and evidence of vascular
268part ii The Dementias: The Major Diseases and Clinical Syndromes
brain injury are associated with both cognitive vivo markers of CVD. Amyloid imaging is
declines over 12years and incident demen- an emerging technology that appears to be a
tia over longer periods. Moreover, many of reasonable measure of the AD process (Fagan
the individuals with incident dementia are etal., 2006; Ikonomovic etal., 2008). Amyloid
diagnosed with AD. MRI measures, however, imaging, therefore, may offer us the oppor-
are not strictly tied to pathology. Fortunately, tunity to better disentangle the indepen-
a number of pathological studies have been dent and combined effects of AD and CVD
performed. pathologies. For example, amyloid imaging
with Pittsburgh Compound B (PiB) finds that
between 30% and 50% of individuals with
Interaction of Cerebrovascular MCI have normal PiB retention (Forsberg
Disease and Alzheimers Disease etal., 2007; Kemppainen etal., 2007; Lopresti
Pathologies on Cognition etal., 2005; Rowe etal., 2007). Other studies
find that PiB retention correlates with epi-
A particularly elegant series of pathologi- sodic memory impairment in MCI patients
cal studies show evidence that postmortem (Pike et al., 2007), that nonmemory MCI
infarction is associated with nearly twice the patients have normal PiB binding (Pike etal.,
likelihood of incident dementia (Schneider 2007), and that PiB+ MCI patients convert
etal., 2003). In addition, when adjusting for to dementia at a significantly higher rate
the extent of associated AD pathology, post- than nonmemory MCI (Forsberg etal., 2007;
mortem infarction significantly adds to the Kemppainen et al., 2007). These data, there-
likelihood of dementia, particularly when fore, suggest that PiB imaging identifies indi-
AD pathology is relatively mild (Schneider viduals with differing etiologies for their MCI
et al., 2004). Interestingly, the presence of syndrome and that PiB- MCI subjects may
the apolipoprotein E 4 (ApoE 4) polymor- include a subset of individuals with CVD as
phism increases the odds of postmortem the predominant pathology. If correct, PiB
infarction (Schneider etal., 2005)and mixed imaging will provide a unique measure of
pathologies, primarily the combination of AD pathology that can be applied to stud-
infarction and AD, are the strongest predic- ies examining the relationship between cog-
tor of dementia within a community-based nition and the complex interaction of CVD
population (Schneider et al., 2007). Finally, and AD pathologies that commonly co-occur
diabetes, a very common vascular risk fac- in older individuals. Early results support
tor, is independently associated with post- this assertion. Recent PiB studies find that
mortem evidence of vascular brain injury amyloid retention is not associated with
but not AD pathology (Arvanitakis et al., WMH and has little or no impact on cogni-
2006). This series of studies emphasizes tion among cognitively normal individuals,
the additive role of CVD to AD in causing whereas MRI measures of CVD have a nega-
clinically expressed dementia. In addition, tive impact on executive function in the same
these data suggest that ApoE may function group of individuals (Marchant etal., 2011).
as a risk factor for both processes as previ- Possibly even more interesting is the recent
ously hypothesized (Decarli, 2004), but that report that amyloid retention is related to the
vascular risk factors may primarily contrib- degree of vascular risk among cognitively
ute to dementia through vascular injury. Of normal individuals (Reed etal., 2011).
course, not all published research supports
this view. For example, a recent report that
studied subjects recruited through memory Conclusion
disorders clinics failed to show a significant
effect of CVD on dementia (Chui etal., 2006). This review summarized a relatively large
Further work is clearly indicated in this area. and growing literature that shows how CVD
and AD processes combine to cause cogni-
tive impairment ranging from subtle cogni-
Future Diagnostic Methods tive impairments in normal older individuals
through MCI, and that CVD likely contrib-
As noted in the previous section, WMH and utes additively to the cognitive effects of AD
MRI infarction appear to be reasonable in pathology. With the advent amyloid imaging
CHAPTER 13. Vascular Cognitive Impairment 269
it will be possible to assess the relative contri- Alzheimers Disease Neuroimaging Initiative.
butions of both pathologies to brain function, Archives of Neurology, 67(11), 13701378.
thereby further elucidating the combined Chui, H.C., Zarow, C., Mack, W.J., Ellis, W.G.,
effects of these two processes on cognitive Zheng, L., Jagust, W. J.,...Vintners, H. V.
(2006). Cognitive impact of subcortical vas-
aging and dementia risk.
cular and Alzheimers disease pathology.
In conclusion, vascular cognitive impair-
Annals of Neurology, 60(6), 67787.
ment can be thought of as the spectrum of Debette, S., Beiser, A., Decarli, C., Au, R.,
cognitive disorders due to symptomatic or Himali, J. J., Kelly-Hayes, M.,...Seshardi, S.
asymptomatic cerebrovascular injury. The (2010). Association of MRI markers of vas-
influence of cerebrovascular disease on brain cular brain injury with incident stroke, mild
function appears to begin relatively early cognitive impairment, dementia, and mortal-
in life, possibly decades before AD pathol- ity. The Framingham Offspring Study. Stroke,
ogy. CVD appears to affect normal cogni- 41(4), 600606.
tive aging, can be the sole cause of MCI, and Decarli, C. (2004). Vascular factors in demen-
tia: An overview. Journal of Neurological
likely contributes much to late-life demen-
Sciences, 226(12), 1923.
tia, even in the presence of AD. Given that
Decarli, C., Massaro, J., Harvey, D., Hald, J.,
the progression of CVD pathophysiology is Tullberg, M., Au, R.,...Wolf, P. A. (2005).
modifiable through various interventions, Measures of brain morphology and infarction
the possible public health benefits of fully in the framingham heart study: Establishing
understanding and remedying the impact what is normal. Neurobiology of Aging, 26(4),
of CVD on cognitive health is likely to be 491510.
substantial. DeCarli, C., Miller, B.L., Swan, G.E., Reed, T., Wolf,
P. A., & Carmelli, D. (2001). Cerebrovascular
and brain morphologic correlates of mild
References
cognitive impairment in the National Heart,
Andre, C. (2010). CADASIL:Pathogenesis, clini- Lung, and Blood Institute Twin Study. Archives
cal and radiological findings and treatment. of Neurology, 58(4), 643647.
Arqivos de Neuropsiquiatria, 68(2), 287299. DeCarli, C., Murphy, D. G., Tranh, M., Grady,
Arvanitakis, Z., Schneider, J. A., Wilson, R. S., C.L., Haxby, J.V., Gillette, J.A.,...Rappoport,
Li, Y., Arnold, S. E., Wang, Z., & Bennett, S.I. (1995). The effect of white matter hyper-
D. A. (2006). Diabetes is related to cerebral intensity volume on brain structure, cognitive
infarction but not to AD pathology in older performance, and cerebral metabolism of glu-
persons. Neurology, 67(11), 19601965. cose in 51 healthy adults. Neurology, 45(11),
Au, R., Massaro, J.M., Wolf, P.A., Young, M.E., 20772084.
Beiser, A., Seshadri, S.,...DeCarli, C. (2006). de Groot, J. C., de Leeuw, F. E., Oudkerk, M.,
Association of white matter hyperintensity Hofman, A., Jolles, J.,& Breteler, M.M. (2001).
volume with decreased cognitive function- Cerebral white matter lesions and subjective
ing:The Framingham Heart Study. Archives of cognitive dysfunction: The Rotterdam Scan
Neurology, 63(2), 246250. Study. Neurology, 56(11), 15391545.
Bastos-Leite, A. J., van der Flier, W. M., van Dichgans, M., Mayer, M., Uttner, I., Bruning,
Straaten, E. C., Staekenborg, S. S., Scheltens, R., Muller-Hocker, J., Rungger, G.,...Gasser,
P., & Barkhof, F. (2007). The contribution of T. (1998). The phenotypic spectrum of
medial temporal lobe atrophy and vascular CADASIL: Clinical findings in 102 cases.
pathology to cognitive impairment in vascu- Annals of Neurology, 44(5), 731739.
lar dementia. Stroke, 38(12), 31823185. Du, A.T., Schuff, N., Laakso, M.P., Zhu, X.P.,
Brust, J. C. M. (1988).Vascular dementia is Jagust, W.J., Yaffe, K.,...Weiner, M.W. (2002).
overdiagnosed. Archives of Neurology, 45, Effects of subcortical ischemic vascular
799801. dementia and AD on entorhinal cortex and
Carmichael, O., Mungas, D., Beckett, L., hippocampus. Neurology, 58(11), 16351641.
Harvey, D., Tomaszewski Farias, S., Reed, Elias, M. F., DAgostino, R. B., Elias, P. K., &
B.,...Decarli, C. (2012). MRI predictors of cog- Wolf, P. A. (1995a). Neuropsychological test
nitive change in a diverse and carefully char- performance, cognitive functioning, blood
acterized elderly population. Neurobiology of pressure, and age: The Framingham Heart
Aging, 33(1), 8395. Study. Experimental Aging Research, 21(4),
Carmichael, O., Schwarz, C., Drucker, D., 369391.
Fletcher, E., Harvey, D., Beckett, L.,...DeCarli, Elias, P. K., DAgostino, R. B., Elias, M. F., &
C. (2010). Longitudinal changes in white mat- Wolf, P.A. (1995b). Blood pressure, hyperten-
ter disease and cognition in the first year of the sion, and age as risk factors for poor cognitive
270part ii The Dementias: The Major Diseases and Clinical Syndromes
performance. Experimental Aging Research, Hachinski, V., Iadecola, C., Petersen, R. C.,
21(4), 393417. Breteler, M. M., Nyenhuis, D. L., Black,
Elias, M. F., Sullivan, L. M., DAgostino, R. B., S. E.,...Leblanc, G. G. (2006). National
Elias, P. K., Beiser, A., Au, R.,...Wolf, P. A. Institute of Neurological Disorders and
(2004). Framingham stroke risk profile and Stroke-Canadian Stroke Network vascular
lowered cognitive performance. Stroke, 35(2), cognitive impairment harmonization stan-
404409. dards. Stroke, 37(9), 222022241.
Elias, M.F., Wolf, P.A., DAgostino, R.B., Cobb, Henon, H., Durieu, I., Guerouaou, D., Lebert,
J., & White, L. R. (1993). Untreated blood F., Pasquier, F.,& Leys, D. (2001). Poststroke
pressure level is inversely related to cogni- dementia:Incidence and relationship to pre-
tive functioning: The Framingham Study. stroke cognitive decline. Neurology, 57(7),
American Journal of Epidemiology, 138, 35364. 12161222.
Esiri, M.M., Nagy, Z., Smith, M.Z., Barnetson, Ikonomovic, M.D., Klunk, W.E., Abrahamson,
L., & Smith, A. D. (1999). Cerebrovascular E. E., Mathis, C. A., Price, J. C., Tsopelas,
disease and threshold for dementia in the N. D., (2008). Post-mortem correlates of in
early stages of Alzheimers disease. Lancet, vivo PiB-PET amyloid imaging in a typical
354(9182), 919920. case of Alzheimers disease. Brain, 131(Pt 6),
Evans, D. A., Funkenstein, H. H., Albert, 16301645.
M. S., Scherr, P. A., Cook, N. R., Chown, Jack, C.R., Dickson, D.W., Parisi, J.E., Xu, Y.C.,
M. J.,...Taylor, J. O. (1989). Prevalence of Cha, P. C., OBrien, P. C.,...Petersen, R. C.
Alzheimers disease in a community popu- (2002). Antemortem MRI findings correlate
lation of older persons. Higher than previ- with hippocampal neuropathology in typical
ously reported. Journal of the American Medical aging and dementia. Neurology, 58, 750757.
Association, 262(18), 25512556. Jack, C.R., Jr., Petersen, R.C., Xu, Y.C., OBrien,
Fagan, A.M., Mintun, M.A., Mach, R.H., Lee, P.C., Smith, G.E., Ivnik, R.J.,...Kokmen, E.
S. Y., Dence, C. S., Shah, A. R.,...Holtzman, (1999). Prediction of AD with MRI-based hip-
D.M. (2006). Inverse relation between in vivo pocampal volume in mild cognitive impair-
amyloid imaging load and cerebrospinal ment. Neurology, 52(7), 13971403.
fluid Abeta42 in humans. Annals of Neurology, Jack, C. R., Jr., Petersen, R. C., Xu, Y. C.,
59(3), 512529. Waring, S. C., OBrien, P. C., Tangalos,
Fein, G., Di Sclafani, V., Tanabe, J., Cardenas, V., E.G.,...Kokmen, E. (1997). Medial temporal
Weiner, M.W., Jagust, W.J.,...Chui, H. (2000). atrophy on MRI in normal aging and very
Hippocampal and cortical atrophy predict mild Alzheimers disease [see comments].
dementia in subcortical ischemic vascular Neurology, 49(3), 786794.
disease. Neurology, 55(11), 16261635. Jagust, W. (2001). Untangling vascular demen-
Forsberg, A., Engler, H., Almkvist, O., Blomquist, tia. Lancet, 358(9299), 20972098.
G., Hagman, G., Wall, A.,...Nordberg, A. Jagust, W. J., Zheng, L., Harvey, D. J., Mack,
(2007). PET imaging of amyloid deposition W. J., Vinters, H. V., Weiner, M. W.,...Chui,
in patients with mild cognitive impairment. H.C. (2008). Neuropathological basis of mag-
Neurobiology of Aging, 29(10), 14561465. netic resonance images in aging and demen-
Gold, G., Bouras, C., Canuto, A., Bergallo, M.F., tia. Annals of Neurology, 63(1), 7280.
Herrmann, F.R., Hof, P.R.,...Giannakopoulos, Jeerakathil, T., Wolf, P. A., Beiser, A., Hald,
P. (2002). Clinicopathological validation J. K., Au, R., Kase, C. S.,...DeCarli, C.
study of four sets of clinical criteria for vas- (2004). Cerebral microbleeds: Prevalence
cular dementia. American Journal of Psychiatry, and associations with cardiovascular risk
159(1), 827. factors in the Framingham Study. Stroke,
Gorelick, P.B., Scuteri, A., Black, S.E., Decarli, 35(8), 18311835.
C., Greenberg, S.M., Iadecola, C.,...Seshadri, Jeerakathil, T., Wolf, P.A., Beiser, A., Massaro, J.,
S. (2011). Vascular contributions to cognitive Seshadri, S., DAgostino, R.B.,& DeCarli, C.
impairment and dementia: A statement for (2004). Stroke risk profile predicts white mat-
healthcare professionals from the American ter hyperintensity volume:The Framingham
Heart Association/American Stroke Study. Stroke, 35(8), 18571861.
Association. Stroke, 42(9), 26722713. Kemppainen, N. M., Aalto, S., Wilson, I. A.,
Gootjes, L., Teipel, S. J., Zebuhr, Y., Schwarz, Nagren, K., Helin, S., Bruck, A.,...Rinne, J.O.
R., Leinsinger, G., Scheltens, P.,...Hampel, (2007). PET amyloid ligand [11C]PIB uptake
H. (2004). Regional distribution of white is increased in mild cognitive impairment.
matter hyperintensities in vascular demen- Neurology, 68(19), 16031606.
tia, Alzheimers disease and healthy aging. Knopman, D.S., Parisi, J.E., Boeve, B.F., Cha,
Dementia and Geriatric Cognitive Disorders, R. H., Apaydin, H., Salviati, A.,...Rocca,
18(2), 180188. W. A. (2003). Vascular dementia in a
CHAPTER 13. Vascular Cognitive Impairment 271
of mild cognitive impairment. New England Schneider, J. A., Arvanitakis, Z., Bang, W., &
Journal of Medicine, 352(23), 23792388. Bennett, D. A. (2007). Mixed brain patholo-
Pike, K. E., Savage, G., Villemagne, V. L., Ng, gies account for most dementia cases
S., Moss, S. A., Maruff, P.,...Rowe, C. C. in community-dwelling older persons.
(2007). Beta-amyloid imaging and memory in Neurology, 69(24), 21972204.
non-demented individuals:Evidence for pre- Schneider, J. A., Bienias, J. L., Wilson, R. S.,
clinical Alzheimers disease. Brain, 130(Pt 11), Berry-Kravis, E., Evans, D. A., & Bennett,
28372844. D. A. (2005). The apolipoprotein E epsilon4
Ranganath, C., Johnson, M. K., & DEsposito, allele increases the odds of chronic cerebral
M. (2003). Prefrontal activity associated with infarction [corrected] detected at autopsy in
working memory and episodic long-term older persons. Stroke, 36(5), 954959.
memory. Neuropsychologia, 41(3), 378389. Schneider, J. A., Wilson, R. S., Bienias, J. L.,
Reed, B. R., Marchant, N. L., Jagust, W. J., Evans, D.A.,& Bennett, D.A. (2004). Cerebral
Decarli, C.C., Mack, W.,& Chui, H.C. (2011). infarctions and the likelihood of dementia
Coronary risk correlates with cerebral amy- from Alzheimer disease pathology. Neurology,
loid deposition. Neurobiology of Aging, 33(9), 62(7), 11481155.
19791987. Schneider, J. A., Wilson, R. S., Cochran, E. J.,
Rockwood, K., Howard, K., MacKnight, Bienias, J. L., Arnold, S. E., Evans, D. A.,
C., & Darvesh, S. (1999). Spectrum of dis- (2003). Relation of cerebral infarctions to
ease in vascular cognitive impairment. dementia and cognitive function in older per-
Neuroepidemiology, 18(5), 248254. sons. Neurology, 60(7), 10821088.
Rockwood, K., Wentzel, C., Hachinski, V., Seshadri, S., Beiser, A., Kelly-Hayes, M., Kase,
Hogan, D. B., MacKnight, C., & McDowell, C.S., Au, R., Kannel, W.B.,& Wolf, P.A. (2006).
I. (2000). Prevalence and outcomes of vascu- The lifetime risk of stroke:Estimates from the
lar cognitive impairment. Vascular Cognitive Framingham Study. Stroke, 37(2), 345350.
Impairment Investigators of the Canadian Seshadri, S.,& Wolf, P.A. (2007). Lifetime risk of
Study of Health and Aging. Neurology, 54(2), stroke and dementia: Current concepts, and
447451. estimates from the Framingham Study. Lancet
Roman, G. C. (2003). Vascular demen- Neurology, 6(12), 11061114.
tia: Distinguishing characteristics, treat- Seshadri, S., Wolf, P.A., Beiser, A., Elias, M.F.,
ment, and prevention. Journal of the American Au, R., Kase, C.S., (2004). Stroke risk profile,
Geriatric Society, 51(5 Suppl Dementia), brain volume, and cognitive function: The
S296S304. Framingham Offspring Study. Neurology,
Roman, G. C., Tatemichi, T. K., Erkinjuntti, 63(9), 15911599.
T., Cummings, J. L., Masdeu, J. C., Garcia, Snowdon, D.A., Greiner, L.H., Mortimer, J.A.,
J. H.,...Hofman, A. (1993). Vascular demen- Riley, K. P., Greiner, P. A., & Markesbery,
tia: Diagnostic criteria for research studies. W. R. (1997). Brain infarction and the clini-
Report of the NINDS-AIREN International cal expression of Alzheimer disease. The
Workshop. Neurology, 43(2), 250260. Nun Study. Journal of the American Medical
Rowe, C. C., Ng, S., Ackermann, U., Gong, Association, 277, 813817.
S. J., Pike, K., Savage, G.,...Villemagne, Swan, G. E., DeCarli, C., Miller, B. L., Reed,
V. L. (2007). Imaging beta-amyloid burden T., Wolf, P. A., & Carmelli, D. (2000).
in aging and dementia. Neurology, 68(20), Biobehavioral characteristics of nonde-
17181725. mented older adults with subclinical brain
Sacco, R. L., Wolf, P. A., Kannel, W. B., & atrophy. Neurology, 54(11), 21082114.
McNamara, P.M. (1982). Survival and recur- Swan, G.E., DeCarli, C., Miller, B.L., Reed, T.,
rence following stroke. The Framingham Wolf, P.A., Jack, L.M.,& Carmelli, D. (1998).
Study. Stroke, 13(3), 290295. Association of midlife blood pressure to
Sayetta, R. B. (1986). Rates of senile demen- late-life cognitive decline and brain morphol-
tia, Alzheimers type, in the Baltimore ogy. Neurology, 51(4), 986993.
Longitudinal Study. Journal of Chronic Disease, Tatemichi, T.K. (1990). How acute brain failure
39(4), 271286. becomes chronic:Aview of the mechanisms
Scheltens, P., Leys, D., Barkhof, F., Kuiper, of dementia related to stroke. Neurology, 40,
M.A., Huglo, D., Weinstein, H.C.,...Valk, J. 16521659.
(1992). Atrophy of medial temporal lobes on Tatemichi, T. K., Desmond, D. W., Mayeux, R.,
MRI in probable Alzheimers disease and Paik, M., Stern, Y., Sano, M.,...Hauser, W.A.
normal aging: Diagnostic value and neuro- (1992). Dementia after stroke: Baseline fre-
psychological correlates. Journal of Neurology, quency, risks, and clinical features in a hospi-
Neurosurgery and Psychiatry, 55, 967972. talized cohort. Neurology, 42, 11851193.
CHAPTER 13. Vascular Cognitive Impairment 273
Tatemichi, T.K., Desmond, D.W.,& Prohovnik, Prevalence and risk factors of silent brain
I. (1995). Strategic infarcts in vascular demen- infarcts in the population-based Rotterdam
tia. Aclinical and brain imaging experience. Scan Study. Stroke, 33(1), 2125.
Arzneimittel-Forschung, 45(3A), 371385. Vermeer, S. E., Prins, N. D., den Heijer, T.,
Tatemichi, T. K., Desmond, D. W., Prohovnik, Hofman, A., Koudstaal, P.J.,& Breteler, M.M.
I., & Eidelberg, D. (1995). Dementia (2003). Silent brain infarcts and the risk of
associated with bilateral carotid occlu- dementia and cognitive decline. New England
sions:Neuropsychological and haemodynamic Journal of Medicine, 348(13), 12151222.
course after extracranial to intracranial bypass Wagle, J., Farner, L., Flekkoy, K., Bruun Wyller,
surgery. Journal of Neurology, Neurosurgery and T., Sandvik, L., Fure, B.,...Engedal, K. (2011).
Psychiatry, 58(5), 633636. Early post-stroke cognition in stroke rehabili-
Tatemichi, T. K., Foulkes, M. A., Mohr, J. P., tation patients predicts functional outcome at
Hewitt, J.R., Hier, D.B., Price, T.R.,& Wolf, 13 months. Dementia and Geriatric Cognitive
P. A. (1990). Dementia in stroke survivors Disorders, 31(5), 379387.
in the stroke data bank cohort. Prevalence, Whitmer, R. A. (2007). Type 2 diabetes and
incidence, risk factors, and computed tomo- risk of cognitive impairment and dementia.
graphic findings. Stroke, 21, 858866. Current Neurology and Neuroscience Reports,
Tullberg, M., Fletcher, E., DeCarli, C., Mungas, 7(5), 373380.
D., Reed, B. R., Harvey, D. J.,...Jagust, W. J. Whitmer, R.A., Gunderson, E.P., Barrett-Connor,
(2004). White matter lesions impair frontal E., Quesenberry, C. P., Jr., & Yaffe, K. (2005).
lobe function regardless of their location. Obesity in middle age and future risk of
Neurology, 63(2), 246253. dementia: A 27 year longitudinal population
van den Boom, R., Lesnik Oberstein, S. A., based study. British Medical Journal, 330(7504),
Spilt, A., Behloul, F., Ferrari, M. D., Haan, 1360.
J.,...Buchen, M.A. (2003). Cerebral hemody- Whitmer, R.A., Gustafson, D.R., Barrett-Connor,
namics and white matter hyperintensities in E., Haan, M. N., Gunderson, E. P., & Yaffe,
CADASIL. Journal of Cerebral Blood Flow and K. (2008). Central obesity and increased risk
Metabolism, 23(5), 599604. of dementia more than three decades later.
van der Flier, W.M., van Straaten, E.C., Barkhof, Neurology, 71(14), 10571064.
F., & Scheltens, P. (2005). NINDS AIREN Whitmer, R. A., Sidney, S., Selby, J., Johnston,
neuroimaging criteria do not distinguish S. C., & Yaffe, K. (2005). Midlife cardiovas-
stroke patients with and without dementia. cular risk factors and risk of dementia in late
Neurology, 65(8), 1341. life. Neurology, 64(2), 277281.
Van der Werf, Y.D., Scheltens, P., Lindeboom, J., Winblad, B., Palmer, K., Kivipelto, M., Jelic, V.,
Witter, M.P., Uylings, H.B.,& Jolles, J. (2003). Fratiglioni, L., Wahlund, L. O.,...Petersen,
Deficits of memory, executive functioning R. C. (2004). Mild cognitive impairment
and attention following infarction in the beyond controversies, towards a consen-
thalamus:Astudy of 22 cases with localised sus: Report of the International Working
lesions. Neuropsychologia, 41(10), 13301344. Group on Mild Cognitive Impairment. Journal
van Dijk, E. J., Prins, N. D., Vermeer, S. E., of Internal Medicine, 256(3), 240246.
Koudstaal, P. J., & Breteler, M. M. (2002). Wolf, P. A., DAgostino, R. B., Belanger,
Frequency of white matter lesions and silent A. J., & Kannel, W. B. (1991). Probability of
lacunar infarcts. Journal of Neural Transmission stroke: A risk profile from the Framingham
Supplemental, 2002(62), 2539. Study. Stroke, 22(3), 312318.
Vermeer, S.E., Longstreth, W.T., Jr.,& Koudstaal, Yoshita, M., Fletcher, E., Harvey, D., Ortega,
P.J. (2007). Silent brain infarcts:Asystematic M., Martinez, O., Mungas, D.M.,...DeCarli,
review. Lancet Neurology, 6(7), 611619. C.S. (2006). Extent and distribution of white
Vermeer, S. E., Koudstaal, P. J., Oudkerk, matter hyperintensities in normal aging,
M., Hofman, A., & Breteler, M. M. (2002). MCI, and AD. Neurology, 67(12), 21922198.
14
Cerebral amyloid angiopathy (CAA) is a cere- (Zhang-Nunes et al., 2006). Autopsy stud-
brovascular disorder that is commonly found ies have suggested that the sporadic form is
in the brains of elderly people (Jellinger, detectable in 10% to 40% of individuals above
2002). CAA-related vascular dysfunction is the age of 60 (Jellinger, 2002), and this figure
caused by deposition of the amyloid- (A) increases to 50% in individuals above the age
peptide in small and medium-sized blood of 90 (McCarron & Nicoll, 2004). In patients
vessels (Vinters 1987; Vonsattel et al., 1991). with concomitant Alzheimers disease (AD),
CAA can lead to lesions typical of cerebral CAA can be found in 80% or more of the
small-vessel disease (SVD). Indeed, all of the affected brains (Ellis etal., 1996; Jellinger, 2002;
classic magnetic resonance imaging (MRI) Xu, Yang, & Wang, 2003). In patients with
markers of SVD can be seen in patients with dementia, these two diseases often coexist and
CAA. These include small, punctate, micro- share the same neuropathologic finding of A
hemorrhages (or microbleeds) (Greenberg, deposition (Selkoe, 2001; Smith& Greenberg,
Finklestein,& Schaefer, 1996; Greenberg etal., 2009). Cognitive impairment has, however,
2009), lacunar infarctions (Kimberly et al., also been observed in CAA in the absence of
2009; Menon & Kidwell, 2009), and white extensive AD pathology (Grabowski, Cho,
matter hyperintensity (WMH) (Holland Vonsattel, Rebeck, & Greenberg, 2001; Natt
etal., 2008; Zhu etal., 2012). Although CAA et al., 2001), and CAA has been increasingly
classically presents with a lobar intracerebral recognized as an independent cause of demen-
hemorrhage (ICH), mounting evidence sug- tia (Arvanitakis etal., 2011; Greenberg, Gurol,
gests that there are many patients with CAA Rosand, & Smith, 2004; Neuropathology
without a major hemorrhage (Greenberg, Group, Medical Research Council Cognitive
Vonsattel, Stakes, Gruber,& Finklestein, 1993; Function and Aging Study, 2001).
Greenberg etal., 2009).
Epidemiology Pathophysiology
CAA occurs in a highly prevalent spo- In its most common form, amyloid angiopa-
radic form and a more rare hereditary form thy results from A deposition in the media
274
CHAPTER 14. Cerebral Amyloid Angiopathy andCognitiveImpairment 275
and adventitia of cerebral small arteries (e.g., thalamus and basal ganglia) and the
and capillaries. After cleavage of the longer brainstem (Herzig etal., 2004; Vinters, 1987).
amyloid precursor protein (APP), A spe- The potential role of peripheral A in the
cies are formed consisting of 40 to 42 amino development of CAA has recently been high-
acids (Price, Tanzi, Borchelt,& Sisodia, 1998). lighted in a transgenic mouse model, which
Although the A peptide is derived from showed acceleration of CAA and A-related
APP in both sporadic CAA and in AD, cer- brain pathology after peripheral injection of
tain hereditary forms of CAA are associ- A-containing inoculates (Eisele etal., 2010).
ated with accumulation of non-A peptides Peripheral A may be an important precur-
(Zhang-Nunes etal., 2006). sor pool for brain A, as several animal mod-
It has been suggested that the A peptide els have demonstrated that it can cross the
is primarily generated by neurons and is bloodbrain barrier (Ghilardi et al., 1996;
drained with interstitial fluid along perivas- Mackic et al., 1998, 2002; Martel, Mackic,
cular spaces to cervical lymph nodes (Herzig, McComb, Ghiso,& Zlokovic, 1996; Poduslo,
Van Nostrand, & Jucker, 2006; Roher et al., Curran, Haggard, Biere,& Selkoe, 1997; Ujiie,
2003; Weller etal., 1998). A is likely actively Dickstein, Carlow,& Jefferies, 2003; Zlokovic
cleared from the central nervous system etal., 1993).
across the bloodbrain barrier through a vari- Cerebrovascular deposition of A in
ety of mechanisms (Bell et al., 2009; Deane patients with sporadic and hereditary forms
et al., 2003, 2004). Impaired clearance may of CAA results in an array of vessel pathol-
lead to amyloid deposits in the vessel wall ogy. This includes loss of smooth muscle
(Fig.14.1) and amyloid plaques in the brain cells, thickening of the vessel wall with lumi-
parenchyma (Deane etal., 2003; Herzig etal., nal narrowing, concentric splitting of the
2006). Overexpression of serum response fac- vessel wall (vessel-in-vessel appearance),
tor (SRF) and myocardin in vascular smooth microaneurysm formation, and perivascular
muscle cells can downregulate lipoprotein microhemorrhage (Grabowski et al., 2001;
receptor-related protein (LRP-1) and initiate Mandybur, 1986; Vinters, 1987; Vinters etal.,
A accumulation (Bell etal., 2009). 1994, 1998; Vonsattel etal., 1991; Zekry etal.,
For reasons yet to be clarified, there is pref- 2003). These pathological findings can also
erential A deposition in the cerebral cortex, be recapitulated in various animal models
particularly the occipital lobe, with relative of CAA resulting from overexpression of
sparing of the deep hemispheric structures the APP gene (Calhoun etal., 1999; Christie,
(A) (B)
Figure14.1 Pathologic appearance of cerebral amyloid angiopathy. (A) Amyloid deposits replace
media and smooth muscle cells causing thickening of the vessel wall (hematoxylin& eosin; original
magnification, 20). (B) Immunoperoxidase staining for amyloid- peptide showing circumferential
staining of leptomeningeal blood vessels (original magnification, 20). (Images courtesy of
Dr.Matthew P.Frosch, MGH) (See color plate section)
276part ii The Dementias: The Major Diseases and Clinical Syndromes
Yamada, Moskowitz, & Hyman, 2001; Fryer Cohen, Hedera, Friedland, & Kalaria, 1996;
et al., 2003; Van Dorpe et al., 2000; Winkler Schmechel etal., 1993).
et al., 2001). Furthermore, deposition of A Interestingly, in AD the presence of the 4
has been shown to affect resting vessel diam- allele is associated with increased risk and
eter (Kimchi, Kajdasz, Bacskai, & Hyman, a more rapid progression of the disease,
2001; Mandybur, 1986) and modify cerebral whereas presence of the 2 allele is associ-
vasoreactivity in animal models (Han et al., ated with decreased risk (Corder etal., 1998).
2008; Niwa, Carlson,& Iadecola, 2000; Niwa, The effect of the different APOE genotypes
Younkin, etal., 2000; Shin etal., 2007)and in in both diseases is likely to be mediated by
patients with CAA (Dumas etal., 2012; Smith the way amyloid accumulation is modulated
et al., 2008). This vascular dysfunction may (Olesen, Mikkelsen, Gerdes, & Jensen, 1997;
underlie the subcortical white matter damage Sanan etal., 1994; Verghese etal., 2011). For
seen in patients with advanced CAA (Gurol example, the 4 allele is thought to increase
etal., 2006; Holland etal., 2008; Smith etal., A aggregation and impair A clearance
2004; Viswanathan etal., 2008). Although the (Verghese etal., 2011).
distribution of white matter disease in CAA In addition to APOE as a risk factor for
appears similar to patients with hyperten- sporadic CAA, there are several genetic
sive vasculopathy (Smith et al., 2010), there mutations that cause rare autosomal domi-
is some suggestion that in at least a subgroup nant familial forms of CAA. Patients with
of CAA patients, the posterior white matter these hereditary forms of CAA usually have
is predominantly affected (Zhu etal., 2012). more severe clinical course and present at
an earlier age (Bornebroek et al., 2003; De
Jonghe etal., 1998; Palsdottir, Snorradottir,&
Genetics Thorsteinsson, 2006; Van Nostrand, Melchor,
Cho, Greenberg, & Rebeck, 2001). To date,
In sporadic CAA, the only specific genetic several mutations have been described, most
risk factor consistently identified has of which involve either missense mutations
been Apolipoprotein E (APOE) genotype. within the A coding region or duplication of
Possession of the APOE type 2 and/or 4 the APP gene. However, mutations in other
is associated with lobar hemorrhage (Biffi, genes unrelated to A such as cystatin C
Sonni, et al., 2010; Greenberg et al., 1998; and transthyretin have also been described
Woo et al., 2002). The presence of either (Ghiso, Pons-Estel, & Frangione, 1986;
APOE 2 or 4 alleles possibly doubles the Jonsdottir& Palsdottir 1993; Palsdottir etal.,
risk of a lobar ICH (odds ratio 2.3; 95% con- 1988; Vidal etal., 1996).
fidence interval 1.24.4) (Woo et al., 2002). The most common form of hereditary CAA
Additionally, the APOE 2 and 4 alleles have is seen in families with autosomal dominant
been associated with an earlier age of onset early-onset AD (ADEOAD). It has been sug-
of a lobar hemorrhage (Greenberg etal., 1998; gested that in 2% to 18% of the individuals
Greenberg, Briggs, etal., 1996)and correlate with ADEOAD, the disorder is caused by
with an increased risk of recurrent hemor- duplication of the APP locus, which often
rhages (ODonnell etal., 2000). causes concomitant CAA (Cabrejo et al.,
The APOE 2 allele alone predisposes 2006; Kasuga et al., 2009; Rovelet-Lecrux
patients with lobar ICH to hematoma expan- et al., 2006; Sleegers et al., 2006). A more
sion (Brouwers et al., 2012) and might have rare form, hereditary cerebral hemorrhage
a role in the severity and clinical course with amyloidosis-Dutch type (HCHWA-D),
of lobar ICH (Biffi et al., 2011). These stud- the first hereditary CAA disorder to be dis-
ies are in line with the finding that APOE covered, is caused by a point mutation at
2 may promote splitting of the vessel wall, codon 693 of APP, which results in modifi-
formation of microhemorrhages, and fibri- cation of the A peptide (Bakker etal., 1991;
noid necrosis leading to vessel breakdown Levy et al., 1990; van Duinen et al., 1987;
(Greenberg et al., 1998; McCarron et al., Wattendorff, Frangione, Luyendijk, & Bots,
1999). In contrast, the APOE 4 allele is asso- 1995). This is a dominantly inherited disor-
ciated with an increase in the amount of vas- der where patients experience recurrent ICH,
cular amyloid (Greenberg, Rebeck, Vonsattel, cognitive decline, and dementia. Although
Gomez-Isla, & Hyman, 1995; Premkumar, cognitive symptoms typically appear after
CHAPTER 14. Cerebral Amyloid Angiopathy andCognitiveImpairment 277
initial stroke, they can manifest as the first TABLE14.1 Boston Criteria for Diagnosis
symptom of the disease (Zhang-Nunes etal., of Cerebral Amyloid Angiopathy (CAA)
2006). Another hereditary CAA form, first Related Hemorrhage
discovered in an Iowa family, is caused by a
1. Definite CAA
point mutation in codon 694 of the APP gene
Full postmortem examination demonstrating
(Grabowski etal., 2001; Van Nostrand etal.,
a. Lobar, cortical, or corticosubcortical
2001). In this disorder, family members may hemorrhage
have dramatically different clinical presenta- b. Severe CAA with vasculopathy
tions, varying from recurrent ICH, to demen- c. Absence of other diagnostic lesion
tia and leukoaraiosis without ICH (Greenberg 2. Probable CAA with Supporting Pathology
etal., 2003). Additionally, hereditary cerebral Clinical data and pathologic tissue (evacuated
hemorrhage with amyloidosis-Icelandic type hematoma or cortical biopsy) demonstrating:
(HCHWA-I) is an autosomal dominant dis- a. Lobar, cortical, or corticosubcortical
order seen in Icelandic families caused by a hemorrhage
b. Some degree of CAA in specimen
point mutation at codon 68 of the cystatin C
c. Absence of other diagnostic lesion
gene. It causes cystatin C, a cysteine protein
3. Probable CAA
inhibitor, to form deposits in cerebral arteries Clinical data and magnetic resonance imaging or
leading to ICHs (Palsdottir etal., 2006). computerized tomography demonstrating:
Screening for hereditary CAA gene muta- a. Multiple hemorrhages restricted to the lobar,
tions among patient with sporadic CAA cortical, corticosubcortical, or cerebellar
appears to have little clinical value because the region
familial and sporadic forms CAA are unlikely b. Age 55
to share individual risk mutations. Therefore, c. Absence of other cause of intracerebral
systematic genetic screening in sporadic CAA hemorrhage*
4. Possible CAA
patients lacking a strong family history of
Clinical data and magnetic resonance imaging or
hemorrhage or dementia is not currently rec-
computerized tomography demonstrating:
ommended (Biffi, Plourde, etal., 2010). a. Single lobar, cortical, or corticosubcortical
hemorrhage
b. Age 55
Diagnosis c. Absence of other cause of intracerebral
hemorrhage*
Although a definitive diagnosis of sporadic
*Potential causes of intracerebral hemorrhage: exces-
CAA can only be made after histological
sive anticoagution (INR > 3.0); antecedent head trauma
investigation of affected brain tissue through or ischemic stroke; central nervous system tumor, vascular
biopsy or autopsy, clinical diagnostic criteria malformation, or vasculitis; blood dyscrasia.
to identify patients with the disease, called
the Boston Criteria, have been developed.
Most reliably used in elderly patients pre- gold standard of pathologic diagnosis from
senting with lobar ICH, the Boston Criteria specimens from autopsy, hematoma evacua-
serve to identify those individuals likely to tion, or cortical biopsy (Knudsen etal., 2001).
have pathologic evidence of advanced CAA Of the 39 cases diagnosed with lobar ICH on
(Table 14.1) (Greenberg, 1998; Knudsen, clinical and radiologic grounds, all 13 cases
Rosand, Karluk, & Greenberg, 2001; van with probable CAA also had a pathological
Rooden etal., 2009). Probable CAA is defined diagnosis of CAA. Sixteen of the 26 cases with
by the presence of multiple, strictly lobar possible CAA had a pathological diagnosis of
hemorrhages (including microhemorrhages CAA. These data demonstrate the high speci-
or microbleeds) detected by gradient-echo ficity of the Boston Criteria to identify patients
MRI with no other definite cause of ICH such with lobar ICH and sporadic CAA (Table14.2).
as trauma, ischemic stroke, tumor, coagulop- For further validation of the Boston Criteria
athy, or excessive anticoagulation (Fig.14.2). and to refine their image components, they
Similarly, possible CAA is defined by the pres- have recently been applied to patients who
ence of a single lobar hemorrhage without were diagnosed with hereditary CAA after
other definite cause (Knudsen etal., 2001). genetic testing. In groups of symptomatic
The Boston Criteria for diagnosis of CAA and asymptomatic patients with HCHWA-D,
have been compared against the established detection of lesions caused by CAA using the
278part ii The Dementias: The Major Diseases and Clinical Syndromes
Figure14.2 Axial slide of gradient recalled echo (GRE) magnetic resonance image (MRI) ofpatient
with probable cerebral amyloid angiopathy demonstrating multiple punctate lobar areas
ofdecreased intensity suggestive of cerebral microbleeds.
Boston Criteria was found to be highly sensi- as superficial siderosis, this finding was
tive, and including microbleeds in the assess- identified by one study in 60% (22 of 38) of
ment further increased the sensitivity (van pathologically verified cases of advanced
Rooden etal., 2009). CAA versus 0 of 22 ICHs due to other causes
Additionally, spontaneous subarachnoid (Linn etal., 2010). Thus, superficial siderosis
hemorrhage localized to the convexity may in elderly individuals with clinical and neu-
be another radiographic manifestation of roimaging features consistent with CAA may
cerebral amyloid angiopathy. Also described be further suggestive of the diagnosis.
*Three hematoma specimens (two probable CAA and one possible CAA) did not con-
tain vessels and were not counted in these figures (Knudsen etal., 2001).
CHAPTER 14. Cerebral Amyloid Angiopathy andCognitiveImpairment 279
et al., 1995) and familial cases (Bornebroek, elucidated, the brain parenchymal injuries
Haan, et al., 1996; Bornebroek, van Buchem, resulting from the cerebrovascular pathol-
et al., 1996; Grabowski et al., 2001; Mead ogy are likely to act as mediators of cognitive
etal., 2000)of CAA, mostly in the absence of decline. Patients with a major hemorrhage
extensive Alzheimer pathology (Grabowski can have abrupt cognitive decline accom-
et al., 2001; Greenberg, Gurol, et al., 2004; panied with focal signs, but the cognitive
Natt etal., 2001). Over 40% of patients with function may recover over time (Korczyn,
CAA-related ICH have some degree of cog- Vakhapova,& Grinberg, 2012). Interestingly,
nitive decline during their life (Vinters, 1987). microbleeds have been shown to be associ-
Interestingly, in very severe cases of CAA, cog- ated independently with loss of cognitive
nitive impairment is a finding independent of functioning and functional dependence (van
a major hemorrhagic stroke (Grabowski etal., Es et al., 2011; Poels et al., 2012; Yakushiji
2001; Greenberg, Gurol, et al., 2004; Natt etal., 2012), and more specifically with frontal
etal., 2001). The MRC study demonstrated a executive dysfunction (Gregoire etal., 2012).
significant association between severe CAA Whether this is due to a direct contribution
pathology and dementia independent for age, of CAA-related microbleeds to cognitive
brain weight, neuritic and diffuse plaques, impairment as suggested in other patholo-
neocortical and hippocampal neurofibrillary gies (Viswanathan etal., 2010; Werring etal.,
tangles, Lewy bodies, and cerebrovascular 2004) or whether microbleeds are a marker
disease (Neuropathology Group, Medical of other CAA-related pathologies such as
Research Council Cognitive Function and white matter hyperintensities (Gurol et al.,
Aging Study, 2001). The Honolulu-Asia Aging 2006), changes in diffusion-tensor measure-
Study (Pfeifer, White, Ross, Petrovitch, & ments (Salat et al., 2006; Viswanathan et al.,
Launer, 2002) found, after controlling for 2008), small infarcts (Kimberly et al., 2009;
potential confounders, the accompanying Soontornniyomkij etal., 2010), or pathologies
presence of CAA in subjects with AD asso- other than CAA like hypertension (Yakushiji
ciated with significantly worse cognitive etal., 2012)remains to be determined.
performance, although CAA was not signifi- Small ischemic infarcts could also play an
cantly overrepresented in demented (55%) important role in developing cognitive impair-
compared with nondemented (38%) brains. ment. Autopsy studies (Chui et al., 2006;
The recent Religious Orders cohort Study Soontornniyomkij etal., 2010)and radiological
(Arvanitakis et al., 2011) showed that mod- studies (Gregoire etal., 2011; Kimberly etal.,
erate to very severe CAA was associated 2009)suggested that CAA-related dementia is
with lower performance in specific cognitive associated with these small silent infarcts,
domains, including lower perceptual speed in both gray and white matter areas, indepen-
and episodic memory. Whether cognition is dent of AD pathology. These ischemic lesions
affected in patients with less severe forms of are a frequent finding in sporadic CAA,
CAA remains uncertain (Greenberg, Gurol, ranging from 37% to nearly 100% of cases in
etal., 2004). autopsy studies (Haglund, Passant, Sjbeck,
In a comprehensive review of the sub- Ghebremedhin, & Englund, 2006; Okamoto
ject, Cordonnier and van der Flier (2011) et al., 2009; Okazaki, Reagan, & Campbell,
concluded that while there is sufficient evi- 1979; Olichney etal., 2000; Soontornniyomkij
dence to suggest that CMBs contribute to etal., 2010; Suter etal., 2002). Neuroimaging
cognitive impairment in association with studies have demonstrated an occurrence of
cerebrovascular disease, the evidence of an approximately 15% of hyperintense lesions
independent effect of CMBs on cognition on diffusion-weighted imaging (DWI) in ICH,
among individuals with AD is less certain. suggestive of ischemic infarction (Garg etal.,
One study suggested an independent effect 2012; Gregoire et al., 2011; Kimberly et al.,
(Goos et al., 2010), whereas another did not 2009; Lansberg etal., 2001; Menon etal., 2012;
(Pettersen etal., 2008). The authors conclude Prabhakaran etal., 2010). Their location, size,
that the evidence may be weak due to the and radiological characteristics correspond
low numbers of individuals in most studies to the ischemic lesions seen on pathologic
(Cordonnier& van der Flier, 2011). examination in CAA patients (Haglund etal.,
Although the exact mechanisms by which 2006; Okamoto et al., 2009; Okazaki et al.,
CAA may cause dementia are not fully 1979; Olichney etal., 2000; Suter etal., 2002).
CHAPTER 14. Cerebral Amyloid Angiopathy andCognitiveImpairment 281
Assuming these ischemic lesions are visually 1996; Hanyu, Tanaka, Shimizu, Takasaki, &
detectable on DWI 10days after an ischemic Abe, 2003; Nakata etal., 2002; Pettersen etal.,
stroke, the estimated prevalence would be 8 2008).
new infarctions per person-year (Kimberly Why certain patients develop CAA, while
et al., 2009). This estimate is strikingly high others develop AD or CAA and AD com-
relative to the estimated incidence of new bined, is not fully understood, but it may in
small hemorrhage ( 1.4 per year) or major, part be explained by differential accumula-
symptomatic ICH ( 0.14 per year) calcu- tion of A species. The cerebrovascular A
lated from other cohorts with advanced CAA deposits in CAA mainly consist of the shorter,
(Greenberg, Eng, Ning, Smith, & Rosand, more soluble A40 form (Herzig etal., 2004),
2004). whereas parenchymal plaques in AD show
White matter damage is common in CAA more A42 species (Jankowsky et al., 2004;
(Gurol etal., 2006; Holland etal., 2008; Smith Johnson-Wood et al., 1997). Increase in the
et al., 2004; Viswanathan et al., 2008) and ratio between A 40 and A 42 may shift
has been associated with cognitive impair- amyloid deposition from the parenchyma
ment in the disease prior to ICH (Smith, to the vessels (Herzig et al., 2006), and this
Rosand, Knudsen, Hylek, & Greenberg, balance between parenchymal and vascular
2002; Viswanathan etal., 2008). White matter amyloid deposits may be the key determi-
damage is suggested to cause cognitive dys- nant in the pathogenesis of the two diseases
function by interrupting white matter fibers (Fryer etal., 2005; Kumar-Singh, 2008; Love,
linking areas of association cortex, leading Miners, Palmer, Chalmers,& Kehoe, 2009).
to difficulty with executive function and Interestingly, the presence of CAA may be
psychomotor speed (Au et al., 2006; Garde, a predisposing factor for inflammatory reac-
Lykke Mortensen, Rostrup,& Paulson, 2005; tion against the active (Ferrer et al., 2004;
Gupta etal., 1988; Schmidt, Petrovic, Ropele, Nicoll etal., 2003; Orgogozo etal., 2003)and
Enzinger,& Fazekas, 2007; Smith etal., 2004). passive (Black et al., 2010) A vaccine stud-
Patients with CAA have larger white matter ied in AD patients. The inflammation seen in
hyperintensity burden on T2-weighted imag- some patients following A42 immunization
ing compared to either healthy elderly sub- may resemble vasogenic edema seen in a sub-
jects (Holland et al., 2008) or patients with group of patients who develop inflammatory
AD (Gurol etal., 2006)and have evidence of CAA (Salloway et al., 2009; Sperling et al.,
tissue microstructural alterations on diffu- 2011, 2012). The inflammation is thought to
sion imaging (Salat etal., 2006; Viswanathan be an immune response to the cerebrovascu-
et al., 2008). These alterations in global dif- lar amyloid deposits behaving as a foreign
fusion tensor imaging measures using frac- material (Greenberg & Frosch, 2011). This
tional anisotropy have been associated with was hypothesized because of the location
cognitive impairment in CAA (Viswanathan of the inflammatory reaction and the close
etal., 2008). relationship to inflammatory cells to cerebro-
Pathologic studies have suggested that vascular amyloid (Anders et al., 1997; Gray
CAA and AD often coexist. In AD patients et al., 1990; Probst & Ulrich, 1985; Yamada
CAA might have an additive effect by etal., 1996). The finding of markers of CAA
increasing dementia severity and, in patients in AD patients may therefore have consid-
with mild AD, it might aggravate cognitive erable implications for ongoing and future
impairment (Heyman etal., 1998; Petrovitch anti-amyloid trials.
et al., 2005; Schneider, Arvanitakis, Bang, &
Bennett, 2007; Snowdon etal., 1997). By con-
trast, CAA and AD can also present as dis- Therapy Considerations and Future Directions
tinct entities. Approximately 60%80% of
patients diagnosed with CAA-related lobar With no evidence-based treatment options
ICH did not show clinical symptoms of available, optimal management of patients
dementia before their initial ICH (Mandybur, with CAA may be a challenge to many clini-
1986; Vinters, 1987). Similarly, only a minor- cians. Blood pressure control may serve as a
ity of patients with AD demonstrates hem- strategy to reduce risk of CAA-related ICH
orrhages suggestive of advanced CAA (Atri recurrence (Arima et al., 2010). However,
etal., 2005; Cordonnier etal., 2006; Ellis etal., its impact on outcomes such as cognitive
282part ii The Dementias: The Major Diseases and Clinical Syndromes
impairment or progression of small-vessel Atri, A., Locascio, J. J., Lin, J. M., Yap, L.,
disease pathology remains to be determined. Dickerson, B. C., Grodstein, F.,...Greenberg,
An important new therapeutic avenue to S. M. (2005). Prevalence and effects of lobar
prevent major clinical consequences of CAA microhemorrhages in early-stage dementia.
Neurodegenerative diseases, 2(6), 305312.
might be A immunotherapy. As animal stud-
Au, R., Massaro, J.M., Wolf, P.A., Young, M.E.,
ies have shown, antiA therapy can reduce
Beiser, A., Seshadri, S.,...DeCarli, C. (2006).
the A burden in cerebral vessels (Prada Association of white matter hyperintensity
et al., 2007; Schroeter et al., 2008; Thakker volume with decreased cognitive function-
etal., 2009). Whether similar results could be ing:The Framingham Heart Study. Archives of
obtained in patients with CAA and whether Neurology, 63(2), 246250.
such therapy could modify clinical course in Bakker, E., van Broeckhoven, C., Haan,
the disease remains to be investigated. J., Voorhoeve, E., van Hul, W., Levy,
E.,...Frangione, B, (1991). DNA diagnosis for
hereditary cerebral hemorrhage with amyloi-
Summary dosis (Dutch type). American Journal of Human
Genetics, 49(3), 518521.
Bell, R. D., Deane, R., Chow, N., Long, X.,
Over recent decades great progress has
Sagare, A., Singh, I.,...Zlokovic, B.V. (2009).
been made in determining the pathophysi- SRF and myocardin regulate LRP-mediated
ology, genetics, and consequences of CAA. amyloid-beta clearance in brain vascular
Mounting evidence is suggesting that CAA cells. Nature Cell Biology, 11(2), 143153.
is an independent cause of cognitive impair- Biffi, A., Anderson, C.D., Jagiella, J.M., Schmidt,
ment. Because this disease is highly prevalent H., Kissela, B., Hansen, B. M.,...Rosand, J.
in the elderly, its contribution to cognitive (2011). APOE genotype and extent of bleed-
dysfunction could be substantial. Ongoing ing and outcome in lobar intracerebral haem-
research aims to develop methods for early orrhage: A genetic association study. Lancet
Neurology, 10(8), 702709.
identification of patients with CAA and to
Biffi, A., Plourde, A., Shen, Y., Onofrio, R.,
reliably determine the burden of CAA in
Smith, E. E., Frosch, M.,...Rosand, J. (2010).
these individuals. Establishing criteria to Screening for familial APP mutations in spo-
reliably diagnose patients before they experi- radic cerebral amyloid angiopathy. PloS One,
ence a lobar ICH or dementia will be a critical 5(11), e13949.
step in the development of new therapeutic Biffi, A., Sonni, A., Anderson, C. D., Kissela,
strategies to prevent the major clinical conse- B., Jagiella, J. M., Schmidt, H.,...Rosand, J.
quences of this devastating disease. (2010). Variants at APOE influence risk of
deep and lobar intracerebral hemorrhage.
Annals of Neurology, 68(6), 934943.
References Black, R.S., Sperling, R.A., Safirstein, B., Motter,
Anders, K. H., Wang, Z. Z., Kornfeld, M., R. N., Pallay, A., Nichols, A., & Grundman,
Gray, F., Soontornniyomkij, V., Reed, M. (2010). A single ascending dose study of
L.A.,...Vinters, H.V. (1997). Giant cell arteri- bapineuzumab in patients with Alzheimer
tis in association with cerebral amyloid angi- disease. Alzheimer Disease and Associated
opathy:Immunohistochemical and molecular Disorders, 24(2), 198203.
studies. Human Pathology, 28(11), 12371246. Bornebroek, M., De Jonghe, C., Haan, J.,
Anonymous. (2012). FDA approves Kumar-Singh, S., Younkin, S., Roos, R., &
18F-florbetapir PET agent. Journal of Nuclear Van Broeckhoven, C. (2003). Hereditary cere-
Medicine, 53(6), 15N. bral hemorrhage with amyloidosis Dutch
Arima, H., Tzourio, C., Anderson, C., type (AbetaPP 693): Decreased plasma
Woodward, M., Bousser, M. G., MacMahon, amyloid-beta 42 concentration. Neurobiology
S.,...Chalmers, J. (2010). Effects of of Disease, 14(3), 619623.
perindopril-based lowering of blood pressure Bornebroek, M., Haan, J., van Buchem, M. A.,
on intracerebral hemorrhage related to amy- Lanser, J. B., de Vries-vd Weerd, M. A.,
loid angiopathy:The PROGRESS trial. Stroke, Zoeteweij, M., & Roos, R. A. (1996). White
41(2), 394396. matter lesions and cognitive deterioration
Arvanitakis, Z., Leurgans, S. E., Wang, Z., in presymptomatic carriers of the amyloid
Wilson, R. S., Bennett, D. A., & Schneider, precursor protein gene codon 693 mutation.
J. A. (2011). Cerebral amyloid angiopathy Archives of Neurology, 53(1), 4348.
pathology and cognitive domains in older Bornebroek, M., van Buchem, M. A., Haan, J.,
persons. Annals of Neurology, 69(2), 320327. Brand, R., Lanser, J. B., de Brune, F. T., &
CHAPTER 14. Cerebral Amyloid Angiopathy andCognitiveImpairment 283
Roos, R.A. (1996). Hereditary cerebral hem- peptide transport across the blood-brain
orrhage with amyloidosis-Dutch type:Better barrier and accumulation in brain. Nature
correlation of cognitive deterioration with Medicine, 9(7), 907913.
advancing age than with number of focal Dierksen, G. A., Skehan, M. E., Khan,
lesions or white matter hyperintensities. M. A., Jeng, J., Nandigam, R. N., Becker,
Alzheimer Disease and Associated Disorders, J.A.,...Greenberg, S.M. (2010). Spatial rela-
10(4), 224231. tion between microbleeds and amyloid
Brouwers, H.B., Biffi, A., Ayres, A.M., Schwab, deposits in amyloid angiopathy. Annals of
K., Cortellini, L., Romero, J.M.,...Goldstein, Neurology, 68(4), 545548.
J. N. (2012). Apolipoprotein e genotype pre- Dumas, A., Dierksen, G. A., Gurol, M. E.,
dicts hematoma expansion in lobar intracere- Halpin, A., Martinez-Ramirez, S., Schwab,
bral hemorrhage. Stroke, 43(6), 14901495. K.,...Greenberg, S. M. (2012). Functional
Cabrejo, L., Guyant-Marchal, L., Laquerrire, MRI detection of vascular reactivity in cere-
A., Vercelletto, M., De la Fournire, F., bral amyloid angiopathy. Annals of Neurology,
Thomas-Antrion, C.,...Hannequin, D. 72(1), 7681.
(2006). Phenotype associated with APP Eisele, Y. S., Obermller, U., Heilbronner,
duplication in five families. Brain, 129(Pt 11), G., Baumann, F., Kaeser, S. A., Wolburg,
29662976. H.,...Jucker, M. (2010). Peripherally applied
Calhoun, M. E., Burgermeister, P., Phinney, Abeta-containing inoculates induce cerebral
A. L., Stalder, M., Tolnay, M., Wiederhold, beta-amyloidosis. Science, 330(6006), 980982.
K. H.,...Jucker, M. (1999). Neuronal overex- Ellis, R.J., Olichney, J.M., Thal, L.J., Mirra, S.S.,
pression of mutant amyloid precursor protein Morris, J.C., Beekly, D.,& Heyman, A. (1996).
results in prominent deposition of cerebro- Cerebral amyloid angiopathy in the brains
vascular amyloid. Proceedings of the National of patients with Alzheimers disease: The
Academy of Sciences USA, 96(24), 1408814093. CERAD experience, Part XV. Neurology, 46(6),
Christie, R., Yamada, M., Moskowitz, M., & 15921596.
Hyman, B. (2001). Structural and functional Ferrer, I., Boada Rovira, M., Snchez Guerra,
disruption of vascular smooth muscle cells in M. L., Rey, M. J., & Costa-Juss, F. (2004).
a transgenic mouse model of amyloid angi- Neuropathology and pathogenesis of
opathy. American Journal of Pathology, 158(3), encephalitis following amyloid-beta immuni-
10651071. zation in Alzheimers disease. Brain Pathology
Chui, H.C., Zarow, C., Mack, W.J., Ellis, W.G., (Zurich), 14(1), 1120.
Zheng, L., Jagust, W.J.,...Vinters, H.V. (2006). Fryer, J. D., Taylor, J. W., DeMattos, R. B.,
Cognitive impact of subcortical vascular and Bales, K. R., Paul, S. M., Parsadanian, M., &
Alzheimers disease pathology. Annals of Holtzman, D. M. (2003). Apolipoprotein E
Neurology, 60(6), 677687. markedly facilitates age-dependent cerebral
Corder, E. H., Lannfelt, L., Bogdanovic, N., amyloid angiopathy and spontaneous hem-
Fratiglioni, L.,& Mori, H. (1998). The role of orrhage in amyloid precursor protein trans-
APOE polymorphisms in late-onset demen- genic mice. Journal of Neuroscience, 23(21),
tias. Cellular and Molecular Life Sciences, 54(9), 78897896.
928934. Fryer, J. D., Simmons, K., Parsadanian, M.,
Cordonnier, C., van der Flier, W. M., Sluimer, Bales, K. R., Paul, S. M., Sullivan, P. M., &
J. D., Leys, D., Barkhof, F., & Scheltens. P. Holtzman, D.M. (2005). Human apolipopro-
(2006). Prevalence and severity of micro- tein E4 alters the amyloid-beta 40:42 ratio and
bleeds in a memory clinic setting. Neurology, promotes the formation of cerebral amyloid
66(9), 13561360. angiopathy in an amyloid precursor protein
De Jonghe, C., Zehr, C., Yager, D., Prada, C.M., transgenic model. Journal of Neuroscience,
Younkin, S., Hendriks, L.,...Eckman, C. B. 25(11), 28032810.
(1998). Flemish and Dutch mutations in amy- Garde, E., Lykke Mortensen, E., Rostrup, E., &
loid beta precursor protein have different Paulson, O.B. (2005). Decline in intelligence
effects on amyloid beta secretion. Neurobiology is associated with progression in white matter
of Disease, 5(4), 281286. hyperintensity volume. Journal of Neurology,
Deane, R., Wu, Z., Sagare, A., Davis, J., Du Yan, Neurosurgery, and Psychiatry, 76(9), 12891291.
S., Hamm, K.,...Zlokovic, B.V. (2004). LRP/ Garg, R. K., Liebling, S. M., Maas, M. B.,
amyloid beta-peptide interaction mediates Nemeth, A.J., Russell, E.J.,& Naidech, A.M.
differential brain efflux of Abeta isoforms. (2012). Blood pressure reduction, decreased
Neuron, 43(3), 333344. diffusion on MRI, and outcomes after intrace-
Deane, R., Du Yan, S., Submamaryan, R. K., rebral hemorrhage. Stroke, 43(1), 6771.
LaRue, B., Jovanovic, S., Hogg, E.,...Zlokovic, Ghilardi, J.R., Catton, M., Stimson, E.R., Rogers,
B. (2003). RAGE mediates amyloid-beta S., Walker, L. C., Maggio, J. E., & Mantyh,
284part ii The Dementias: The Major Diseases and Clinical Syndromes
P.W. (1996). Intra-arterial infusion of [125I]A Greenberg, S. M., Shin, Y., Grabowski, T. J.,
beta 140 labels amyloid deposits in the aged Cooper, G. E., Rebeck, G. W., Iglesias,
primate brain in vivo. Neuroreport, 7(1517), S.,...Baron, J. C. (2003). Hemorrhagic stroke
26072611. associated with the Iowa amyloid precursor
Ghiso, J., Pons-Estel, B.,& Frangione, B. (1986). protein mutation. Neurology, 60(6), 10201022.
Hereditary cerebral amyloid angiopathy:The Greenberg, S. M., Vernooij, M. W., Cordonnier,
amyloid fibrils contain a protein which is a C., Viswanathan, A., Al-Shahi Salman, R.,
variant of cystatin C, an inhibitor of lysosomal Warach, S.,...Breteler, M.M. (2009). Cerebral
cysteine proteases. Biochemical and Biophysical microbleeds:Aguide to detection and inter-
Research Communications, 136(2), 548554. pretation. Lancet Neurology, 8(2), 165174.
Grabowski, T. J., Cho, H. S., Vonsattel, J. P., Greenberg, S. M., Vonsattel, J. P., Segal,
Rebeck, G. W., & Greenberg, S. M. (2001). A. Z., Chiu, R. I., Clatworthy, A. E., Liao,
Novel amyloid precursor protein muta- A.,...Rebeck, G. W. (1998). Association of
tion in an Iowa family with dementia and apolipoprotein E epsilon2 and vasculopathy
severe cerebral amyloid angiopathy. Annals of in cerebral amyloid angiopathy. Neurology,
Neurology, 49(6), 697705. 50(4), 961965.
Gray, F., Vinters, H. V., Le Noan, H., Salama, Greenberg, S. M., Vonsattel, J. P., Stakes, J. W.,
J., Delaporte, P.,& Poirier, J. (1990). Cerebral Gruber, M., & Finklestein, S. P. (1993). The
amyloid angiopathy and granulomatous clinical spectrum of cerebral amyloid angi-
angiitis: Immunohistochemical study using opathy: Presentations without lobar hemor-
antibodies to the Alzheimer A4 peptide. rhage. Neurology, 43(10), 20732079.
Human Pathology, 21(12), 12901293. Gregoire, S. M., Charidimou, A., Gadapa, N.,
Greenberg, S.M. (1998). Cerebral amyloid angi- Dolan, E., Antoun, N., Peeters, A.,...Werring,
opathy: Prospects for clinical diagnosis and D. J. (2011). Acute ischaemic brain lesions
treatment. Neurology, 51(3), 690694. in intracerebral haemorrhage: Multicentre
Greenberg, S. M., Briggs, M. E., Hyman, B. T., cross-sectional magnetic resonance imaging
Kokoris, G. J., Takis, C., Kanter, D. S., Kase, study. Brain, 134(Pt 8), 23762386.
C.S.,& Pessin, M.S. (1996). Apolipoprotein E Gregoire, S.M., Smith, K., Jger, H.R., Benjamin,
epsilon 4 is associated with the presence and M., Kallis, C., Brown, M.M.,...Werring, D.J.
earlier onset of hemorrhage in cerebral amy- (2012). Cerebral microbleeds and long-term
loid angiopathy. Stroke, 27(8), 13331337. cognitive outcome: Longitudinal cohort
Greenberg, S. M., Eng, J. A., Ning, M., Smith, study of stroke clinic patients. Cerebrovascular
E. E., & Rosand, J. (2004). Hemorrhage bur- Diseases (Basel), 33(5), 430435.
den predicts recurrent intracerebral hemor- Gupta, S. R., Naheedy, M. H., Young, J. C.,
rhage after lobar hemorrhage. Stroke, 35(6), Ghobrial, M., Rubino, F. A., & Hindo, W.
14151420. (1988). Periventricular white matter changes
Greenberg, S.M., Finklestein, S.P.,& Schaefer, and dementia. Clinical, neuropsychological,
P. W. (1996). Petechial hemorrhages accom- radiological, and pathological correlation.
panying lobar hemorrhage: Detection Archives of Neurology, 45(6), 637641.
by gradient-echo MRI. Neurology, 46(6), Gurol, M.E., Irizarry, M.C., Smith, E.E., Raju, S.,
17511754. Diaz-Arrastia, R., Bottiglieri, T.,...Greenberg,
Greenberg, S. M., & Frosch, M. P. (2011). Life S.M. (2006). Plasma beta-amyloid and white
imitates art: Anti-amyloid antibodies and matter lesions in AD, MCI, and cerebral amy-
inflammatory cerebral amyloid angiopathy. loid angiopathy. Neurology, 66(1), 2329.
Neurology, 76(9), 772773. Haglund, M., Passant, U., Sjbeck, M.,
Greenberg, S. M., Grabowski, T., Gurol, M. E., Ghebremedhin, E., & Englund, E. (2006).
Skehan, M. E., Nandigam, R. N., Becker, Cerebral amyloid angiopathy and cortical
J. A.,...Johnson, K. A. (2008). Detection of microinfarcts as putative substrates of vascu-
isolated cerebrovascular beta-amyloid with lar dementia. International Journal of Geriatric
Pittsburgh compound B. Annals of Neurology, Psychiatry, 21(7), 681687.
64(5), 587591. Han, B.H., Zhou, M.L., Abousaleh, F., Brendza,
Greenberg, S. M., Gurol, M. E., Rosand, R. P., Dietrich, H. H., Koenigsknecht-Talboo,
J., & Smith, E. E. (2004). Amyloid J.,...Zipfel, G. J. (2008). Cerebrovascular
angiopathy-related vascular cognitive dysfunction in amyloid precursor protein
impairment. Stroke, 35(11 Suppl 1), 26162619. transgenic mice:Contribution of soluble and
Greenberg, S. M., Rebeck, G. W., Vonsattel, insoluble amyloid-beta peptide, partial resto-
J. P., Gomez-Isla, T., & Hyman, B. T. (1995). ration via gamma-secretase inhibition. Journal
Apolipoprotein E epsilon 4 and cerebral hem- of Neuroscience, 28(50), 1354213550.
orrhage associated with amyloid angiopathy. Hanyu, H., Tanaka, Y., Shimizu, S., Takasaki,
Annals of Neurology, 38(2), 254259. M., & Abe, K. (2003). Cerebral microbleeds
CHAPTER 14. Cerebral Amyloid Angiopathy andCognitiveImpairment 285
Olesen, O. F., Mikkelsen, J. D., Gerdes, C., & Y.,...Bleck, T. P. 2010. Acute brain infarcts
Jensen, P. H. (1997). Isoform-specific bind- after spontaneous intracerebral hemor-
ing of human apolipoprotein E to the rhage: A diffusion-weighted imaging study.
non-amyloid beta component of Alzheimers Stroke, 41(1), 8994.
disease amyloid. Brain Research Molecular Prada, C.M., Garcia-Alloza, M., Betensky, R.A.,
Brain Research, 44(1), 105112. Zhang-Nunes, S.X., Greenberg, S.M., Bacskai,
Olichney, J.M., Hansen, L.A., Hofstetter, C.R., B.J.,& Frosch, M.P. (2007). Antibody-mediated
Lee, J. H., Katzman, R., & Thal, L. J. (2000). clearance of amyloid-beta peptide from cere-
Association between severe cerebral amy- bral amyloid angiopathy revealed by quanti-
loid angiopathy and cerebrovascular lesions tative in vivo imaging. Journal of Neuroscience,
in Alzheimer disease is not a spurious one 27(8), 19731980.
attributable to apolipoprotein E4. Archives of Premkumar, D. R., Cohen, D. L., Hedera, P.,
Neurology, 57(6), 869874. Friedland, R. P., & Kalaria, R. N. (1996).
Orgogozo, J-M., Gilman, S., Dartigues, J. F., Apolipoprotein E-epsilon4 alleles in cerebral
Laurent, B., Puel, M., Kirby, L. C.,...Hock, amyloid angiopathy and cerebrovascular
C. (2003). Subacute meningoencephalitis in pathology associated with Alzheimers dis-
a subset of patients with AD after Abeta42 ease. American Journal of Pathology, 148(6),
immunization. Neurology, 61(1), 4654. 20832095.
Palsdottir, A., Abrahamson, M., Thorsteinsson, Price, D. L., Tanzi, R. E., Borchelt, D. R., &
L., Arnason, A., Olafsson, I., Grubb, A., & Sisodia, S. S. (1998). Alzheimers dis-
Jensson, O. (1988). Mutation in cystatin C ease:Genetic studies and transgenic models.
gene causes hereditary brain haemorrhage. Annual review of genetics, 32, 461493.
Lancet, 2(8611), 603604. Probst, A., & Ulrich, J. (1985). Amyloid angi-
Palsdottir, A., Snorradottir, A. O., & opathy combined with granulomatous angi-
Thorsteinsson, L. (2006). Hereditary cystatin itis of the central nervous system:Report on
C amyloid angiopathy:Genetic, clinical, and two patients. Clinical Neuropathology, 4(6),
pathological aspects. Brain Pathology (Zurich), 250259.
16(1), 5559. Roher, A. E., Kuo, Y. M., Esh, C., Knebel, C.,
Petrovitch, H., Ross, G. W., Steinhorn, S. C., Weiss, N., Kalback, W.,...Kokjohn, T. A.
Abbott, R. D., Markesbery, W., Davis, (2003). Cortical and leptomeningeal cerebro-
D.,...White, L. R. (2005). AD lesions and vascular amyloid and white matter pathology
infarcts in demented and non-demented in Alzheimers disease. Molecular Medicine,
Japanese-American men. Annals of Neurology, 9(34), 112122.
57(1), 98103. Rovelet-Lecrux, A., Hannequin, D., Raux,
Pettersen, J. A., Sathiyamoorthy, G., Gao, G., Le Meur, N., Laquerrire, A., Vital,
F. Q., Szilagyi, G., Nadkarni, N. K., St A.,...Campion, D. (2006). APP locus duplica-
George-Hyslop, P.,...Black, S. E. (2008). tion causes autosomal dominant early-onset
Microbleed topography, leukoaraiosis, and Alzheimer disease with cerebral amyloid
cognition in probable Alzheimer disease from angiopathy. Nature Genetics, 38(1), 2426.
the Sunnybrook dementia study. Archives of Salat, D.H., Smith, E.E., Tuch, D.S., Benner, T.,
Neurology, 65(6), 790795. Pappu, V., Schwab, K.M.,...Greenberg, S.M.
Pfeifer, L. A., White, L. R., Ross, G. W., (2006). White matter alterations in cerebral
Petrovitch, H.,& Launer, L.J. (2002). Cerebral amyloid angiopathy measured by diffusion
amyloid angiopathy and cognitive func- tensor imaging. Stroke, 37(7), 17591764.
tion: The HAAS autopsy study. Neurology, Salloway, S., Sperling, R., Gilman, S., Fox, N.C.,
58(11), 16291634. Blennow, K., Raskind, M.,...Grundman, M.
Poduslo, J.F., Curran, G.L., Haggard, J.J., Biere, (2009). A phase 2 multiple ascending dose
A.L.,& Selkoe, D.J. (1997). Permeability and trial of bapineuzumab in mild to moder-
residual plasma volume of human, Dutch ate Alzheimer disease. Neurology, 73(24),
variant, and rat amyloid beta-protein 1-40 20612070.
at the blood-brain barrier. Neurobiology of Sanan, D. A., Weisgraber, K. H., Russell,
Disease, 4(1), 2734. S. J., Mahley, R. W., Huang, D., Saunders,
Poels, M. M. F., Ikram, M. A., van der Lugt, A.,...Roses, A. D. (1994). Apolipoprotein
A., Hofman, A., Niessen, W. J., Krestin, E associates with beta amyloid peptide of
G. P.,...Vernooij, M. W. (2012). Cerebral Alzheimers disease to form novel mono-
microbleeds are associated with worse cog- fibrils. Isoform apoE4 associates more
nitive function: The Rotterdam Scan Study. efficiently than apoE3. Journal of Clinical
Neurology, 78(5), 326333. Investigation, 94(2), 860869.
Prabhakaran, S., Gupta, R., Ouyang, B., Schmechel, D.E., Saunders, A.M., Strittmatter,
John, S., Temes, R. E., Mohammad, W. J., Crain, B. J., Hulette, C. M., Joo,
288part ii The Dementias: The Major Diseases and Clinical Syndromes
S. H.,...Roses, A. D. (1993). Increased amy- Smith, E. E., Vijayappa, M., Lima, F., Delgado,
loid beta-peptide deposition in cerebral cor- P., Wendell, L., Rosand, J.,& Greenberg, S.M.
tex as a consequence of apolipoprotein E (2008). Impaired visual evoked flow veloc-
genotype in late-onset Alzheimer disease. ity response in cerebral amyloid angiopathy.
Proceedings of the National Academy of Sciences Neurology, 71(18), 14241430.
USA, 90(20), 96499653. Snowdon, D.A., Greiner, L.H., Mortimer, J.A.,
Schmidt, R., Petrovic, K., Ropele, S., Enzinger, Riley, K. P., Greiner, P. A., & Markesbery,
C., & Fazekas, F. (2007). Progression of W. R. (1997). Brain infarction and the clini-
leukoaraiosis and cognition. Stroke, 38(9), cal expression of Alzheimer disease. The
26192625. Nun Study. Journal of the American Medical
Schneider, J. A., Arvanitakis, Z., Bang, W., & Association, 277(10), 813817.
Bennett, D. A. (2007). Mixed brain patholo- Soontornniyomkij, V., Lynch, M. D., Mermash,
gies account for most dementia cases S., Pomakian, J., Badkoobehi, H., Clare, R.,&
in community-dwelling older persons. Vinters, H. V. (2010). Cerebral microinfarcts
Neurology, 69(24), 21972204. associated with severe cerebral beta-amyloid
Schroeter, S., Khan, K., Barbour, R., Doan, angiopathy. Brain Pathology, 20(2), 459467.
M., Chen, M., Guido, T., .
.
.
Games, D. Sperling, R., Salloway, S., Brooks, D.J., Tampieri,
(2008). Immunotherapy reduces vascular D., Barakos, J., Fox, N. C.,...Grundman, M.
amyloid-beta in PDAPP mice. Journal of (2012). Amyloid-related imaging abnormali-
Neuroscience, 28(27), 67876793. ties in patients with Alzheimers disease
Selkoe, D.J. (2001). Alzheimers disease:Genes, treated with bapineuzumab: A retrospective
proteins, and therapy. Physiological Reviews, analysis. Lancet Neurology, 11(3), 241249.
81(2), 741766. Sperling, R. A., Jack, C. R., Jr., Black, S. E.,
Shin, H. K., Jones, P. B., Garcia-Alloza, M., Frosch, M. P., Greenberg, S. M., Hyman,
Borrelli, L., Greenberg, S. M., Bacskai, B.T.,...Schindler, R.J. (2011). Amyloid-related
B. J.,...Ayata, C. (2007). Age-dependent imaging abnormalities in amyloid-modifying
cerebrovascular dysfunction in a transgenic therapeutic trials: Recommendations from
mouse model of cerebral amyloid angiopathy. the Alzheimers Association Research
Brain, 130(Pt 9), 23102319. Roundtable Workgroup. Alzheimers and
Silbert, P. L., Bartleson, J. D., Miller, G. M., Dementia, 7(4), 367385.
Parisi, J. E., Goldman, M. S., & Meyer, F. B. Suter, O-C., Sunthorn, T., Kraftsik, R., Straubel,
(1995). Cortical petechial hemorrhage, leu- J., Darekar, P., Khalili, K.,& Miklossy, J. (2002).
koencephalopathy, and subacute demen- Cerebral hypoperfusion generates cortical
tia associated with seizures due to cerebral watershed microinfarcts in Alzheimer dis-
amyloid angiopathy. Mayo Clinic Proceedings, ease. Stroke, 33(8), 19861992.
70(5), 477480. Sveinbjornsdottir, S., Sigurdsson, S.,
Sleegers, K., Brouwers, N., Gijselinck, I., Aspelund, T., Kjartansson, O., Eiriksdottir,
Theuns, J., Goossens, D., Wauters, J.,...Van G., Valtysdottir, B.,...Launer, L. J. (2008).
Broeckhoven, C. (2006). APP duplication is Cerebral microbleeds in the population based
sufficient to cause early onset Alzheimers AGES-Reykjavik study:Prevalence and loca-
dementia with cerebral amyloid angiopathy. tion. Journal of Neurology, Neurosurgery, and
Brain, 129(Pt 11), 29772983. Psychiatry, 79(9), 10021006.
Smith, E. E., & Greenberg, S. M. (2009). Thakker, D. R., Weatherspoon, M. R.,
Beta-amyloid, blood vessels, and brain func- Harrison, J., Keene, T. E., Lane, D. S.,
tion. Stroke, 40(7), 26012606. Kaemmerer, W. F.,...Shafer, L. L. (2009).
Smith, E.E., Gurol, M.E., Eng, J.A., Engel, C.R., Intracerebroventricular amyloid-beta anti-
Nguyen, T.N., Rosand, J.,& Greenberg, S.M. bodies reduce cerebral amyloid angiopa-
(2004). White matter lesions, cognition, and thy and associated micro-hemorrhages in
recurrent hemorrhage in lobar intracerebral aged Tg2576 mice. Proceedings of the National
hemorrhage. Neurology, 63(9), 16061612. Academy of Sciences USA, 106(11), 45014506.
Smith, E.E., Nandigam, K.R., Chen, Y.W., Jeng, Ujiie, M., Dickstein, D. L., Carlow, D. A., &
J., Salat, D., Halpin, A.,...Greenberg, S. M. Jefferies, W.A. (2003). Blood-brain barrier per-
(2010). MRI markers of small vessel disease meability precedes senile plaque formation in
in lobar and deep hemispheric intracerebral an Alzheimer disease model. Microcirculation,
hemorrhage. Stroke, 41(9), 19331938. 10(6), 463470.
Smith, E.E., Rosand, J., Knudsen, K.A., Hylek, Van Dorpe, J., Smeijers, L., Dewachter, I.,
E.M.,& Greenberg, S.M. (2002). Leukoaraiosis Nuyens, D., Spittaels, K., Van Den Haute,
is associated with warfarin-related hemor- C.,...Van Leuven, F. (2000). Prominent cere-
rhage following ischemic stroke. Neurology, bral amyloid angiopathy in transgenic mice
59(2), 193197. overexpressing the London mutant of human
CHAPTER 14. Cerebral Amyloid Angiopathy andCognitiveImpairment 289
without neurological disorder. Stroke, 43(7), M.P.,& Greenberg, S.M. (2006). The cerebral
18001805. beta-amyloid angiopathies: hereditary and
Yamada, M., Itoh, Y., Shintaku, M., Kawamura, sporadic. Brain Pathology (Zurich), 16(1), 3039.
J., Jensson, O., Thorsteinsson, L.,...Otomo, Zhu, Y-C., Chabriat, H., Godin, O., Dufouil, C.,
E. 1996. Immune reactions associated with Rosand, J., Greenberg, S.M.,...Viswanathan,
cerebral amyloid angiopathy. Stroke, 27(7), A. (2012). Distribution of white matter hyper-
11551162. intensity in cerebral hemorrhage and healthy
Zekry, D., Duyckaerts, C., Belmin, J., Geoffre, aging. Journal of Neurology, 259(3), 530536.
C., Moulias, R.,& Hauw, J.J. (2003). Cerebral Zlokovic, B.V., Ghiso, J., Mackic, J.B., McComb,
amyloid angiopathy in the elderly: Vessel J. G., Weiss, M. H., & Frangione, B. (1993).
walls changes and relationship with demen- Blood-brain barrier transport of circulating
tia. Acta Neuropathologica, 106(4), 367373. Alzheimers amyloid beta. Biochemical and
Zhang-Nunes, S. X., Maat-Schieman, M. L., Biophysical Research Communications, 197(3),
van Duinen, S. G., Roos, R. A., Frosch, 10341040.
15
Jeremy D. Schmahmann
This chapter presents a clinical perspective may be atypical, as occurs in primary pro-
on the evaluation of a patient with impair- gressive aphasia, or an apraxia-agnosia
ment of cognitive function. The principal goal syndrome, but Alzheimers disease has a
here is to establish a diagnosis. Determining profile sufficiently well defined that it can be
what disease process is causing the demen- strongly suspected on clinical grounds alone.
tia shapes the clinicians understanding of When the clinical history and examination
the pathophysiology of the process, pro- of a patient with cognitive decline do not
vides insights into prognosis, and guides conform to this rather stereotyped picture of
management. Alzheimers disease, the clinicians level of
It is useful to keep the profile of Alzheimers suspicion should be great that the diagnosis
disease in mind as one approaches the ques- lies elsewhere.
tion of cognitive decline. Alzheimers disease
is characterized by the insidious develop-
ment and progression of cognitive decline Acute Confusion Versus Dementia
in a person usually in the seventh or eighth
decades: initially, the signs are forgetfulness; At the outset it is imperative to distinguish an
then true memory loss for recently acquired acute or subacute (and often life-threatening)
information more than prior knowledge, and acute confusional state from dementia. Abrupt
impaired new learning; followed by deficits onset within hours to days of lethargy, confu-
in language, praxis, visual-spatial aware- sion, and disorientation, or aphasia, memory
ness, and loss of previously acquired skills loss, impaired concentration, and inability to
required for functioning at home and at perform complex functions such as driving,
work. This occurs in the setting of generally dressing, or taking care of personal hygiene
preserved but vacuous social interactions need to be urgently assessed. The history of
and an essentially normal elementary neuro- an acute or subacute onset may have a pre-
logical examination early in the course except cipitant such as head trauma, or associated
for release phenomena. The presentation symptoms pointing to bacterial, fungal, or
291
292 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
comprehensive history, careful and directed said, and to whom, may not be concerning,
examination, and consideration of appropri- unless the patient is young (under 55years)
ate special investigations. The general prin- and there are other worrisome features such
ciples to be considered in the history are the as a strong family history of dementia and
background of the patient and family, who changes in personality or lifestyle.
provides the history; the time course of the True loss of memory for important aspects
illnessits onset and duration; the principal of work, recent major events, and impor-
defining features of the condition; its pro- tant family milestones, however, does raise
gression over time and the sequence of loss concern. Are there associated features in the
of function; and the associated neurological/ medical and neurological history that lead to
medical/psychiatric issues. The examination suspicion of specific etiologic agents associ-
includes a general medical examination, neu- ated with memory loss such as new medica-
rologic elementary examination, and mental tions (beta blockers, sedatives, psychotropics),
status examination, including both neuro- alcohol consumption, depression, metabolic
logic and psychiatric aspects. disorders such as hypothyroidism, prior gas-
The first part of this chapter takes this clini- trectomy to suggest vitamin B12 or thiamine
cal approach to the differential diagnosis of deficiency, or risk factors for human immu-
the many disorders under consideration (see nodeficiency virus (HIV) infection? Are there
Table 15.2). Accurate diagnosis is likely to be neighborhood symptoms and signs, such as
successful when the examiner adopts a sys- early and prominent change in personality
tematic approach to each aspect of the exam, (frontotemporal dementia), focal weakness,
looking for clues to the core features of the paresthesia, or visual loss (focal brains lesions
case. These are elicited by methodical and such as abscess or brain tumor), gait distur-
hypothesis-driven exploration, allowing the bance and incontinence (normal pressure
examiner to select appropriate and targeted hydrocephalus, Binswangers disease), sub-
investigations. The importance of this diag- acute onset of dementia with myoclonus and
nostic method cannot be overstated, particu- ataxia (Creutzfeldt-Jakob disease), or associ-
larly in the challenging scenario of the patient ated movement disturbances (Huntingtons
with cognitive decline, and even more so and Parkinsons diseases)?
when the cognitive change is rapid. Is the problem memory loss or a memory
lapse? Is loss of memory transient, lasting
seconds to minutes (as in seizures), or hours
The History (as in partial complex status, or transient
global amnesia)? Did headache occur around
The ability of a patient to present a coherent, the time of the memory lapse (seen in compli-
logical, and chronological account of himself cated migraine)?
or herself is an integral part of the mental state Does the family use the term loss of mem-
evaluation. Patients with acute confusion or ory to mean aphasia or apraxia? Can the his-
dementia do not provide their own history. tory differentiate between hemianopsia and a
Major deficits or nonsequiturs in the history parietal neglect syndrome? Are there features
should be the tip-off that there is something suggestive of alien hand syndrome?
amiss in the cognitive profile. Assuming that Are changes in personality the major or
the history taker is compulsive, poor histo- principal problems reported to the physi-
ries are given by poor historians, and usu- cian? Frontal lobe tumors such as meningio-
ally for definable reasons. mas or gliomas, or frontotemporal dementia
What is the chief complaint? Is it memory may present with changes in drive, ambition,
loss and, if so, what is lost. Forgetfulness judgment, and social and personal responsi-
in later life is common and while interest bility. These disorders may, for example, turn
in the earliest harbingers of Alzheimers is a pleasant, mild-mannered and hard-working
growing, this complaint is not necessarily individual into a stubborn, neglectful, apa-
indicative of a major neurological disorder. thetic, rigid, obsessional, and disinhibited
Forgetting what you went there for and person who engages in socially inappro-
having trouble in dinner conversation com- priate and embarrassing behavior, but not
ing up with names of people, but neverthe- associated with memory loss. The examiner
less remembering who they are, what they needs to interpret changes in behavior in the
TABLE15.2 Dementia:An Approach to Differential Diagnosis by Category and Disease
Trauma
Diffuse axonal injury, hemorrhage
Chronic subdural hematoma
Postconcussion syndrome
Chronic traumatic encephalopathy
Inflammation/Infection
Herpes simplex encephalitis
HIV and infectious complications
Focal cerebritis/abscess
Subacute bacterial endocarditis
Prion diseaseCJD, variant
Progressive multifocal leukoencephalopathy
Lyme encephalopathy (with or without meningitis)
Subacute or chronic meningitis (tuberculosis, cryptococcus, cysticercosis, Listeria)
Neurosyphilis (general paresis, gumma, meningovascular)
Cerebral sarcoidosis
Subacute sclerosing panencephalitis
Whipples disease of the brain
Neoplastic
Tumorbenign (frontal meningioma, clivus chordoma invading medial temporal structures)
Tumormalignant, 1/2; presentation depends on location
Intravascular lymphoma
Paraneoplastic limbic encephalitis
Radiation necrosis
Postchemotherapy cognitive impairment (chemobrain)
Metabolic/Hormonal
Renaluremic encephalopathy (acute or chronic) and dialysis dementia
Hepatic encephalopathy (acute or chronic)
Hypercapnea/hyperviscosity/hypoxemia (acute or chronic)
Vitamin B1 (thiamine) deficiency (Wernicke-Korsakoff)
Vitamin B3 deficiency (nicotinic acid/niacinPellagra; dermatitis, diarrhea, dementia)
Vitamin B12 deficiency (+/- pernicious anemia)
Hypothroidism (myxedema madness)
Vitamin E deficiency (neuropathy, ataxia, encephalopathy in Celiac disease)
Acute intermittent porphyria
Vascular
Focal vascular syndromes (thalamus, inferotemporal, anterior cingulate, bifrontal, triple border-zone
watershed infarction, cerebellar posterior lobe)
Multi-infarct dementia
Binswanger progressive subcortical ischemic leukoencephalopathy
Cerebral amyloid angiopathy +/ amyloid vasculitis
Diffuse hypoxic/ischemic injury
PRES (posterior reversible encephalopathy syndrome)
Thrombotic thrombocytopenic purpura
CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts, leukoencephalopathy,
migraine)
MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes)
Autoimmune
Nonparaneoplastic limbic encephalitis
Hashimoto encephalopathy (steroid-responsive encephalopathy syndrome [SREAT])
Systemic lupus erythematosus
Isolated angiitis of the nervous system
Temporal arteritis
Wegeners granulomatosis
Polyarteritis nodosa
Susac syndrome
(continued)
TABLE15.2Continued
Iatrogenic/Drugs/Toxins
Medications:beta blockers, neuroleptics, antidepressants, anticonvulsants, histamine/dopamine
blockade, methotrexate
Alcohol (Wernicke-Korsakoff, Marchiafava-Bignami)
Heroin:chasing the dragon leukoencephalopathy
Mescaline, phencyclidine, cocaine
Marijuana psychosis
Toxic exposure:carbon monoxide, toluene, lead, mercury
Poisoning:arsenic, cyanide
Demyelinating
Acquired
Multiple sclerosis, Schilders, Balos sclerosis
ADEM (acute disseminated encephalomyelitis)
Toxins
Delayed posthypoxic leukoencephalopathy
Electricity-induced demyelination
Decompression sickness demyelination
Genetic
Adult-onset leukodystrophy with neuroaxonal spheroids
X-linked adrenoleukodystrophy
Metachromatic leukodystrophy
Globoid cell leukodystrophy
Vanishing white matter disease
Obstructive/Mechanical
Obstructive hydrocephalus
Normal pressure hydrocephalus
Sagging brain syndromemimics frontotemporal dementia
Late-Life Degenerative Disorders
Alzheimer's disease
Frontotemporal dementia/Pick's disease
Parkinsons disease
Progressive supranuclear palsy
Corticobasal degeneration
Lewy body disease
Huntingtons disease
ALS-dementia-Parkinsons complex
Primary progressive aphasia as manifestation of diseases of progranulin, tau, TDP-43
Posterior cortical atrophy as manifestation of Alzheimers disease
Wilsons disease
Neurodegeneration with brain iron accumulation
Cerebellar Related
Cerebellar cognitive affective syndrome in pure cerebellar diseasegenetic or acquired
Autosomal dominant spinocerebellar ataxias (SCAs)
Recessively inherited ataxias and complex hereditary spastic paraplegias
Fragile X tremor ataxia syndrome (FXTAS)
Dentatorubropalidoluysian atrophy (DRPLA)
Gordon Holmes syndrome
Superficial siderosis
Sagging brain syndrome
Langerhans cell histiocytosis
Cerebellar agenesis
Very Rare Pediatric Degenerative Disorders With Adult Presentations
MERRF (mitochondrial encephalopathy with ragged red fibers)
Niemann-Pick type C
Gangliosidosis 2 (GM2/Adult Tay-Sachs)
Alexander disease
Lafora progressive myoclonus epilepsy
Cerebrotendinous xanthomatosis
PLO-SL (polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy)
Neuronal intranuclear inclusion disease
296 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
light of the patients prior personality, life- or is there marked asymmetry to the motor
style, and accomplishments, and then test presentation as occurs in corticobasal degen-
cognitive functions in order to diagnose and eration? Are there predominantly psychiatric
treat the underlying disorder or behavioral symptoms such as auditory hallucinations,
abnormality. paranoia, delusional thinking, thought
Could there be depression of which both broadcasting, or anxiety and phobia that may
the family and the patient are unaware? What be overwhelming and limiting the patients
are the circumstances leading up to the eval- activities, interests, and abilities? And are
uation? Is there a family history, or a past per- there circumstances in the history (injury at
sonal history, of depression? Is there evidence work, outstanding litigation) that would lead
of the vegetative symptoms of depression the examiner to suspect that secondary gain
loss of weight, appetite, energy, interest, may play a role in the patients complaints of
concentration? Is the sleep cycle reversed, or disturbed memory, impaired concentration,
does the patient awake in the early hours of and so on.
the morning for no apparent reason? Is there a family history of dementia
What is the time course of the illness? Is it (Alzheimers disease, Huntingtons disease)
an insidiously progressive constellation dif- or psychiatric illness (bipolar affective dis-
ficult to date precisely in its onset, lasting at order, schizophrenia)? Is there a potentially
least months, and probably years, as would relevant history of illness or risk factors such
be the case in most patients with degenera- as HIV disease, systemic cancer (paraneo-
tive dementias? Or is the course rapidly pro- plastic limbic encephalitis), alcohol use, and
gressive and aggressively debilitating over previous surgery (thyroidectomy/ radiation,
weeks and months, as occurs in viral or Bilroth II gastrectomy)?
prion diseases (progressive multifocal leu- What medications is the patient taking?
koencephalopathy, HIV, Creutzfeldt-Jakob Beta blockers, psychotropics, sedating anti-
[CJD]), subacute or chronic meningitides depressants, anticonvulsants at high levels or
(tuberculosis, cryptococcus, neurocysticerco- in multiple combinations, H2-receptor block-
sis, listeriosis), and limbic encephalitis (para- ers, dopamine blockers used for nonneuro-
neoplastic, or non-tumor-related immune logic purposes such as metoclopramide, and
disorders including Hashimoto encephalop- many others agents can produce substantial
athy and voltage-gated potassium channel cognitive impairment particularly in elderly
antibody [VGKC-Ab] syndrome)? Are there patients, or in those whose coping mecha-
precise definable points of decompensation nisms are already limited, as in those with
(stepwise progression) with perhaps some borderline intellectual function at baseline.
improvement but not a return to baseline, as
occurs in patients with vascular dementias or
multiple sclerosis? Is there a specific identifi- The Examination
able initiating event to the behavioral change,
such as traumatic brain injury and repetitive The examination may be diagnostic, or at
closed head trauma, intracranial hemorrhage least help limit the range of possible differen-
from arteriovenous malformation rupture, tial diagnoses. This includes a general medi-
systemic illness, or cardiac bypass surgery? cal examination, an elementary neurologic
Are there associated elementary neuro- examination, and a detailed mental state
logical symptoms in the history, such as evaluation.
focal or transient deficits that accompany
cerebrovascular disease, the dementia associ-
ated with multiple sclerosis, chronic hepatic General Medical Examination
encephalopathy, or alcohol-related demen-
tia? Are there disturbances of gait and blad- A review of the list of diseases associated with
der function, suggesting normal pressure changes in cognitive function underscores the
hydrocephalus, Binswangers disease, or need for a thorough general medical exami-
the cognitive changes seen in patients with nation in order to detect the physical find-
inherited or acquired cerebellar ataxias? Is ings associated with these conditions. This
falling a prominent and early complaint, as includes the typical signs of an overactive
may occur in progressive supranuclear palsy, or hypofunctioning thyroid gland; stigmata
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 297
in Whipples disease of the central nervous radicular pains in the thoracic distribution
system caused by convergence failure and occur in syphilis, diabetes, and Lyme disease.
impoverishment of extraocular movements. Corticospinal tract signs occur late in pri-
This may be accompanied by the mouth and mary degenerative dementias. If these fea-
jaw movements of oculomasticatory myor- tures are evident early, they make diagnoses
hythmia, a striking constellation in this rare such as Alzheimers, FTD, and Parkinsons
disorder. disease less likely. Long tract signs are found
Focal cranial mono- or polyneuropathies in the amyotrophic lateral sclerosispar-
raise suspicion for life-threatening illnesses, kinsonismdementia complex described
including malignant meningeal infiltration, initially in Guam, now recognized as part
chronic basilar meningitides (e.g., cryptococ- of a spectrum of the manifestations of the
cosis, tuberculosis), and infectious vasculop- progranulin gene with brain deposits of the
athies (e.g., syphilis) that may be associated ubiquitinated TAR-DNA binding protein
with hydrocephalus, parenchymal brain (TARDBP or TDP-43; Hasegawa et al., 2007;
involvement, or apparently silent subcortical Yu et al., 2010). Corticospinal features raise
strokes. Pagets disease of bone may cause the suspicion for focal structural disease
compressive cranial neuropathies (mostly such as occurs in vascular syndromes. Large
VIIIth nerve) and hydrocephalus. Superficial arteriovenous malformations may produce
siderosis that produces progressive deafness a vascular steal phenomenon; intellectual
and cerebellar dysfunction as a consequence decline becomes evident as the hemipare-
of the insidious layering of blood products sis and hyperreflexia worsen over the years
on the surface of the cerebellum and brain- in the affected extremities. Multi-infarct
stem may also result in cognitive impair- dementia reflects the location, number, and
ment. Susac syndrome is an inflammatory size of strokes identified on the imaging
vasculopathy that produces multifocal brain studies. Multiple strokes on imaging stud-
demyelination, including the corpus callo- ies are a prerequisite for this diagnosis. The
sum, along with hearing loss and visual loss dementia results from involvement of the
from branch retinal artery occlusion. Hearing multiple different cortical and subcortically
loss is also a relatively common occurrence based systems that subserve intellect, emo-
in mitochondrial disorders such as mitochon- tion, and memory. Binswangers progressive
drial encephalomyopathy, lactic acidosis, and subcortical leukoencephalopathy presents
stroke-like episodes (MELAS), which affects with cognitive decline and intellectual and
cognition and may lead to dementia. emotional blunting, change in gait (slowing,
The masked facies of parkinsonism, and falling), and often with incontinence, making
rarely the trombone tremor of tertiary syphi- it difficult to distinguish clinically from nor-
lis, may be evident. The nature of dysarthria mal pressure hydrocephalus (NPH). The two
is an important clue to the underlying diag- are alike for good reasonthe white matter
nosis in dementia, as it can suggest extra- adjacent to the ventricles is compromised
pyramidal or cerebellar disease, or bulbar in both, in Binswangers by true ischemia,
involvement as occurs in the ALS-dementia and in NPH presumably by compression
complex. of the descending corticospinal tracts and
Peripheral neuropathy raises the possibil- the intra- and interhemispheric association
ity of vitamin B12 or multiple vitamin defi- fibers by the slowly enlarging ventricles.
ciency states, alcohol excess, hypothyroidism, The diagnosis is suggested by the clinical
neurosyphilis, HIV, and vasculitis (systemic triad (ataxia, incontinence, and dementia).
lupus erythematosus, polyarterities nodosa), The radiographic studies, stroke risk (lipids,
all of which can be associated with struc- blood pressure, smoking, family history, cor-
tural cerebral changes that cause dementia or onary and/or peripheral vascular disease),
altered behaviors. Neuropathy and dementia and results of therapeutic spinal tap help
may also be seen as paraneoplastic effects of determine which is the more likely diagno-
carcinoma, heavy metal intoxication (lead, sis. Amyloid deposition in cerebral vessels
mercury, arsenic), and adrenoleukodystro- is incriminated as a cause of massive lobar
phy. Lyme disease may be associated with hemorrhage, but this entity also produces
cognitive changes as well as peripheral neu- dementia in the absence of frank hemor-
ropathy or polyradiculopathy. Lancinating rhage (Viswanathan & Greenberg, 2011),
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 299
sometimes with superimposed episodes of spinal fluid analysis, visual and somatosen-
transient unresponsiveness. Diagnosis in sory evoked potentials).
vivo is supported by susceptibility sequence Extrapyramidal findings are expected in
magnetic resonance imaging (MRI) detection Parkinsons disease, neuroleptic-induced
of multiple microhemorrhages at cortical syndromes including confusion in the
white matter boundaries. Autopsy findings elderly, PSP, Lewy body disease, and the
show areas of microscopic and small macro- Parkinsonian variant of MSA. Patients with
scopic hemorrhage in the setting of amyloid- Alzheimers disease have extrapyrami-
laden blood vessels throughout the brain. dal features late in the course of the illness.
Other entities associated with behavioral In contrast, the young patient (30s) with
changes and long tract signs include diseases early-onset autosomal dominant Alzheimers
not generally considered high on the differ- disease from presenilin mutations can have
ential in elderly persons. Multiple sclerosis marked extrapyramidal features of dystonia
(MS) should be considered in a previously and bradykinesia, together with myoclonus
healthy young adult who presents with cog- that becomes marked as the illness rapidly
nitive changes and long tract signs which evolves.
may be related to concomitant myelopathy Patterns of sensory loss point to periph-
or involvement of the white matter in the eral nerve disease, brainstem syndromes,
cerebral hemispheres. Brainstem and optic or cerebral hemispheric lesions. Primary
nerve disease may be missing, and the tell- sensory loss (touch, pin, vibration, posi-
tale internuclear ophthalmoplegia and tion) is unlikely to be present in degenera-
abnormal evoked responses may be absent. tive dementias, but it may occur with lesions
Cerebral predominant MS can present with of the sensory thalamus and in diseases of
depression, and the diagnosis can be missed white matter such as multi-infarct dementia
until the course is advanced. The differential and MS. Impaired graphesthesia and mis-
diagnosis of the leukoencephalopathies pre- localization of stimulus in the presence of
senting with dementia includes degenera- intact primary sensation occur in degenera-
tive diseases more usually seen in children. tive dementias such as Alzheimers disease,
X-linked adrenoleukodystrophy manifests reflecting parietal lobe involvement.
in adulthood in 3% of cases, with dementia Cerebellar features in a rapidly dementing
accompanying long tract signs, hemianopsia, illness, together with spontaneous myoclo-
dysarthria, cortical blindness, and seizures. nus and/or stimulus-evoked startle myoclo-
Autosomal recessive metachromatic leuko- nus raise the possibility of Creutzfeldt-Jakob
dystrophy presents in adulthood as a white disease. The cerebellar features may be pre-
matter disorder with personality change and dominant, and the cerebellar variant of the
cognitive deficits. Krabbess globoid cell leu- illness has cerebellar features as the primary
kodystrophy, also autosomal recessive, has clinical manifestations until fairly late in
rarely been described in adults, with hemi- the course (Brownell & Oppenheimer, 1965;
paresis and ataxia accompanying the demy- Foley& Denny-Brown, 1955). Lesions of the
elinating dementia. Subacute sclerosing cerebellum that affect the limbic and cognitive
panencephalitis (SSPE, a late complication cerebellum in the vermis and posterior lobes,
of measles infection) also produces intense respectively, produce the cerebellar-cognitive
abnormalities in white matter as well as cor- affective syndrome (Schmahmann &
tex, with long tract signs and cortical blind- Sherman, 1998). This includes deficits in
ness accompanying the dementia. An elderly executive function, visual-spatial disorgani-
patient with episodic attacks of generalized zation, impaired verbal fluency, and blunted
weakness and fatigue associated with minor or inappropriate affect. If the lesion spares
neurologic signs may suggest a pattern of the sensorimotor cerebellum in the cerebellar
ischemic disease such as Binswangers. But anterior lobe, the patient will not be expected
if the stroke profile is unimpressive, and the to have gait ataxia or extremity dysmetria.
episodes are too long to conform to transient Release phenomena are helpful in the
ischemic attack, seizure, or migraine, then it examination. They are not specifically local-
is worthwhile considering late-life MS and its izing unless asymmetric, but they usu-
differential diagnosis, and investigating these ally implicate the prefrontal cortex and its
entities with the appropriate studies (MRI, connections. Palmar grasps and traction
300 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
responses so strong as to allow the examiner resemble a loss of memory, whereas in fact
to lift the patient off the examining table can the patient is essentially not there when
be impressive, as are the root, snout, and suck the memories are supposed to be laid down.
reflexes and the palmar grasp. These can be Brief staring spells lasting moments, flut-
the only hard neurologic findings in patients tering of the eyelids, smacking of the lips,
with Alzheimers disease outside the men- an unexpected repetition of a movement or
tal state examination. The glabellar tap sign sentence, or apparent inattentiveness to the
(failure to suppress the blink reflex with tap- examiners questions may be clues to the
ping the forehead) is not a frontal-release presence of an underlying complex partial
phenomenon but indicates extrapyramidal seizure disorder. This needs to be differenti-
disturbance as occurs in Parkinsons disease. ated from confused distractibility. The elec-
The palmomental reflex may be interesting to troencephalogram is of particular benefit in
observe but also occurs in healthy individu- this scenario.
als and is not particularly useful for diagnos- We are reluctant as physicians to entertain
tic purposes. the possibility of feigned physical signs, and
Abulia is the neurologic equivalent of sometimes the differentiation between neu-
psychomotor retardation, with slowness, rologic disease, conversion disorder, and sec-
decreased responsiveness, and apathy ondary gain can be difficult. Acareful inquiry
(Fisher, 1983). The patient is slowed mentally into the background circumstances and reli-
and physically, may have paratonic rigidity ance upon the need for neurologic symptoms
(geggenhalten), does not generally initiate and signs to conform to known patterns of
spontaneous conversation or action, and may injury and deficit are helpful in sorting out
produce accurate answers to mental state the psychological/psychiatric/neurologic
questions but usually after a disquietingly overlap.
prolonged delay. This poverty of spontane-
ity is a hallmark of dorsolateral prefrontal
pathology, the opposite of the gregarious and Mental State Examination
disinhibited, inappropriate jocularity that
characterizes orbitofrontal cortex lesions. The nature of the cognitive profile allows the
Apart from mass or other destructive lesions examiner to draw upon structure-function
of the frontal lobes, many illnesses that result correlations in the nervous system to localize
in widespread white matter damage produce the lesion in cortical and subcortical areas.
a similar syndrome. This includes many of The pattern of involvement of the affected
the white matter dementias that spare the regions generally reflects the underlying
cerebral cortex and the deep nuclei but dev- pathology, particularly in the neurodegenera-
astate the long association fiber tracts that tive dementias such as Alzheimers and FTD.
link cortical association areas. There are Discussion of the mental state examination
many causes of white matter dementia (see and of the neural substrates that subserve the
Table 15.3), but they often have a frontal lobe different elements of cognition is found else-
flavor that includes abulia as a hallmark of where in this volume.
the presentation. Brain imaging is strikingly
abnormal in these cases and helps direct
the appropriate evaluation. Subcortical Brain Imaging
dementias, including Parkinsons disease,
Huntingtons disease, and PSP, among oth- Patterns of disease that cause dementia can be
ers, also produce slowness of response, but so distinctive on brain imaging that the radio-
these entities are usually accompanied by graphic findings help structure the diagnostic
overt movement disorders. thoughts and the further approach to evalu-
Brief lapses of consciousness may be dis- ation and management. MRI is the preferred
cernible in the examination of a patient with and most sensitive method, but computerized
frequent partial seizures. These can be so tomography (CT) is an acceptable alterna-
frequent as to interfere with the patients tive when MRI is not available or contrain-
ability to pay attention to his or her envi- dicatedas in the patient with a permanent
ronment, learn new material, and keep cardiac pacemaker. Note that brain imaging
track with ongoing activities. This could is an extension of the clinical examination
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 301
(continued)
302 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
TABLE15.3Continued
Neoplastic Gliomatosis cerebri
Diffusely infiltrative gliomas
Lymphomatosis cerebri
Langerhans cell histiocytosis
Focal white matter tumors
Hydrocephalic Early hydrocephalus
Normal pressure hydrocephalus
Degenerative White matter changes in Alzheimers disease
Effects of aging on myelin
and supplements, but does not replace the disorders from diffuse conditions such as
traditional clinical method. MR-negative toxic, metabolic, and infectious etiologies.
neurology in the absence of a clearly for- Together with brain imaging and first-line
mulated hypothesis derived from the history laboratory tests, it should not be difficult to
and examination (as in early Alzheimers diagnose mental state changes from brain
disease prior to hippocampal atrophy) is tumor, abscess, cerebritis, or hemorrhage,
both frustrating and misleading. On the other and a wide array of metabolic insults that
hand, obvious findings on MRI, ranging from can cause cognitive decline, or precipitate or
butterfly glioma spreading across the corpus worsen incipient or previously unrecognized
callosum, to multifocal lesions as in cerebral cognitive impairment. Common metabolic
amyloid angiopathy and progressive multi- abnormalities include those accompanying
focal leukoencephalopathy, or normal pres- renal, hepatic, cardiac, and pulmonary fail-
sure hydrocephalus, help set the stage for the ure; severe anemia; and dehydration (Table
further workup and treatment. 15.2). Three particularly useful clinical signs
pointing to a metabolic encephalopathy are
fluctuating level of arousal, wandering of
Diseases That Cause Dementia, Developing attention or easy distractibility with or with-
Over Days to Weeks out agitation, and asterixisthe sudden,
brief, and repeated loss of power in anti-
The timing of disease onset and progres- gravity muscles such as when the wrists are
sion provides clues to the diagnosis. Acute held in extension with the arms outstretched.
life-threatening encephalopathies that Myoclonus, the brief, intermittent, positive
develop into fulminant form in a matter contraction of groups of muscles in the limbs
of hours are not considered here, as these individually or together, occurs in a range of
hyperacute diseases do not enter the differ- metabolic derangements such as magnesium
ential diagnosis of dementia (e.g., bacterial deficiency and drug overdose with lithium,
meningitis, and encephalitides such as east- in hypoxemic ischemic encephalopathy,
ern equine, western equine, and West Nile Hashimotos encephalopathy, and in neuro-
virus). A number of illnesses with subacute degenerative disorders, including presenilin
progression over weeks to months may have early-onset Alzheimers and corticobasal
an abrupt onset, and these are considered degeneration, in addition to CJD.
first before a discussion of more unusual
forms of dementing disorders with a chronic
course over years. Metabolic Disorders
toxins, vitamin deficiency states (B1, B3, B12, used for pain management, such as gabapen-
and E), and altered thyroid metabolism. tin and related compounds, anticonvulsant
medications used for their analgesic proper-
ties, and narcotics that are considered mild
Alcohol in the younger individual but have dispro-
portionate effects in the elderly. The key to
The older individual who may be alone, prevention of confusion with these agents in
depressed, or forgetful can indulge in alcohol the geriatric population is to use the smallest
use which will cause confusion when taken dose of medication possible, raising the dose
in larger amounts, or exacerbate any underly- in small increments over time depending on
ing cognitive impairment even at levels that clinical response.
were previously tolerated. A history of alco-
holism is not necessarily present. Apart from
inebriation, neuropsychiatric complications Thiamine Deficiency:Wernicke
of alcohol use are the alcohol withdrawal Korsakoff Syndrome and Marchiafava
syndrome, which comes on usually within 1 Bignami Disease
to 3 days of cessation of alcohol and includes
confusion, agitation, and autonomic features Most commonly occurring in the setting of
(McKeon, Frye, & Delanty, 2008). When left prolonged alcohol use, thiamine (vitamin B1)
untreated (by benzodiazepines), the severe deficiency is a treatable cause of confusion
and persistent alcohol withdrawal syndrome and a preventable form of dementia. Other
progresses to full-blown delirium tremens, a clinical scenarios that place the patient at
potentially fatal disorder largely because of risk for thiamine deficiency are hyperemesis
the cardiac manifestations of the autonomic gravidarum because of the intractable vomit-
storm (Kelly & Renner, 2008). Excessive ing that leads to decreased oral intake, and
alcohol use is also associated with thiamine previous gastrectomy or gastric surgery for
deficiency, which causes Wernickes enceph- weight loss that can lead to impaired absorp-
alopathy, Korsakoff amnestic syndrome, and tion of this essential vitamin in the small
possibly Marchiafava-Bignami disease, dis- intestine. Wernicke syndrome is recognized
cussed later. by the tetrad of confusion, ataxia, nystag-
mus, and oculomotor impairments such as
sixth nerve palsy (impaired lateral rectus
Medications movement). The percentage of patients who
experience all these findings in the early
The use of prescription medications for neu- stage of the syndrome is small. The recent
ropsychiatric indications (psychotropics, onset of confusion is the most consistent fea-
tricyclic antidepressants, benzodiazepines), ture, and it is the reason for the use of thia-
as well as a large number of medically indi- mine so liberally in confused patients in the
cated agents from beta blockers to hista- emergency room. The metabolically active
mine antagonists, can cause confusion in form of thiamine (thiamine pyrophosphate)
the elderly person, particularly if taken in is necessary for glucose metabolism, and
higher doses or more frequently than pre- therefore administering glucose to a patient
scribed. Inappropriate or incorrect use of with a clinical or subclinical thiamine defi-
hypoglycemic agents, for example, can pro- ciency exacerbates the thiamine deficiency
duce episodes of confusion that are otherwise and can either precipitate or worsen the clini-
unexplained unless the history is carefully cal syndrome. This explains why thiamine is
elicited. Polypharmacy in the older patient administered before dextrose is given intra-
is an established reality because so many ail- venously to the acutely confused patient in
ments in later years respond well to the judi- the emergency room. The common practice
cious use of carefully selected therapeutic of administering the thiamine-narcan-D50
agents. The use of prescription medications cocktail to these patients also addresses
targeted to each of these disorders sets up the possibility of confusion and encepha-
the higher likelihood of drug interactions lopathy resulting from sedating narcotic
and additive neuropsychiatric effects. Some drugs. Korsakoff syndrome is the long-term
of the common offending agents are those sequel of untreated thiamine deficiency, the
304 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
clinical manifestation of hemorrhagic necro- pyramidal sign with true weakness, primitive
sis of the mammillary bodies, dorsomedial reflexes, rigidity, incontinence, sensory symp-
nucleus of thalamus, and periqueductal grey toms, and gaze palsy or diplopia. Seizures
in the brainstem (Victor, Adams, & Collins, may occur. Cerebrospinal fluid (CSF) may
1971). There is also involvement of the cer- show elevated protein, but leukocytosis in
ebellar dentate nuclei in the acute stage of this setting generally reflects central nervous
Wernickes (Bae, Lee, Lee, Choi, & Suh, 2001). system (CNS) infection (Hillbom et al., 2013).
The amnestic syndrome of Korsakoff syn- Chronic cases have thinning of the corpus cal-
drome is characterized by profound loss of losum and a cognitive profile that conforms to
the ability to lay down new memories, with a frontal lobe syndrome, together with signs
preservation of prior knowledge and recall of interhemispheric disconnection.
of events prior to the initiating illness. The
anterograde amnesia occurs in isolation and
is not associated with the penumbra of other Pellagra
cognitive domains as in Alzheimers disease.
Treatment of the syndrome is by prevention Malnutrition and undernutrition occur world-
of the thiamine deficiency and early recogni- wide, and developed nations are not immune
tion of its appearance in the appropriate clini- to the neurological manifestations of a poor
cal context. diet. Pellagra results from deficiency of nico-
Marchiafava Bignami disease refers to tinic acid (niacin, vitamin B3) or tryptophan,
the necrosis of the corpus callosum seen in which is converted to niacin. Poor diet, alco-
the setting of excessive alcohol use, as well holism, and gastrointestinal disorders with
as in cases of malnutrition. It was originally malabsorption are common precipitants.
described as a fatal disease affecting heavy Hartnup disease, an autosomal recessive con-
consumers of red wine, but brain imaging dition, prevents absorption of tryptophan and
has allowed premortem diagnosis, and not produces a pellagra-like disorder. Pellagra is
all patients succumb. The relationship to thia- known as the three Dsdermatitis, diar-
mine deficiency has been suggested, not least rhea, and dementia, with a fourth D (death)
by improvement in the condition in patients reflecting the unfortunate course if unrecog-
treated promptly with vitamin B1, but this is nized. It is a particularly challenging diagno-
not yet definitive. MRI shows acute demy- sis to make in cases in which the expected skin
elination in the splenium or the genu of the manifestations are absent, depriving the clini-
corpus callosum or the entire callosum, best cian of one of the didactic hallmarks of the ill-
seen on diffusion-weighted imaging but ness. The dermatitis develops on exposed skin
also on fluid attenuated inversion recovery surfaces, but if the patient is not exposed to
sequence (FLAIR) and T2, or as a hypoden- ultraviolet rays by virtue of habit and clothing,
sity on CT. Based on imaging features, type these features may be missing. In this circum-
A is characterized by acute to subacute stance, knowledge of the clinical background
onset of impairment of consciousness and of the patient is paramount. In a Hungarian
pyramidal tract syndromes, with imaging neuropathology surveillance program for
showing callosal edema, and a less favor- CJD, 5 of 59 patients who came to autopsy
able prognosis with considerable disability showed neuropathological features of pel-
and fatality. Type B lacks major impairment lagra encephalopathy with widespread chro-
of level of consciousness, is characterized by matolytic neurons. The course was between 2
acute to subacute onset of cognitive impair- and 24 months, with clinical signs manifesting
ment, dysarthria, gait disturbance and signs as rapid-onset dementia, cerebellar ataxia, and
of interhemispheric disconnection, partial corticospinal signs (Kapas et al., 2012). Pellagra
T2-hyperintense lesions on early MRI, and a encephalopathy is characterized clinically
generally favorable prognosis with treatment by rapidly progressive dementia, fluctuating
(Heinrich, Runge, & Khaw, 2004). The range cognition and frontal disinhibition, release
of clinical manifestations includes confusion, phenomena, startle myoclonus, decreased
delirium, unconsciousness, impaired mem- arousal, a cerebellar motor syndrome, hyper-
ory and/or disorientation, with impaired reflexia, peripheral neuropathy, autonomic
gait, dysarthria, nystagmus, mutism, signs dysfunction, and cranial neuropathies (Ishii
of disconnection or split brain syndrome, & Nishihara, 1981). In the alcoholic patient, it
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 305
can be a challenge to distinguish the acute and such as celiac disease, poor diet, and some
persistent confusional state, disorientation, inherited disorders (ataxia with vitamin E
agitation, irritability, paranoia, and halluci- deficiency; Schuelke, 2013) include the cer-
nations of pellagra from alcohol withdrawal. ebellar motor syndrome of truncal and limb
Knowing of, and suspecting the disease, is the ataxia with dysarthria, loss of deep tendon
key to providing the appropriate therapy. reflexes, markedly diminished perception
of vibration and position, ophthalmople-
gia, ptosis, and muscle weakness (Schuelke,
Vitamin B12 Deficiency 2013; Sokol, 1988). Behavioral and personal-
ity disorders have been noted in the setting of
The myelopathy of pernicious anemia character- vitamin E deficiency in patients with chronic
istically includes upper motor neuron findings liver disease, which of course is a confound
from involvement of the lateral corticospinal in the evaluation of cognition. Burns and
tracts, and impaired position and vibration Holland (1986) reported that in their study
sense from damage to the posterior columns of an elderly psychiatric population, nearly
subacute combined degeneration of the spinal 60% of the patients with dementia had serum
cord (the differential diagnosis of which is HIV, vitamin E levels below the accepted normal
neurosyphilis, and copper deficiency). Both range, and they postulated that an absolute
the myelopathy and the dementia of vitamin or relative deficiency of vitamin E could
B12 deficiency can occur in the absence of the lower the age of onset or increase the rate
hematological parameters of macrocytic mega- of progression of dementia in Alzheimers
loblastic anemia, which require associated folic disease. A quarter century later, it appears
acid deficiency. Reliance on the hematologic that higher vitamin E levels are associated
parameters for the suspicion of B12-deficient with reduced risk of cognitive impairment
cognitive decline is a recipe for diagnostic fail- in noncognitively impaired elderly adults
ure. Cognitive impairment in B12 deficiency (Mangialasche et al., 2013).
includes mania, depression, and psychosis,
with deficits in memory, concentration, visuo-
spatial performance, and executive functions Thyroid Disorders
(Osimani, Berger, Friedman, Porat-Katz, &
Abarbanel, 2005). Relative or absolute B12 Myxedema madness is an old term refer-
deficiency is implicated in exacerbation of ring to the cognitive deficits of apathy, inat-
cognitive failure in patients with other disor- tention, and forgetfulness, and psychiatric
ders, including Alzheimers disease (Meins, symptoms of depression, mania, and psy-
Muller-Thomsen,& Meier-Baumgartner, 2000; chosis with delusions and hallucinations
Werder, 2010). Low normal levels of vitamin that occur in the setting of frank hypothy-
B12 appear to be prevalent in the population, roidism (Heinrich & Grahm, 2003). The pres-
and this is therefore an important entity to con- ence of cognitive and affective impairments
sider and test for in the appropriate clinical con- in patients with subclinical hypothyroidism
text. Elevated levels of methylmalonic acid and as measured by elevated thyroid-stimulating
homocysteine will provide laboratory support hormone (Davis, Stern, & Flashman, 2003) is
for the suspicion of B12 deficiency when the sufficient indication to ensure that thyroid
B12 level itself is borderline. More specific tests levels are checked in patients with cogni-
for pernicious anemia causing B12 deficiency tive decline, be it acute or chronic. Patients
include antibodies to gastric parietal cells and with the hyperthyroidism of Graves disease
intrinsic factor. These are indicated when there report emotional lability, irritability, insom-
is no clear dietary basis of the disorder or a his- nia, restlessness, agitation, depression, and
tory of prior gastric or duodenal resection. anxiety as well as deficits in memory and
concentration (Trzepacz, McCue, Klein,
Levey, & Greenhouse, 1988; Vogel et al.,
2007), and these improve markedly follow-
Vitamin E ing treatment. When the associated medical
features of thyroid dysfunction are evident,
The most common findings in vitamin E the diagnosis is readily suspected, but this is
deficiency, seen in malabsorption syndromes not always the case. Clinical suspicion and
306 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
appropriate laboratory tests are needed to catastrophic illnesses that develop over hours
ensure that these metabolic disorders with or days. The neurotropic double-stranded
relatively high prevalence are not missed. DNA Herpes simplex virus is a little differ-
ent in that its course can be more indolent,
coming on over days or weeks or more. Most
Acute Intermittent Porphyria cases are caused by HSV-1 (which cause cold
sores) and are likely the result of retrograde
This autosomal dominant disorder of enzymes transmission from the trigeminal ganglion,
in the haem biosynthetic pathway presents in or from the olfactory nerve (Dinn, 1980).
acute crisis with gastrointestinal (abdominal Early symptoms that include change in taste
pain, nausea, and vomiting), cardiac (hyper- or smell may be dismissed; the apathy, irri-
tension and tachycardia), and neurologi- tability, and memory loss or confusion from
cal symptoms and signs. Neuropsychiatric involvement of the medial temporal and
manifestations range from anxiety and emo- orbitofrontal cortices (Fig. 15.1) may not be
tional lability to confusion and frank psy- striking at the outset; and the low-grade
chosis, while more widespread neurological fever is nonspecific. Neurological deficits
involvement includes generalized seizures, soon set in, however, with a range of lan-
painful motor neuropathy leading to flaccid guage impairments reflecting the evolving
quadriparesis, and bulbar involvement with aphasia from spread to the ventral prefrontal
aphonia, dysphagia, and respiratory paraly- and temporal cortices and the language path-
sis. The diagnosis, once suspected, is made ways that connect them. Confusion mounts,
by detecting increased serum levels of delta and the patient develops focal or generalized
aminolaevulinic acid and porphobilinogen seizures or lapses directly into status epi-
(PBG), as well as elevated PBG in the urine lepticus or coma. A high level of suspicion
(Disler& Eales, 1982; Whatley& Badminton, is needed to make the diagnosis urgently
2013). Acute intermittent porphyria has a high and initiate treatment with acyclovir as the
prevalence in individuals of Scandinavian agent of choice, as early treatment can stop
descent. Variegate porphyria, which can also the illness, limit further neuronal destruc-
present with an acute neurological crisis, is tion, and improve prognosis for survival
common in southern Africa. and recovery of neuropsychiatric function.
Seizures are a major long-term complication,
particularly when seizures are evident at the
Rapidly Progressive Dementia (Other time of the acute illness (Sellner & Trinka,
Than Metabolic Disorders) 2012). Persistent amnesia is a complica-
tion of damage to bilateral medial temporal
Other than the metabolic disorders discussed structures critical to memory formation and
previously, the following conditions should consolidation. The triad of fever, confusion,
be at the top of the list of diseases to con- and aphasia should be an instant tip-off to
sider in a patient with a rapidly progressive Herpes simplex encephalitis, but the differ-
dementing disorder, both because some are ential diagnosis of this presentation includes
readily treatable, and because of the impor- diseases with very different etiologies and
tance of the diagnosis for the patient and treatmentssubacute infectious endocardi-
family. These are infections, limbic and other tis, temporal arteritis, and thrombotic throm-
immune mediated encephalitides the prion bocytopenic purpura.
diseases, stroke syndromes and vasculitides, In subacute infectious endocarditis (SBE)
focal lesions that produce new onset demen- fever results from the systemic low-grade
tia, and cancers presenting in atypical ways bacterial infection. Almost 30% of SBE
such as stroke and meningeal infiltration. patients experience neurological manifesta-
tions, the commonest of which is confusion
(Jones& Siekert, 1989). Aphasia results from
Herpes Simplex Encephalitis focal infarction in language cortex produced
by the infectious vasculitis in the salient arte-
Viral encephalitides are not usually con- rial supplyfor example, inferior division
sidered in the differential diagnosis of a of the middle cerebral artery or its posterior
subacute encephalopathy because these are temporal branch.
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 307
as much as 4 years. Many of the antibodies itself, but by the T-cell-mediated immune
identified to date are linked with specific response against the neuronal antigen, lead-
types and locations of tumors. There are ing to the inflammation and neurodegen-
instances of tumor-associated LE in which no eration that characterizes the disorder. These
antibodies have yet been identified; cases of antibody-mediated disorders are associated
LE with identified antibodies that may not principally with tumors of the lung, breast,
be associated with underlying tumor; and ovaries, and testicles (see Table 15.4). Because
cases of LE that respond to immunotherapy of the neurodegeneration produced by the
in which there is neither identified tumor nor cell-mediated immune response, recovery
an identified antibody. of neurological function after treatment is
Thus, LE may be categorized as follows: only occasionally successful. The second is
when antibodies target intracellular syn-
LE associated with antibodies from an aptic proteins (such as glutamic acid decar-
identified tumor boxylase and amphiphysin) during synaptic
LE in which tumor is found but no anti- vesicle fusion and reuptake, but T-cell medi-
bodies are detected ated pathogenetic mechanisms may also be
LE in which there are antibodies but important. A third category of more recently
no tumor (i.e., not a paraneoplastic described LE cases are defined by antibody
phenomenon) attack against cell surface or synaptic pro-
LE (after a full diagnostic evaluation is teins, including the N-methyl-D-aspartate
otherwise negative) in which there is (NMDA), -amino-3-hydroxy-5-methyl-4-
neither antibody identified nor a tumor isoxazolepropionic acid (AMPA), gamma-
detected, but the patient responds well to aminobutyric acid-B (GABA-B), glycine, and
immunotherapy the metabotropic glutmate receptor mGluR5,
as well as two proteins previously thought to
Three different antigen-antibody scenarios be VGKCs but are now known as leucine-rich
have clinical relevance for the diagnosis and glioma-inactivated protein 1 (LGI1) and con-
management of LE. The first is when anti- tactin-associated protein-like 2 (Caspr2; see
bodies produced in response to the tumor Table 15.5). In these disorders, the antibody
that target neuronal epitopes (the part of the directly attacks the cell-surface target pro-
antigen that is recognized by the immune ducing the symptoms, and importantly, these
system) are directed against nuclear or cyto- disorders are usually not associated with an
plasmic proteins such as Hu, Yo, and Ma2. underlying malignancy (Irani et al., 2010).
But antibodies have limited access to these Seizures, psychosis, and confusion with
neuronal antigens, and therefore the princi- memory loss are the hallmark of these disor-
pal pathology is caused not by the antibody ders, which have a time course of onset over
PCD, paraneoplastic cerebellar degeneration; PNS, paraneoplastic neurological syndromes; SCLC, small-cell lung cancer.
Source:From Graus and Dalmau (2012); reproduced with permission.
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 309
NMDAR Encephalitis Ovarian teratoma (rare in children, present in 58% older than
18years)
GABABR Limbic encephalitis SCLC (70%)
CASPR2 Morvans syndrome Thymoma (38%)
AMPAR Limbic encephalitis SCLC, breast, thymus (60%)
VGCC PCD SCLC (>95%)
mGluR5 Limbic encephalitis Hodgkins disease (two cases reported only)
days to weeks. Further, they often respond inflammation; serum and CSF markers for
dramatically and completely to appropriate the antibodies that have been indentified in
immune-based therapies. Morvan syndrome, these disorders; CT of neck, chest, abdomen,
associated with Caspr2 and with thymoma in and pelvis; and ultrasound, if necessary, of
about 50% of cases, is characterized by neu- the testicles. Whole-body positron emis-
romyotonia with myokymia on electromy- sion tomography (PET) scan is necessary if
ography (100%), neuropsychiatric features the level of suspicion remains high but the
(insomnia, 89.7%; confusion, 65.5%; amnesia, first-line modalities do not identify tumor.
55.6%; hallucinations, 51.9%), dysautonomia Management includes definitive treatment
(hyperhidrosis, 86.2%; cardiovascular, 48.3%), of the underlying tumor when present, and
and neuropathic pain including painful mus- immunotherapy with a combination, often
cle cramps (62.1%; Irani et al., 2012). This in successive order, of corticosteroids, intra-
condition responds to thymectomy either venous immunoglobulin, plasmapheresis,
alone or in combination with immune modu- and more recently, cyclophosphamide and
lation (Abou-Zeid, Boursoulian, Metzer, & rituximab, managed by a team of physicians
Gundogdu, 2012; Lancaster & Dalmau, 2012). with the appropriate and necessary skill set
The NMDA receptor antibody syndrome to handle these complex cases. Psychiatric
associated with ovarian teratomas includes symptoms and seizures are all managed as
psychiatric symptoms, catatonia, agitation, indicated.
seizures, decreased level of consciousness,
autonomic instability, and abnormal move-
ments. Executive dysfunction and psychiat- Hashimoto Encephalopathy
ric symptoms endure after the acute phase
has subsided. The glycine receptor antibody An acute or subacute cognitive and psychi-
syndrome is a progressive encephalomy- atric syndrome occurs in the setting of anti-
elitis with rigidity and myoclonus. And the bodies directed against the thyroid gland
mGluR5 antibody syndrome that occurs in (thyroglobulin, thyroid peroxidase) not nec-
the setting of Hodgkins lymphoma produces essarily associated at the same time with the
a constellation of psychiatric symptoms, cog- symptoms or metabolic markers of thryo-
nitive impairment, and memory loss termed toxicosis or hypothyroidism (Brain, Jellinek,
the Ophelia syndrome (Lancaster et al., 2011). & Ball, 1966). The disorder disproportion-
The approach to the diagnosis involves ately affects women (F:M, 4:1), and the
a full clinical evaluation because the fea- constellation includes personality change,
tures that characterize limbic encephali- dementia, seizures, psychosis, myoclonus,
tis are shared by other disorders as well. altered consciousness, and sometimes gait
Investigations include brain MRI for the impairment. The course may be relaps-
telltale FLAIR and T2 hyperintensities in ing and remitting. The manifestations can
limbic cortices; spinal tap for stigmata of be varied, however, and a high level of
310 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
Figure15.3 T1-weighted axial magnetic resonance imaging (MRI) (left) and fluid attenuated
inversion recovery sequence (FLAIR)-weighted MRI images (middle and right) show white
matter attenuation in an elderly man with Binswangers progressive ischemic subcortical
leukoencephalopathy.
(DEsposito, Verfaellie, Alexander, & Katz, imaging characteristics, but the diagnosis is
1995; Heilman& Sypert, 1977)and the ante- not always evident from brain imaging, and
rior thalamus (Schmahmann, 2003)sub- biopsy may be indicated to determine opti-
cortical nodes and pathways critical for mal management. This approach is further
declarative memory. The precise nature of necessitated in the case of brain tumors (pri-
a focal space-occupying lesion (tumor, sar- mary or secondary) by the evolving sophis-
coidosis, tuberculoma, syphilitic gumma, tication of pharmocogenomics in targeting
and toxoplasmosis; Fig. 15.7) may be sug- chemotherapeutic agents to different tumor
gested by the clinical background and the types.
Figure15.6 Postgadolinium sagittal T1-weighted magnetic resonance image (MRI) (left) and
coronal image (right) identifying a contrast-enhancing mass (glioblastoma multiforme) centered in
the splenium of the corpus callosum.
Figure15.7 Coronal T1-weighted magnetic resonance imaging (MRI) scans in the coronal plane
(left) and sagittal plane (right) following administration of gadolinium in a patient with HIV and
cerebral toxoplasmosis. Multiple contrast enhancing lesions are identified, some of which are ring
enhancing.
314 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
with apathy, withdrawal, and then psycho- the history of cognitive and behavioral neuro-
sis. The advanced disease is characterized by science. According to Pearce (2012), GPI was
a stereotyped picture of severe multidomain a crucial starting point in which the causes of
dementia, mutism, incontinence, paraplegia, mental illness were slowly transformed from
and myoclonus (Harris, Jeste, Gleghorn, & psychogenic disturbances of mind and spir-
Sewell, 1991; Navia, Jordan, & Price, 1986; its to organically determined diseases. Once
Schmahmann, 1997; 1998). Note that the a major cause of long-term neurological dis-
paraplegia may arise either from severe bilat- ability, including dementia, GPI remains an
eral cerebral disease or from the associated important consideration in the patient with
finding of vacuolar myelopathy (Gabuzda atypical and rapidly progressive dementia,
& Hirsch, 1987). White matter pathology in both in the era of global health and easy access
patients with HIV raises the specter of PML to international travel from countries where
(Schutte, Ranchhod, Kakaza, & Pillay, 2013), the disease incidence is high, and in devel-
but HIV encephalopathy in the absence of oped countries in the setting of the immu-
the full AIDS spectrum includes a clinically nocompromised host with HIV (Knudsen,
relevant leukoencephalopathy (Fig. 15.8), 2013). Tertiary syphilis is characterized by a
as well as axonal damage and neuronal loss subacute onset of disorientation, forgetful-
induced directly by the human immunodefi- ness, and impaired judgment, together with
ciency virus (Gray et al., 2001), the neurobe- psychiatric symptoms, including depression,
havioral manifestations of which include mania, and psychosis (Stefani et al., 2013). In
slowing of information processing, forget- addition to the dementia, behavioral abnor-
fulness, executive dysfunction, and affective malities, and chronic psychosis, tertiary
changes, including notably, depression. It syphilis patients may also experience acute
now also appears that even in the setting of transverse myelitis, chronic myelopathy, and
chronic HIV infection managed successfully syphilitic amyotrophy (Kayal, Goswami,
with CART, progressive changes in the brain, Das, & Paul, 2011). In a recent study of 116
including white matter changes in the frontal patients in China (Zheng et al., 2011), mani-
lobes and neuronal damage to the basal gan- festations included progressive cognitive
glia, can lead to progressive neurocognitive and behavioral deterioration, accompanied
decline (Gongvatana et al., 2013). by psychotic and/or affective behavioral
disorders, hyper-reflexia, frontal release
signs (suck reflex), the Argyll-Robertson
Neurosyphilis pupil, and focal or multifocal brain atrophy
on imaging. This description is consistent
This sexually transmitted disease is caused with classical accounts (see Pearce, 2012) of
by the spirochete Treponema pallidum. Tertiary disease onset 12 to 20 years after primary
syphilis patients suffering from general pare- infection of a progressive mainly frontotem-
sis of the insane (GPI) hold a pivotal niche in poral meningoencephalitis characterized by
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 315
pyramidal weakness, impaired personality active infection, during which 12.5% of the
and memory, mania, erratic judgment, apa- 40 patients studied met criteria for demen-
thy, violence, congestive attacks, and epi- tia. Cognitive decline was less prominent in
lepsy, together with Argyll-Robertson pupils patients in whom the cysts had calcified, and
and concurrent tabes dorsalis. The pattern whereas these patients did not meet criteria
of presentation of GPI may not always be for dementia, more than 50% of this group of
discretely different from the pattern of cog- 40 patients evaluated was impaired on tests
nitive decline in Alzheimers disease. Wang of memory, attention, executive functions,
et al. (2011) found that patients with mild language, and visuospatial skills.
GPI had a pattern of cognitive impairment Listeria monocytogenes, a gram-positive
that resembled the memory, language, and bacterium that is spread by contaminated
executive deficits in mild Alzheimers dis- food, is a concern in patients chronically
ease together with atrophy of the medial immunosuppressed on steroids. The menin-
temporal lobes. The GPI patients had more goencephalitis produces focal neurological
abnormal signs on neurological examina- deficits (Pollock, Pollock,& Harrison, 1984),
tion, however. Diagnosis is established only and it has been associated with persistent
if there is clinical suspicion that motivates the cognitive decline, with impaired short-term
further investigation, or a standard approach memory, concentration, and apathy, as well
to testing that is designed to detect and not as catatonia (Kellner, Sonntag, & Strian,
miss the disease. Meningovascular syphilis 1990), mania, depression, and psychosis
can cause stroke at cerebral and spinal levels, (Duncan, 1989).
and falls within the differential diagnosis of Cryptococcal meningitis may affect immu-
ischemic disorders with or without cogni- nocompetent hosts but is more prevalent in
tive manifestations. Diagnosis of syphilis is immune-compromised individuals, notably
supported by CSF lymphocytic pleocytosis those with long-term corticosteroid use, but
and high protein levels, and serological tests, most dramatically in individuals infected
including the CSF nontreponemal Venereal with HIV (Pyrgos, Seitz, Steiner, Prevots, &
Disease Reference Laboratory (VDRL) test Williamson, 2013). After the acute illness
and the serum treponemal T. pallidum par- has been treated, its principal mechanism
ticle agglutination assay (TPPA), T. palli- for causing long-term cognitive change is
dum haemagglutination assay (TPHA), and through noncommunicating hydrocephalus
enzyme immunosorbent assay (EIA) IgG/ from obstruction of CSF flow at the foramina
IgM. Treatment with appropriate doses and of Luschka and Magendie, or communicating
durations of antibiotics (penicillin remains hydrocephalus by prevention of CSF resorp-
the drug of choice for all stages) cures the tion through the Pacchionian granulations at
illness. The diagnosis should be suspected the vertex. During the active infection, the
and tested for in any patient whose course problem of elevated ICP without hydroceph-
is remotely atypical for Alzheimers disease, alus produces a combination of headache
particularly if there are both cognitive and as well as confusion and obtundation that
psychiatric features. can be life-threatening and which requires
ventriculoperitoneal shunting (Petrou et al.,
2012).
Other Subacute and Chronic Meningitides
Figure 15.10 Axial fluid attenuated inversion recovery sequence (FLAIR)-weighted magnetic
resonance imaging (MRI) scans (from ventral to dorsal, right to left) in a middle-aged man with
mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) showing
signal abnormality and mild vasogenic edema in the left cerebral cortex and subjacent white matter
of the posteromedial temporal lobe, occipital lobe, and medial and lateral parietal convexities. These
findings resolved radiographically and clinically following treatment with intravenous high-dose
methylprednisolone. (From Walcott et al., 2012)
DNA mutations (DiMauro & Hirano, 2001; or together with the cortical injury. The pre-
Sproule & Kaufmann, 2008). It is charac- cise cause of the acute event and its patho-
terized by headache, depression, seizure, physiology is not fully established, although
encephalopathy, and recurrent neurological hypotheses have been offered together with
deficits labeled stroke-like because of their evidence that the acute episodes can resolve
abrupt onset and focal manifestation. Other with the use of corticosteroids (Walcott et al.,
systemic manifestations include cardiomy- 2012). Other therapeutic approaches have
opathy, diabetes mellitus, and sensorineural met with variable success, including the use
hearing loss. The diagnosis is suggested by of coenzyme Q-10, arginine, and succinate.
the combination of stroke-like episodes, pro- One may be alerted to test for this unusual
gressive encephalopathy leading to demen- disorder when a relatively young person
tia, and convulsive or noconvulsive seizures. presents with recurrent episodes of confu-
The range of clinical manifestations reflects sion and focal neurological deficits, and brain
the phenomenon of heteroplasmy, with vari- imaging shows acute ischemic injury in the
able penetrance occurring in different cells. atypical pattern of being confined to the cor-
The most frequent causative genetic muta- tex but in a distribution that does not match
tion is the A-to-G transition at position 3243 a known vascular territory. The serum lactic
of the mitochondrial genome, which can be acid is elevated, muscle biopsy shows the
tested in commercial laboratories. Psychiatric expected ragged red fibers (subsarcolem-
presentations are described, including con- mal aggregates of enlarged and abnormal
fusion, aggression, hallucinations, and para- mitochondria on the Gomori trichome stain),
noia (Kaufman, Zuber, Rueda-Lara, & Tobia, and gene testing identifies the mitochondria
2010; Kim, Schmahmann, Falk, Stern, & mutation. When the case is rapidly evolving,
Norris, 1999). The progressive elaboration of one does not have the luxury of time to wait
structural deficits over time leads to a multi- for the genetic diagnosis to be established;
domain dementia. The location of the lesions in these cases, muscle biopsy to confirm the
in the acute episodes determines the nature clinical suspicion is a defensible approach.
of the clinical presentation, and the key fea-
ture on brain imaging is that the lesion is not
confined to vascular territories (Fig. 15.10). Prion Disease
The stroke-like episodes may be principally
located in the cerebral cortex, but they can This group of disorders is presented last in
also involve white matter, independently this category only because it is presently
320 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
incurable, but it is of great clinical and neu- neurodegenerative diseases and are sufficient
robiological importance and is always to be to create distinct protein-based infectious ele-
considered in the differential diagnosis of ments (Jackson et al., 2013). It is therefore
rapidly progressive dementia. Prion protein important for the clinician to consider prion
C is a normal alpha helical, transmembrane diseases as more than just an academic exer-
protein encoded by PRNP gene on chromo- cise about rare conditions, because the bio-
some 20. Diseases of human prions include logical principles governing prions may have
Creutzfeldt-Jakob disease (CJD), fatal familial direct relevance for some of the most perva-
insomnia, Gerstmann-Straussler-Scheinker sive and presently intractable neurodegen-
syndrome (GSS), and kuru. A brain disease erative disorders in clinical practice.
in sheep, scrapie, was described in 1732 and
was subsequently recognized as a transmis-
sible spongiform encephalopathy (Alper, Creutzfeldt-Jakob Disease
Cramp, Haig, & Clarke, 1967; Prusiner, 1982).
Kuru was the first transmissible spongiform A common polymorphism at codon 129 of the
encephalopathy (TSE) recognized in humans, prion protein (PrP) gene encodes methionine
described in the Fore tribes of Papau, New (Met) or valine (Val) and influences suscepti-
Guinea who engaged in ritual endocanni- bility in familial cases of Creutzfeldt-Jakob dis-
balism (Brown, 1954; Gajdusek, Gibbs, & ease (CJD), and the specific genotype at codon
Alpers, 1966; Zigas & Gajdusek, 1957). Kuru 129 influences the phenotype of sporadic CJD
affected the women and children of the tribe (Palmer, Dryden, Hughes, & Collinge, 1991).
who ingested brain tissue. Tremor (shivering Five phenotypically distinct subtypes of the
= kuru) and cerebellar ataxia, with demen- PrP have been identified in the more common
tia and myoclonus commenced within 924 sporadically presenting cases of CJD, based
months (Collinge et al., 2008). The hypothesis on the Met/Val polymorphic genotype of
that TSE was caused by an infectious agent codon 129 of the PrP gene (the great major-
consisting solely of proteins without nucleic ity of which are homozygous for either Met or
acid was developed when Alper, Cramp, Val) and the presence of either one of the two
Haig, and Clarke (1967) showed that scrapie protease K-resistant PrPSc types identified as
was very resistant to radiation, and Griffith 1 and 2 (Cali et al., 2009).
(1967) proposed mechanisms whereby this Creutzfeldt-Jakob disease has an incidence
may happen. The emerging biology of these of about 1 case per million. In medical cen-
noninfectious particles later named prions ters that serve large populations, it is not
(Prusiner, 1982) initiated the study of pro- unreasonable to expect to see a patient with
tein misfolding or conformational change as this disorder a few times annually. Sporadic
the cause of the spongiform encephalopathy CJD accounts for 85%95% of cases, famil-
characteristic of CJD, and which has become ial transmission occurs in 5%15%, and iat-
recognized as the basis for a wide range of rogenic transmission in <5% of cases (from
neurodegenerative diseases (e.g., Takalo, human-derived pituitary hormone therapy,
Salminen, Soininen, Hiltunen, & Haapasalo, dural grafts and dural material for emboli-
2013). The brain pathology of kuru was sub- zation, cornea and liver transplants, neuro-
sequently shown to include plaques reactive surgical instruments, and depth electrodes).
to the prion protein in sheep with scrapie The mean age of onset is in the early 60s. The
(PrPSc). The PrPSc is a beta-helical, intracel- mean duration of the illness is 45 months
lular protein that is protease resistant and and rarely more than 2 years. The disease
polymerizes into fibrils or rods. In humans, presents with the triad of ataxia, dementia,
mutations in different regions of the prion and myoclonus, in varying combinations
protein are associated with infectious neu- and in varying degrees. The dementia may
rodegenerative diseases that have very include problems with concentration, mem-
different clinical manifestations and neuro- ory, judgment, personality, and depression
pathological lesions, a phenomenon that is or disinhibition. The ataxia is not necessarily
now being explored in the knock-in mouse typical of cerebellar gait impairment, as the
model, which shows that single codon dif- gait may fail for reasons related to noncer-
ferences in a single gene in an otherwise nor- ebellar systems engaged in the complex act
mal genome can cause remarkably different of walking. Myoclonus occurs commonly,
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 321
Figure15.11 Axial diffusion-weighted magnetic resonance imaging (MRI) scans in two patients
with Creutzfeldt-Jakob disease. Signal abnormality is seen maximally in the thalamus and caudate
nucleus with mild involvement of the putamen and insular cortices in one case (left). Asymmetric
L>R cortical ribbon signal hyperintensity is evident in the second case (right).
provoked by acoustic, tactile, or visual startle (Fig.15.11). Treatment trials have been disap-
in 90% of cases. Approaching the patient with pointing, and successful therapies are yet to
an ophthalmoscope may be sufficient to pro- be developed. Management of seizures with
voke a truncal myoclonic jerk. Early visual antiepileptic agents and of myoclonus with
loss reflects occipital location of the pathol- benzodiazepines and levetiracetam can be
ogy in the Heidenhain variety (Cooper, effective as symptom-based interventions.
Murray, Heath, Will, & Knight, 2005), and Variant CJD is the human counterpart to
cerebellar ataxia and oculomotor abnormali- bovine spongiform encephalopathy (BSE)
ties in the Brownwell-Oppenheimer variant acquired by ingesting contaminated beef
(1965) reflecting the cerebellar predominant or beef products with BSE. It is exceed-
location of the disease. Extrapyramidal (bra- ingly rare. Described in 1996 (World Health
dykinesia, rigidity) and corticospinal find- Organization, 1996), it affects younger
ings such as spasticity and hyperreflexia individuals (mean age 29), has a relatively
(40%80%) reflect the basal ganglia and slower progression (mean 14months), and is
motor cortical involvement, and thalamic marked by the psychiatric presentation with
pathology adds to the complexity of the depression, anxiety, and psychosis, followed
cognitive, affective, and sensorimotor phe- 46 months later by ataxia, dysarthria, and
nomena. The diagnosis is supported by dementia. Sensory abnormalities are notable,
finding periodic triphasic waves on EEG in myoclonus is occasionally observed, diffuse
67%95% of cases, with a sensitivity of 67% slowing is detected on EEG (not triphasic
and specificity of 86%. CSF analysis includes waves), and unlike CJD, the MRI is not defin-
elevated protein and a modest leukocytosis itive. The PrPSc subtype 4 may be identified
with the presence of 14-3-3 protein, which on biopsy of lymph tissue such as the tonsil,
has a sensitivity of 53% to 85% and speci- but this raises considerable issues of steril-
ficity of 95%. The pathology is spongiform ity and transmissibility for personnel and
degeneration and astrogliosis diffusely dis- equipment. The brain pathology includes
tributed throughout the cortex, basal ganglia, diffuse spongiform changes and kuru-like
thalamus, and cerebellum. The diagnostic plaquesdense amyloid deposition sur-
procedure of choice is MRI that shows hyper- rounded by a halo of vacuolation (Ironside,
intense signal on diffusion-weighted imaging 1998; Mastrianni, 2003).
(DWI) and FLAIR imaging in the locations Fatal familial insomnia is an autosomal
most affected, including the cerebral cor- dominant disorder caused by a D178N muta-
tical ribbon, thalamus, and basal ganglia tion of the prion protein gene on chromosome
322 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
20 in conjunction with methionine at codon posterior brain lesions. PML is the result of
129 mutation of the prion protein gene (Tian infection of CNS myelin-producing oligoden-
et al., 2013). The disease rarely presents as a droglia by the JC polyomavirus. It occurs in
nonfamilial case. It has a mean age of onset the immunocompromised host, most com-
of 35 to 61 years and a mean duration of 13 monly in the setting of HIV disease with CD4
months. Pathological findings include neuro- lymphocyte count <200 cells/mm3, nonsolid
nal dropout and gliosis primarily within the malignancies such as Hodgkins disease and
thalamus and inferior olivary nucleus, with other lymphomas, chronic corticosteroid or
relative lack of spongiform degeneration in immunosuppressive therapy following organ
the cerebral cortex (DeArmond & Prusiner, transplantation, and more recently, in the set-
1997). The illness is characterized by rap- ting of treatment with natalizumab for auto-
idly progressive insomnia, abnormal sleep immune disorders such as multiple sclerosis,
architecture on EEG, prominent autonomic rheumatoid arthritis, and systemic lupus ery-
alterations (hypertension, episodic hyper- thematosis. Brain MRI is strongly suggestive,
ventilation, excessive lacrimation, sexual revealing multifocal, nonconfluent, bilateral,
and urinary tract dysfunction, change in asymmetric white matter hyperintensities
basal body temperature), and dementia with in juxta-cortical white matter on FLAIR and
confusion, impaired concentration, poor T2-weighted imaging (Fig. 15.12). These only
memory, and hallucinations. Brainstem and occasionally enhance with gadolinium; about
cerebellar involvement manifest as verti- 15% in HIV-associated PML, up to 40% in
cal gaze palsy, nystagmus, dysarthria, and natalizumab-associated disease (Berger et al.,
ataxia. Myoclonus, spasticity, and extrapy- 2013). Confluent areas of white matter abnor-
ramidal features are also described (Brown mality may extend across the corpus callosum
& Mastrianni, 2010; Lugaresi et al., 1986; Xie and down into deep regions as well, includ-
etal., 2013). ing the white matter tracts that traverse sub-
Gerstmann-Straussler-Scheinker is an cortical nuclei such as thalamus. It can extend
extremely rare, autosomal dominant disor- into the cerebral peduncle, and when PML
der caused by mutations in the prion protein involves cerebellum it can envelope the deep
gene. Insidious onset commences around nuclei with a curved appearance (shrimp
age 30 to 50, and the course averages about sign, N. Venna, personal communication;
3 to 7years. Some patients have a predomi- Sahraian, Radue, Eshaghi, Besliu, & Minagar,
nantly cerebellar motor presentation; oth- 2012; Schmahmann, 1998; Schutte, Ranchhod,
ers have a cognitive decline with features Kakaza, & Pillay, 2013). The leukoencepha-
suggestive of a frontotemporal dementia. lopathy of PML differs from that of HIV leu-
Pyramidal involvement is heralded by spas- koencephalopathy, which tends to be diffuse,
ticity; extrapyramidal involvement manifests bilateral, symmetric, and predominantly in
with bradykinesia, increased muscle tone the periventricular white matter. Diagnosis
with or without cogwheeling, and masked of PML can be established from the clinical
facies. The pathology includes kuru-like setting, the brain imaging findings, and the
amyloid plaques, which bind to PrP, and presence of JC virus in the CSF detected by
AD-like tangles (Brown & Mastrianni, 2010; polymerase chain reaction. Brain biopsy is
DeArmond& Prusiner, 1997). seldom required, and when performed, it
shows the characteristic triad of multifocal
demyelination, hyperchromatic, enlarged oli-
Uncommon Disorders With Multidomain godendroglial nuclei with nuclear inclusions
Subacute Cognitive Decline (JC virus), and enlarged bizarre astrocytes
with lobulated hyperchromatic nuclei (Berger
Progressive Multifocal Leukoencephalopathy et al., 2013). The illness has a mortality rate of
30% to 50% in the first few months without
Depending on the location of the pathology treatment, but this has improved in patients
in progressive multifocal leukoencephalopa- with HIV since the introduction of combina-
thy (PML), this disorder may present with tion antiretroviral therapy (CART), and in the
subacute cognitive decline in up to one half case of natalizumab, removal of the inciting
of affected patients rather than sensorimotor agent hastened by the use of plasmapheresis
impairment, or visual loss that occurs with and corticosteroids to manage the immune
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 323
Figure15.12 Brain magnetic resonance imaging (MRI) scans in two young men with progressive
multifocal leukoencephalopathy in the setting of HIV. Hyperintense signal is seen in the right
occipital cortex and white matter in the axial T2-weighted image in one case who presented with
a left homonymous hemianopsia (A). The other patient with prominent abulia has multiple areas
of signal hyperintensity on fluid attenuated inversion recovery sequence (FLAIR)-weighted axial
images; bilaterally in the frontal lobes straddling the corpus callosum, in the right posterior parietal
cortex (B), and in the deep white matter of the left hemisphere including the thalamus (C).
a predilection for the midbrain and hypothal- regions, and the basal ganglia. The diagnosis
amus (Fig. 15.15), and has four main clini- is confirmed by polymerase chain reaction on
cal presentations (Gerard et al., 2002; Smith, blood and CSF, which may also reveal foamy
French, Gottsman, Smith, & Wakes-Miller, PAS-positive mononuclear cells. Diagnosis
1965). (1) Oculomasticatory myorhythmia may require duodenal biopsy, and in extraor-
consists of pendular convergent oscillations dinary cases when clinical suspicion is high,
of both eyes with concurrent contractions of brain biopsy may be necessary looking for
the jaw and tongue, occurring at a rate of 1 granulomatous inflammation with granu-
to 2 Hz, associated also with semirhythmic lar ependymitis, microglial nodules, neu-
blinking, and movements of the proximal ronal loss, and rod-shaped bacilli within
upper and lower extremities (oculo-facial- macrophages and glia demonstrable with sil-
skeletal-myorhythmia). (2) Supranuclear ver stains. Cephalosporins are the treatment
vertical ophthalmoplegia may be accompa- of choice.
nied by horizontal gaze palsy, with absent
pupil response with attempted convergence
but preserved with light (the opposite of the Dementia From Diseases Predominantly
Parinaud syndrome). (3) Cognitive changes Affecting Cerebral White Matter
evolving over weeks or months include an
amnestic syndrome with confabulation, The concept of white mater dementia intro-
delusional thinking, confusion, apathy, and duced in 1998 (Filley, 1998, 2012; Filley,
disorientation, and personality changes Franklin, Heaton, & Rosenberg, 1988) rests
include irritability, depression, paranoia, and on the fact that the cerebral white matter
hallucinations. (4) Hypothalamic involve- conveys the association fiber tracts linking
ment produces sleep disruption, polydipsia, cerebral cortical association areas with each
hyperphagia, hypothermia, syndrome of other, as well as the striatal and projection
inappropriate antidiuretic hormone secre- fibers that link the association cortices with
tion, and amenorrhea. MRI reveals T-2 and their interconnected subcortical nodes in the
FLAIR hyperintense lesions in hypothala- basal ganglia, thalamus, and cerebrocerebel-
mus, rostral brainstem, medial temporal lar circuits (Schmahmann & Pandya, 2006,
326 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
cognitive and psychiatric features. Hearing testing. Treatment is with aggressive and
loss is reported in 86% of cases, but at dis- prolonged immunosuppressants to prevent
ease onset the expected triad of impaired the multiphasic form of the illness.
vision, hearing, and mentation occurs in
only 13% of cases. The encephalopathy
occurs in 76% of cases over the course of Acquired Leukodystrophies
the illness and is characterized by cogni-
tive impairment, mainly deficits in memory, In delayed posthypoxic leukoencephalopa-
concentration, and executive functions; thy, massive cerebral demyelination with
confusion with disorientation; and changes delayed onset occurs in the setting of a
in behavior and personality with apathy, unique combination of factors precipitating a
psychosis, and decreased arousal. Personal hypoxemic ischemic event. The sequence of
experience of one case was a severe amnes- events most commonly described is an onset
tic dementia in a man in his 30s, associated over hours of a sublethal dose of the three
with hearing loss, cerebellar motor findings, main forms of cerebral hypoxemia described
and branch retinal artery occlusions on the by Plum and Posner (1966). Namely,
diagnostic test of fluorescein angiography. anoxic anoxia (low environmental tension,
The brain MRI is very suggestive, if not depressed respirations, impaired pulmonary
pathognomonic, showing what have been function), anemic anoxia (the oxygen-carry-
called snowball lesions in the corpus cal- ing capacity of blood is depleted as occurs
losum (Fig. 15.17), with multiple lesions with carbon monoxide), and ischemic anoxia
string of pearlsin the internal capsule (poor cerebral blood flow as in cardiac fail-
(bright on diffusion-weighted imaging). The ure). Common scenarios include overdose of
diagnosis can be established by a combina- medication that both depress respiration and
tion of clinical features, MRI findings, and blood pressure such as hydrocodone, expo-
fluorescein angiography and audiology sure to carbon monoxide (Lee & Marsden,
328 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
1994), slow and prolonged hypoxemia with to recognize this rare but essentially pathog-
hypotension as occurs in strangulation with nomonic narrative of the acute initiating
attempted suicide, partial airway obstruction event followed by a period of near normalcy
or prolonged respiratory arrest, and hem- and then the subacute slide (days to a week
orrhagic shock. The characteristic feature or two) into the rigid akinetic mute state
is the near-death experience of the patient accompanied by new, diffuse leukoencepha-
(Chen-Plotkin, Pau, & Schmahmann, 2008) lopathy. This entity needs to be differentiated
with unresponsiveness or coma for a period from acute disseminated encephalomyelitis
of minutes to hours, followed by complete (ADEM) and other toxic leukoencephalopa-
or near-complete recovery to full motor and thies that have a different history and imag-
cognitive health for a period of 23 weeks. ing pattern, so as to avoid invasive diagnostic
The patient then slides into a neuropsychiat- procedures such as brain biopsy. Hyperbaric
ric decline of altered behavior, forgetfulness, oxygen treatment for acute carbon monox-
inattention, confusion, gait impairment, bra- ide poisoning appears warranted (Weaver,
dykinesia, and incontinence, progressing to Valentine, & Hopkins, 2007), but there are no
hypokinesia and immobility to the point of studies of this approach in the patient with
akinetic mutism with striking generalized hypoxic ischemic injury entering phase 2 of
rigidity and cortical blindness (Chen-Plotkin, the illness (the decline after recovery). The
Pau, & Schmahmann, 2008; Shprecher & predilection for this complication of hypoxia
Mehta, 2010; Schmahmann, other unpub- is not known, and the suggestion that partial
lished cases). The brain MRI typically shows arylsulfatase deficiency is responsible in sus-
symmetric white matter T2 and FLAIR hyper- ceptible individuals (Weinberger, Schmidley,
intensities, with diffusion-weighted imaging Schafer, & Raghavan, 1994) has not been
showing restricted diffusion of the white borne out by subsequent studies.
matter confirmed on apparent diffusion coef- Professional underwater divers report prob-
ficient mapping. Over a matter of weeks, and lems with long- and short-term memory and
more notable some months later, is a dra- impaired concentration (Todnem, Nyland,
matic loss of volume of cerebral white mat- Kambestad, & Aarli, 1990). Divers who have
ter with ex vacuo hydrocephalus (Fig. 15.18). experienced decompression sickness (Caisson
Recovery is variable. Some patients may disease, nitrogen gas embolism after surfac-
return to a more functional baseline, although ing too rapidly from depths greater than 10
psychiatric features and executive failure per- meters) have impairments in thinking, visual-
sist (Shprecher & Mehta, 2010; Schmahmann, spatial function, and memory, along with sub-
unpublished data), while in other cases the cortical white matter abnormalities on brain
rigid akinetic state persists with only mini- MRI (Levin et al., 1989). Seven of 19 divers
mal improvement over time. It is important studied with a battery of neuropsychological
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 329
tests (Peters, Levin, & Kelly, 1977) performed in attention, concentration, and verbal learn-
significantly below a control group on verbal ing and recall as well as anxiety and somatic
and nonverbal tests, and they had impaired preoccupations (Duff & McCaffrey, 2001).
memory with marked disruption of storage Psychiatric diagnoses including depression
of new information, reduced attention span with or without posttraumatic stress disor-
(tested with forward digit span), slowed pro- der were reported in 78% of a sample of 86
cessing speed (Trails A test), and deficient patients who suffered electrical injury, and
mental flexibility (Trails B test; Peters, Levin, these patients also showed impairments on
& Kelly, 1977). These cognitive features may tests of attention, verbal memory, and execu-
occur together with or independent of the tive function (Ramati et al., 2009).
acute sequelae of decompression sickness, Toxic leukoencephalopathies result from
ranging from spinal cord lesions with paraly- exposure to agents that have a predilection
sis, to hemianopsia, confusion, and coma, and for the cerebral white matter. Toluene (meth-
more chronic neurological findings such as ylbenzene) is a household and industrial
cerebellar ataxia and facial paralysis (Peters, organic solvent used in glue and spray paint.
Levin, & Kelly, 1977). Further, elderly recre- It produces euphoria when inhaled and is a
ational compressed-air divers who have not major drug of abuse. It produces an essen-
experienced decompression sickness (the tially pure leukoencephalopathy with selec-
bends) have white matter hyperintensities tive myelin loss that spares the cerebral cortex,
on brain MRI greater in number and size than neurons, and axons in all but the most severe
controls, which correlate with the number cases (Filley, Heaton, & Rosenberg, 1990;
of hours of diving and are associated with Rosenberg et al., 1988). The clinical manifesta-
decreased mental flexibility and poorer per- tion is a syndrome of dementia, ataxia, dysar-
formance on tasks of visual tracking (Tetzlaff thria, and spasticity. Brain MRI reveals diffuse
et al., 1999). cerebral and cerebellar white matter hyper-
Electrical injury produces long-term cog- intensity. The degree of cerebral involve-
nitive and neuropsychiatric sequelae fol- ment strongly correlates with the severity of
lowing lightning strikes, and industrial or dementia. Autopsy reveals selective myelin
residential accidents. These include deficits loss that spares the cerebral cortex.
330 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
3 4
3
2
Cho Lac 2
Cr NAA
1 1
Figure 15.20 Axial fluid attenuated inversion recovery sequence (FLAIR)-weighted magnetic
resonance imaging (MRI) in the axial plane (A through D, ventral to dorsal) in a young man
following heroin inhalation, or chasing the dragon. Corresponding 1H magnetic resonance
spectrography imaging in two of the images shows characteristic lactate peak and decreased
N-acetyl aspartic acid (NAA). (From Kriegstein et al. 1999 reproduced with permission)
Hall, 2008). Clinical and MRI findings can that are autosomal recessive, and X-linked
progress after cessation of drug use. The adrenoleukodystrophy. Collectively, the
brain shows spongiform degeneration of incidence of these conditions rivals that of
white matter with relative sparing of U-fibers MS. The incidence of adrenoleukodystro-
(Kriegstein et al., 1999). The MRS evidence phy alone is 1 in 17,000, or 20,000 patients
of lactate peak, mitochondrial swelling and annually in the United States (Bezman et al.,
distended endoplasmic reticulum in oligo- 2001). (For further discussion of these disor-
dendrocytes, and apparent benefit of antioxi- ders, see Costello, Eichler, & Eichler, 2009;
dants and mitochondrial cofactors suggest Kohlschutter & Eichler, 2011; Schmahmann,
mitochondrial dysfunction (impaired energy Smith, Eichler, & Filley, 2008.) Related genetic
metabolism at the cellular level) as a basis white matter predominant disorders include
for this disorder (Bartlett & Mikulis, 2005; MELAS and FXTAS, and they are described
Kriegstein et al., 1999; Wolters et al., 1982). elsewhere in this chapter.
Notably, cocaine use can produce a similar Adult-onset leukodystrophy with neuroax-
syndrome, sometimes with good recovery. onal spheroids (AOLNAS) is a familial or spo-
The precise pathophysiology is unknown radic disorder characterized radiographically
(Bartlett & Mikulis, 2005; Bianco, Iacovelli, by symmetric, bilateral, T2 hyperintense and
Tinelli, Lepre, & Pauri, 2011). T1 hypointense MRI signal involving frontal
lobe white matter. Neuropathological exami-
nation demonstrates a severe leukodystrophy
Genetic Diseases with myelin and axonal loss, gliosis, macro-
phages, and axonal spheroids, with early and
The leukodystrophies are a heterogeneous severe frontal white matter involvement, and
group of genetic diseases involving dysmy- complete sparing of cerebral cortical neu-
elination, and some are a result of substrate rons (Freeman et al., 2009; Marotti, Tobias,
accumulation due to enzymatic defects. This Fratkin, Powers, & Rhodes, 2004). Freeman
group includes adult-onset leukodystrophy et al. (2009) detected abnormalities in mito-
with neuroaxonal spheroids, metachromatic chondrial enzymes and complex 1 deficiency
leukodystrophy, globoid cell leukodystro- in one case suggesting mitochondrial dys-
phy, and vanishing white matter disease function. The genetic basis at least in a subset
332 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
of cases has been defined in a recent report by relentlessly progressive dementia with
(Kleinfeld et al., 2013) showing a disease- inattention, amnesia, impaired cognitive
causing mutation in the colony-stimulating flexibility, problem-solving skills, and visual
factor 1 receptor (CSF1R) gene. The disorder spatial disorganization. This progressed to
presents with executive system dysfunction stereotyped nonmeaningful but complex
and other neurobehavioral deficits, progress- behaviors, relentless wandering, persevera-
ing to dementia. The extent and degree of tion, apraxia, and posterior aphasia with
change outside the frontal lobe correlates fluent jargon, impaired comprehension, and
with disease duration. The white matter con- poor repetition. In this case there was relative
taining long association tracts interconnect- sparing of elementary motor features, normal
ing parietal, temporal, and occipital lobes reflexes, and plantar responses, but striking
with the frontal lobe are affected early and release phenomena were present, including
most severely. The rostral and caudal parts of palmar grasp, snout, root, and suck reflexes
the corpus callosum are also involved early (Schmahmann & Eichler in Schmahmann,
in the course, reflecting loss of white mat- Smith, Eichler, & Filley, 2008). These very
ter, particularly in the prefrontal and poste- severe cases of global impairment including
rior parietal association areas. In contrast, aphasias (Edwin et al., 1996) have marked
projection pathways are spared until late in brain atrophy on MRI along with the white
the illness, as exemplified in a patient whose matter damage. The characteristic finding is
cortical blindness corresponded to the late symmetric, posterior parietal and occipital
pathological changes in the sagittal stratum periventricular white matter lesions, with a
that contains the optic radiations (Freeman garland of gadolinium contrast enhancement
et al., 2009). This dichotomy of early demen- (Melhem, Barker, Raymond, & Moser, 1999;
tia, but late failure of gait, strength, dexter- Melhem, Loes, Georgiades, Raymond, &
ity, and sensation, provides an interesting Moser, 2000) reflecting inflammatory demy-
glimpse into the clinicopathological distinc- elination (Fig. 15.21A). MRI spectroscopy
tion between association and projection fiber in normal-appearing white matter on con-
tract involvement in AOLNAS, and the func- ventional MRI (Eichler, Barker, et al., 2002;
tional contributions of these different white Eichler, Itoh, et al., 2002) shows increased
matter tracts (Schmahmann, Smith, Eichler, & choline and decreased N-acetylaspartate.
Filley, 2008). Metachromatic leukodystrophy (MLD) is a
X-linked adrenoleukodystrophy (X-ALD) lysosomal storage disorder resulting from a
is characterized by impaired ability to deficiency of aryl sulfatase A leading to intra-
degrade very long chain fatty acids (VLCFA) cellular accumulation of sulfatides. Adult
that causes malfunction of the adrenal cortex onset is rare and includes psychosis, behav-
and nervous system myelin (Moser, Smith, ioral disturbances, and dementia (Austin
Watkins, Powers, & Moser, 2000). It pres- et al., 1968; Hyde, Ziegler, & Weinberger,
ents in childhood in approximately 35% of 1992). MRI reveals diffuse white matter
patients. Affected boys develop normally lesions (periventricular, centrum semiovale,
until 4 to 8 years of age, then suffer demen- corpus callosum, internal capsule, cerebel-
tia and progressive neurologic decline that lum; Fig. 15.21B). Punctuate striated (tigroid)
leads to a vegetative state and death. More enhancement corresponds to patchy areas
than 90% have adrenal insufficiency. It pres- of preserved myelin (Faerber, Melvin, &
ents as adrenomyeloneuropathy in young Smergel, 1999).
adulthood in 35% to 40% of patients, with Globoid cell leukodystrophy (GLD), or
progressive paraparesis and sphincter dis- Krabbes disease, is caused by deficiency of the
turbances leading to death in 20% of these enzyme galactosyl ceramidase (GALC) that is
patients in <2 years from rapidly progres- responsible for converting galactosylceramide
sive inflammatory demyelination (Eichler into galactose and ceramide, leading to accu-
et al., 2007; van Geel, Bezman, Loes, Moser, mulation of galactosylceramide that prompts
& Raymond, 2001). Cerebral X-ALD in adult- a macrophagocytic response, and psycho-
hood manifests with impaired psychomotor sine that leads to death of myelin-producing
speed, spatial cognition, memory, and execu- oligodendrocytes (see Kohlschutter &
tive functions. This can lead to a presentation Eichler, 2011). Rare adult-onset cases mani-
characterized in one man in his sixth decade fest slowly evolving hemiparesis, intellectual
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 333
Figure 15.21 Magnetic resonance imaging (MRI) appearance of (A) X-linked adrenoleukodystrophy
(X-ALD), T1-weighted image postgadolinium; (B) metachromatic leukodystrophy (MLD), fluid
attenuated inversion recovery sequence (FLAIR)-weighted image; (C) globoid cell leukodystrophy
(GLD), T2-weighted image; and (D) vanishing white matter disease (VWMD), T1-weighted image.
(From Schmahmann, Smith, Eichler, & Filley, 2008, reproduced with permission)
impairment, cerebellar ataxia, visual failure, at this point in our understanding, an inter-
and spastic paraplegia. Brain imaging reveals esting quirk of medical history. The abun-
symmetrical involvement of the basal ganglia, dance of evidence from neuroanatomical
thalami, and posterior aspect of the centrum studies, behavioral investigation in animals,
semiovale (Fig. 15.21C; Baram, Goldman, & clinical reports of patients suffering from a
Percy, 1986) leading to marked cerebral and wide variety of disorders, task-based func-
cerebellar atrophy. tional neuroimaging experiments, resting-
Vanishing white matter disease, also state functional connectivity mapping, and
known as CNS hypomyelination, is caused most recently neuromodulation of cerebel-
by a defect in any one of the five subunits lum producing improvements in neuropsy-
of eukaryotic initiation factor 2B (eIF2B) chiatric disorders makes it clear that the
(van der Knaap, Pronk, & Scheper, 2006), a cerebellum, like basal ganglia and thalamus,
highly conserved, ubiquitously expressed is a noncerebral structure with a wide range
protein that plays an essential role in the ini- of engagement in the neural control of senso-
tiation of protein synthesis. Manifestations rimotor function, intellect, and emotion (for
range from prenatal-onset white matter dis- review see Koziol et al., 2013; Schmahmann,
ease to juvenile or rarely, adult-onset ataxia, 2004, 2010). In considering the dementias,
dementia, seizures, and ovarian insufficiency there are two avenues of approach with
(Schiffmann & Elroy-Stein, 2006; Schiffmann respect to the cerebellum. The first is the
et al., 1994). The course is chronic and pro- nature of the cognitive and affective profile
gressive, with episodic declines following in patients with injuries confined to the cer-
stressors such as fever, head trauma, or peri- ebellum. The second is the range of cogni-
ods of fright. MRI is striking and shows van- tive and neuropsychiatric phenomena that
ishing white matter over time (Fig. 15.21D), occur either as a result of cerebellar injury or
with variable involvement of cerebellum and as a consequence of damage to noncerebel-
brainstem. Neuropathological abnormalities lar structure in disorders that have a major
indicate a unique and selective disruption of cerebellar signature motorically and/or ana-
oligodendrocytes and astrocytes with spar- tomico-pathologically (i.e., on brain imaging
ing of neurons. Autopsy confirms white mat- or at autopsy).
ter rarefaction and cystic degeneration. There
is no inflammatory response.
The Cerebellar Cognitive Affective Syndrome
memory; difficulties with spatial cognition, basis (e.g., Baillieux et al., 2010; Tavano et al.,
including visual-spatial organization and 2007; Tedesco et al., 2011), and patients with
memory; personality change with blunting cerebellar disorders ranging from near-total
of affect or disinhibited and inappropriate cerebellar agenesis (Fig. 15.23) to cerebellar
behavior; and language deficits, including hemorrhage (Fig. 15.24) continue to exem-
agrammatism and dysprosodia (Fig. 15.22; plify this constellation. The neuropsychiatric
Levisohn, Cronin-Golomb, & Schmahmann, presentations of the CCAS reflect dysregula-
2000; Schmahmann & Sherman, 1997, 1998). tion of affect that occurs when lesions involve
The cerebellar cognitive affective syndrome the limbic cerebellum (vermis and fastigial
(CCAS) likely reflects disruption of the cer- nucleus). In adults and children with congen-
ebellar modulation of neural circuits that link ital and acquired cerebellar lesions, observed
cerebellum in a bidirectional manner with behaviors include distractibility and hyper-
the cerebral association and limbic/paralim- activity, impulsiveness, disinhibition, anxi-
bic areas that govern cognition and emotion ety, ritualistic and stereotypical behaviors,
(Schmahmann, 1991, 2010; Schmahmann & illogical thought and lack of empathy, and
Sherman, 1998). Subsequent studies have aggression and irritability (Schmahmann,
provided confirmatory evidence for the exis- Weilburg, & Sherman, 2007). Ruminative
tence of this syndrome and its anatomical and obsessive behaviors, dysphoria and
Figure15.22 T1-weighted coronal magnetic resonance imaging (MRI) of the brain of a young
woman performed following resection of a midline cerebellar ganglioglioma. Her responses
when asked to draw a clock, bisect a line, and write a sentence reflect the executive dysfunction,
visual spatial disorganization, and linguistic deficit (agrammatism) that characterize the
cerebellar cognitive affective syndrome. (From Schmahmann and Sherman, 1998, reproduced with
permission)
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 335
depression, tactile defensiveness and sensory 1991, 1996), the symptom complexes in each
overload, apathy, childlike behavior, and putative domain reflect either exaggeration
inability to appreciate social boundaries and (overshoot or hypermetria) or diminution
assign ulterior motives can also be evident. (undershoot or hypometria) of responses to
These disparate neurobehavioral profiles the internal or external environment, with
cluster in five major domains, characterized some patients fluctuating between these two
broadly as disorders of attentional control, states. These observations and notions have
emotional control, and social skill set as well implications for understanding and manag-
as autism spectrum disorders and psychosis ing the patient with disorders of cognition
spectrum disorders. Within the context of the and emotional modulation in the setting of
dysmetria of thought theory (Schmahmann, cerebellar injury.
Figure 15.25 T1-weighted magnetic resonance imaging (MRI) scans (left axial, right midsagittal) in
a teenager with spinocerebellar ataxia type 2. Clinical features were notable for cognitive failure as
the earliest manifestation, followed by progressive dysarthria, ataxia, and extremity dysmetria as
well as oculomotor paresis.
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 337
predominantly within the frontal lobe along cortical atrophy are seen on brain imaging,
with generalized but frontal predominant with patchy areas of hyperintensity in cerebral
cerebral atrophy (Jacquemont et al., 2003). white matter that may predate the ataxia and
Neuropathology reveals parenchymal pallor, that evolve over time, together with T2 bright
spongiosis, and enlarged inclusion-bearing and T1 dark lesions of thalamus in the three
astrocytes in cerebral white matter, and wide- cases personally followed by the author (Fig.
spread intranuclear and astroglial inclusions 15.27). Neuropathological studies available to
in brain, cranial nerve nuclei, and autonomic date show atrophy and severe neuronal loss
neurons of the spinal cord, with spongiosis and gliosis in the inferior olives, cerebellum,
in the MCPs (Greco et al., 2006). Cognitive and areas CA3 and CA4 of the hippocampus
decline likely reflects both the deafferentation (Holmes, 1908; Margolin et al., 2013).
of associative and paralimbic input to the cer-
ebellum by the MCP lesions (Schmahmann,
1991, 2004; Schmahmann & Pandya, 1997) as Langerhans Cell Histiocytosis
well as the disruption of cerebral long associ-
ation fiber tracts from the lesions of the cere- Clonal proliferation of bone marrowderived
bral white matter, particularly those within Langerhans cells or circulating plasmacytoid
the prefrontal cortex. monocytes causes a granulomatous disorder,
Langerhans cell histiocytosis (LCH). It occurs
mostly in children but also in adulthood. CNS
Gordon Holmes Syndrome involvement may be a primary or a secondary
phenomenon resembling paraneoplastic or
This recessively inherited disorder is charac- immune-mediated processes. Primary brain
terized by cerebellar ataxia, hypogonadotropic involvement manifests as granulomas of the
hypogonadism, and dementia (Holmes, 1908; meninges, hypothalamic pituitary region
Seminara, Acierno, Abdulwahid, Crowley, with diabetes insipidus and anterior pituitary
& Margolin, 2002). It was recently shown to hormone deficiency, and multifocal intracere-
be caused by mutations in genes engaged bral histiocytic granulomas with symptoms
in ubiquitination (RNF216 and OTUD4; dependent on location (Prayer, Grois, Prosch,
Margolin et al., 2013) and in protein misfold- Gadner, & Barkovich, 2004). Secondary LCH
ing (STUB that encodes the protein CHIP; Shi is a neurodegenerative disorder (ND-LCH)
et al., 2014). The hypogonadotropic hypogo- with bilateral symmetric lesions in the cer-
nadism presents in early adulthood, leading ebellum and basal ganglia, characterized by
to progressive dysarthria and ataxia, with T-cell-dominated inflammation leading to
personality change, memory loss, and even- neuronal and axonal destruction with second-
tually mutism at end stage. Cerebellar and ary demyelination (Grois, Prayer, Prosch, &
Figure 15.27 Midsagittal T1-weighted magnetic resonance imaging (MRI) scan (left) showing
cerebellar volume loss in a young woman with Gordon Holmes syndrome as defined genetically
in Margolin et al. (2013). The axial fluid attenuated inversion recovery sequence (FLAIR)-weighted
MRI scans show white matter hyperintensities scattered bilaterally throughout the forceps minor
and major, the corona radiata, and notably in the thalamus as well.
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 339
Figure 15.28 Axial T2-weighted magnetic resonance imaging (MRI) scans through the cerebellum in
a young man with the neurodegenerative form of Langerhans cell histiocytosis. Hyperintense signal
abnormality in the cerebellar white matter (left) on the MRI performed at age 8 years gives way to
cerebellar atrophy when scanned at age 17 years (right). (From Schmahmann, Weilburg, & Sherman,
2007, reproduced with permission)
Lassmann, 2005; Prosch, Grois, Wnorowski, as dural arteriovenous fistulae, other vascu-
Steiner, & Prayer, 2007; van der Knaap, lar malformations, or prior trauma that cause
Pronk, & Scheper, 2008; Wnorowski et al., deposition of hemosidderin over the superfi-
2008). Brain MRI shows symmetrical, nonen- cial layers of the CNS (Fig. 15.29; Kumar etal.,
hancing, T2-bright signal in the cerebellum. 2006). The cerebellum and eighth cranial
Similar abnormality can be seen in posterior nerves are the most severely affected, with
periventricular cerebral white matter. Over involvement to a lesser extent of the orbital
time the imaging findings evolve to marked and medial prefrontal cortices, sometimes
cerebellar and/or cerebral atrophy (Fig. 15.28; with layering of hemorrhage also over the
Prosch, Grois, Wnorowski, Steiner, & Prayer, cerebral convexities. The typical presentation
2007; van der Knaap, Pronk, & Scheper, 2008; is with cerebellar ataxia, hearing loss, and
Wnorowski et al., 2008). Cerebellar motor anosmia, although chronic recurrent spinal
signs may be accompanied by cognitive location of the hemorrhage can have clinical
impairment and neuropsychiatric features features in common with amyotrophic lat-
such as obsessive-compulsive disorder (Grois eral sclerosis (Payer, Sottas, & Bonvin, 2010).
et al., 2010; Shuper et al., 2000). Children with Cognitive and affective changes are routinely
ND-LCH have impaired attention, intellectual reported. These generally conform to the
function, verbal and visual memory, linguistic CCAS and include impairments of visual
skills, and mathematical skills, and those with recall and executive functions, together with
hypothalamic damage may have abnormal deficits in theory of mindthe ability to
eating patternsbinge eating, anorexia, or represent other peoples mental states (van
bulimia, with rage attacks, claustrophobia, Harskamp, Rudge, & Cipolotti, 2005).
agoraphobia, depression, and aggression
(Nanduri et al., 2003). These cognitive and
neuropsychiatric features are also described Niemann-Pick Disease Type C
in adults in whom the cerebellar motor find-
ings may be relatively modest but the brain This rare autosomal recessive neurovisceral
imaging findings of cerebellar involve- lipid storage disease resulting from muta-
ment are marked (Poretti, Boltshauser, & tions in NPC1 (95% of cases) or NPC2 pres-
Schmahmann, 2012; Schmahmann, Weilburg, ents in adulthood in about 5% of cases, at a
& Sherman, 2007). mean age of 25 +/ 9.7 years (see Maubert,
Hanon, & Metton, 2013; Mengel et al., 2013;
Sevin et al., 2007). Neurological manifesta-
Superficial Siderosis tions in adults are cerebellar ataxia (76%),
vertical supranuclear ophthalmoplegia
This unusual condition results from repeated (75%), dysarthria, (63%), cognitive impair-
subarachnoid hemorrhage from such entities ment with deficits in memory and executive
340 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
Figure 15.29 Magnetic resonance imaging (MRI) in a middle-aged man with superficial siderosis.
Left, midsagittal T1-weighted MRI shows cerebellar volume loss and hypointense signal notably at
the superior vermis. Middle and right images, axial gradient echo (susceptibility-weighted scans)
show marked hypointense signal reflecting hemosidderin overlying the cerebellum at both the
superior and inferior aspects.
very poor performance levels much earlier. patients by ensuring a good nights sleep.
This increased the risk of premature demen- Note also that one needs to enquire specifi-
tia later on, even in the absence of an accel- cally about the features of rapid eye move-
erated decline. These are relevant factors in ment (REM) sleep behavior disorder with
assessing the cognitive state of a person with thrashing movements of the arms and legs,
epilepsy who is thought to be undergoing and loud vocalization sometimes with terror,
cognitive decline. Knowledge of the patients as this is a useful pointer to the early stages of
premorbid baseline is particularly relevant in neurodegenerative synucleinopathies mani-
this circumstance. festing as the extrapyramidal disorders Lewy
body disease, Parkinsons disease, and mul-
tiple system atrophy (Ferini-Strambi, 2011).
Sleep Deprivation and Cognition
no aphasic disorder; calculation of vary- being bilateral and more easily evinced by
ing degrees of complexity was possible attracting attention to something other than
though slow with the commission of many the hand. The tendon reflexes tended to be
errors; no apraxic or agnosic abnormalities lively, especially in the legs, and were some-
were noted; spatial orientation was intact times accompanied by extensor plantar
though temporal orientation tended to be reflexes on one or both sides, which were
inexact. Other items of behaviour change more frequent in states of mutism or stupor.
consisted of inattentiveness and sporadic We came to recognize the clinical state
incontinence of sphincters, especially uri- as being different from that of other dis-
nary, which appeared to embarrass others eases which impair intellectual function
more than the patient. As the hydrocephalic in late life. We watched for it particularly
symptomatology became more severe the amongst the patients suspected of having a
patient would for long periods remain dementing degenerative disease and found
mute and relatively motionless, episodes that those in whom poor memory, psycho-
that resembled catatonia or early parkin- motor impairment, uncertainty of gait and
sonism. Questions tended to evoke action sphincteric incontinence were early symp-
rather than reply, and verbal responses if toms, and where the evolution of the illness
made at all were usually monosyllabic. occurred over a few weeks to months and
One patient sat for hours with a newspa- fluctuated, should be suspected as having
per in hand or idly staring at a television hydrocephalus rather than presenile or
set, rarely looking understandingly at senile brain atrophy.
either. Visual fixation and following move- Reversibility of the disorder of atten-
ments of eyes would occur and at times tion, memory, thinking and activity was
all types of visual stimuli would seem to more rapid than correction of the gait
be equally attractive, thus revealing what abnormality. In several instances a few
might be termed a distractability of atten- weeks elapsed before locomotion became
tion. Sphincteric incontinence was more dependable, long after intellect had either
frequent at this stage. The most advanced been restored to normal or had reached a
stages of the condition were attended by level of improvement from which it devi-
stupor with grasp and sucking reflexes and ated little (page 1137).
Babinski signs, but no paralysis of limbs.
This could progress to coma. Adams noted that the EEG was abnormal
Disturbance of gait and other neurological in all cases (generalized slowing is common;
abnormalities: Difficulty in walking was frontal intermittent rhythmic delta may occur
noted in each of our cases but it was dif- late). As pointed out by the originators of the
ficult to characterize. The mildest degree concept in 1965, the cognitive, gait, and blad-
consisted of a slight uncertainty, a tendency der manifestations are likely the result of
to make a misstep in one or other direction compression and stretching of brain tissue
which could lead to a fall. Tandem walking in frontocentral regions with involvement
was difficult. Patients preferred to steady of the long association fiber tracts and the
themselves and gain security by taking corpus callosum, explaining why NPH pres-
the arm of a companion or touching an ents early on with a frontal lobe neurobehav-
article of furniture. More severe degrees of ioral syndrome. As the projection fibers and
gait disturbance amounted to an unsteadi- thalamocortical fibers become progressively
ness reminiscent of what has been termed involved, the pyramidal findings and altera-
an apraxia of gait or Bruns frontal lobe tions in level of arousal are affected.
ataxia. As the hydrocephalus worsened
standing and walking became impossible.
In contrast, limb movements were quite Sagging Brain Syndrome
facile showing only slight hesitancy or
slowness. Intracranial hypotension results from occult
A tendency to suck and grasp was vari- or known sources of leakage of CSF from the
ably present in the more advanced stages of subarachnoid space. Spontaneous intracra-
disease; the latter took more the form of an nial hypotension has long been recognized
instinctual grasping than true grasp reflex, as a cause of orthostatic headache (present
344 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
in the erect position, abating with recum- unpublished), the sagging brain syndrome
bency). Other symptoms include neck pain, (SBS) produces motor slowing with cautious
nausea, vomiting, dizziness, hearing loss, and unsteady gait, urinary incontinence,
diplopia, visual blurring, interscapular pain, dysarthria, and dysphagia. There is change
and radicular upper extremity symptoms. in personality characterized predominantly
Characteristic imaging features include dif- by disinhibited and (sexually) inappropriate
fuse pachymeningeal gadolinium enhance- behaviors coupled with apathy, lack of con-
ment, sinking of the brain, subdural fluid cern and empathy, and/or affective changes
collections, enlargement of the pituitary, and with depression and anxiety. Confusion, for-
engorgement of venous sinuses and the epi- getfulness, executive dysfunction including
dural venous plexus (Mokri, 2004). These impaired working memory, and obsessive-
findings together with CSF lymphocytic pleo- compulsive stereotypies are common features.
cytosis, elevated protein, normal glucose, Aphasias are notably absent. Identifying the
and negative culture can lead to the mistaken CSF leak is the key to targeted interven-
diagnosis of aseptic meningitis (Balkan etal., tion. Some patients improve with prolonged
2012). Chronic CSF leak with downward recumbency and autologous epidural blood
displacement of the intracranial contents patch. The acquired dementia of the SBS with
can mimic Chiari 1 malformation (Atkinson, its characteristic clinical and imaging features
Weinshenker, Miller, Piepgras, & Mokri, 1998) may be rare, but it is important to recognize
and produce distortion and expansion of the because of the potential for improvement
midbrain (Fig. 15.30) with few neurological with treatment, and to avoid unnecessary
signs, or patients may become drowsy and investigations and misdiagnosis.
even lapse into coma due to central hernia-
tion (Savoiardo et al., 2007). It has recently
been recognized that this constellation has a Other Rare Neurodegenerative
major impact on cognition with behavioral Disorders With Cognitive Change
and cognitive dysfunction accompanied by
daytime somnolence and headache, and all There are a number of rare neurodegenerative
eight patients in the original report showed disorders that usually present in childhood
evidence on brain PET scan of hypometabo- but that can also manifest in adults and some-
lism of the frontotemporal regionshence, time with a subacute presentation (see Coker,
the frontotemporal brain sagging syndrome 1991). These are exemplified by the following.
(Wicklund et al., 2011). In the three cases fol- Wilsons disease (hepatolenticular degener-
lowed by the author (Schmahmann, as yet ation; Wilson, 1912)is an autosomal recessive
Figure15.30 T1-weighted magnetic resonance imaging (MRI) scans in the midsagittal plane (left)
and coronal plane (right) show the essential features of the sagging brain syndrome. There is
sinking and distortion of the midbrain, diencephalon, and corpus callosum, and crowding of the
posterior fossa. This middle-aged man presented as a case of frontotemporal dementia.
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 345
insight, and impaired gait, with ataxia, cho- examined and followed to autopsy had
rea, and progressively severe myoclonus Lewy body disease present in a precipitous
leading to mutism and demise within 6years. manner, apparently fine one day, and con-
The combination of brain MRI and PET scan, fused and disoriented the next. The reason
CSF markers for Alzheimers disease, and the for these rapid declines has not been defined.
PS1 gene testing permitted a diagnosis dur- Clues to the diagnosis are found in the motor
ing life that was helpful in planning manage- and cognitive features on examination. That
ment and counseling. is, the case can be typical of the usual pre-
This chapter concludes where it started, sentation in all respects but for the timing of
with the observations of the UCSF survey the onset. Caution is warranted in reaching
of patients referred for possible CJD. Fully a diagnosis of these as-yet-untreatable dis-
39% (26 patients out of 67) of these rapidly orders, given the multitude of potentially
deteriorating cases were found at autopsy to treatable conditions outlined before, and the
be neurodegenerative (CBD, FTD, LBD, AD, possibility of intercurrent treatable illness
and PSP; see Table 15.1). Personal experience such as a urinary tract infection exacerbating
provides anecdotal support for these empiric or precipitating the apparently sudden cog-
observations and makes the point that there nitive decline.
are patients in whom these usually slowly A practical list of disorders that should be
evolving disorders have a more rapid, foremost in the consideration of subacute and
subacute onset. Two patients personally rapidly progressive dementias is in Table15.6
Investigations are performed in a stepwise and logical sequence, determined by the degree of clinical
suspicion.
First LevelFor All Patients
A. CBC, ESR, BUN, creatinine, electrolytes, glucose, calcium, magnesium, LFTs, TSH, B12, RPR, chest
X-ray, EKG, urinalysis and culture, MRI with gadolinium if suspect enhancing lesions; magnetic
susceptibility study for microhemorrhages for amyloid (CT head +/- contrast, if MRI not available),
neuropsychological testing
B. First level of evaluation if indicated based on the initial history and exam:
HIV, ANA, HbA1c, blood gas, blood culture, thiamine and red cell transketolase, Lyme titer and Western
blot, vitamin E, FTA, PPD, lactate, pyruvate, ACE, porphyrins, methylmalonic acid, homocysteine, toxic
screen (drugs, poisons, metals)
EEG
Second Level
Spinal tapcells, protein, glucose, fungus, TB, virus, cytology, HSV-PCR, CSF a, tau, Lyme titer and
Western blot, VDRL, oligoclonal banding, IgG, 14-3-3, glutamine, lactate, measles antibody
Vascular workup:lipid profile/anticardiolipin antibodies/carotid noninvasives/Holter monitor/
echocardiogram
Quantitative plasma amino acids, quantitative urine organic acids
Vasculitis workup if ANA+ (anti-dsDNA, Ro, La, Sm, RNP, ANCA, C3, C4, CH50)
Limbic encephalitis paraneoplastic and autoimmune antibodies, CT chest, abdomen and pelvis,
mammogram, testicular ultrasound
All-night sleep study, pO2
Third Level
PET/SPECT
Cerebral angiography for vasculitis, intravascular lymphoma
Fluorescein angiography
Gene testinge.g., PS1, PS2, MAPT, TDP-43, CADASIL, MELAS, SCAs, FXTAS
Biopsy:brain/meninges, nerve/muscle, skin, liver, kidney
Diagnostic Evaluations in Extremely Rare Disorders
Low serum ceruloplasmin, high urine and liver copper levels in Wilsons disease
Very long chain fatty acidsALD
WBC arylsulfatase AMLD
Serum hexosaminidase Aand BTay Sachs/Sandhoff
WBC for galactocerebroside beta-galactosidaseKrabbes leukodystrophy
Serum cholestanol or urine bile acidscerebrotendinous xanthomatosis
WBC beta-galactosidaseGM1 gangliosidosis
Skin biopsy for biochemical testing of fibroblastsNiemann-Pick type C
X-rays of hands for bone cysts, bone or skin biopsy for abnormal fat cellspolycystic lipomembranous
osteodysplasia with sclerosing leukoencephalopathy
Urine mucopolysaccharides elevated, serum alpha-N-acetyl glucosaminidase-deficient,
mucopolysaccharidoses
Indications for Brain Biopsy
Focal, relevant lesion(s) of undetermined cause, after extensive evaluation
Distinguish primary CNS lymphoma from PML and other entities if necessary
Central nervous system vasculitis
Rare pediatric neurodegenerative diseases presenting in adulthood:Krabbes disease (PAS + histiocytes);
Kufs disease, intranuclear fingerprint pattern, and osmophilic granules on electron microscopy;
Alexanders disease, Rosenthal fibers; neuronal intranuclear (eosinophilic) inclusion disease
348 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
Organization for Rare Disorders, and RO1 AJNR American Journal of Neuroradiology, 22,
MH 64044 and MH 67980. 14801482.
Baehring, J.M., Longtine, J.,& Hochberg, F.H.
(2003). A new approach to the diagnosis and
References treatment of intravascular lymphoma. Journal
Abou-Zeid, E., Boursoulian, L. J., Metzer, of Neurooncology, 61, 237248.
W. S., & Gundogdu, B. (2012). Morvan syn- Baillieux, H., De Smet, H. J., Dobbeleir, A.,
drome:Acase report and review of the litera- Paquier, P. F., De Deyn, P. P., & Marien,
ture. Journal of Clinical Neuromuscular Disease, P. (2010). Cognitive and affective distur-
13, 214227. bances following focal cerebellar damage
Adams, R. D. (1966). Further observations on in adults: A neuropsychological and SPECT
normal pressure hydrocephalus. Proceedings study. Cortex, 46, 869879.
of the Royal Society of Medicine, 59, 11351140. Balkan, I. I., Albayram, S., Ozaras, R., Yilmaz,
Adams, R.D., Fisher, C.M., Hakim, S., Ojemann, M. H., Ozbayrak, M., Mete, B.,...Tabak, F.
R. G., & Sweet, W. H. (1965). Symptomatic (2012). Spontaneous intracranial hypotension
occult hydrocephalus with normal syndrome may mimic aseptic meningitis.
cerebrospinal-fluid pressure. Atreatable syn- Scandinavian Journal of Infectious Diseases, 44,
drome. New England Journal of Medicine, 273, 481488.
117126. Baram, T. Z., Goldman, A. M., & Percy, A. K.
ACR Ad Hoc Committee. (1999). The American (1986). Krabbe disease:Specific MRI and CT
College of Rheumatology nomenclature and findings. Neurology, 36, 111115.
case definitions for neuropsychiatric lupus Bartlett, E., & Mikulis, D. J. (2005).
syndromes. Arthritis and Rheumatism, 42, Chasing chasing the dragon with
599608. MRI: Leukoencephalopathy in drug abuse.
Alkali, N.H., Bwala, S.A., Nyandaiti, Y.W.,& British Journal of Radiology, 78, 9971004.
Danesi, M. A. (2013). NeuroAIDS in Berger, J.R. (2011). The clinical features of PML.
sub-Saharan Africa:Aclinical review. Annals Cleveland Clinic Journal of Medicine, 78(Suppl
of African Medicine, 12, 110. 2), S812.
Alper, T., Cramp, W.A., Haig, D.A.,& Clarke, Berger, J. R., Aksamit, A. J., Clifford, D. B.,
M. C. (1967). Does the agent of scrapie rep- Davis, L., Koralnik, I. J., Sejvar, J. J.,...Nath,
licate without nucleic acid? Nature, 214, A. (2013). PML diagnostic criteria:Consensus
764766. statement from the AAN Neuroinfectious
Armstrong, M. J., Litvan, I., Lang, A. E., Bak, Disease Section. Neurology, 80, 14301438.
T.H., Bhatia, K.P., Borroni, B.,...Weiner, W.J. Bezman, L., Moser, A. B., Raymond,
(2013). Criteria for the diagnosis of cortico- G. V., Rinaldo, P., Watkins, P. A., Smith,
basal degeneration. Neurology, 80, 496503. K. D.,...Moser, H. W. (2001). Adrenoleukod
Asztely, F., & Kumlien, E. (2012). The diagno- ystrophy:Incidence, new mutation rate, and
sis and treatment of limbic encephalitis. Acta results of extended family screening. Annals
Neurological Scandinavica, 126, 365375. of Neurology, 49, 512517.
Atkinson, J.L., Weinshenker, B.G., Miller, G.M., Bianco, F., Iacovelli, E., Tinelli, E., Lepre, C., &
Piepgras, D.G.,& Mokri, B. (1998). Acquired Pauri, F. (2011). Recurrent leukoencephalopa-
Chiari I malformation secondary to sponta- thy in a cocaine abuser. Neurotoxicology, 32,
neous spinal cerebrospinal fluid leakage and 410412.
chronic intracranial hypotension syndrome Bloch, O., & McDermott, M. W. (2012).
in seven cases. Journal of Neurosurgery, 88, Lumboperitoneal shunts for the treatment
237242. of normal pressure hydrocephalus. Journal of
Austin, J., Armstrong, D., Fouch, S., Mitchell, C., Clinical Neuroscience, 19, 11071111.
Stumpf, D., Shearer, L., & Briner, O. (1968). Boerner, R. J., & Kapfhammer, H. P. (1999).
Metachromatic leukodystrophy (MLD). 8. Psychopathological changes and cogni-
MLD in adults; diagnosis and pathogenesis. tive impairment in encephalomyelitis dis-
Archives of Neurology, 18, 225240. seminata. European Archives of Psychiatry and
Back, T., Grunig, S., Winter, Y., Bodechtel, U., Clinical Neuroscience, 249, 96102.
Guthke, K., Khati, D., & von Kummer, R. Braga-Neto, P., Pedroso, J.L., Alessi, H., Dutra,
(2013). Neuroborreliosis-associated cere- L. A., Felicio, A. C., Minett, T.,...Barsottini,
bral vasculitis: Long-term outcome and O. G. (2012). Cerebellar cognitive affective
health-related quality of life. Journal of syndrome in Machado Joseph disease: Core
Neurology, 260, 15691575. clinical features. Cerebellum, 11, 54956.
Bae, S. J., Lee, H. K., Lee, J. H., Choi, C. G., & Brain, L., Jellinek, E. H., & Ball, K. (1966).
Suh, D. C. (2001). Wernickes encephalopa- Hashimotos disease and encephalopathy.
thy: Atypical manifestation at MR imaging. Lancet, 2, 512514.
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 349
Bratton, R. L., Whiteside, J. W., Hovan, M. J., incubation periods at the end of the epi-
Engle, R. L., & Edwards, F. D. (2008). demic in Papua New Guinea. Philosophical
Diagnosis and treatment of Lyme disease. Transactions of the Royal Society of London
Mayo Clinic Proceedings, 83, 566571. B:Biological Sciences, 363, 37253739.
Brismar, J., Gascon, G.G., von Steyern, K.V.,& Cooper, F.E., Grube, M., Elsegood, K.J., Welch,
Bohlega, S. (1996). Subacute sclerosing pan- J. L., Kelly, T. P., Chinnery, P. F., & Griffiths,
encephalitis: Evaluation with CT and MR. T.D. (2010). The contribution of the cerebel-
AJNR American Journal of Neuroradiology, 17, lum to cognition in Spinocerebellar Ataxia
761772. Type 6. Behavioral Neurology, 23, 315.
Brown, K., Mastrianni, J. A. (2010). The prion Cooper, S. A., Murray, K. L., Heath, C. A.,
diseases. Journal of Geriatric Psychiatry and Will, R. G., & Knight, R. S. (2005). Isolated
Neurology, 23, 277298. visual symptoms at onset in sporadic
Brown, W. T. (1954). Papua New Guinea con- Creutzfeldt-Jakob disease: The clinical phe-
trol reports. [Kainantu Patrol Report No 8 of notype of the Heidenhain variant. British
1953/54], Department of District Services Journal of Ophthalmology, 89, 13411342.
and Native Affairs, Australia New Guinea Cornejo, R., Venegas, P., Goni, D., Salas, A., &
Administrative Unit. Romero, C. (2010). Successful response to
Brownell, B.,& Oppenheimer, D.R. (1965). An intravenous immunoglobulin as rescue ther-
ataxic form of subacute presenile polioen- apy in a patient with Hashimotos encepha-
cephalopathy (Creutzfeldt-Jakob Disease). lopathy. British Medical Journal Case Reports,
Journal of Neurology, Neurosurgery and 2010. pii:bcr0920103332.
Psychiatry, 28, 350361. Corsellis, J.A., Goldberg, G.J.,& Norton, A.R.
Burk, K. (2007). Cognition in hereditary ataxia. (1968). Limbic encephalitis and its associa-
Cerebellum, 6, 280286. tion with carcinoma. Brain, 91, 481496.
Burns, A.,& Holland, T. (1986). Vitamin E defi- Costello, D.J., Eichler, A.F.,& Eichler, F.S. (2009).
ciency. Lancet, 1, 805806. Leukodystrophies: Classification, diagnosis,
Cali, I., Castellani, R., Alshekhlee, A., Cohen, and treatment. Neurologist, 15, 319328.
Y., Blevins, J., Yuan, J.,...Gambetti, P. (2009). DEsposito, M., Verfaellie, M., Alexander,
Co-existence of scrapie prion protein types M. P., & Katz, D. I. (1995). Amnesia follow-
1 and 2 in sporadic Creutzfeldt-Jakob ing traumatic bilateral fornix transection.
disease: Its effect on the phenotype and Neurology, 45, 15461550.
prion-type characteristics. Brain, 132, Darnell, R., & Posner, J. (2011). Paraneoplastic
26432658. syndromes. Contemporary neurology series, Vol
Castillo, P., Woodruff, B., Caselli, R., Vernino, 79. NewYork, NY:Oxford University Press.
S., Lucchinetti, C., Swanson, J.,...Boeve, B. Davis, J.D., Stern, R.A.,& Flashman, L.A. (2003).
(2006). Steroid-responsive encephalopathy Cognitive and neuropsychiatric aspects of sub-
associated with autoimmune thyroiditis. clinical hypothyroidism: Significance in the
Archives of Neurology, 63, 197202. elderly. Current Psychiatry Reports, 5, 384390.
Chakor, R.T.,& Santosh, N.S. (2013). Subacute De Michele, G., Maltecca, F., Carella, M., Volpe,
sclerosing panencephalitis presenting as G., Orio, M., De Falco, A.,...Bruni, A. (2003).
rapidly progressive young-onset dementia. Dementia, ataxia, extrapyramidal features,
Journal of the Pakistan Medical Association, 63, and epilepsy: Phenotype spectrum in two
921924. Italian families with spinocerebellar ataxia
Chen-Plotkin, A.S., Pau, K.T.,& Schmahmann, type 17. Neurological Sciences, 24, 166167.
J. D. (2008). Delayed leukoencephalopathy DeArmond, S., & Prusiner, S. (1997). Prion
after hypoxic-ischemic injury. Archives of diseases. In P. Lantos & D. Graham (Eds.),
Neurology, 65, 144145. Greenfields neuropathology (6th ed., pp. 235
Chong, J.Y., Rowland, L.P.,& Utiger, R.D. (2003). 280). London, UK:Edward Arnold.
Hashimoto encephalopathy: Syndrome or DiMauro, S., & Hirano, M. (2001). MELAS.
myth? Archives of Neurology, 60, 164171. In: Pagon RA, Adam MP, Bird TD, Dolan
Chu-Shore, C. J., Major, P., Camposano, S., CR, Fong CT, Smith RJH, Stephens K, edi-
Muzykewicz, D., & Thiele, E. A. (2010). The tors. GeneReviews [Internet]. Seattle
natural history of epilepsy in tuberous sclero- (WA): University of Washington, Seattle;
sis complex. Epilepsia, 51, 12361241. 19932014.
Coker, S.B. (1991). The diagnosis of childhood Dinn, J.J. (1980). Transolfactory spread of virus
neurodegenerative disorders presenting as in herpes simplex encephalitis. British Medical
dementia in adults. Neurology, 41, 794798. Journal, 281, 1392.
Collinge, J., Whitfield, J., McKintosh, E., Frosh, Disler, P.B.,& Eales, L. (1982). The acute attack
A., Mead, S., Hill, A.F.,...Alpers, M.P. (2008). of porphyria. South African Medical Journal, 61,
A clinical study of kuru patients with long 8284.
350 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
Dorr, J., Krautwald, S., Wildemann, B., Jarius, Fallon, B.A., Keilp, J.G., Corbera, K.M., Petkova,
S., Ringelstein, M., Duning, T.,...Kleffner, E., Britton, C.B., Dwyer, E.,...Sackeim, H.A.
I. (2013). Characteristics of Susac syn- (2008). A randomized, placebo-controlled trial
drome:Areview of all reported cases. Nature of repeated IV antibiotic therapy for Lyme
Reviews Neurology, 9, 307316. encephalopathy. Neurology, 70, 9921003.
Drulovic, J., Andrejevic, S., Bonaci-Nikolic, B.,& Fallon, B.A., Petkova, E., Keilp, J.G.,& Slavov,
Mijailovic, V. (2011). Hashimotos encepha- I. (2009). A randomized, placebo-controlled
lopathy: A long-lasting remission induced trial of repeated IV antibiotic therapy for
by intravenous immunoglobulins. Vojnosanit Lyme encephalopathy prolonged lyme dis-
Pregl, 68, 452454. ease treatment: Enough is enough. Author
Duff, K., & McCaffrey, R. J. (2001). Electrical Reply. Neurology, 72, 383384.
injury and lightning injury: A review of Ferini-Strambi, L. (2011). Does idiopathic REM
their mechanisms and neuropsychologi- sleep behavior disorder (iRBD) really exist?
cal, psychiatric, and neurological sequelae. What are the potential markers of neurode-
Neuropsychology Reviews, 11, 101116. generation in iRBD? Sleep Medicine, 12(Suppl
Dumas, J.A., Makarewicz, J., Schaubhut, G.J., 2), S43S49.
Devins, R., Albert, K., Dittus, K.,& Newhouse, Ferreri, A.J., Campo, E., Seymour, J.F., Willemze,
P. A. (2013). Chemotherapy altered brain R., Ilariucci, F., Ambrosetti, A.,...Ponzoni, M.
functional connectivity in women with breast (2004). Intravascular lymphoma:Clinical pre-
cancer: A pilot study. Brain Imaging and sentation, natural history, management and
Behavior, 7(4), 524532. prognostic factors in a series of 38 cases, with
Duncan, J. M. (1989). Listeria and psychiatric special emphasis on the cutaneous variant.
syndromes. British Journal of Psychiatry, 154, British Journal of Haematology, 127, 173183.
887. Filley, C. M. (1998). The behavioral neurol-
Ebi, J., Sato, H., Nakajima, M., & Shishido, F. ogy of cerebral white matter. Neurology, 50,
(2013). Incidence of leukoencephalopathy 15351540.
after whole-brain radiation therapy for brain Filley, C. M. (2001). The behavioral neurol-
metastases. International Journal of Radiation ogy of white matter. New York, NY: Oxford
Oncology and Biological Physics, 85, 12121217. University Press.
Edwin, D., Speedie, L. J., Kohler, W., Naidu, S., Filley, C.M. (2012). Behavioral neurology of white
Kruse, B., & Moser, H. W. (1996). Cognitive matter. New York, NY: Oxford University
and brain magnetic resonance imaging find- Press.
ings in adrenomyeloneuropathy. Annals of Filley, C. M., Franklin, G. M., Heaton, R. K., &
Neurology, 40, 675678. Rosenberg, N. L. (1988). White matter
Eichler, F., Mahmood, A., Loes, D., Bezman, dementia: Clinical disorders and implica-
L., Lin, D., Moser, H. W., & Raymond, G. V. tions. Neuropsychiatry Neuropsychology and
(2007). Magnetic resonance imaging detection Behavioral Neurology, 1, 239254.
of lesion progression in adult patients with Filley, C.M., Heaton, R.K., Nelson, L.M., Burks,
X-linked adrenoleukodystrophy. Archives of J.S.,& Franklin, G.M. (1989). A comparison
Neurology, 64, 659664. of dementia in Alzheimers disease and mul-
Eichler, F. S., Barker, P. B., Cox, C., Edwin, D., tiple sclerosis. Archives of Neurology 1989; 46,
Ulug, A.M., Moser, H.W.,& Raymond, G.V. 157161.
(2002). Proton MR spectroscopic imaging pre- Filley, C.M., Heaton, R.K.,& Rosenberg, N.L.
dicts lesion progression on MRI in X-linked (1990). White matter dementia in chronic tol-
adrenoleukodystrophy. Neurology, 58, 901907. uene abuse. Neurology, 40, 532534.
Eichler, F. S., Itoh, R., Barker, P. B., Mori, S., Fisher, C. M. (1983). Honored guest presenta-
Garrett, E.S., van Zijl, P.C.,...Melhem, E.R. tion: Abulia minor vs. agitated behavior.
(2002). Proton MR spectroscopic and diffu- Clinical Neurosurgery, 31, 931.
sion tensor brain MR imaging in X-linked Fliessbach, K., Helmstaedter, C., Urbach,
adrenoleukodystrophy: Initial experience. H., Althaus, A., Pels, H., Linnebank,
Radiology, 225, 245252. M.,...Schlegel, U. (2005). Neuropsychological
Eide, P. K., & Sorteberg, W. (2010). Diagnostic outcome after chemotherapy for primary CNS
intracranial pressure monitoring and surgi- lymphoma: a prospective study. Neurology,
cal management in idiopathic normal pres- 64, 11841188.
sure hydrocephalus: A 6-year review of 214 Foley, J., & Denny-Brown, D. (1955). Subacute
patients. Neurosurgery, 66, 8091. progressive encephalopathy with bulbar
Faerber, E. N., Melvin, J., & Smergel, E. M. myoclonus. Excerpta Medica (Amsterdam),
(1999). MRI appearances of metachromatic Sect. VIII, 782784.
leukodystrophy. Pediatric Radiology, 29, Freeman, S. H., Hyman, B. T., Sims, K. B.,
669672. Hedley-Whyte, E. T., Vossough, A., Frosch,
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 351
M. P., & Schmahmann, J. D. (2009). Adult Gray, F., Adle-Biassette, H., Chretien, F., Lorin de
onset leukodystrophy with neuroaxonal la Grandmaison, G., Force, G.,& Keohane, C.
spheroids:clinical, neuroimaging and neuro- (2001). Neuropathology and neurodegenera-
pathologic observations. Brain Pathology, 19, tion in human immunodeficiency virus infec-
3947. tion. Pathogenesis of HIV-induced lesions of
Gabuzda, D. H., & Hirsch, M. S. (1987). the brain, correlations with HIV-associated
Neurologic manifestations of infection with disorders and modifications according
human immunodeficiency virus. Clinical to treatments. Clinical Neuropathology, 20,
features and pathogenesis. Annals of Internal 146155.
Medicine, 107, 383391. Greco, C. M., Berman, R. F., Martin, R. M.,
Gajdusek, D. C., Gibbs, C. J., & Alpers, M. Tassone, F., Schwartz, P. H., Chang,
(1966). Experimental transmission of a A.,...Hagerman, P.J. (2006). Neuropathology
Kuru-like syndrome to chimpanzees. Nature, of fragile X-associated tremor/ataxia syn-
209, 794796. drome (FXTAS). Brain, 129, 243255.
Ganz, P. A., Kwan, L., Castellon, S. A., Gregory, A., & Hayflick, S. (2013).
Oppenheim, A., Bower, J. E., Silverman, Neurodegeneration with brain iron accu-
D. H.,...Belin, T. R. (2013). Cognitive mulation disorders overview. In: Pagon RA,
complaints after breast cancer treat- Adam MP, Bird TD, Dolan CR, Fong CT, Smith
ments:Examining the relationship with neu- RJH, Stephens K, editors. GeneReviews
ropsychological test performance. Journal of [Internet]. Seattle (WA): University of
the National Cancer Institute, 105, 791801. Washington, Seattle; 19932014.
Garrard, P., Martin, N.H., Giunti, P.,& Cipolotti, Griffith, J.S. (1967). Self-replication and scrapie.
L. (2008). Cognitive and social cognitive func- Nature, 215, 10431044.
tioning in spinocerebellar ataxia: A prelimi- Grigg-Damberger, M., & Ralls, F. (2012).
nary characterization. Journal of Neurology, Cognitive dysfunction and obstructive sleep
255, 398405. apnea:From cradle to tomb. Current Opinion
George, J. N. (2006). Clinical practice. in Pulmonary Medicine, 18, 580587.
Thrombotic thrombocytopenic purpura. New Grigsby, J., Brega, A.G., Engle, K., Leehey, M.A.,
England Journal of Medicine, 354, 19271935. Hagerman, R. J., Tassone, F.,...Reynolds,
Gerard, A., Sarrot-Reynauld, F., Liozon, A. (2008). Cognitive profile of fragile X pre-
E., Cathebras, P., Besson, G., Robin, mutation carriers with and without frag-
C.,...Rousset, H. (2002). Neurologic pre- ile X-associated tremor/ataxia syndrome.
sentation of Whipple disease: Report of 12 Neuropsychology, 22, 4860.
cases and review of the literature. Medicine Grois, N., Fahrner, B., Arceci, R. J., Henter,
(Baltimore), 81, 443457. J. I., McClain, K., Lassmann, H.,...Prayer,
Geschwind, D. H. (1999). Focusing attention D. (2010). Central nervous system disease
on cognitive impairment in spinocerebellar in Langerhans cell histiocytosis. Journal of
ataxia. Archives of Neurology, 56, 2022. Pediatrics, 156, 873881, 881 e1.
Geschwind, M.D., Shu, H., Haman, A., Sejvar, Grois, N., Prayer, D., Prosch, H., & Lassmann,
J.J.,& Miller, B.L. (2008). Rapidly progressive H. (2005). Neuropathology of CNS disease
dementia. Annals of Neurology, 64, 97108. in Langerhans cell histiocytosis. Brain, 128,
Geschwind, N. (1965a). Disconnexion syn- 829838.
dromes in animals and man. I. Brain, 88, Hagerman, R.,& Hagerman, P. (2013). Advances
237294. in clinical and molecular understanding of the
Geschwind, N. (1965b). Disconnexion syn- FMR1 premutation and fragile X-associated
dromes in animals and man. II. Brain, 88, tremor/ataxia syndrome. Lancet Neurology,
585644. 12, 786798.
Goldman-Rakic, P. S. (1988). Topography of Hajj-Ali, R. A., Singhal, A. B., Benseler, S.,
cognition: Parallel distributed networks in Molloy, E.,& Calabrese, L.H. (2011). Primary
primate association cortex. Annual Review of angiitis of the CNS. Lancet Neurology, 10,
Neuroscience, 11, 137156. 561572.
Gongvatana, A., Harezlak, J., Buchthal, S., Hakim, S., & Adams, R. D. (1965). The special
Daar, E., Schifitto, G., Campbell, T.,...Navia, clinical problem of symptomatic hydrocepha-
B. (2013). Progressive cerebral injury in the lus with normal cerebrospinal fluid pressure.
setting of chronic HIV infection and antiret- Observations on cerebrospinal fluid hydro-
roviral therapy. Journal of Neurovirology, 19, dynamics. Journal of Neurological Sciences, 2,
209218. 307327.
Graus, F., & Dalmau, J. (2012). Paraneoplastic Halperin, J. J. (2008). Prolonged Lyme disease
neurological syndromes. Current Opinion in treatment: Enough is enough. Neurology, 70,
Neurology, 25, 795801. 986987.
352 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
Halperin, J.J. (2010). Nervous system Lyme dis- observations in 29 cases. Annals of Neurology,
ease. Journal of the Royal College of Physicians, 72, 241255.
Edinburgh, 40, 248255. Ironside, J. W. (1998). Neuropathological find-
Harris, M. J., Jeste, D. V., Gleghorn, A., & ings in new variant CJD and experimental
Sewell, D. D. (1991). New-onset psychosis transmission of BSE. FEMS Immunology and
in HIV-infected patients. Journal of Clinical Medical Microbiology, 21, 9195.
Psychiatry, 52, 369376. Ishii, K., Kanda, T., Harada, A., Miyamoto,
Hasegawa, M., Arai, T., Akiyama, H., Nonaka, N., Kawaguchi, T., Shimada, K.,...Mori, E.
T., Mori, H., Hashimoto, T.,...Oyanagi, K. (2008). Clinical impact of the callosal angle
(2007). TDP-43 is deposited in the Guam in the diagnosis of idiopathic normal pres-
parkinsonism-dementia complex brains. sure hydrocephalus. European Radiology, 18,
Brain, 130, 13861394. 26782683.
Heilman, K. M., & Sypert, G. W. (1977). Ishii, N.,& Nishihara, Y. (1981). Pellagra among
Korsakoffs syndrome resulting from bilat- chronic alcoholics: Clinical and pathological
eral fornix lesions. Neurology, 27, 490493. study of 20 necropsy cases. Journal of Neurology,
Heinrich, A., Runge, U., & Khaw, A. V. Neurosurgery and Psychiatry, 44, 209215.
(2004). Clinicoradiologic subtypes of Jackson, W.S., Borkowski, A.W., Watson, N.E.,
Marchiafava-Bignami disease. Journal of King, O.D., Faas, H., Jasanoff, A.,& Lindquist,
Neurology, 251, 10501059. S. (2013). Profoundly different prion diseases
Heinrich, T. W., & Grahm, G. (2003). in knock-in mice carrying single PrP codon
Hypothyroidism presenting as psycho- substitutions associated with human dis-
sis: Myxedema madness revisited. Primary eases. Proceedings of the National Academy of
Care Companion, Journal of Clinical Psychiatry, Science USA, 110, 1475914764.
5, 260266. Jacquemont, S., Hagerman, R. J., Leehey,
Helmstaedter, C.,& Elger, C.E. (2009). Chronic M., Grigsby, J., Zhang, L., Brunberg,
temporal lobe epilepsy:Aneurodevelopmen- J. A.,...Hagerman, P. J. (2003). Fragile X pre-
tal or progressively dementing disease? Brain, mutation tremor/ataxia syndrome:Molecular,
132, 28222830. clinical, and neuroimaging correlates. American
Henderson, R.D., Rajah, T., Nicol, A.J.,& Read, Journal of Human Genetics, 72, 869878.
S. J. (2003). Posterior leukoencephalopathy Jim, H.S., Phillips, K.M., Chait, S., Faul, L.A.,
following intrathecal chemotherapy with Popa, M.A., Lee, Y.H.,...Small, B.J. (2012).
MRA-documented vasospasm. Neurology, 60, Meta-analysis of cognitive functioning in
326328. breast cancer survivors previously treated
Hillbom, M., Saloheimo, P., Fujioka, S., with standard-dose chemotherapy. Journal of
Wszolek, Z. K., Juvela, S., & Leone, M. A. Clinical Oncology, 30, 35783587.
(2013). Diagnosis and management of Jones, E.G.,& Powell, T.P. (1970). An anatomi-
Marchiafava-Bignami disease: A review of cal study of converging sensory pathways
CT/MRI confirmed cases. Journal of Neurology, within the cerebral cortex of the monkey.
Neurosurgery and Psychiatry, 85(2), 168173. Brain, 93, 793820.
Holle, J.U.,& Gross, W.L. (2011). Neurological Jones, H. R., Jr., & Siekert, R. G. (1989).
involvement in Wegeners granulomatosis. Neurological manifestations of infective
Current Opinion in Rheumatology, 23, 711. endocarditis. Review of clinical and thera-
Holmes, G. (1908). A form of familial degenera- peutic challenges. Brain, 112(Pt 5), 1295315.
tion of the cerebellum. Brain, 30, 466488. Jongen, P. J., Ter Horst, A. T., & Brands, A. M.
Hyde, T.M., Ziegler, J.C.,& Weinberger, D.R. (2012). Cognitive impairment in multiple
(1992). Psychiatric disturbances in metachro- sclerosis. Minerva Medicine, 103, 7396.
matic leukodystrophy. Insights into the neu- Joseph, F.G., Lammie, G.A.,& Scolding, N.J.
robiology of psychosis. Archives of Neurology, (2007). CNS lupus: A study of 41 patients.
49, 401406. Neurology, 69, 644654.
Irani, S. R., Alexander, S., Waters, P., Kleopa, Kapas, I., Majtenyi, K., Toro, K., Keller, E.,
K. A., Pettingill, P., Zuliani, L.,...Vincent, Voigtlander, T., & Kovacs, G. G. (2012).
A. (2010). Antibodies to Kv1 potassium Pellagra encephalopathy as a differential
channel-complex proteins leucine-rich, glioma diagnosis for Creutzfeldt-Jakob disease.
inactivated 1 protein and contactin-associated Metabolic Brain Disease, 27, 231235.
protein-2 in limbic encephalitis, Morvans Kaufman, K.R., Zuber, N., Rueda-Lara, M.A.,&
syndrome and acquired neuromyotonia. Tobia, A. (2010). MELAS with recurrent com-
Brain, 133, 27342748. plex partial seizures, nonconvulsive status
Irani, S.R., Pettingill, P., Kleopa, K.A., Schiza, epilepticus, psychosis, and behavioral distur-
N., Waters, P., Mazia, C.,...Vincent, A. (2012). bances: Case analysis with literature review.
Morvan syndrome: Clinical and serological Epilepsy and Behavior, 18, 494497.
CHAPTER 15. The Differential Diagnosis of Rapidly Progressive and Rare Dementias 353
Kayal, A.K., Goswami, M., Das, M.,& Paul, B. (2010). Cognitive impairment in ARCA-1, a
(2011). Clinical spectrum of neurosyphilis in newly discovered pure cerebellar ataxia syn-
North East India. Neurology India, 59, 344350. drome. Cerebellum, 9, 443453.
Kellner, M., Sonntag, A., & Strian, F. (1990). Lafosse, J. M., Corboy, J. R., Leehey, M. A.,
Psychiatric sequelae of listeriosis. British Seeberger, L. C., & Filley, C. M. (2007). MS
Journal of Psychiatry, 157, 299. vs. HD: Can white matter and subcorti-
Kelly, J.,& Renner, A.J. (2008). Alcohol-related cal gray matter pathology be distinguished
disorders. In T. Stern, J. Rosenbaum, M. Fava, neuropsychologically? Journal of Clinical and
J. Biederman,& S. Rauch (Eds.), Massachusetts Experimental Neuropsychology, 29, 142154.
General Hospital comprehensive clinical psychia- Lancaster, E., & Dalmau, J. (2012). Neuronal
try (pp. 337354). Philadelphia, PA:Mosby. autoantigenspathogenesis, associated dis-
Kim, H., Schmahmann, J.S. K., Falk, W., Stern, orders and antibody testing. Nature Reviews
T., & Norris, E. (1999). A neuropsychiatric Neurology, 8, 380390.
presentation of mitochondrial myopathy, Lancaster, E., Martinez-Hernandez, E., Titulaer,
encephalopathy, lactic acidosis and stroke-like M. J., Boulos, M., Weaver, S., Antoine,
episodes. Medicine and Psychiatry, 2, 39. J. C.,...Dalmau, J. (2011). Antibodies to
Kishore, N., Kimchi, E., Cunningham, M., metabotropic glutamate receptor 5 in the
Frosch, M.,& Schmahmann, J. (April 4, 2013). Ophelia syndrome. Neurology, 77, 1698701.
A neuropsychiatric case study of early onset Larner, A. J. (2013). Presenilin-1 mutations
familial Alzheimers Disease. Paper presented in Alzheimers disease: An update on
at the Annual Meeting of the American genotype-phenotype relationships. Journal of
Neuropsychiatric Association, Boston, MA. Alzheimers Disease, 37, 653659.
Kitagawa, Y., Gotoh, F., Koto, A.,& Okayasu, H. Lasek, K., Lencer, R., Gaser, C., Hagenah, J.,
(1990). Stroke in systemic lupus erythemato- Walter, U., Wolters, A.,...Binkofski, F. (2006).
sus. Stroke, 21, 15331539. Morphological basis for the spectrum of
Kleinfeld, K., Mobley, B., Hedera, P., Wegner, A., clinical deficits in spinocerebellar ataxia 17
Sriram, S., & Pawate, S. (2013). Adult-onset (SCA17). Brain, 129, 23412352.
leukoencephalopathy with neuroaxonal Lee, M.S.,& Marsden, C.D. (1994). Neurological
spheroids and pigmented glia: Report of sequelae following carbon monoxide poison-
five cases and a new mutation. Journal of ing clinical course and outcome according to
Neurology, 260, 558571. the clinical types and brain computed tomog-
Knudsen, R. (2013). Neurosyphilis: Overview raphy scan findings. Movement Disorders, 9,
of syphilis of the CNS. Medscape. Retrieved 550558.
March 2014, from http://emedicine.med- Leehey, M. A., Munhoz, R. P., Lang, A. E.,
scape.com/article/1169231-overview. Brunberg, J. A., Grigsby, J., Greco,
Kohlschutter, A.,& Eichler, F. (2011). Childhood C.,...Hagerman, R. J. (2003). The fragile X
leukodystrophies: A clinical perspective. premutation presenting as essential tremor.
Expert Reviews in Neurotherapy, 11, 14851496. Archives of Neurology, 60, 117121.
Kothbauer-Margreiter, I., Sturzenegger, M., Levin, H. S., Goldstein, F. C., Norcross, K.,
Komor, J., Baumgartner, R., & Hess, C. W. Amparo, E. G., Guinto, F. C., Jr., & Mader,
(1996). Encephalopathy associated with J. T. (1989). Neurobehavioral and magnetic
Hashimoto thyroiditis: Diagnosis and treat- resonance imaging findings in two cases of
ment. Journal of Neurology, 243, 585593. decompression sickness. Aviation, Space, and
Koziol, L. F., Budding, D., Andreasen, N., Environmental Medicine, 60, 12041210.
DArrigo, S., Bulgheroni, S., Imamizu, Levisohn, L., Cronin-Golomb, A., &
H.,...Yamazaki, T. (2013). Consensus Schmahmann, J.D. (2000). Neuropsychological
paper: The cerebellums role in movement consequences of cerebellar tumour resection
and cognition. Cerebellum, 13(1), 151177. in children: Cerebellar cognitive affective
Kriegstein, A. R., Shungu, D. C., Millar, W. S., syndrome in a paediatric population. Brain,
Armitage, B. A., Brust, J. C., Chillrud, 123(Pt 5), 10411050.
S.,...Lynch, T. (1999). Leukoencephalopathy Lorincz, M. T. (2010). Neurologic Wilsons
and raised brain lactate from heroin vapor disease. Annals of the New York Academy of
inhalation (chasing the dragon). Neurology, Sciences, 1184, 173187.
53, 17651773. Lugaresi, E., Medori, R., Montagna, P., Baruzzi, A.,
Kumar, N., Cohen-Gadol, A. A., Wright, R. A., Cortelli, P., Lugaresi, A.,...Gambetti, P. (1986).
Miller, G.M., Piepgras, D.G.,& Ahlskog, J.E. Fatal familial insomnia and dysautonomia with
(2006). Superficial siderosis. Neurology, 66, selective degeneration of thalamic nuclei. New
11441152. England Journal of Medicine, 315, 9971003.
Laforce, R., Jr., Buteau, J. P., Bouchard, J. P., Mangialasche, F., Solomon, A., Kareholt, I.,
Rouleau, G.A., Bouchard, R.W.,& Dupre, N. Hooshmand, B., Cecchetti, R., Fratiglioni,
354 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
Offiah, C., & Hall, E. (2008). Heroin-induced Peters, B. H., Levin, H. S., & Kelly, P. J. (1977).
leukoencephalopathy:Characterization using Neurologic and psychologic manifestations
MRI, diffusion-weighted imaging, and MR of decompression illness in divers. Neurology,
spectroscopy. Clinical Radiology, 63, 14652. 27, 125127.
Organization, W.H. (1996). Public health issues Petrou, P., Moscovici, S., Leker, R.R., Itshayek,
and clinical and neurological characteristics of E., Gomori, J. M., & Cohen, J. E. (2012).
the new variant of Creutzfeldt-Jakob disease Ventriculoperitoneal shunt for intracranial
and other human and animal transmissible hypertension in cryptococcal meningitis
spongiform encephalopathies:Memorandum without hydrocephalus. Journal of Clinical
from two WHO meetings. Bulletin of the World Neuroscience, 19, 11751176.
Health Organization, 74, 453463. Plum, F.,& Posner, J. (1966). Diagnosis of stupor
Orsi, L., DAgata, F., Caroppo, P., Franco, A., and coma. Philadelphia, PA:F.A. Davis.
Caglio, M. M., Avidano, F.,...Mortara, P. Pollock, S. S., Pollock, T. M., & Harrison, M. J.
(2011). Neuropsychological picture of 33 spi- (1984). Infection of the central nervous sys-
nocerebellar ataxia cases. Journal of Clinical tem by Listeria monocytogenes:Areview of
and Experimental Neuropsychology, 33, 315325. 54 adult and juvenile cases. Quarterly Journal
Osawa, A., Maeshima, S., Kubo, K., & Itakura, of Medicine, 53, 331340.
T. (2006). Neuropsychological deficits associ- Poretti, A., Boltshauser, E., & Schmahmann,
ated with a tumour in the posterior corpus J. (2012). Paraneoplastic cerebellar syn-
callosum:Areport of two cases. Brain Injury, dromes: Neurodegeneration in Langerhans
20, 673676. cell histiocytosis. In E. Boltshauser & J.
Osimani, A., Berger, A., Friedman, J., Schmahmann (Eds.), Cerebellar disorders
Porat-Katz, B. S., & Abarbanel, J. M. (2005). in children. Clinics in developmental medi-
Neuropsychology of vitamin B12 deficiency cine No. 191192 (pp. 351357). London,
in elderly dementia patients and control UK:MacKeith Press.
subjects. Journal of Geriatric Psychiatry and Prayer, D., Grois, N., Prosch, H., Gadner, H.,&
Neurology, 18, 3338. Barkovich, A. J. (2004). MR imaging pre-
Ozturk, A., Gurses, C., Baykan, B., Gokyigit, sentation of intracranial disease associated
A., & Eraksoy, M. (2002). Subacute scleros- with Langerhans cell histiocytosis. American
ing panencephalitis: Clinical and magnetic Journal of Neuroradiology, 25, 880891.
resonance imaging evaluation of 36 patients. Prosch, H., Grois, N., Wnorowski, M., Steiner,
Journal of Child Neurology, 17, 2529. M.,& Prayer, D. (2007). Long-term MR imag-
Palmer, M. S., Dryden, A. J., Hughes, J. T., & ing course of neurodegenerative Langerhans
Collinge, J. (1991). Homozygous prion cell histiocytosis. AJNR American Journal of
protein genotype predisposes to sporadic Neuroradiology, 28, 10221028.
Creutzfeldt-Jakob disease. Nature, 352, Prusiner, S. B. (1982). Novel proteinaceous
340342. infectious particles cause scrapie. Science, 216,
Paloneva, J., Autti, T., & Hakola, P. (2002). 136144.
Polycystic lipomembranous osteodyspla- Pyrgos, V., Seitz, A. E., Steiner, C. A.,
sia with sclerosing leukoencephalopathy. Prevots, D. R., & Williamson, P. R. (2013).
In: Pagon RA, Adam MP, Bird TD, Dolan Epidemiology of cryptococcal meningitis in
CR, Fong CT, Smith RJH, Stephens K, edi- the US:19972009. PLoS One, 8, e56269.
tors. GeneReviews [Internet]. Seattle Ramati, A., Rubin, L.H., Wicklund, A., Pliskin,
(WA): University of Washington, Seattle; N. H., Ammar, A. N., Fink, J. W.,...Kelley,
19932014 K.M. (2009). Psychiatric morbidity following
Pandya, D. N., & Kuypers, H. G. (1969). electrical injury and its effects on cognitive
Cortico-cortical connections in the rhesus functioning. General Hospital Psychiatry, 31,
monkey. Brain Research, 13, 1336. 360366.
Payer, M., Sottas, C., & Bonvin, C. (2010). Rao, S.M., Leo, G.J., Bernardin, L.,& Unverzagt,
Superficial siderosis of the central nervous F. (1991). Cognitive dysfunction in multiple
system: Secondary progression despite sclerosis. I. Frequency, patterns, and predic-
successful surgical treatment, mimicking tion. Neurology, 41, 685691.
amyotrophic lateral sclerosis. Case report Rennebohm, R., Susac, J.O., Egan, R.A.,& Daroff,
and review. Acta Neurochirugica (Wien), 152, R. B. (2010). Susacs Syndromeupdate.
14111416. Journal of Neurological Sciences, 299, 8691.
Pearce, J. M. (2012). Brain disease leading to Rodin, G.,& Ahles, T.A. (2012). Accumulating
mental illness: A concept initiated by the evidence for the effect of chemotherapy on
discovery of general paralysis of the insane. cognition. Journal of Clinical Oncology, 30,
European Neurology, 67, 272278. 35683569.
356 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
dementias: A case report. Journal of Geriatric complications of Whipples disease. Brain, 88,
Psychiatry and Neurology, 10, 514. 137150.
Sciascia, S., Bertolaccini, M. L., Baldovino, S., Sokol, R.J. (1988). Vitamin E deficiency and neu-
Roccatello, D., Khamashta, M.A.,& Sanna, G. rologic disease. Annual Review of Nutrition, 8,
(2013). Central nervous system involvement 351373.
in systemic lupus erythematosus: Overview Sonneville, R., Klein, I., de Broucker, T.,& Wolff,
on classification criteria. Autoimmune Reviews, M. (2009). Post-infectious encephalitis in
12, 426429. adults: diagnosis and management. J Infect
Sellner, J., & Trinka, E. (2012). Seizures and 2009; 58, 321328.
epilepsy in herpes simplex virus encephali- Sproule, D. M., & Kaufmann, P. (2008).
tis: Current concepts and future directions Mitochondrial encephalopathy, lactic acido-
of pathogenesis and management. Journal of sis, and strokelike episodes: Basic concepts,
Neurology, 259, 20192030. clinical phenotype, and therapeutic man-
Seminara, S.B., Acierno, J.S., Jr., Abdulwahid, agement of MELAS syndrome. Annals of the
N. A., Crowley, W. F., Jr., & Margolin, D. H. NewYork Academy of Sciences, 1142, 133158.
(2002). Hypogonadotropic hypogonadism Stadelmann, C., Albert, M., Wegner, C.,& Bruck,
and cerebellar ataxia: Detailed phenotypic W. (2008). Cortical pathology in multiple
characterization of a large, extended kin- sclerosis. Current Opinion in Neurology, 21,
dred. Journal of Clinical Endocrinology and 229234.
Metabolism, 87, 16071612. Stefani, A., Riello, M., Rossini, F., Mariotto, S.,
Sepulveda-Falla, D., Glatzel, M., & Lopera, Fenzi, F., Gambina, G.,...Monaco, S. (2013).
F. (2012). Phenotypic profile of early-onset Neurosyphilis manifesting with rapidly
familial Alzheimers disease caused by progressive dementia: Report of three cases.
presenilin-1 E280A mutation. Journal of Neurological Sciences, 34(11), 20272030.
Alzheimers Disease, 32, 1-12. Susac, J.O. (1994). Susacs syndrome:The triad
Sevin, M., Lesca, G., Baumann, N., Millat, G., of microangiopathy of the brain and retina
Lyon-Caen, O., Vanier, M. T., & Sedel, F. with hearing loss in young women. Neurology,
(2007). The adult form of Niemann-Pick dis- 44, 591593.
ease type C. Brain, 130, 120133. Takalo, M., Salminen, A., Soininen, H., Hiltunen,
Sharma, O. P. (1997). Neurosarcoidosis: A per- M.,& Haapasalo, A. (2013). Protein aggrega-
sonal perspective based on the study of 37 tion and degradation mechanisms in neuro-
patients. Chest, 112, 220228. degenerative diseases. American Journal of
Shi, C. H., Schisler, J. C., Rubel, C. E., Tan, S., Neurodegenerative Diseases, 2, 114.
Song, B., McDonough, H.,...Xu, Y.M. (2014). Tan, I. L., McArthur, J. C., Clifford, D. B.,
Ataxia and hypogonadism caused by the loss Major, E. O., & Nath, A. (2011). Immune
of ubiquitin ligase activity of the U box pro- reconstitution inflammatory syndrome in
tein CHIP. Human Molecular Genetics, 23(4), natalizumab-associated PML. Neurology, 77,
10131024. 10611067.
Shprecher, D.,& Mehta, L. (2010). The syndrome Tavano, A., Grasso, R., Gagliardi, C., Triulzi, F.,
of delayed post-hypoxic leukoencephalopa- Bresolin, N., Fabbro, F.,...Borgatti, R. (2007).
thy. NeuroRehabilitation, 26, 6572. Disorders of cognitive and affective develop-
Shuper, A., Stark, B., Yaniv, Y., Zaizov, R., ment in cerebellar malformations. Brain, 130,
Carel, C., Sadeh, M., & Steinmetz, A. (2000). 26462660.
Cerebellar involvement in Langerhans cell Tedesco, A.M., Chiricozzi, F.R., Clausi, S., Lupo,
histiocytosis: A progressive neuropsychi- M., Molinari, M.,& Leggio, M.G. (2011). The
atric disease. Journal of Child Neurology, 15, cerebellar cognitive profile. Brain, 134(Pt 12),
824826. 36723686.
Sjaastad, O., & Nordvik, A. (1973). The corpus Terushkin, V., Stern, B.J., Judson, M.A., Hagiwara,
callosal angle in the diagnosis of cerebral M., Pramanik, B., Sanchez, M.,& Prystowsky,
ventricular enlargement. Acta Neurological S. (2010). Neurosarcoidosis: Presentations
Scandinavica, 49, 396406. and management. Neurologist, 16, 215.
Sjowall, J., Ledel, A., Ernerudh, J., Tetzlaff, K., Friege, L., Hutzelmann, A., Reuter,
Ekerfelt, C., & Forsberg, P. (2012). M., Holl, D., & Leplow, B. (1999). Magnetic
Doxycycline-mediated effects on persistent resonance signal abnormalities and neuropsy-
symptoms and systemic cytokine responses chological deficits in elderly compressed-air
post-neuroborreliosis: A randomized, pro- divers. European Neurology, 42, 194199.
spective, cross-over study. BMC Infectious Tian, C., Liu, D., Sun, Q. L., Chen, C., Xu, Y.,
Disease, 12, 186. Wang, H.,...Dong, X.P. (2013). Comparative
Smith, W.T., French, J.M., Gottsman, M., Smith, analysis of gene expression profiles between
A. J., & Wakes-Miller, J. A. (1965). Cerebral cortex and thalamus in Chinese fatal familial
358 Part iiThe Dementias: The Major Diseases and Clinical Syndromes
Alzheimers disease (AD) is the most com- the index patient with early-onset AD demen-
mon cause of neurodegenerative demen- tia, was believed to represent a very rare
tia. In the next two to three decades, with condition that caused presenile dementia.
changing demographics and longevity on the It was not until the mid-to-latter part of the
rise, a worldwide pandemic of clinical AD 20th century that the link was made that AD
and dementia is anticipatedthat is, unless greatly contributed, if not caused, most cases
highly effective preventative or curative of senile dementia in older individuals. In
treatments are forthcoming. While our under- the past two decades, there has finally been
standing of the scope of the AD problem and better appreciation that the AD spectrum is
diagnostics has greatly increased in the last the most common cause of neurodegenera-
three decades, our understanding regarding tive dementias, that it encompasses wide age
the etiology, pathophysiology, and therapeu- ranges and heterogeneous presentations,
tics in AD remains in its nascency. Similar to and that in any individual it proceeds along
most chronic diseases in the elderly, AD can a lengthy clinical course that develops, pro-
be managed via a multifactorial approach gresses, and manifests insidiously over one
of nonpharmacological and pharmacologi- or more decades. Brain systems that are pri-
cal interventions that provide variable, but marily affected and are most vulnerable often
measurable and overall meaningful, benefits become symptomatic first in AD.
in slowing clinical decline. However, AD can- The classic AD presentation (typical AD)
not yet be prevented, cured, or blocked from involves initial memory difficulties attribut-
ultimately progressing to cause debilitation able to dysfunction of medial temporal lobe
and death. Until highly potent therapeutic structures, particularly the entorhinal cor-
options become available, clinicians have tex and hippocampus, and associated pari-
an obligation to be knowledgeable about etal memory processing regions. However,
this common and costly condition, and they as the disease progresses, patients accrue
have a duty to compassionately diagnose, additional deficits in parietal and frontal
treat, and care for affected individuals, their regions, thus affecting executive functions,
loved ones, and caregivers using all options language, visuospatial systems, personality
available. and, ultimately, motor programming sys-
When first described in 1906 by Professor tems. Atypical presentations of AD (atypi-
Alois Alzheimer, the case of August Dieter, cal AD) involving primarily disturbances in
360
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 361
language, executive function and behavior, Johnson, & Arrighi, 2008). In the United
or visuospatial function are now formally rec- States, AD is the only top 10 cause of mor-
ognized as part of the AD clinical syndrome. tality that is still significantly on the rise (see
Beyond disturbances in cognitive abilities, Fig. 16.1; Alzheimers-Association, 2013).
there is often an overlay of accumulating Cases of AD are also projected to potentially
neuropsychiatric and behavioral symptoms triple in the United States over the next three
and personality changes that include apa- to four decades (see Fig. 16.2; Hebert, Weuve,
thy, anxiety, depression, irritability, agitation, Scherr, & Evans, 2013) and to double every
delusions, hallucinations, impulsivity, insen- 20 years around the world. AD does not
sitivity, and sleep problems. Many of these, always cause impairment in isolation; more
including anxiety, sleep difficulties, apathy, than have half of AD cases around the world
and irritability, may, in retrospect, be the will likely be due to mixed AD and vascular
earliest symptoms. These symptoms, along etiology (Prince et al., 2013; Saxena, 2012;
with common prominent A signs (amne- Wimo& Prince, 2010).
sia, aphasia, agnosia, apathy, and anxiety; The complex genetics of the most common
and others such as apraxia, acalculia, admin- form of AD dementia, the sporadic late-onset
istrative [executive] and attentional deficits; type, is not well understood, nor are the etiol-
see Chapter 19), contribute to progressive ogy or pathophysiology of AD. The leading
difficulties in executing activities of daily liv- models of AD etiology posit a central and
ing (ADLs) and self-care, and the emergence early role of accumulation of synapto- and
of problem behaviors. Taken together, these neurotoxic forms of the amyloid-beta pro-
eventually lead to disability and complete tein (A) in inducing pathological processes
dependence on others. involving activation of inflammatory and
As the population ages in the developing microglial cascades, broad ionic and neu-
world, and as the percentage of elderly with rotransmitter abnormalities, mitochondrial
dementia increases with age, the burden of dysfunction, and oxidative stress. In the
care and the costs of AD will also increase prevailing model, these processes are then
(Alzheimers-Association, 2013; Prince posited to lead to hyperphosphorylation of
et al., 2013; Ziegler-Graham, Brookmeyer, the microtubule stabilizing protein tau and
Percentage
70
60 + 68%
50
40
30
20
10
0
8% 2%
10 16%
20 23%
30
42%
40
50
Millions of people
Ages 6584 Ages 7584 Age 85+
with Alzheimers
16
14 13.8
12 11.6
10 8.4
8
5.8
6
4.7
4
2
0
therapies seek to minimize the effects of dis- reinforcing the behavioral and environmen-
abling problem symptoms, to slow clinical tal care plan. Use of neuroleptic medications
progression, and to mitigate care burden in (e.g., antipsychotics) in AD is sometimes
AD. Currently available anti-AD medica- necessary as a last resort in severe and refrac-
tions are not disease modifying but are dis- tory cases or in situations where safety risk is
ease course modifying by slowing clinical, high, but it comes with a high clinical thresh-
if not neuropathological, progression. From a old and high long-term risk-benefit ratio.
clinical viewpoint, therapies aim to preserve, Persistent multifactorial treatment and care
for longer than would be possible without in AD can delay time to reaching costly clini-
intervention, cognition, independence, qual- cal milestones:the late stages of illness when
ity of life, and comfort. From a health eco- individuals require 24-hour supervision and
nomics perspective, therapies that minimize care, and which is often, in developed coun-
caregiver burden and delay nursing home tries, provided in an institutional setting. AD
entry translate into significant increases in care in the end stages of the illness should be
productivity and savings of health care dol- palliative and focus on facilitating a good
lars (Cappell, Herrmann, Cornish,& Lanctot, death. Clinicians can, by maintaining a pro-
2010; Weycker etal., 2007). active, positive, flexible, multifactorial, and
Pharmacotherapy in AD first involves a individualized approach to compassionately
thorough review of a patients existing medi- caring for patientcaregiver dyads, provide
cations and supplements in order to eliminate meaningful care that is not only invaluable to
redundancies and potentially inappropri- patients, families, and caregivers on a micro
ate and deleterious treatments. Currently, level, but that is also cost-effective and ben-
FDA-approved anti-AD pharmacotherapies eficial to society on the macro level.
(the acetyl cholinesterase inhibitors (ChEIs)
donepezil, galantamine, and rivastigmine,
and the NMDA antagonist memantine) Epidemiology and Risk Factors
can offer meaningful benefit by potentially
reducing short-term as well as long-term Alzheimers disease and dementia are on
clinical progression of symptoms. First-line the rise in the United States, in developed
treatment for behavioral problems is non- countries, and globally. As longevity trends
pharmacological and involves identifying the continue to ensure that most individuals will
trigger for the problem behavior. Once the live well into their 70s, 80s, or 90s, the preva-
trigger is identified, it is necessary to institute lence of AD dementia is anticipated to rise
appropriate interventions, make environ- dramatically, two- to three-fold in the com-
mental modifications, and then to evaluate ing three to four decades (see Fig. 16.2). The
the impact of the interventions. Finally, it major risk factors of developing AD demen-
is important to complete the loop by itera- tia (see Table 16.1) are older age (past age 65,
tively and flexibly adjusting, as necessary, or but particularly past age 80) (see Fig. 16.2);
*Currently a nonmodifiable risk factor, but clinical trials with amyloid-modifying drugs are about to begin (see
Chapter18).
364part ii The Dementias: The Major Diseases and Clinical Syndromes
family history of AD or dementia in a first- or until age 91.3 In the 34 countries that are
second-degree blood relative (approximately members of the Organization of Economic
two- to six-fold relative risk [RR]); vascular Cooperation and Development (OECD), the
risk factors (diabetes, hypertension, dyslipid- proportion of those aged 80 years and over
emia, metabolic syndrome, smoking), altered will increase from 4% of the total population
cerebral perfusion, cerebrovascular injury in 2010 to 10% in 2050 (Prince et al., 2013).
and stroke; severe or repeated brain trauma; Between 2010 and 2050 in the United States,
female gender; race (in the United States, the percentage of people age 65 and older is
African American and Hispanic race are at 1.5- expected to increase from 14% to 20% of the
to 2-fold RR compared to White Caucasians); population (Vincent& Velkof, 2010). By 2050,
markers of low cognitive reserve (low educa- the number of Americans age 85 years and
tional, professional, or social attainment; low older will nearly quadruple to 21 million,
intelligence); Trisomy 21 (Down syndrome), which will result in an additional 13 mil-
and genetic markers for higher susceptibility, lion oldest-old Americans who will be at the
most notably individuals who carry one or highest risk for developing AD (Hebert etal.,
two 4 alleles of the apolipoprotein-E (APOE) 2013; Vincent& Velkof, 2010)(see Fig. 16.2).
gene (APOE-4) (3-fold and 8- to 10-fold The 2010 Alzheimers Disease International
RR, respectively, compared to homozygous (ADI) and the 2012 World Health Organization
APOE-3/3s). Deterministic dominantly (WHO) World Dementia Report estimate the
inherited AD mutations are rare and account total number of people with dementia world-
for 1%2% or less of AD cases, most of whom wide in 2010 at 35.6million and project a near
develop AD dementia before age 60. Finally, doubling every 20 years, to 65.7 million in
individuals who have positive biomarkers of 2030 and 115.4million in 2050 (Saxena, 2012;
A accumulation (e.g., CSF or amyloid-PET Wimo& Prince, 2010). These reports estimate
profile of the AD trait) suggesting cerebral a total number of new cases of dementia each
amyloidosis are at increased risk of progress- year worldwide of nearly 7.7million, which
ing to MCI and dementia stages of AD (see translates into one new case of dementia
Chapters17, 18, and 22). every 4 seconds; the vast majority, 60%80%,
Alzheimers disease is strongly associated of these cases are due to AD or mixed demen-
with increasing age beyond 65. The preva- tia due to a combination of pathology due
lence of AD is estimated to approximately to AD and vascular dementia (Prince et al.,
double every 5years from age 65 to 85 going 2013; Saxena, 2012; Wimo& Prince, 2010).
from approximately 1%2% at age 65 to more Estimates using data from the 2010 US
than 30%50% by age 85. With the advent of Census and the Chicago Health and Aging
greater longevity in all populations, barring Project (CHAP) and older AD criteria (e.g.,
development of a substantial medical break- the 1984 NINCDS-ADRDA AD criteria) place
through that will effectively prevent, retard, the current number of individuals with AD
stop, or cure AD, countries that will expe- in the United States at 5.2 million (Hebert
rience a large demographic shift to greater et al., 2013) (see Fig. 16.2). Of these 5.2 mil-
numbers of elderly individuals over age 65 lion, approximately 5 million are age 65 or
in the coming decades will also experience older while 200,000 are younger individuals
a commensurate large increase in the preva- who can be classified as having early-onset
lence (number of cases) of AD. In high- and AD. Current estimates are that 11% (1 in
middle-income countries falling mortality for 9) of individuals age 65 and older, and 32%
older adults, due to improvements in adult (1 in 3)of individuals 85 and older have AD
medicine and health care, are co-occurring (Hebert et al., 2013). The prevalence of all
with falling fertility rates (fewer children forms of dementia from population-based
being born per adults) and improvements studies, including the Aging, Demographics,
in child health, therefore causing further and Memory Study (ADAMS), are that 13.9%
increased life expectancy. For example, in (approximately 1 in 7)of Americans age 71 and
Japan, total life expectancy is now 86years at older have dementia of any kind (including
birth for women and 79years for men; those AD) (Plassman etal., 2007; Wilson, Leurgans,
reaching the age of 60 can be expected, on Boyle,& Bennett, 2011). Early-onset AD cur-
average, to survive until age 88.1, and those rently accounts for approximately 4% of AD
reaching the age of 80, to survive, on average, cases. Of the remaining 96% of AD cases who
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 365
are 65 and older (late-onset AD), 13% are about two thirds of Americans with AD
between age 65 and 74, 44% are between age who are age 65 and older are women. This
75 and 84, and 38% are 85 or older. is principally due to greater longevity in
The prevalence of AD in the United women compared to men. Recent estimates
States is expected to nearly triple over the suggest that 16% of US women and 11% of
next 3540 years (Alzheimers-Association, US men age 71 and older are affected by AD
2013; Hebert et al., 2013) (see Fig. 16.2); this and related dementias (Hebert et al., 2013;
is mainly due to the upcoming age demo- Seshadri etal., 1997).
graphic the silver tsunami. The number Racial differences in US prevalence esti-
and percentage of Americans who will be mates for AD and associated dementias sug-
among the oldest-old will increase substan- gest that, proportional to their population
tially in the next three decades due to a com- compared to Whites, older African Americans
bination of increasing longevity and the baby are more than 1.52 times and older Hispanics
boomer generation entering the high AD risk are 1.41.5 times more likely to be affected
age category of 65 and older. Currently the 85 by AD and dementias than older Whites
and older US population includes approxi- (Gurland et al., 1999; Potter et al., 2009). In
mately 2million individuals with AD, or 40% addition to genetic differences, disparities in
of all people with AD who are age 65 and health conditions related to cerebrovascular
older. Recent projections by Hebert and col- health, such as stroke, diabetes, hyperten-
leagues are that in year 2031, when the first sion, and educational and socioeconomic
wave of baby boomers reaches age 85, more factors, have been especially strongly impli-
than 3 million individuals age 85 and older cated as the driving factors that account for
will be affected with AD (Hebert etal., 2013). the significant differential racial prevalence
There will be a 40% increase from 2013 to 2025 proportions (Alzheimers-Association, 2013).
in the number of Americans affected by AD; The concept of cognitive reserve has also
going from approximately 5.2million now to been implicated as a factor that can mediate
7.1million in 2025 (Hebert etal., 2013). Using the manifestation of AD dementia (Mitchell,
year 2000 and 2010 US census data, the num- Shaughnessy, Shirk, Yang,& Atri, 2012; Stern,
ber of people age 65 and older with AD is 2009). Stern observed that individual dif-
projected to nearly triple from approximately ferences in how people process tasks allow
5 million now to between 13.8 and 16 mil- some people to cope better than others with
lion individuals by 2050 (Hebert etal., 2013; brain pathology; Stern has defined cogni-
Hebert, Scherr, Bienias, Bennett, & Evans, tive reserve as the brains capacity to main-
2003). tain cognitive function despite neurologic
The increasing incidence of new AD cases damage or disease (Stern, 2009). The related
in the United States is also projected to con- concepts of brain reserve, neural reserve,
tinue to rise rapidly in the coming decades. and neural compensation, along with cogni-
While compared to 2000 (411,000 new annual tive reserve, have several roots but all posit
AD cases), there was a 10% increase in 2010 that the brain has the ability to functionally
(454,000 new annual cases) in the estimated compensate for neurological damage. These
number of new AD cases per year, projections concepts can help to explain early findings of
estimate a 50% increase by 2030 (615,000 new discrepancies between clinical severity/cog-
annual cases) and a 130% increase (959,000 nitive performance and measures of disease
new annual cases) by 2050 (Hebert, Beckett, burden. These observations include findings
Scherr,& Evans, 2001). Future estimates that of high amyloid plaque counts in individuals
will utilize the recently updated or new AD who performed well on cognitive tests, pres-
criteria, including the AA-NIA (Alzheimers ence of AD neuropathology in the absence
Association-National Institute of Aging), of clinical dementia, and that 10%40% of
DSM-5 (Diagnostic and Statistical Manual of individuals who exceeded pathological bur-
Mental Disorders), and IWG (International den for amyloid burden by PIB-PET scan-
Working Group) criteria would greatly ning or plaque and tangle burden at autopsy
increase the incidence and prevalence of AD showed no previous cognitive impairments
as they all place emphasis on early detection. (Blessed, Tomlinson,& Roth, 1968; Katzman,
Alzheimers disease is approximately 1988; Rentz et al., 2010). While there is no
twice more prevalent in women than men; one measure of cognitive reserve, proxies
366part ii The Dementias: The Major Diseases and Clinical Syndromes
for it have been proposed that include years variations and environmental factors likely
of education; performance on tests of intel- interact to cause complex diseases such as AD.
ligence, measures of verbal literacy, word Despite great effort, only three Mendelian
reading, and vocabulary; occupational attain- genetic causes of AD have been identified; all
ment; level of participation in social, mental, of these result in autosomal dominant famil-
and leisure activities; and physiological, ial AD (FAD), and individuals who carry the
structural, and neuroimaging measures of mutation have a 95% or more lifetime risk
brain function (e.g., brain volume, cortical to develop the clinical manifestation of AD
thickness, neuronal count, synaptic density, dementia if they live beyond the expected
activity of brain regions on functional neu- range for age of disease onset, which is
roimaging). Years of education, performance often before age 65. These early-onset AD
on tests of estimated intelligence, and occu- (dementia onset prior to age 65)dominantly
pational attainment have all been implicated inherited genetic mutations are due to the
as factors that may account for differential Amyloid Precursor Protein (APP), Presenilin
prevalence among populations with lower 1 (PSEN1), and Presenilin 2 (PSEN2) muta-
versus higher levels of AD (Fratiglioni, tions. PSEN1 mutations account for 60% of
Paillard-Borg, & Winblad, 2004; Mitchell dominantly inherited AD, and APP muta-
et al., 2012; Stern et al., 1994). For example, tions account for about 15%. PSEN2 muta-
in the Washington Heights longitudinal tions that cause AD are very rare and have
observational cohort study, the relative risk only been described in 22 families (Loy,
of developing dementia was approximately Schofield, Turner, & Kwok, 2014). However,
twice greater in low education as well as in overall, all three gene mutations only account
low occupation groups compared groups for 1% or less of all AD cases (Loy etal., 2014).
with high levels (Stern etal., 1994). As a complex genetic disease, there are
Finally, there is a very high prevalence of likely many genetic variations that contrib-
an Alzheimers-like dementia syndrome in ute to risk. The genetic AD susceptibility fac-
older individuals with Trisomy 21: Down tor with the greatest risk identified to date
syndrome (DS). While there are no widely is the apolipoprotein-E (APOE) gene. Of the
accepted criteria to characterize dementia three alleles of APOE (2, 3, and 4), pos-
in DS, about 40% of such individuals over session of one or more 4 alleles confers a
60 years of age have a diagnosis of demen- higher risk, relative to having the 3 allele,
tia (Margallo-Lana et al., 2003). By age 40, for accelerated A deposition and manifest-
virtually all individuals with DS accumulate ing the AD clinical phenotype. Possessing
significant AD-like brain pathology due to the 2 allele appears to delay A deposition
higher production and deposition of amy- and to be relatively protective. Meanwhile,
loid as well as some neurofibrilliary tangles the SorL1 gene mutation has been implicated
secondary to increased tau hyperphosphor- in late-onset AD (age 65 or older); it interacts
ylation (Hanney et al., 2012). The cause is with APOE, affects APP trafficking, and gene
believed to be due to more copies of the amy- product overexpression reduces A produc-
loid precursor protein (APP) gene, which is tion by decreasing APP and -secretase inter-
located on chromosome 21. There are over 5.8 actions (Ballard et al., 2011; Rogaeva et al.,
individuals with DS worldwide, and even in 2007; Scherzer etal., 2004).
the absence of a dementia diagnosis, the mil-
lions of individuals with DS over age 40 are
at high risk for accelerated cognitive decline The Amyloid Cascade Hypothesis
of about 11% per year (Hanney et al., 2012; ofAlzheimers Disease
Morris& Alberman, 2009).
The leading hypothesis for the etiology of AD
has been the amyloid hypothesis (Hardy &
Genetics and Etiology Higgins, 1992; Selkoe, 1991) and remains
controversial (Davies, 2000; Hyman, 2011;
The genetics and the etiology of AD are com- Zlokovic, 2011) (see Fig. 16.3). All known
plex and incompletely understood. While AD gene mutations affect A metabolism
degree of AD risk attributable to genetics to increase relative or absolute production
has been estimated at 70%, many genetic of the A42 form of the polypeptide; this
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 367
(A)
Amyloid cascade hypothesis
Dementia
Figure16.3 Hypothesis regarding the etiology of Alzheimers disease (AD) dementia. (A) The
amyloid cascade hypothesis revised (Hardy and Selkoe). The leading model for AD etiology posits
the sequence of pathogenic events that lead to AD dementia. Curved violet arrows indicate that
A oligomers directly injure synapses and neurites of brain neurons as well as activating microglia
and astrocytes. The hypothesis remains controversial and several others have been proposed
(Davies, 2000, Zlokovic, 2011), including (B) the two-hit vascular hypothesis (Zlokovic, 2011)of AD,
which posits that vascular factors and injury all converge on a common final disease pathway that
involves brain microvascular dysfunction and/or neuronal degeneration (hit one), which results in
further neuronal injury and degeneration due to amyloid- accumulation and tau pathology. BBB,
bloodbrain barrier.
368part ii The Dementias: The Major Diseases and Clinical Syndromes
(B)
Vascular factors
(Hypertension, diabetes,
cardiac disease and/or stroke)
Hit one
App expression
and processing
Amyloid- Amyloid-
Toxic accumulates clearance production Capillary hypoperfusion
Hit two
Amyloid- p-tau
Dementia
Figure16.3Continued
formations, whether intra- or extracellular, local disruption of the neuropil, loss of den-
are associated with direct and indirect synap- dritic spines, remodeling of neurites, and
totoxicity and neurotoxicity that can lead to the inflammatory cascade. Over time, this
neurodegeneration. process becomes increasingly decoupled
from amyloid in the amyloid-independent
second stage to cause further neurofibril-
The Two-Stage Amyloid-Dependent and lary tangle (NFT) formation, neuronal and
Amyloid-Independent Hypothesis of synaptic loss, glial activation and responses
Alzheimers Disease in limbic and association cortices and later
throughout the cortical mantle, and finally
While the amyloid hypothesis remains a extensive neurodegeneration and the discon-
leading hypothesis in the field, there are nection and disruption of intrinsic cognitive
many other hypotheses, including those that and behavioral networks, which ultimately
view amyloid formation as a by-product leads to organ failure (Hyman, 2011). This
and not a root cause of AD, and variants hypothesis also serves to support the critical
and reformulations to the amyloid hypoth- amyloid link found in genetics.
esis that have been proposed. For example,
a two-stage reformulated hypothesis has
been proposed (Hyman, 2011), which posits The Two-Hit Vascular Hypothesis
that the pathogenic process of AD may have ofAlzheimers Disease
an amyloid-dependent first phase, led by
soluble oligomeric and fibrillar A accumu- Another emerging hypothesis is the two-hit
lation, that starts a pathogenic cascade of vascular hypothesis for AD (Zlokovic,
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 369
2011) (see Fig. 16.3B). A significant propor- in three or more generations and the age of
tion of confirmed cases of AD at autopsy in onset is less than 60years. If there are two or
older patients contain mixed vascular pathol- more first-degree relatives and age of onset
ogy and small-vessel disease. There is sub- is less than 61 years, the probability is 68%,
stantial overlap in the risk factors for AD and but this probability falls to 15% with age of
the risk factors for cerebrovascular disease onset less than 65years, and to <1% for age
(e.g., hypertension and diabetes). Finally, of onset greater than 65years old (Loy etal.,
cerebral ischemia, leukoaraiosis, transient 2014). Causative mutations are rare both in
ischemic attacks, and infarcts all increase the patients with onset later than 65 as well as in
risk of AD. Taking these observations into those with early onset but who do not have
consideration, Zlokovic proposed a model in a family history. The latter can be concealed
which microvascular dysfunction (Hit one) by nonpaternity and reduced penetrance
induces and aggravates -amyloid accumula- confounds.
tion (Hit two). In this formulation vascu-
lar factors are posited to all converge on a
common final disease pathway that involves Susceptibility Alzheimers Disease Mutations
brain microvascular dysfunction and/or
degeneration, as well as amyloid- and tau The APOE gene is associated with relatively
pathology. Hit one is posited to proceed accelerated deposition of A in individuals
along a non-amyloid- pathway caused by with one or two e4 alleles and higher risk of
vascular risk factors and conditions that manifesting Alzheimers dementia. Relative
lead to bloodbrain barrier dysfunction and to individuals with the common APOE 3/
a reduction in cerebral blood flow (oligae- 3 genotype, individuals with the APOE 2/
mia), thus initiating a cascade of events that 2, 3/4, 4/4 genotypes are 0.5, 3, and 810
precedes dementia. In the non-amyloid- times more likely to develop Alzheimers
pathway (see the Fig.16.3b, shown in green dementia, respectively (Corder etal., 1993; Loy
boxes) early neuronal dysfunction is caused etal., 2014). APOE is a major cholesterol trans-
by toxic accumulates and capillary hypoper- port protein and is the major lipoprotein in the
fusion (Zlokovic, 2011). This vascular injury brain; it binds Adifferent APOE isoforms
then induces Hit Two, which proceeds have different cholesterol transport and A
along an amyloid- pathway by reducing binding efficienciesand is involved with A
amyloid- clearance at the bloodbrain bar- clearance, amyloid load (it is codeposited with
rier and increasing its production from the it in neuritic plaques), and cholinergic dys-
amyloid- precursor protein (APP), leading function (Ballard et al., 2011). Other recently
to amyloid- accumulation (the amyloid- identified risk genes have significantly less
pathway; see the figure, shown in red boxes). effect than APOE in AD and include genes
Increases in amyloid- then amplify neuro- that increase risk for NFTs including GSK3
nal dysfunction, accelerate neurodegenera- (tau phosphorylation), DYRK1A (tau phos-
tion and dementia, and contribute to disease phorylation), and Tau, and genes that affect
self-propagation. Neurofibrillary tangle for- other mechanisms, which include TOMM40
mation is then caused by hyperphosphory- (mitochondrial protein that interacts with
lation of tau (p-tau), which can be induced APP), CLU (chaperone protein involved in A
by amyloid- accumulation and/or vascular formation), and PICALM (phosphatidylino-
hypoperfusion. sitol binding clathrin assembly protein in
endosomes)see AlzGene Database (www.
alzgene.org) for regularly updated synop-
Deterministic Alzheimers Disease Mutations sis of genetic association studies (Bertram,
McQueen, Mullin, Blacker,& Tanzi, 2007).
Multigenerational inheritance and young age The first step in genetic assessment of AD
of onset (<60 years of age) are the key ele- is to obtain a thorough family history from
ments that suggest a high likelihood of find- multiple first-degree family relatives (and
ing a causative mutation in one of the known spouses for collateral information). Next, a
AD genes. There is an 86% probability of find- detailed history should establish the demen-
ing a pathogenic mutation in PSEN1, APP, or tia phenotype, including age of onset of pri-
PSEN2, if there are affected family members mary and salient symptoms, progression of
370part ii The Dementias: The Major Diseases and Clinical Syndromes
symptoms and signs, age of death, availabil- Presentations of AD in the MCI phase of
ity of medical records, and pathological diag- the illness (MCI due to AD) are reviewed
nosis. When there is a high index of suspicion in greater detail in Chapters 17, 19, and 20.
for a pathogenic AD, the affected individual Early neuropsychiatric symptoms of AD are
should be offered testing, and if a known reviewed in Chapter 21. In the earliest clini-
mutation is detected, then early genetic con- cal stages a relatively isolated impairment in
sultation should be recommended. memory formation and inefficiency in learn-
ing is typical, and if function and behavior are
not significantly affected, then the individual
Clinical Features is likely in the transitional MCI due to AD
stage of the AD clinical spectrum. While the
Clinical symptoms in patients with AD do not amnestic presentation of MCI (a-MCI) due to
necessarily present or progress in a uniform AD is the most common, multidomain a-MCI
pattern. While certain core clinical features in and nonamnestic MCI can also be associated
typical (or classic) AD are remarkably con- with AD pathology, the former much more
sistent (e.g., early difficulty with formation of than the latter. The MCI syndrome signifi-
new memories and learning, apathy, mood cantly increases the annual rate (incidence)
changes, irritability, anosognosia), atypical of progression to the Alzheimers demen-
presentations of the AD clinical syndrome are tia stage by six- to eight-fold, from approxi-
still more common in older patients than typ- mately 1%2% per year for individuals 65 and
ical presentations of much less common neu- older to approximately 15% per year. With the
rodegenerative dementing conditions (e.g., advent of more recent use of biomarkers of
FTD, CBD, MSA, PSP). This is due to (1)the amyloid deposition (e.g., amyloid-PET and
high prevalence AD pathology contributing CSF amyloid levels) and neurodegeneration
to dementia symptoms in the old (>65years of (e.g., structural MRI, FDG-PET, and CSF tau
age) and especially in the elderly population and phospho-tau levels), progression rates
over 80years of age where coexistent AD and can be further refined in individuals who
vascular-ischemic pathology can additively have the clinical MCI phenotype and possess
contribute to a mixed dementia syndrome; zero, one, or more positive AD biomarkers;
and (2)selective vulnerability (and selective the incidence rates may be two to three times
resilience) of cognitive and behavioral net- higher (8% vs. 17%22%) (Petersen et al.,
works in any individual patient can trump 2013)in those with one or more positive AD
the nature of the underlying neuropathology. biomarkers than those who are biomarker
While the predominant presentation of negative.
AD is an amnestic one (typical AD) where
the individual has poor recent and day-to-
day memory and better memory for remote Mild Alzheimers Disease Versus Normal
events, there can be large heterogeneity in Cognitive Aging:Whats Normal and
the AD clinical phenotype; this is particularly WhatsNot
true regarding the most prominent and initial
cognitive, behavioral, and functional deficits, While the etiology and mechanisms that
and the course of symptom progression and underlie AD and cognitive aging are both
clinical decline. Recently, atypical presenta- incompletely understood, it is more appar-
tions/variants of AD (atypical AD) have been ent that cognitive impairments and dementia
formally recognized as part of AD clinical in Alzheimers disease do not represent the
criteria; for example, the 2011 NIA-AA AD normal aging process but rather a disease
criteria recognize nonamnestic AD presen- process with its own, rather heterogeneous,
tations that include language, visuospa- clinical phenotype and spectrum.
tial, and executive dysfunction features
(McKhann etal., 2011). Yet the final common
pathway of all neurodegenerative demen- Cognitive Aging and Changes in Cognitive
tias converges to leave individuals who are Domains Across the Life Span
completely dependent on caregivers and are
bereft of any significant cognitive, daily liv- The phenomena of cognitive aging, and
ing, or motor function. the mechanisms underlying it, are not well
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 371
Memory
Poor recent/day to day memory Disorientation in time and place
Better memory for remote than recent past Impaired recall and recognition memory
Repetitive in conversation Loses information over a delay
Mislays objects Consistent performance
Would get lost if unaccompanied Impaired working memoryreduced digit and word
span, patent loses track of test instructions
Language
Difficulty finding words Conversational speech hesitant and halting, with
unfinished sentence
Difficulty remembering peoples names Word retrieval difficulty
Loses train of thought in conversation Impaired repetition, with phonemic errors
Difficulty following group conversation Impaired sentence comprehension
Reads less Difficulty following multistage commands
Difficulty writing, producing a signature Problems with left/right (spatial) commands
Reading consistent with conversational speech
Impaired writing and spelling
Calculation
No longer deals with bills, household accounts Impaired mental and written arithmeticespecially
subtractions involving holding and manipulating
numbers, carrying across columns
Difficulty reckoning change
Perception, Spatial Skills, Praxis
Slow to locate and/or identify objects (doesn't Impaired object perception for degraded stimuli/
see things in front of him) unusual Views
Difficulty remembering locations of objects (puts Visually based errors on perceptual tasks
things in wrong place)
Disoriented in familiar environment Slow to localize stimuli in visual field
Difficulty negotiating stairs (judging depth) Impaired space perception
Car accidents suggesting poor spatial judgement Loss of spatial configuration of drawings
(e.g., hitting parked car)
Difficulty executing manual tasks with spatial Spatially impaired reproduction of hand postures
demands (folding clothes, dressing laying table)
Impaired gestural praxis (spatial configuration and
position in space)
Executive Skills
Difficulty working out use of gadgets (e.g., Poor executive test performance. Patient
washing machine, TV remote control) overloaded by complex tasks
Difficulty organizing household affairs
Difficulty grasping complex ideas
Behaviour
More irritable Socially appropriate. Preserved social facade
More anxious Anxious/low mood depending on insight
Less confidenttakes a backseat in social
groups
Physical status
Minimal physical symptoms Few signsmild akinesia and rigidity
Slowingusually mid-course Myoclonus, impaired tactile localization
show consistent difficulty with learning and (and have difficulty retracing their steps); be
remembering new information; they may highly repetitive with questions and state-
partially or entirely forget important con- ments (e.g., repeatedly ask for the same infor-
versations, life events, dates, appointments, mation, make the same statements, or tell
and obligations; misplace or lose belongings the same stories); and increasingly need to
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 373
having to look up a recipe; needing greater can translate into significant difficulties with
time or help to use a new device, tool, or pro- work and particularly with driving.
gram; having to be reminded of details of a Individuals who are undergoing normal
conversation; or sometimes losing concen- cognitive aging can have changes in their
tration and being distracted during a task, vision related to their eyes as opposed to
the frequency of these occurrences is signifi- how their brain integrates and interprets
cantly greater in AD. Occasionally making a visual images. For example, they may have
poor decision, being distractible (especially shortsightedness or loss of visual clarity, due
in the context of multitasking or not being to cataracts, and low visual acuity, due to
present in the moment), or making an occa- changes in the retina.
sional careless mistake is normal.
Visuospatial Function
Personality, Mood, Motivation, Behavior, and
Regarding visual and spatial relationships Neuropsychiatric Symptoms
patients with AD, even in the mild stages, can
have trouble understanding or interpreting As detailed in Chapter 2, as well as in
visual images and spatial relationships, and Chapters19, 24, 25, and 26, the neuropsychi-
navigating through space. This may include atric symptoms of AD and dementias, while
not appreciating the big picture or objects varied, are common and can predate clinical
that are right in front of them, and having diagnosis by years. The NPI questionnaire
difficulty judging distances, colors and con- (see Chapter19) provides a good instrument
trasts, and reading. For some individuals, to detect and track neuropsychiatric symp-
these kinds of problems can be a predomi- toms in AD.
nant and presenting sign of AD (i.e., patients Individuals with AD can have signifi-
with the visuospatial variant of AD). This cant changes and impairments in social
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 375
interactions, mood, and affect that include that leads to the dementia stage, Alzheimers
being less self-motivated and more apathetic; dementia, is now believed to start decades
having more anxiety and low mood; being prior to the onset of clinical symptoms. Jack
less inhibited and more insensitive in their et al. (2010) proposed a model of AD bio-
actions; being more irritable and easily agi- marker pathology that involves a progres-
tated; becoming more perseverative, fixated, sive sequence of measurable biochemical,
and compulsive; and paying less attention to neurophysiological, and neuroanatomical
grooming and hygiene. For example, individ- alterations that can be potentially detected
uals with early or progressing AD can show years prior to psychometrically and clinically
diminished initiative and greater passivity noticeable deterioration in cognition, behav-
and withdrawal from activities and work. ior, and function.
They may appear less confident and start Typical AD neuropathology starts and
to remove themselves from hobbies, social spreads in a remarkably consistent pattern.
functions and interactions, work projects, The neuropathological hallmark of AD con-
and interests such as engaging in exercise sists of a widespread but regionally specific
and hobbies, and keeping up with a favor- pattern of intraparenchymal diffuse and
ite sports team. They may show significant neuritic -amyloid (A) plaques (cortical lay-
changes in mood, behavior, and personality, ers II and III) and intracytoplasmic (initially,
and reactions to events and stressors. For and then extracellular) NFTs (cortical layers
example, they may become more anxious, III and V) with synaptic and neuronal loss,
depressed, and fearful; be easily upset and and gliosis (see Fig.6.6 in Chapter6) (Braak,
angry at home, at work, with friends, or in Alafuzoff, Arzberger, Kretzschmar, & Del
places where they are out of their comfort Tredici, 2006; Hyman etal., 2012; Jellinger&
zone or when a routine is changed; be less Bancher, 1998; Parvizi, Van Hoesen, &
inhibited, appropriate, and sensitive and Damasio, 2001). Amyloid plaques con-
more judgmental in their comments and sist mostly of extracellular deposits of the
actions; become paranoid that others are 42-amino acid polypeptide A (A-42),
stealing from them or want to hurt them; which is cleaved via the enzymes secre-
develop fixed delusions such as their spouse tase and secretase from the larger inter-
is having an affair; become very obsessive, membrane amyloid precursor protein (APP).
compulsive, and fixated about a particular Soluble A-42 oligomers (212 or more) are
story, event, or behavior such as constantly considered synapto- and neurotoxic and to
watching a particular TV channel, talking play an integral role in the amyloidogenic
about the same news subject, and repeating pathway of AD pathogenesis. Cleavage
the same actions such as wiping the table or of APP by -secretase produces shorter A
scratching; or develop hoarding habits. fragments that enter a nonamyloidogenic
Occasionally having less energy, being pathway that is considered pathogenic.
more tired and weary, feeling less social, APP is an integral membrane protein that is
wanting to stick to routine, and experienc- expressed in many tissues but that is most
ing anxiety and fluctuations in mood in reac- concentrated in the neurons and synapses.
tion to life stressors, events, and health and The APP gene is located on Chromosome 21,
physiological changes is a normal part of liv- and while its primary function is unknown, it
ing and cognitive aging; having major and has been implicated as a modulator of neural
sustained changes in personality, behavior, plasticity, synaptic formation, and modeling,
comportment, and social interactions is not. and to play a role in memory and learn-
Such changes cannot be simply ignored in ing. Neurofibrillary tangles (NFTs) consist
older individuals and explained as normal of intracellular (then extracellular) depos-
aging idiosyncrasies, eccentricity, and its of hyperphosphorylated tau protein, a
quirkiness. microtubule-stabilizing protein.
At death, gross examination of the brain
reveals that more than 90% of patients with
Neuropathology clinical AD have substantial loss of brain
weight and atrophy (with shrinkage of gyri
In Alzheimers disease, like all other dement- and widening of sulci) that is more marked
ing neurodegenerative conditions, the process in the temporal (particularly the hippocampi
376part ii The Dementias: The Major Diseases and Clinical Syndromes
and medial temporal lobes), frontal, and the previous guidelines from 1997 in several
parietal lobes. There is relative sparing of important areas; these include that a clinical
primary motor and sensory cortices (less so diagnosis of dementia is no longer required
with olfaction than in the visual cortex) in for a neuropathological diagnosis of AD to be
AD. Ex vacuo dilation of the ventricles and made, that in addition to the Braak& Braak
pallor of the nucleus coeruleus is also often NFT stage (Braak & Braak, 1991) and the
seen. Many patients with AD also show CERAD (Consortium to Establish a Registry
evidence of cortical and cortico-subcortical for Alzheimers Disease) neuritic plaques
microhemorrhages related to cerebral amy- scores, the new guidelines also incorporate
loid angiopathy-related vasculopathy and the Thal Phase (Thal, Rub, Orantes,& Braak,
leakage (see Chapter 14; Attems, Jellinger, 2002)for A regional accumulation. Whereas
Thal, & van Nostrand, 2011); evidence for the previous guidelines offered little guid-
these types of cerebral microhemorrhages, ance on neuropathology related to comorbid
from hemosiderin microdeposition, can be conditions, regions to sample and stain, and
seen during life by gradient echo or suscep- reporting and clinicopathological correlation,
tibility weighted MRI sequences in 15%20% the new criteria offer explicit recommenda-
of patients with AD (Atri etal., 2005). tions and guidelines.
The hippocampal formation, entorhinal The CERAD classification scheme placed
and perirhinal cortices, and their related emphasis on neuritic plaques based on using
memory networks show a selective vulner- silver stain and/or thioflavin S to determine
ability for the earliest micropathology in burden in the worst areas by examination of
AD; the large hippocampal pyramidal neu- frontal, temporal, and parietal cortex. Neuritic
rons and entorhinal stellate neurons are par- plaque density is reported as absent/none,
ticularly susceptible to NFT formation (Lace sparse, moderate, or frequent. When there is
et al., 2009). Usually AD tangle pathology evidence of any neuritic plaques, based on
then spreads to homotypical association cor- age category (<50, 5075, or >75years of age)
tices, whereas heterotypical motor and visual and presence or absence of clinical dementia,
cortices are often relatively spared until later a classification of definite AD, probable AD,
stages of the disease. and possible AD is made.
Though not specific to AD, the cholinergic The Braak & Braak staging scheme
neurons of the nucleus basalis of Meynert (Braak& Braak, 1991), Stage IVI, is based on
and substantia innominata undergo either silver staining techniques and assesses NFT
primary or retrograde degeneration, and the distribution. Based on brain autopsy and
large cholinergic neurons of the neostriatum clinical data from 83 individuals with and
(caudate nucleus, putamen, nucleus accum- without dementia, Braak & Braak Staging
bens) often also undergo neurofibrillary assumes that AD NFT pathology is tempo-
degeneration in AD. Limbic thalamic nuclei, rally acquired and progresses in a stereo-
including the anterior and dorsomedial typed spatiotemporal order. Stages I and II
nuclei, also appear selectively vulnerable to represent transentorhinal disease; none of
neurofibrillary tangles in AD and show neu- the cases had clinical diagnosis of dementia.
ronal loss. Patients with AD often also depict Stages III and IV represent limbic disease;
neurpathological changes in the amygdala 5/10 Stage III cases and 5/10 Stage IV cases
and in important brainstem adrenergic (locus had clinical diagnosis of dementia. Stages
coeruleus) and serotonergic (dorsal and V and VI represent isocortical disease; all
median raphe) projection nuclei. AD patients cases with Stage V or VI NFT pathology had
with greater extrapyramidal symptoms dur- a clinical diagnosis of dementia.
ing life also often have tangle-related neuro- The Thal Phase classification of regional
nal loss in the pars compacta of the substantia A distribution (Thal et al., 2002) utilizes
nigra. antibody based methods to assess parenchy-
The most current neuropathological crite- mal A deposits (cerebral amyloid angiopa-
ria for AD are the 2012 National Institutes of thy [CAA] is excluded from this assessment)
Aging (NIA)-Alzheimers Association (AA) according to five progressive stages: 1
guidelines for the neuropathological assess- Neocortical; 2Allocortex (hippocampal);
ment of AD (Hyman etal., 2012). The new 3Thalamus, striatum, nucleus basalis of
2012 guidelines/criteria are different from Meynert; 4Brainstem; and 5Cerebellum.
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 377
TABLE16.3 The IWG-Dubois New Lexicon Criteria for the Alzheimers Disease Spectrum
Panel:Anew lexicon to Alzheimers disease
This term refers to patients who fully fulfil the diagnostic criteria for typical AD and additionally
present with clinical and brain imaging/biological evidence of other comorbid disorders such as
cerebrovascular disease or Lewy body disease.
TABLE16.3Continued
Asymptomatic at-risk state for ADthis state can be identified in vivo by evidence of amyloidosis in the
brain (with retention of specific PET amyloid tracers) or in the CSF (with changes in amyloid , tau, and
phospho-tau concentrations). In the absence of knowledge about the value of these biological changes
to predict the further development of the disease the asymptomatic phase of AD should still be referred
to as an at-risk state for AD.
PresymptomaticADthis state applies to individuals who will develop AD. This can be ascertained
only in families that are affected by rare autosomal dominant monogenic AD mutations
(monogenic AD)
Alzheimers pathology
This term refers to the underlying neurobiological changes responsible for AD that span the earliest
pathogenic events in the brain and that include specific neuronal brain lesions (senile neuritic plaques
and neurofibrillary tangles synaptic loss, and vascular amyloid deposits within the cerebral cortex).
This term can be applied irrespective of the existence of clinical manifestation.
Mild cognitive impairment (MCI)
This term applies to individuals with measurable MCI in the absence of a significant effect on
instrumental activities of daily living. This diagnostic label is applied if there is no disease to which
MCI can be attributed. It remains a term of exclusion for individuals who are suspected to have but
do not meet the proposed new research criteria for AD, in that they deviate from the clinicobiological
phenotype of prodromal AD because they have memory symptoms that are not characteristic of AD or
because they are biomarker negative.
phenotype and brain pathology (i.e., AD-type Lewy bodies, the FTD spectrum, or vascular
brain pathology and typical AD symptoms dementia), there was only Picks disease and
are synonymous) such that having AD little appreciation of mixed dementia, there
pathology meant the clinical AD demen- was a much greater belief that reversible sys-
tia phenotype was present and that if there temic disorder mimicking AD was common
was no AD dementia phenotype then no AD (e.g., vitamin B12 and thyroid deficiency),
brain pathology was present. However, it is and the dominantly inherited monogenic
now established that 20%40% of individu- causes of AD (mutations in APP, PS-1 and
als age 70 and older who do not show the PS-2 genes) had not been identified. The pos-
dementia phenotype nonetheless possess AD sible AD dementia classification in the 1984
brain pathology at autopsy or biomarker evi- criteria included a very heterogeneous group
dence consistent with the AD cerebral amy- of individuals, many of whom would now
loidosis profile (see Chapter22). AD severity be classified as MCI (not necessarily due
was considered binary (nondemented ver- to AD).
sus demented) as opposed to being on a The 2011 NIA-AA criteria for AD demen-
continuum; the 1984 criteria did not account tia update the 1984 NINCDS-ADRDA
for cognitive impairment that did not reach Alzheimers disease criteria and incorporate
the dementia threshold. The 1984 criteria more recent clinical, imaging, and laboratory
also only recognized AD presenting as an innovations. First, an updated definition of
amnestic disorder, defined definite AD by all-cause dementia is provided utilizing core
requiring tissue confirmation from biopsy clinical criteria (see Table 16.4). The defini-
or autopsy, and imposed strict age cutoffs tion requires cognitive or behavioral symp-
for AD (4090years of age). The 1984 crite- toms of sufficient magnitude to interfere
ria were also drafted during a period when with usual work or daily function; evalu-
many common non-AD dementias were ation of cognitive change and impairment
neither well understood nor defined (e.g., via subjective (history from the patient and
there was no definition of dementia with a knowledgeable informant) and objective
TABLE16.5 2011 NIA-AA Core Clinical Criteria for Probable Alzheimers Disease Dementia
deficits fall under either an amnestic (deficit allele of the apolipoprotein E gene, however,
in short-term and recent memory and learn- is not sufficiently specific to be considered in
ing) or nonamnestic (language, visuospa- this category.
tial, or executive dysfunction) presentation.
The salient exclusion criteria are evidence Possible Alzheimers Disease Dementia
for prominent features that are consistent
with (1) vascular cognitive impairment/ A diagnosis of possible AD dementia should
dementia (e.g., temporally related strokes; be made if either the individual has an atypi-
multiple infarcts; extensive leukoaraiosis); cal course or an etiologically mixed presentation.
(2) DLB (see Chapter 12); (3) bvFTD (see In patients with an atypical course the core
Chapter 8); (4) semantic-variant or nonflu- clinical criteria in terms of the nature of the
ent/agrammatic-variant PPA (see Chapter9); cognitive deficits for AD dementia are met,
or (5) evidence for another concurrent, but either there has been a report of sudden
active neurological disease, or a nonneuro- onset of cognitive impairment or there is
logical medical comorbidity or use of medi- insufficient historical detail or objective cog-
cation that could have a substantial effect on nitive documentation of progressive decline.
cognition. By definition, all patients who Patients with an etiologically mixed pre-
previously met criteria for probable AD by sentation meetall core clinical criteria for AD
the 1984 NINCDSADRDA criteria still meet dementia but have evidence of (a)concomi-
the 2011 NIA-AA criteria for probable AD tant cerebrovascular disease, defined by a his-
dementia. tory of stroke temporally related to the onset
or worsening of cognitive impairment; or the
presence of multiple or extensive infarcts or
Probable Alzheimers Disease Dementia With
severe white matter hyperintensity burden;
Increased Level of Certainty
or (b)features of dementia with Lewy bodies
This classification (see Table 16.6) can be other than the dementia itself; or (c)evidence
assigned to individuals who meet the crite- for another neurological disease or a nonneu-
ria for probable AD dementia and are either rological medical comorbidity or medication
clearly declining (worsening) by history and use that could have a substantial effect on
testing (probable AD dementia with evidence cognition. Of note, a diagnosis of possible
of documented decline) or are known to carry AD by the 1984 NINCDS-ADRDA criteria
a causative AD mutation. would not necessarily meet the 2011 NIA-AA
Documented cognitive decline in patients criteria for possible AD dementia. Such a
with probable AD dementia increases the patient would need to be re-evaluated.
certainty that the condition represents an
active, evolving pathologic process, but it Probable Alzheimers Disease Dementia
does not specifically increase the certainty With Evidence of the Alzheimers Disease
that the process is that of AD pathophysiol- Pathophysiological Process
ogy. However, in carriers of a causative AD
mutation (APP, PSEN1, PSEN2) who meet In individuals who meet the core clinical cri-
criteria for probable AD dementia, the cer- teria for probable AD dementia, biomarker
tainty that the condition is caused by AD evidence consistent with an AD profile
pathology is increased. Carriage of the 3/4 increases the probability that the basis of the
In persons who meet the core clinical criteria for Probable AD dementia
1. Probable AD dementia with documented decline
Can be diagnosed when there is evidence of progressive cognitive decline on subsequent evaluations based on:
(i) Information from informants, and
(ii) Cognitive testing in the context of either formal neuropsychological evaluation or standardized
mental status examinations.
2. Probable AD dementia in a carrier of a causative AD genetic mutation
Can be diagnosed when there is evidence of a causative genetic mutation (in APP, PSEN1, or PSEN2).
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 383
clinical dementia syndrome is the AD patho- 2011). Based on the results of AD biomarker
physiological process (see Chapters 17, 18, tests that can fall into three categories:clearly
and 22). Currently, the major AD biomarkers positive, clearly negative, and indeterminate.
can be broadly divided into two classes based Table 16.7 from McKhann etal. (2011) pro-
on the biology that they measure: (1) bio- vides operational classifications (lowest, inter-
markers of brain amyloid-beta (A) protein mediate, high, uninformative) for the utility
deposition that include low CSF A42 and and probability that the underlying dement-
positive amyloid-PET imaging; and (2) bio- ing process is due to AD pathophysiology.
markers of downstream neuronal degenera-
tion or injury that include an AD CSF profile Pathophysiologically Proven Alzheimers Disease
of elevated total tau and phosphorylated tau Dementia
(p-tau); an AD FDG-PET profile of decreased
uptake in temporal and parietal cortices; and The diagnosis of pathophysiologically proven
disproportionate atrophy on structural mag- AD dementia applies if the individual meets
netic resonance imaging in medial, basal, and the clinical and cognitive criteria for AD
lateral temporal lobes, and medial parietal dementia, and the neuropathological exami-
cortices. nation, using widely accepted criteria, dem-
However, due to lack of widespread stan- onstrates the presence of the AD pathology
dardization, availability, and longitudinal (Hyman & Trojanowski, 1997; Hyman et al.,
data, the use of AD biomarker tests for rou- 2012).
tine clinical diagnostic purposes is not cur-
rently recommended. Their use to enhance
Dementia Unlikely to be Due to Alzheimers
certainty of AD pathophysiological process
Disease
has been deemed as potentially useful in
three circumstances: investigational stud- The individual does not meet clinical criteria
ies, clinical trials, and as optional clinical tools for AD dementia or (1)regardless of meeting
for use where available and when deemed clinical criteria for probable or possible AD
appropriate by the clinician (McKhann etal., dementia, there is sufficient evidence for an
Probable AD dementia
Based on clinical criteria Uninformative Unavailable, conflicting, Unavailable, conflicting,
or indeterminate or indeterminate
With three levels of Intermediate Unavailable or Positive
evidence of AD indeterminate
Intermediate Positive Unavailable or
indeterminate
Pathophysiological process High Positive Positive
Possible AD dementia
(atypical clinical
presentation)
Based on clinical criteria Uninformative Unavailable, Unavailable, conflicting,
conflicting,or or indeterminate
indeterminate
With evidence of AD High but does not Positive Positive
pathophysiological rule out second
process etiology
Dementia-unlikely due to AD Lowest Negative Negative
A, amyloid-beta; AD, Alzheimer's disease; CSF, cerebrospinal fluid; FDG, fluorocleoxyglucose; MRI, magnetic reso-
18
alternative diagnosis such as HIV dementia, that are of unclear etiology or thought to be
dementia of Huntingtons disease, or oth- related to medications or dehydration, sub-
ers that rarely, if ever, overlap with AD; or clinical cognitive impairment or dementia
(2) regardless of meeting clinical criteria for should be considered high in the differential
possible AD dementia, both -amyloid and diagnosis as a potential major contributing
neuronal injury biomarkers consistent with cause that warrants further investigation.
AD biology are negative. For details of history and cognitive test-
ing, please refer to Chapter19 on the screen-
ing clinical mental status examination and
Evaluation of Alzheimers Disease:History, Chapter 20 on neuropsychological evalu-
Cognitive Testing, and Laboratory and Imaging ation. For further details of studies in AD,
Studies please refer to Chapter22.
History should be obtained from the indi-
In the absence of a request for an evaluation vidual as well as knowledgeable and reliable
of cognitive change or dementia, clinicians collateral informant. In addition to cognitive
need to have a high index of suspicion for symptoms and dementia warning signs, his-
cognitive, functional, or behavioral changes tory should also include an assessment of
and dementia warning signs in older current and previous level of function and
patients. Diminished cognitive capacity can activities of daily living in the home and the
seriously affect the ability of patients to man- community; changes in social interactions,
age their medications and follow medical rec- personality, or behavior; and heightening of
ommendations. As detailed previously, there premorbid personality traits (e.g., hoarding
are no specific laboratory or imaging studies she always had a hard time throwing things
that, in isolation or combination, definitively away but now her whole house is overflow-
rule-in the diagnosis of AD dementia; the AD ing with junk; irritability, agitation, or
dementia diagnoses require the presence of a aggressionhe always had a short fuse and
clinical dementia syndrome that is consistent a temper, but its much worse recentlyvery
by history and clinical (cognitive, functional, small things can set him off). Qualitative
and behavioral) profile with an AD presenta- and quantitative assessment of cognition,
tion, which can be further supported by an function, and behavior should be flexibly
AD biological profile, but that is not excluded individualized with the consideration of the
by substantial evidence to support presence individuals level of education and likely
of another neurological, psychiatric, or medi- intelligence, previous level of function and
cal condition that can account or contribute accomplishments, primary language, and
to the cognitive and behavioral deficits. ethnic and cultural considerations.
Unrecognized cognitive impairments
affect patient health and safety, and clinicians
may contribute to poor patient outcomes by History of Present Illness
violating primum non-nocere (above all
do no harm) when we form wrong impres- In obtaining history, it is important to assess
sions and plans based on unreliable infor- both the initial presenting symptoms as well
mation from a patient who may be forgetful as the most salient symptoms, complaints,
or has unrecognized diminished cognitive and problems, and how they have pro-
capacity. In older patients with escalating gressed. These questions include the follow-
decompensation of otherwise well-managed ing:(1)When was the last time the patients
and stable chronic medical condition, such as thinking was normal? (2) In retrospect,
diabetes, hypertension, congestive heart fail- what was the first major change that was
ure; new onset sleep, confusion, delirium (in noticed? (3)What is now the most prominent
the context of medical illness, medications or symptom or change? (4) What is the most
surgery), weight-loss, failure to thrive, anxi- bothersome symptom, problem or behav-
ety, social withdrawal, apathy, depressive ior? and (5)How have these symptoms pro-
and behavioral symptoms (e.g., agitation, gressed? It is important to delineate both the
personality changes, hoarding, delusions); course (e.g., generally linear decline versus
and symptoms of presyncope, syncope, TIA clearly stepwise decline) and the pace (e.g.,
or chronic dizziness, unsteadiness, and falls very slow initially but more rapid in the last
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 385
6months) of the progression of symptoms and making household repairs; and managing
problems, including any major fluctuations or medications) and basic ADLs (e.g., dressing,
full or partial recovery. Other important ques- eating, bathing, grooming, feeding, mobil-
tions include whether there are any (1)major ity, toileting, continence) that are related to
fluctuations in symptoms on a day-to-day (or changes in cognition and behaviors. Amulti-
hour-to-hour) basis; (2) unusual associated domain review of the frequency and severity
features (e.g., falls, focal weakness, tremor, of any personality changes, neuropsychiatric
myoclonus, episodes of unresponsiveness, symptoms, and problem behaviors should
changes in speech or handwriting, major include false beliefs and delusions, hallucina-
personality changes, food cravings, or odd tions, apathy and indifference, anxiety, irrita-
behaviors); and (3) temporal associations bility and lability, dysphoria and depression,
with symptoms onset or worsening (e.g., a inappropriate elation or euphoria, agitation
stepwise decline after a major illness or sur- and aggression, disinhibition and impulsiv-
gery; happening mostly at night or when ity, aberrant or repetitive motor behaviors,
the patient is tired). For example, regard- disrupted sleep and aberrant nighttime behav-
ing the onset and pace of progression, rapid iors, changes in eating habits and tastes, or
onset and deterioration (hours and days) is aberrant oral intake. Distress in caregivers due
most consistent with an overlying encepha- to these changes and symptoms should also be
lopathy/delirium, whereas a more subacute formally quantified (see Chapters 19, 20, and
onset and progression (over weeks and 27, and the NPI questionnaire as an example of
months) may be more indicative of an over- a suitable instrument) (Cummings etal., 1994).
lying indolent or chronic infection, metabolic
disorder, mass lesion, medication side effect,
sequelae of vascular insults and infarcts, or Review of Systems
hydrocephalus; all these may be overlying
and decompensating a subclinical cognitive A thorough review of symptoms can be very
vulnerability in individuals with undetected informative regarding potential confounders
cognitive impairment or dementia. and contributing causes to cognitive decom-
Purely neurodegenerative causes of demen- pensation and unmasking of the AD clinical
tia have an insidious onset and slow progres- phenotype. It also plays an important role in
sion over many months and years but can be excluding potential primary causes other than
unmasked in the context of encephalopathy/ AD. Symptoms relating to chronic infection
delirium or other cognitive stressors. (e.g., Lyme disease, syphilis, HIV), malig-
nancy, autoimmune and collagen-vascular
disease (e.g., Lupus, Giant Cell Arthritis),
Review of Cognitive, Functional, and hormone and vitamin deficiency are par-
andNeuropsychiatric Domains ticularly relevant to address. Neurological
symptoms, including dysarthria, tremor,
Ideally, there should be a comprehensive imbalance, poverty of movements, difficulty
domain-by-domain review of cognitive sys- walking or shuffling gait, abnormal move-
tems, daily function, and neuropsychiatric ments, stiffness, incoordination, numbness or
symptoms and problem behaviors. Review dysesthesia, weakness, and dysphagia, can be
of cognitive systems should include changes helpful to alert the clinician to non-AD causes
and problems with memory, orientation, lan- or contributing conditions (e.g., parkinsonian
guage, attention, executive functions, judg- syndromes). It is highly recommended to
ment, reasoning, problem solving, visuospatial always specifically ask about falls, balance,
functions, and insight. Review of any changes sleep, appetite, weight changes, incontinence,
to daily level of function should assess both choking or coughing with food, and new or
instrumental ADLs (e.g., keeping appoint- unusual visual problems and headaches.
ments and checkbook; making payments
and managing finances; shopping; handling
money; engaging in hobbies; driving; commut- Pertinent Past Medical History
ing and traveling; preparing meals and cook-
ing; using tools, electronics, and appliances; This should include eliciting history
doing laundry; cleaning and housekeeping; regarding all potential cardiovascular and
386part ii The Dementias: The Major Diseases and Clinical Syndromes
cerebrovascular risk factors such as transient alerts regarding problem behaviors or cogni-
ischemic attack (TIA) or stroke, hyperten- tive and functional trends. Social history can
sion, dyslipidemia, diabetes, arrhythmias, also provide clues regarding interpersonal
coronary artery or vascular disease, myocar- relationships and support networks.
dial infarction, congestive heart failure, and
related procedures, smoking, and snoring
or obstructive sleep apnea. Other important Hobbies, Community Activities, and
past medical history items to be delineated Health-Related Habits
are history of seizures or epilepsy, concus-
sion or traumatic brain injury (including These can inform the physician regarding
duration of loss of consciousness and any past and current level of engagement, activ-
sequelae), meningoencephalitis, delirium/ ity, and performance. Does the individual
encephalopathy, immunosuppression, malig- exercise regularly? What is the current level
nancy, hormonal disorders, thyroid disease of alcohol intake (specifically quantify)? Has
or deficiency, vitamin deficiency (particularly there been a history of past heavy drinking,
vitamin B12 deficiency), severe lung disease, alcohol problems, or drug use?
exposure to toxic substances (at work or
environmentally), excessive alcohol use or
alcoholism, substance abuse, clinical mood Family History
disorder, depression or anxiety, electrocon-
vulsive therapy (ECT), or other neurological It is important to ask whether any family
or psychiatric condition. It is also important member (parents, siblings, children, aunts/
to discuss developmental and school history uncles, cousins, etc.) has ever been diag-
and ask about any potential long-standing nosed with (or is highly suspected to have
learning, attentional, or cognitive problems. had) Alzheimers disease or suffered from
For example, did the individual repeat a dementia or senility. Even if the answer
grade, receive extra academic support, or is no, it is valuable to follow up by asking
attend a special education program? whether any such relative ever needed sup-
port for living when older due to changes in
mental function or behavior, or whether any
Medication and Supplement History relative was placed in a nursing home and, if
so, when and why. The ages of parents and
There should be special attention to medica- siblings should be noted. For instance, if the
tions that are included in the updated Beers patients parents died at relatively younger
Criteria that are potentially inappropriate ages (<65 years) of causes unrelated to
in older individuals due to potential cogni- dementia (e.g., cardiac, cancer), they would
tive side effects (American Geriatric Societ not have lived long enough to express the
[AGS], 2012). Particular attention should be late-onset AD phenotype if they possessed
paid to use of medications with strong anti- the trait. Family history regarding other neu-
cholinergic effects (e.g., diphenhydramine, rological and psychiatric diagnoses should
scopolamine, antimuscarinic agents used also be sought. When a potentially affected
for urinary incontinence, antispasmod- relative is identified, the age of onset, nature
ics, skeletal muscle relaxants, and tricyclic and progression of symptoms, age at death,
antidepressants, and some antipsychotics), and pathological confirmation of a diagnosis
benzodiazepines, sedative-hypnotics, and should be noted.
narcotics (see Table 16.8).
and support systems, and access and use of studies aid to exclude common comorbid
machines and tools that may cause danger to conditions in older individuals that can
self or others can be gathered during the ini- contribute to cognitive impairment in sus-
tial evaluation. For example, it is very impor- ceptible individuals and can be treated. It is
tant to inquire about the details of driving, exceedingly rare for a hormonal or vitamin
access to firearms, the use of the stove and deficiency, or metabolic, infectious, autoim-
power tools, and wandering. mune, toxic, neoplastic, or paraneoplastic
condition to mimic the clinical phenotype
of typical late-onset AD dementia. While
Laboratory Studies many of these comorbid conditions can cause
decompensation of cognitive and behavioral
There are no laboratory studies that rule in function in susceptible individuals with sub-
the diagnosis of AD dementialaboratory clinical or unrecognized mild impairments
388part ii The Dementias: The Major Diseases and Clinical Syndromes
or dementia, they are rarely the sole cause. with a low-threshold for reason, initially or
Ajudicious and stepwise approach to screen- performed later based an individuals par-
ing labs that stresses more common and ticular clinical and epidemiological profile,
reversible conditions, along with prioritizing and findings on exam or past lab testing. For
less invasive and more cost-effective tests, example, an individual living in an endemic
is suggested in evaluating individuals who area for Lyme disease who has a history of a
present with a typical AD dementia profile. tick bite (with or without a rash) or a patient
In individuals presenting with symptoms found to have unexplained or previously
consistent with early-onset, highly atypical, undiagnosed distal symmetric neuropathy
or rapidly progressive dementia, a more com- on exam (several of these labs can be then
prehensive approach to laboratory evalua- be informative depending on index of sus-
tion should be pursued (also see Chapters15 picion, including HgA1c, lead, Lyme, RPR,
and 22), which includes assessment of spinal HIV, ANA, SPEP, and lipid profile).
fluid and/or obtaining amyloid brain PET Standard brain imaging, preferably brain
to confirm the AD profile of abnormalities MRI, should be obtained as part of the initial
(i.e., low CSF A42, high tau and phospho-tau evaluation of dementia. Administration of a
with a amyloid-tau index [ATI] of less than contrast agent is not routinely indicated; nor
1.0; excessive and widespread binding of an is additional Tier 3 or 4 blood tests and stud-
amyloid PET agent in the brain) and exclu- ies such as EEG and vascular brain imaging
sion of other less common dementing syn- in most individuals with LoAD who have a
dromes (e.g., Hashimotos encephalopathy/ typical AD profile and essentially normal ele-
SREAT). mental neurological examination and routine
A multitiered and individualized approach screening laboratories.
to laboratory screening in the evaluation
of AD dementia is suggested here (see
Table16.9). It is reasonable to include most, Biomarkers in Clinical Practice
if not all, Tier 1 labs to evaluate all individu-
als who present with dementia symptoms. Use of AD biomarkers is not recommended
These laboratory tests are widely available, for routine use in clinical practice (Albert
low cost, and relatively high yield with etal., 2011; Jack etal., 2011; McKhann etal.,
respect to broadly screening for common 2011; Sperling et al., 2011). For a review of
abnormalities in older adults. For example, CSF and neuroimaging biomarkers, includ-
thyroid and vitamin B12 deficiency are com- ing CSF measurements of A, tau, and
mon and can cause neurological, including phospho-tau; FDG-PET; amyloid-PET; and
cognitive, decompensation in susceptible structural volumetry, and their potential uses
individuals. Measurement of serum homo- in different stages of the AD clinical spectrum,
cysteine levels can provide a functional/bio- see Chapters 17, 18, and 22. In highly select
chemical test of vitamin B12 deficiency that situations, such as evaluation of early-onset,
is inexpensive, and when elevated, and can atypical, and/or rapidly progressive demen-
support functional B12 deficiency even when tia, a dementia subspecialist may consider
serum B12 levels fall within the normal obtaining additional biomarker data to help
range; hyperhomocystenemia is also asso- determine etiology. Finding consistent AD
ciated with vascular damage and cardio/ biomarker patterns of abnormalities in CSF
cerebrovascular risk. Anemia, dehydration (low A42, high phospho-tau and tau with a
(suggested by BUN:Cr ratio of >20:1), hypo/ relative amyloid-to-tau/p-tau index of <1.0),
hypernatremia, hypomagnesemia, hypercal- amyloid-PET (abnormal uptake of amyloid
cemia (and hypocalcemia), hypo/hypergly- tracer), FDG-PET or SPECT (bilateral parietal
cemia, uremia, and hepatic dysfunction can and temporal hypometabolism in early/mild
also decompensate cognitive function. ESR AD), and bi-hippocampal and cortical atro-
and CRP can provide a very broad screen phy in other temporal and parietal regions
for systemic indolent or insidious inflamma- on structural imaging (see Chapter 22) in
tory/autoimmune, infectious, and neoplas- an individual would be highly supportive
tic processes (e.g., undetected lung, liver or that AD-related pathology may be primar-
colon cancer). Tier 2 labs are not suggested ily causative or contributory to his or her
in all individuals, but they can be ordered, dementia syndrome.
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 389
1 Serum TSH, B12, homocysteine, CBC with Always or often A broad and relatively
imaging differential, complete metabolic panel All individuals inexpensive lab
(including calcium, magnesium, liver screen
function tests), ESR, CRP Brain MRI (or
brain MRI without gadolinium (preferable) CT). Assess for
or noncontrast head CT hippocampal and
2 Serum Ammonia, lead, Lyme antibody, RPR, HIV, Frequently or cortical atrophy
ANA, SPEP, methylmalonic acid (MMA), sometimes consistent with
HgbA1c, lipid profile, folate, PT, PTT Individualize AD; contributing
based on infarcts,
epidemiology, leukoaraiosis, and
and profile of microhemmorhage;
history, exam, rule out
or lab/studies hydrocephalus,
3 Serum Thyroid peroxidase antibodies (TPO)*, Occasionally or mass lesions.
Urine antithyroglobulin antibodies (TGA) *, sparingly Recommend most Tier
CSF FTA-ABS, ACE, ANCA, viral antibody Include some 3 and 4 tests to be
Imaging studies (hepatitis B/C, EBV, CMV) of these done by a specialist
Other Urinalysis, urine culture, UPEP, Bence-Jones tests based or in consultation
proteins on atypical with specialist
Cell count, glucose, total protein, AD CSF clinical profile, TPO and TGA for
biomarker panel (AB-42, tau, phospho-tau) early-onset*, Hashimotos
with calculation of Amyloid-Tau Index (ATI)*; or high index encephalopathy/
Lyme PCR; viral PCRs and cultures, VDRL, of clinical SREAT
T.pallidum PCR; suspicion Assessment of
MR or CT angiogram of head and neck, early-onset AD
carotid ultrasound, brain MRI with should include CSF
gadolinium or head CT with contrast, chest analysis for AD
films, brain FDG-PET (or SPECT) scan* biomarkers (and/or
EEG brain amyloid-PET)
4 Serum AD mutation genetic panel*, APOE allele Very sparingly or and brain FDG-PET
Urine genotype*, paraneoplastic antibody panel, rarely (or SPECT) scan
CSF anti-voltage-gated potassium channel Include based to establish AD
Imaging (VGKC) antibody, non-Lyme tick borne on index of biological trait
Other disease panel (Ehrlichiosis, Babesiosis, suspicion along with clinical
Anaplasmosis, Rickestsiosis, Powassan), in atypical phenotype
copper and ceruloplasmin, tumor markers, cases or rapid See text above
rheumatological studies progression and Chapter22
24-hour urine collection for heavy metals, regarding role of
porphyria, and/or copper genetic testing in
Protein 14-3-3, neuron-specific enolase (NSE), dominantAD
T.whipplei PCR, paraneoplastic antibody See Chapter15
panel, anti-voltage-gated potassium regarding
channel (VGKC) antibody, cytology, flow comprehensive
cytommetry, other stains and cultures for testing for rare or
infectious agents (bacterial, fungal, AFB) rapidly progressive
CT of chest/abdomen/pelvis, cerebral dementia
angiogram, brain amyloid tracer-PET scan*, syndromes
body PET scan
Brain and/or meningeal vessels biopsy
*Consider in individuals with phenotype of early-onset AD and selected individuals with atypical AD presentation.
390part ii The Dementias: The Major Diseases and Clinical Syndromes
in identification and planning for current therapeutic alliance between the clinician the
and future personal, psychological, medi- patientcaregiver dyad.
cal, and legal needs; optimizing behavioral
approaches and strategies to care; institut-
ing stage-appropriate nonpharmacological Long-Term Treatment
interventions and pharmacological treat- Expectations:SlowingDecline
ments; and promoting a healthy lifestyle for
both the patient and caregivers. A success- The current AD treatment paradigm is to
ful long-term pharmacotherapy plan with reduce progression of symptoms and dis-
anti-AD medications, principally involv- ability. Despite ongoing efforts, a cure for
ing combination treatment with a ChEI and AD dementia appears to still be far away
memantine, requires sustaining a solid foun- (see Chapter 23). In contrast to the other
dation of psychoeducation, use of behavioral leading medical causes of mortality in the
care strategies, and maintaining clarity in United States, AD therapeutic research
treatment goals, expectations, and a strong has taken place mostly for a few decades
392part ii The Dementias: The Major Diseases and Clinical Syndromes
him or her to fully participate in the manner very distressful. For example, telling some
that had been the norm. This is a delicate bal- forgetful patients that they have a doctors
ance that has to be achieved on a moving tar- appointment in 2days or that they are going
get. Doing so does not imply, and should not to travel on the weekend can be highly dis-
be interpreted as, disrespect or dishonesty. tressing, even when it is a potentially plea-
The process should be driven by appreciating surable activity or appointment. The patient
the patients diminished capacity and driven may experience anticipatory anxiety, or, even
by doing no harm/nonmaleficence and when the patient forgets the exact reason (e.g.,
benevolence; these trump autonomy when appointment or travel), she or he may con-
the patients diminished capacity poses a sig- tinue to experience underlying fear or worry
nificant risk of distress and harm for self and that she or he may have forgotten something,
others. is not prepared, or that something bad is
Engaging in an open process of commu- going to happen. For some patients it is bet-
nication, planning, decision making, and ter to wait until the last moment to get them
implementation that relies on the patients ready and to inform them that we have to
previous abilities to reason and appreciate go out now.
consequences, have insight and foresight, An approach of providing information and
to make good judgments and decisions, to requests in short and easy-to-understand
relate associations and remember facts, and phrases (i.e., easily digestible chunks) and
to correctly execute decisions and wants can simple step-by-step commands, and only
be frustrating, distressing, and dangerous at the time when the individual with AD
at times. For example, at different stages is ready and absolutely needs to know this
relying on the patient to be responsible information (i.e., is prepared or needs to
or to monitor her or his own medications, eat) can be very pragmatic and appropri-
investments, driving, guns, power tools, ate, particularly as the individual progresses
transportation, and meals, even when the to the moderate stages of AD dementia and
patient emphatically expresses the desire for experiences greater difficulty with receptive
it, can be risky and lead to catastrophe (see language, understanding, reasoning, plan-
Chapter28). ning, making decisions, insight, judgment,
A kind, respectful, and yet pragmatic and anticipatory anxiety.
approach to communication and shared deci-
sion making has to be adapted to the patients
capacities and may necessitate simplifying Environmental Modification, Establishing
information and language, providing infor- Simple Routines, and Maintaining Consistency
mation piecemeal and at the appropriate
time, and sometimes a degree of maternal- Modifying the patients environment to suit
ism and paternalism. For example, in the the needs and capacities of the individual
patient with advanced dementia who still patient is also very important. In general, it
insists on driving despite multiple attempts is best to create a calm, simple, and soothing
and conversations to bring him or her to environment that feels secure and familiar
appreciate their clearly diminished capacity to the patient (e.g., old pictures, a favorite
and very high risk, a pragmatic approach of comfy chair or couch, some memorabilia, soft
removing the car and allowing the moment favorite or music from their childhood or early
to pass by addressing the immediate need adulthood playing), is quiet, and is not over-
for transportation but stating that the car stimulating and full of distractions (e.g., not
is still in the shop under repair can allow cold, crowded, noisy, or too bright). Having
time for adjustment by the patient and for the TV playing in the background all the time
progression of illness to serve as a solution. may not only be overstimulating but may also,
It is also very common for older patients with at times, serve as a BPSD trigger for aggres-
dementia to develop significant anticipatory sive or inappropriately sexualized behaviors
anxiety in the face of even minor changes (see Chapter 25). Occasionally, patients may
of routine and impending activities, travel, develop attachments and be soothed by secu-
and appointments. This anxiety can, in many rity objects, akin to the security blanket or a
patients, serve to significantly decompensate favorite stuffed animal that can provide com-
the patients diminished capacities and be fort and security to young children.
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 395
and potentially deleterious medications. For infections (e.g., urinary tract infections, pneu-
example, diphenhydramine, often taken as monia). Other conditions such as pain, for
an over-the-counter drug combination with example from arthritis, constipation, hunger,
acetaminophen for sleep and pain relief, and thirst, and fatigue, are also very common in
many medications prescribed for anxiety patients with AD dementia, and, particularly
(e.g., benzodiazipines), urinary incontinence in later stages when patients cannot appro-
(e.g., those with high anticholinergic activ- priately recognize or communicate their
ity), and sleep are listed as medications to symptoms, can lead to BPSD, particularly
be avoided in the elderly. Such medications, anxiety, irritability, agitation, aggression,
according to the Beers Criteria, are generally and sleep-wake disturbances. Depression,
contraindicated in the elderly, require close anxiety, and sleep problems should also be
scrutiny, and can be particularly deleterious identified and appropriately treated. When
in cognitively vulnerable older persons (AGS, necessary, cautious and judicious use of
2012; Rudolph etal., 2008)(see Table16.8). other, non-anti-AD medications can nonethe-
less significantly contribute to the compre-
hensive AD therapeutic plan.
Identification and Treatment of Comorbid
Conditions That Decompensate Dementia
Antipsychotics:Use With Extreme Caution
The weakest link shows itself first; similarly, andOnly in Particular Circumstances
systemic conditions can affect cognitive
and functional compensatory mechanisms Another class of medications to be used with
in the brain of individuals with dementia. extreme caution, with ongoing monitoring,
Treating these conditions can affect better and only under strict circumstances, are anti-
cognition, function, and behavior in patients psychotics (also known as neuroleptics) (see
with AD dementia. A striking example of a Chapter24). Though antipsychotics are com-
common clinical scenario is an elderly indi- monly used in an off-label manner in clinical
vidual (with or without a known diagnosis practice in the United States, they carry an
of cognitive impairment or dementia) who FDA black-box warning for use in demen-
is brought to the emergency department for tia. Short- and long-term antipsychotic use
confusion, lethargy, and change in mental in patients with dementia is associated with
status and found to have a urinary tract infec- substantial risk of cognitive decline, mor-
tion (UTI) or pneumonia. In this scenario, the bidity (e.g., parkinsonism, falls, pneumonia,
weakest link, the patients cognitive reserve, cardio- and cerebrovascular events), and
has become decompensated, manifesting in mortality; they should be used as a last resort
worsening cognitive impairments clouded for severe refractory behavioral disturbances
by delirium (also known as encephalopa- without an identifiable and treatable cause
thy) (Fong et al., 2012; Rudolph et al., 2008, (e.g., severe aggression and agitation not
2010). In many undiagnosed individuals, this due to delirium, pain, or infection) or when
is often indicative of a failed stress test that a serious risk of immediate harm or safety
has unmasked an underlying true subclini- exists that cannot be otherwise ameliorated.
cal or undiagnosed cognitive impairment or The antipsychotic risperidone is approved in
dementia. In patients with known demen- Europe by the EMA for short-term, 12-week
tia, this is often a trigger for rapid deterio- use in dementia when there is refractory
ration in cognition, function, and BPSD. In severe agitation or psychosis. Antipsychotics
many conditions, the symptoms and signs of should optimally only be prescribed after a
decompensation are more subtle and chronic. careful evaluation by a dementia care special-
Screening studies, particularly Tier 1 and Tier ist and with the consent of caregivers; their
2 studies discussed previously, can identify cautious use in this manner should be limited
many common conditions that exacerbate to the lowest effective dosages for short dura-
dementia symptoms. These include dehy- tions. The continued use of antipsychotics
dration, electrolyte and metabolic derange- requires ongoing monitoring, assessment of
ments, anemia, cardiac or cerebral ischemia, risk-benefit, and understanding and consent
hypoxia, thyroid and vitamin deficien- from the family regarding the goals of treat-
cies (e.g., vitamin B12 deficiency), as well as ment and the potential clinical trade-offs.
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 397
regain, and once a problem behavioral pat- modulatory neurotransmitter whose role in
tern is established it is hard to eliminate or the neocortex includes arousal (Jones, 2005),
suppress indefinitely. The anti-AD medica- attention (Himmelheber, Sarter, & Bruno,
tions are best thought of as chronic, albeit 2000), as well as learning and memory (Atri
modest, supportive crutches or lids on boil- etal., 2004; Hasselmo, 2006), the cholinergic
ing pots; acute and high potency treatments hypothesis regarding AD posits that patients
and cures they are notunfortunately, the with AD have a central ACh (cholinergic)
pot will ultimately boil over in the long term. deficit with resultant reduction in choliner-
It is therefore important for clinicians to effec- gic neurotransmission. Low levels of choline
tively communicate the practical issues asso- acetyltransferase (ChAT), an enzyme that
ciated with pharmacologic treatment that catalyzes the synthesis of ACh, in the brain
include its rationale and the expectations for is believed to be at least partially responsible
treatment outcomes. for a decreased synthesis of ACh in choliner-
What to expect, when to start and stop gic neurons affected by AD pathology. Lower
pharmacological therapy, and how to moni- levels of ACh, in, turn affect reduced cholin-
tor progression and medication side effects ergic neurotransmission and hence contrib-
are all crucial questions for patients, families, ute to inefficient and disordered memory and
caregivers, and treating clinicians to discuss cognitive processing, and abnormal function
openly. For clinicians, an appropriate per- and behavior in AD.
spective about AD outcomes and treatment Through early observations that choliner-
expectations is especially important to guide gic blockade with scopolamine impairs epi-
stage-appropriate individualized care. To sodic memory function (see Atri et al., 2004
maximize treatment adherence and benefits, for a review), and that ChEIs such as phy-
it is crucial to effectively communicate that sostigmine can reverse these impairments
the current treatment and disease course par- (but have strong peripheral nervous system
adigm in AD includes progression of symp- side effects including nausea and vomit-
toms, long-term global decline in function, ing), centrally acting ChEIs were specifically
accumulation of disability, and a loss of inde- developed as anti-AD medications to inhibit
pendence in late-stage disease. In the long acetylcholinesterase by more selectively
run, our current treatments of AD dementia delaying the breakdown of ACh in choliner-
mitigate decline but do not prevent it. gic synapses in the CNS. With the introduc-
tion of tacrine in 1993, ChEIs were the first
drug class approved for the treatment of AD.
Cholinesterase Inhibitors The current generation of anti-AD ChEIs in
routine use includes donepezil, rivastigmine,
Cholinesterase inhibitors developed for the and galantamine (see Table 16.11).
treatment of AD dementia were produced a
result of rational drug design. ChEIs facili-
tate central cholinergic activity by reducing Pharmacokinetics and Characteristics
the physiological breakdown of ACh by the
enzyme acetylcholinesterase (AChE) in the Although there are mechanistic and phar-
synaptic cleft. Inhibition of AChE by ChEIs macokinetic differences among the available
thus enhances cholinergic neurotransmission. ChEI drugs (see Table 16.11), there are no
quality data to support that there are signifi-
cant differences between them with respect
Acetylcholine and Cholinesterase Inhibitor to aggregate efficacy in AD dementia. An oral
Mechanism of Action in Alzheimers Disease formulation of all three ChEIs is now generi-
cally available in the United States. Donpezil
The central nervous system (CNS) functions and rivastigmine have approved FDA-label
of acetylcholine (ACh) include modulation of indications in mild, moderate, and severe AD
sleep, wakefulness, learning, and memory; dementia; galantamine has an FDA-approved
suppression of pain at the spinal cord level; indication for mild and moderate AD.
and essential roles in neural plasticity, early Donepezil (introduced in 1997) remains the
neural development, immunosuppression, most frequently prescribed ChEI in the United
and epilepsy (Atri, 2011). As an important States (~70% of prescriptions). Rivastigmine
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 399
*Rivastigmine has plasma half-life of 23.4 hours but a duration of action for AChE inactivation of 9 hours.
** Rivastigmine is a pseudo-irreversible inhibitor of AChE and BuChE.
AChE, acetylcholinesterase; BuChEI, butyrylcholinesterase inhibitor; galantamine ER, galantamine extended-release
capsules; nAChR agonist, nonpotentiating ligand of the nicotinic receptor; Tmax=time to maximum plasma concentration.
in cognition, activities of daily living, and the sole medication in its class. Memantine
global status, and in ameliorating BPSD and affects glutamatergic transmission; it is a low
caregiver burden (Atri, Rountree, Lopez, & to moderate affinity N-methyl-d-aspartate
Doody, 2012; Ballard et al., 2011; Birks, 2006; (NMDA)-receptor open-channel blocker,
Cummings, 2004; Cummings, Schneider, which, in a voltage-dependent manner,
Tariot, Kershaw, & Yuan, 2004; Cummings modulates calcium flux through the opened
et al., 2006; Farlow & Cummings, 2007; channel.
Farlow et al., 2000; Greenberg et al., 2000;
Howard et al., 2012; Mohs et al., 2001; Raina
et al., 2008; Rockwood, 2004; Rountree et al., Glutamate and Memantine Mechanism
2012; Tayeb, Yang, Price, & Tarazi, 2012; van ofAction in Alzheimers Disease
de Glind et al., 2013). A majority of RCTs have
been conducted in patients with MMSEs in Glutamate is the major excitatory neu-
the range of 1026 (roughly considered rotransmitter in the neocortex and plays
equivalent by some to the range of perfor- an important role in memory and learning
mance in individuals with mild to moderate (Riedel, Platt,& Micheau, 2003). The gluta-
AD), have been of 6 months duration, and matergic hypothesis links cognitive decline
have demonstrated average MMSE treatment in patients with AD to neuronal damage
gains of 1.52 points over 612 months, and a resulting from overactivation of NMDA
43% increase in the likelihood of remaining receptors by glutamate (Francis, 2005).
functionally stable at 12 months compared Glutamatergic transmission is disrupted in
to placebo (Ballard et al., 2011; Mohs et al., AD and the sustained low-level activation of
2001). Several RCTs and meta-analyses have NMDA receptors, which are pivotal in learn-
demonstrated similar benefits in patients ing and memory, may result from deficien-
with moderate to severe AD dementia (Black cies in glutamate reuptake by astroglial cells
et al., 2007; Bullock et al., 2005; Cappell et al., in the synaptic cleft, and the NMDA subtype
2010; Doody et al., 2001; Farlow et al., 2011; of ionotropic glutamate receptors has been
Feldman et al., 2001; Feldman, Schmitt, & implicated (Francis, 2005; Parameshwaran,
Olin, 2006; Gauthier et al., 2002; Howard et Dhanasekaran, & Suppiramaniam, 2008;
al., 2012; Winblad et al., 2006, 2009). In the few Parsons, Danysz, Dekundy, & Pulte, 2013).
studies that have directly compared cholines- While synaptic NMDA receptor activation
terase inhibitors to each other, no significant may be neuroprotective, there is evidence to
differences were found (Bullock et al., 2006; support that aberrant activation of extrasyn-
Wilcock et al., 2003). In longer term open- aptic NMDA receptors may be neurotoxic
label trials, including extension trials from and lead to calcium-induced excitotoxicity,
the original placebo-controlled, randomized neuronal amyloid-beta release, and neu-
studies, the cognitive benefits of the ChEIs rodegeneration (Bordji, Becerril-Ortega, &
appear to continue for at least 24 years Buisson, 2011; Parsons et al., 2013).
(Burns, Gauthier, & Perdomo, 2007; Doody Memantine preferentially targets extrasyn-
et al., 2001; Raskind, Peskind, Truyen, aptic NMDA receptor signaling pathways.
Kershaw, & Damaraju, 2004). Long-term It has been further posited that due to aber-
prospective observation clinical cohort stud- rant glutamatergic exposure and stimula-
ies have also provided support for signifi- tion in AD, synaptic signal-to-noise ratio is
cant benefits of sustained ChEI treatment on degraded, leading to failure or inefficient
ameliorating decline in cognition and func- neural transmission (Francis, 2005; Parsons
tion, delaying institutionalization, but not etal., 2013).
altering survival (Gillette-Guyonnet et al., Physiological NMDA receptor activ-
2006; Wattmo et al., 2011a; Wallin et al., 2004; ity is critical for normal neuronal function.
Wallin et al., 2007; Wallin et al., 2011). However, excessive exposure to glutamate
or overstimulation of its membrane recep-
tors leads to excitotoxic neuronal injury
NMDA Antagonists (Memantine) or death. Excitotoxic neuronal cell dam-
age is mediated in part by overactivation
Memantine was the last FDA-approved treat- of NMDA-type receptors, which results
ment for AD dementia (2002) and remains in excessive Ca(2+) influx through the
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 401
receptor-associated ion channel and subse- cleared and does not affect the hepatic
quent free radical formation (Lipton, 2007). CYP450 enzyme system.
Thus, potential neuroprotective agents that
excessively block NMDA receptor activity
will likely produce unacceptable clinical and Safety and Tolerability of Memantine
cognitive side effects (e.g., hallucinations
with phencyclidine). However, meman- Titrated appropriately, memantine has a
tine, through its action as an uncompeti- highly favorable safety and tolerability pro-
tive, low-to-moderate affinity, open-channel file. Mild and transient treatment-emergent
blocker may preferentially block excessive side effects include confusion, dizziness, con-
NMDA receptor activity without disrupting stipation, headache, and somnolence; these
normal activity (Lipton, 2007). Entering the may be encountered during, or soon after,
receptor-associated ion channel preferen- titration to the maximum total daily dose
tially when it is excessively open, and with of 10 mg twice daily for immediate-release
a fast off-rate, memantine does not substan- memantine or 28 mg once daily for meman-
tially accumulate in the channel to interfere tine extended release. In patients with severe
with subsequent normal synaptic transmis- renal insufficiency (creatinine clearance
sion (Lipton, 2007). <30 mL/min) a dose adjustment to 5 mg
twice daily for immediate-release memantine
and 14 mg daily for memantine extended
Pharmacokinetics and Characteristics release is recommended. Memantine can be
taken with or without food, does not produce
Memantine is available in immediate-release significant changes in heart rate or blood
twice daily (expected to be available generi- pressure, and does not have significant inter-
cally in the United States by mid-2014) and actions with other medications, including the
extended-release once daily (recently avail- ChEIs. Due to its mechanism of action, how-
able in the United States) preparations. The ever, coadministration with other medica-
pharmacokinetic profiles and characteris- tions that have antiglutamatergic effects (e.g.,
tics of these formulations are reviewed in amantadine, dextromethorphan) should be
Table 16.12 Memantine is mostly renally approached with caution.
*Memantine does not significantly inhibit the CYP450 hepatic enzyme system
**Renal excretion is the main factor for memantine eliminationmaximum dosages are halved in individuals with
CrCl<30.
+
Memantine extended release absorption is slower after food than on an empty stomach; peak plasma concentrations are
achieved 18 hours on an empty stomach and 25 hours after food.
#
Memantine extended release affects a slower release compared to memantine and a potentially higher target dose (com-
pared with twice-daily 10-mg dosing of immediate-release memantine it achieved a 48% higher steady-state maximum
plasma concentration (Cmax) and 33% higher area under the plasma concentration time curve from time 0 to 24 hours
(AUC024))
Tmax=time to maximum plasma concentration.
402part ii The Dementias: The Major Diseases and Clinical Syndromes
memantine alone (Parsons et al., 2013) (see use of ChEI and memantine combination
Fig. 16.4). According to this model, since therapy is supported by a sound scientific
memantine and the ChEIs intervene at sepa- basis and rationale.
rate points of the disrupted signaling cas-
cades in AD, memantine, acting at the NMDA
receptor, and ChEIs, by delaying breakdown Efficacy in Short-Term Randomized,
of ACh at cholinergic synapses, together Double-Blind, Placebo-Controlled Trials
act to better facilitate LTP and successful
memory processing. As seen in Figure 16.4, Three 24-week, randomized, double-blind,
memantine is posited to lower the pathologi- placebo-controlled trials (RCTs) have inves-
cally increased tonic level of excitation of the tigated the efficacy and safety of meman-
glutamatergic synapse at rest (neuron 2see tine 2028 mg/day in combination with a
Fig. 16. 4). A dual impact is hypothesized ChEI (see Table 16.13) (Tariot et al., 2004;
from this: (1) reduction of the background Porsteinsson etal., 2008). Two of these trials
noise, so that incoming physiological signals were conducted with patients in the moder-
can be better distinguished; and (2)reduction ate to severe range of AD severity and were
of the constant pathological influx of Ca2+, successful in demonstrating efficacy on mul-
thereby reducing the likelihood of the neuron tiple prespecified outcome measures at study
from being stimulated in a way that would endpoint (Tariot et al., 2004). Another study
cause dysfunction, synaptotoxicity, and, ulti- conducted in patients in the mild to moder-
mately, cell death (neuron 2). In this model, ate AD severity range failed to demonstrate
combination treatment reduces the overall statistically significant results on prespecified
tonic activation of NMDA receptors, which outcomes and is considered an underpow-
delays neurodegeneration of cholinergic ered and indeterminate study by some (Atri
neurons bearing NMDA receptors and thus etal., 2013; Porsteinsson etal., 2008). All three
facilitates synaptic NMDA receptor activa- studies demonstrated overall good tolerabil-
tion. Supplementing this effect, the ChEIs are ity and safety for combination treatment com-
posited to amplify (i.e., bring toward normal) pared to chronic baseline ChEI monotherapy.
the AD pathologically weakened signal from The first RCT of anti-AD combination
cholinergic neurons by delaying ACh break- treatment assessed the efficacy of admin-
down at cholinergic nerve endings such that istration of memantine (10 mg twice daily)
neurotransmission (to neuron 3)is preserved versus placebo to patients with moderate
by the improved signal detected against to severe AD (MMSE 514; n = 404) receiv-
the lowered background noise (Fig. 16.4). ing stable donepezil therapy (Tariot et al.,
Together, these effects are posited to help 2004). Relative to placebo, memantine pro-
maintain glutamatergic/cholinergic signal- duced significant benefits in all primary and
ing cascades and to consequently facilitate secondary outcome measures and all four
LTP and memory processing (Parsons etal., key symptom domains of ADcognition,
2013). function, behavior, and global status (Tariot
Not only do ChEIs and memantine work et al., 2004). Notably, the average score on
via different mechanisms, thus providing the primary outcome measure of cognition,
a dual pharmacologic strategy, but in vitro the Severe Impairment Battery (SIB), was 0.9
and animal data suggest that the combina- points better at the 24-week study endpoint
tion of a ChEI and memantine may, under than at baseline with ChEI-memantine treat-
certain conditions, act potentially synergis- ment. In contrast, with donepezil-placebo
tically to increase release of hippocampal treatment SIB scores worsened by 2.5 points
ACh (Ihalainen et al., 2011). In preclinical in the same interval. Combination treatment
animal models, both ChEIs and memantine effect sizes on cognition (SIB) and global
have been observed to improve memory per- severity (CIBIC-plus) were 0.4 and 0.24,
formance (Wise & Lichtman, 2007; Yamada respectively. Several post-hoc analyses of
et al., 2005). As they work via potentially this data have identified specific significant
complementary mechanisms and data sup- benefits of memantine add-on treatment
port benefits of these drugs in improving relative to chronic donepezil monotherapy;
memory performance in animal models, the these include the following (1) decreases in
Normal
signal
noise
Glia
AChE
Neuron 1
Neuron 2 Neuron 3
AChE
Glia
Alzheimers Disease
signal
noise
Glia
AChE
Neuron 1
Neuron 2 Neuron 3
AChE
Glia
AChE
Glia
AChE
Neuron 1
Neuron 2 Neuron 3
AChE
Glia
Glia
Abeta
Glutamate AMPA Na+ Oligomers Ach Choline Acetylcholinesterase
Glutamate 2+
Uptake NMDA Ca Mg2+ Acetate Ach Receptor
Memantine Cholinesterase Inhibitor
Figure16.4 Mechanism of action for ChEIs, memantine, and combination treatment with both
in Alzheimers disease (AD) (from the Parsons etal. three-neuron model for the action of
memantine and the AChEIs in AD; Parsons etal., 2013).
TABLE16.13 Level Iand Level II Evidence Grade Controlled Clinical Efficacy and Effectiveness Studies of and Memantine Add-on Combination Therapy
Study Design No. of Duration AD Stage Study Goal Primary End Points Results Evidence
Patients or Mean Level
Follow-up
Tariot etal. RCTefficacy 404 24 weeks Moderate Safety and efficacy of Cognition:SIB Significantly Better outcome ClassI
(2004) trial severe adding 10 mg twice Function:ADCS-ADL19 with addition of memantine
daily memantine Safety& tolerability:TEAE vs. placebo in all primary
immed iate-release endpoints; good safety
to stable background profile and well tolerated
donepezil treatment
Porsteinsson RCTefficacy 433 24 weeks Mild Safety& efficacy of Cognition:ADAS-cog No statistical treatment ClassII
etal. (2008) trial moderate adding 20 mg once Global Change:CIBIC-Plus differences on primary
daily memantine Safety& tolerability:TEAE endpoints; underpowered
immediate-release to study*; good safety profile
stable background ChEI and well tolerated
treatment (donepezil,
rivastigmine, or
galantamine)
Grossberg RCTefficacy 677 24 weeks Moderate Safety and efficacy of Cognition:SIB Significantly Better outcome ClassI
etal. (2013) trial severe adding 28 mg once Function:ADCS-ADL19 with addition of memantine
daily memantine Behavior:NPI vs. placebo in all primary
extended-release to Global Change:CIBIC-Plus endpoints (SIB and
stable background ChEI Fluency:VFT CIBIC-Plus), and secondary
treatment (donepezil, Safety and endpoints of NPI and VFT,
rivastigmine, or tolerability:TEAE but not ADLs. Good safety
galantamine) profile and well tolerated
Howard etal. RCT 295 52 weeks Moderate Comparative effectiveness Cognition:SMMSE Significantly better outcomes ClassII (due
(2012) effectiveness severe of discontinuing Function:BALDS on SMMSE, BALDS, to >72%
trial background donepezil Behavior:NPI and NPI at 52 week attrition and
and adding placebo QOL:DEMQOL-proxy endpoint for all treatment inadequate
or memantine, or Caregiver health:GHQ-12 groups compared to power
continuing donepezil discontinuation of
and adding placebo or donepezil and starting
memantine placebo; overall, treatment
groups undifferentiated at
52-weeks
(continued)
TABLE16.13Continued
Study Design No. of Duration AD Stage Study Goal Primary End Points Results Evidence
Patients or Mean Level
Follow-up
Atri etal. CLOC 382 Mean Mild, Long-term clinical Cognition:BDS Significantly slower trajectory ClassII
(2008) effectiveness 2.5years moderate, effectiveness of Function:ADL of cognitive and functional
cohort study and severe combination therapy decline for CT; slower
(CT) vs. ChEI alone vs. decline in cognition for
standard care without ChEI than standard care;
ChEI or memantine effect sizes increase with
time on CT
Lopez etal. CLOC 943 Mean Mild, Effects of combination Time to nursing home Longer time to nursing ClassII
(2009) effectiveness 5.2years moderate, therapy vs. ChEI alone admission or death home admission for CT
cohort study and severe vs. standard care without over ChEIs alone, and for
ChEI or memantine on ChEIs vs. standard care. No
time to death or nursing differences in time to death.
home admission
Rountree etal. CLOC 641 Mean Mild, Clinical effectiveness of Cognition:ADAS-cog, Treatment persistence ClassII
(2009) effectiveness 3.0years moderate, persistence of anti-AD MMSE, BPMSE associated with significant
cohort study and severe therapies with ChEI, Function:PSMS& IADL benefits in outcomes (slower
memantine, and CT Severity:CDR-sb decline) in all domains;
treatment benefits are
cumulative
Gillette- CLOC 686 Mean Mild, Delineation and Cognition:ADAS-cog, Significantly lower rates of ClassII
Guyonnet effectiveness 2.6years moderate, comparison of rates of MMSE, Function:ADL deterioration on MMSE and
etal. (2012) cohort study and severe deterioration on clinical Behavior:NPI ADAS-cog in treated
measures between ChEI Severity:CDR-sb AD patients compared to
and/or memantine untreated patients in the
treated and untreated Pre-ChEI era. No Pre-ChEI
(historical) cohorts vs. post-ChEI/memantine
era comparative data for
ADL, NPI, and CDR
*Numerically favorable results observed for CT at an effect size (0.12) that was lower than the effect size estimate (0.325) the study was powered for to detect a statistically significant difference.
ADAS-cog, AD Assessment Scale-cognitive subscale; ADCS-ADL19, modified 19-item AD Cooperative StudyActivities of Daily Living Inventory; ADL, Weintraub Activities of Daily Living Scale;
BALDS, Bristol Activities of Daily Living scale; BDS, Blessed Dementia Scale; BPMSE, Baylor Profound Mental Status Examination; ChEI, cholinesterase inhibitor; CIBIC-Plus, Interview-Based Impression
of Change Plus Caregiver Input; CLOC, controlled long-term observational prospective clinical cohort; CT, combination therapy (ChEI plus memantine); DEMQOL-proxy, Health-related Quality of Life;
GHQ-12, General Health Questionnaire 12-item; IADL, instrumental activities of daily living; MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric Inventory; PSMS, Physical Self-Maintenance
Scale; RCT, randomized clinical trial; SIB, Severe Impairment Battery; SMMSE, standardized MMSECDR-sb, Clinical Dementia Rating-Sum of Boxes; TEAE, Treatment Emergent Adverse Event reporting;
VFT, semantic verbal fluency test.
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 407
frequency, severity, and duration of existing Porsteinsson et al. study in mild to moder-
neuropsychiatric and behavioral symptoms, ate subjects was underpowered to be able
in addition to a reduction in the emergence to detect a potentially statistically signifi-
of these symptoms; (2)lowering of caregiver cant benefit of combination therapy in this
distress and burden; (3) improved daily population, and that, along with increased
functioning in ADLs that require greater severity range-, ChEI type- and dose-related
connectedness/autonomy and higher level heterogeneities, may have contributed to the
functions; and (4) better cognitive perfor- observed null results. This hypothesis was
mance related to memory, language, and tested in a recent post-hoc meta-analysis
praxis (Cummings etal., 2006; Feldman etal., that included this data. This study reported
2006; Schmitt etal., 2006). significant results with effect size estimates
The second 24-week RCT assessed the in the 0.210.36 range for multiple domains
efficacy of administration of memantine (20 (cognition, function, global status) in favor
mg once daily) versus placebo to patients of stable donepezil-memantine add-on com-
with mild to moderate AD (MMSE 1022; bination therapy in patients in the moderate
n=433) taking a stable dose of any approved range of severity (MMSE 10-19) (Atri et al.,
ChEI therapy (donepezil, rivastigmine, 2013). Long-term effectiveness studies in
galantamine) (Porsteinsson et al., 2008) and clinical cohorts of patients with AD demen-
failed to meet a priori outcome endpoints tia support beneficial combination treatment
in cognition and daily functioning. There effects for at least 2 years; these benefits
were no significant differences observed in were not limited to patients with moderate
tolerability and safety between the meman- or severe stage dementia but were statisti-
tine and placebo groups. There were also cally observed in the later years of treatment
no clinically significant differences between (Atri, Shaughnessy, Locascio, & Growdon,
treatment groups in laboratory tests, vital 2008). For example, Atri etal. observed that
signs measurements, or electrocardiogram in mild AD, cognitive and functional effects
parameters. A greater proportion of partici- of combination therapy over ChEI monother-
pants in the memantine group (9.7%) than apy have small effect sizes (0.100.21 range)
in the placebo group (5.0%) demonstrated a within the first year of treatment (Atri etal.,
significant weight increase (at least 7% over 2008)but manifest larger benefits (effect sizes
the baseline value), which may be a clinically in the 0.340.73 range) as treatment continues
important beneficial side effect in this often over 4years.
frail elderly populationa population that is Unless similar studies in mild AD are pow-
highly susceptible to anorexia and weight ered accordingly (and/or are appropriately
loss due to potential side effects from ChEIs extended to multiple years), they may not be
and from low caloric intake due to forgetful- able to adequately address whether an actual
ness, depression, and apathy. treatment benefit has been missed due to
Other than dementia stage (as gauged by inadequate design (an indeterminate study)
MMSE inclusion criteria:314 versus 1022), or that it simply does not exist. Statistically
the major inclusion and design differences failing to observe an effect (i.e., to reject the
between these first two RCTs were that the null hypothesis) is not the same as confirm-
Porsteinsson etal. (2008) study (MMSE 10-22) ing that a significant effect does not exist (i.e.,
allowed use of any ChEI (not just donepezil) to confirm the null hypothesis of equiva-
and had a once daily dosing regimen using lence)absence of evidence is not evidence
immediate-release memantine (as opposed to of absence. This is an important caveat for
a twice daily dosing in the Tariot etal., 2004, the interpretation of studies with design or
study). The observed effect size of 0.118 on execution limitations that produce potential
the ADAS-cog cognitive outcome, which was bias (e.g., disproportional and nonrandom
numerically in a favor of ChEI-memantine missing data between comparison groups),
add-on combination treatment but was not unplanned variability, and results that fail
statistically significant (p=0.18), was a much to meet a priori criteria to detect a difference
lower value than was used a priori (effect size in outcomes at the desired significance level.
of 0.325) to power the study for an adequate Also, results from studies that fail to reject
sample size to be able to reliably detect a pos- the null hypothesis cannot be interpreted
sible treatment effect. This suggests that the as having demonstrated equivalence of
408part ii The Dementias: The Major Diseases and Clinical Syndromes
treatments. To show this, an appropriate Howard et al., 2012; Lopez et al., 2009) (for
equivalence analysis must be designed that reviews see Atri etal., 2012; Rountree etal.,
specifies the parameters for treatments being 2012).
deemed equivalent (e.g., less than a +/ 0.5 The DOMINO-AD 52-week RTC in
point difference in drug-placebo perfor- patients with moderate to severe AD (MMSE
mance on the MMSE at 24 weeks). 513) in the United Kingdom treated in
The third and final short-term RCT was a the community was a recently reported
recently published study by Grossberg etal. effectiveness study (Howard et al., 2012).
(2013) that also demonstrated multidomain Despite its significant methodological limi-
superiority of ChEI-memantine add-on tations, which included high and imbal-
combination treatment compared to chronic anced attrition (72% overall; attrition was
ChEI-placebo add-on treatment in 661 sub- significantly less in patients on 2 vs. 1 vs.
jects with AD in the moderate to severe no anti-AD medications) and inadequate
range (MMSE 3-14; Grossberg et al., 2013). power and analysis to demonstrate poten-
This study was novel in that it utilized a tial equivalence of treatments at 52 weeks,
once-daily memantine extended-release it nonetheless provided further evidence to
preparation at a higher dose of 28 mg daily. support that, compared to discontinuation
It also allowed baseline ChEI treatment of donepezil, the continuation of donepezil,
with any oral ChEI preparation (donepe- and the starting of memantine treatment
zil, rivastigmine, galantamine). Significant despite discontinuation of donepezil, pro-
combination treatment benefits were vided significant benefits on cognition,
observed at the 24-week study endpoint on function, and behavior (Atri et al., 2013;
primary and secondary outcome measures Howard etal., 2012; Shaw, 2012). The addi-
in the domains of cognition, global status, tion of memantine to donepezil to achieve
neuropsychiatric symptoms and behaviors, combination therapy was again well toler-
and verbal fluency (p <.01 for all). Activities ated (significantly fewer patients withdrew
of daily living showed statistical trends in who were on combination treatment) and
favor of combination treatment at weeks 18 no less effective, while discontinuation of
(p = .068) and 24 (p = .155). The combina- donepezil was clearly detrimental to cogni-
tion treatment again showed an expected tion and function (Atri etal., 2013; Howard
and good profile of overall tolerability and etal., 2012; Shaw, 2012).
safety. Long-term observational clinical cohort
studies performed in naturalistic settings
with prospectively collected data show simi-
Longer Term Randomized Controlled lar patterns to RCTs. They provide supportive
Trials,Open-Label Extensions, and Level II grade and more generalizable evi-
Naturalistic Observational Clinical dence to patients treated in clinical practice
CohortStudies that combination treatment is more effective
than monotherapy, and that monotherapy
The preponderance of evidence from longer is better than no antidementia medication
term clinical studies also supports that the treatment (Atri etal., 2008, 2012; Gauthier&
benefits of anti-AD medications, particularly Molinuevo, 2013; Lopez etal., 2009; Rountree
in combination, are sustained for 1 or more et al., 2009). In patient cohorts, long-term
years when treatment is continued (see Table ChEI-memantine combination therapy sig-
16.13). Multiple, open-label extension studies nificantly reduced cognitive and functional
of short-term RCTs have reported sustained decline (see Fig. 16.5), and delayed time to
benefits for persistent treatment with ChEIs nursing home admission, compared to ChEI
(35 years) (Doody et al., 2001; Lyketsos, monotherapy and to standard care with-
Reichman, Kershaw, & Zhu, 2004; Raskind out a ChEI or memantine (Atri et al., 2008;
et al., 2004; Rogers, Doody, Pratt, & Ieni, Gillette-Guyonnet et al., 2011; Lopez et al.,
2000) and memantine (52 weeks) (Reisberg 2009; Rountree etal., 2009). Furthermore, the
et al., 2006). Longer RCTs and long-term benefits of combination therapy accumulate
observational clinical cohort studies also with time on treatment and are sustained for
support effectiveness of ChEI, memantine, years (Atri etal., 2008; Rountree etal., 2009).
and combination therapy (Atri et al., 2008; Benefits of anti-AD medications significantly
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 409
(a) 5
*p<0.05, **p<0.01, ***p<0.001
Worsening
15
***
###
**
20
*
ChEI+Memantine Combination Therapy
25 ChEI Monotherapy
No medication (standard care only)
30
0 1 2 3 4
Years
(b) 20
*p<0.05, versus no medication;
30 * ***p<0.001 versus no medication;
###p<0.001 versus ChEI
Predicted mean level of
***
###
ADL dependence (%)
40 monotherapy
***
###
Worsening
50
***
###
60
ChEI+Memantine Combination Therapy
70 ChEI Monotherapy
No medication (standard care only)
80
0 1 2 3 4
Years
Figure16.5 Clinical effectiveness of ChEI-memantine add-on combination treatment to reduce
long-term progression of cognitive and functional decline in Alzheimers disease (AD) dementia.
(A) Estimated trajectory of cognitive decline over 4years for groups of patients with AD dementia
starting with 10 errors on the BDS (~MMSE 22)is lowest in the combination treatment group. (B)
Estimated trajectory of functional decline over 4years for groups of patients with AD starting with
25% dependence on the Weintraub ADL scale is lowest in the combination treatment group. Similar
graphs (not shown) demonstrate significant benefits of combination treatment to reduce clinical
progression in groups of patients with very mild and with severe AD dementia (Atri etal., 2008).
increased with treatment persistence in sev- followed annually for a mean duration of
eral symptom domains (cognition, func- 5.2 years, those patients taking combination
tion, global severity) and in all stages of AD therapy were three to seven times less likely
(Rountree et al., 2009). Gillette-Guyonnet to be placed in a nursing home than patients
et al. (2011) also reported slower decline of receiving ChEI monotherapy. The same study
cognition associated with anti-AD medica- found no association with anti-AD medica-
tion use in France. tion use and time to death; similar results
were reported by Rountree and colleagues,
who also concluded that anti-AD medica-
Delaying Major Clinical Milestones:Nursing tions do not prolong survival (Rountree
Home Placement and Death et al., 2012), and by Wallin and colleagues,
who reported early response to chronic ChEI
There is evidence that ChEI and memantine, treatment was associated with delayed insti-
especially in combination, delay clinically tutionalization but not with increased sur-
relevant endpoints, particularly nursing vival (Wallin et al., 2011). These data infer
home placement. Several studies support that anti-AD treatments with ChEIs and
delayed nursing home placement in patients memantine, alone or in combination, may
treated with ChEIs (Lopez etal., 2005, 2009; cause an expansion of the mid- to late-stages
Wallin etal., 2011), memantine (Wimo etal., of AD-related disability, thus to effectively
2003), and combination therapy (Lopez etal., delay end-stage disability and to produce a
2009). In two separate cohort analyses total- contraction of the end/terminal stages of AD
ing more than 932 patients with AD demen- without prolonging life in the profound and
tia (mean MMSE 18.8 at baseline study entry) end stages of AD.
410part ii The Dementias: The Major Diseases and Clinical Syndromes
(A)
2.0
Donepezil (n = 72)
LS mean change from baseline
p = 0.0116
Improvement
1.0 p = 0.0380
p = 0.0348
0.5
0.0
Worsening
0.5
1.0 ur
ns ns ion ia ty ria y n ity ur g
sio tio ss or xie ho ath ibi
tio bil vio vio tin
lu a e s ph An p Ap h la a a /ea
De cin gr /dy /eu sin ty/ eh eh ite
llu ag ion Di ili or
b b
pe
t
Ha n/ ion t ab t me
at
io es
s
Ela Irr
it mo t-t
i Ap
it pr nt gh
Ag De r ra Ni
A be
(B)
0.3
Arithmetic mean change from baseline
Improvement
0.2
0.1 ***
0.0
0.1 *** **
0.2
Worsening
0.3
0.4
0.5
Memantine Placebo
0.6
s s n ia ty ria ce n ty ur ur ge
s ion t ion s sio h or
n xie pho r en i b itio abili vio vio han
elu ina re sp A eu f e h / l h a a
eh ite c
D llu
c gg n/
dy n/ dif sin bility be eb
/a tio /in Di or pe
t
Ha tio
n
ss
io l a h y i t a o t t i m
ita e E p at Irr t m h t- Ap
pr A n g
Ag De er
ra Ni
Ab
Figure16.6 Complementary efficacy of anti- Alzheimers disease (AD) medications (ChEIs,
memantine) on amelioration of behavioral and psychological symptoms of dementia (BPSD) as
measured by NPI domains in AD dementia. (A) Donepezil, compared to placebo, treatment was
associated with significant behavioral benefits over 24 weeks in the NPI subdomains of depression/
dysphoria, anxiety, and apathy (Feldman etal., 2005); and (B) memantine, compared to placebo,
treatment was associated with significant behavioral benefits over 24 weeks in the NPI subdomains of
delusions, agitation/aggression, and irritability/lability (Gauthier etal., 2008).
higher dose of 28 mg once daily memantine to background donepezil 10 mg daily did not
extended release, AEs with a frequency of at result in an AE profile that was significantly
least 5.0% that were more prevalent in the different compared to donepezil and placebo
ChEI-memantine extended-release group (see Table 16.14); there were also approxi-
than the ChEI-placebo group were diarrhea mately half as many reports of agitation as
(5.0% vs. 3.9%) and headache (5.6 vs. 5.1%) an AE in donepezil-memantine combination
(Grossberg etal., 2013). In a meta-analysis of treatment compared to donepezil-placebo
520 subjects, adding memantine 20 mg daily (Atri etal., 2013).
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 413
Patients with AEs 206 (76.6) 186 (74.1) 144 (75.8) 136 (73.5)
Dizziness 20 (7.4) 19 (7.6) 17 (8.9) 16 (8.6)
Agitation 17 (6.3)* 29 (11.6) 9 (4.7)* 19 (10.3)
Confusional state 15 (5.6) 6 (2.4)
Diarrhea 14 (5.2) 21 (8.4) 12 (6.3) 14 (7.6)
Nasopharyngitis 14 (5.2) 6 (2.4)
Falls 11 (4.1) 15 (6.0) 10 (5.3) 11 (5.9)
Urinary tract infection 10 (5.3) 8 (4.3)
Depression 6 (3.2) 11 (5.9)
Note:Incidence of AEs over 24 weeks was similar between the patients treated with memantine added to donepezil
versus placebo added to donepezil (Atri etal., 2013).
Data are number (%).
a
Moderate to severe AD (MMSE 519 at baseline), receiving donepezil (10 mg/day).
b
Moderate AD (MMSE 1019 at baseline), receiving donepezil (10 mg/day).
*p <.05 versus placebo added to donepezil.
APT, all patients treated; AD, Alzheimers disease; AE, adverse event. denotes AEs with an incidence <5% in both
treatment groups in the respective severity subgroup.
Evidence-Based Medication Therapeutics by severe > moderate >> mild and very severe
Stage of Alzheimers Disease >> very mild and in MCI; the latter are from
subsets of patients in long-term observational
In the United States, the ChEIs donepezil cohorts. Some of this evidence is reviewed
and rivastigmine are FDA approved for use according to stage of disease severity.
in mild, moderate, and severe AD dementia, Overall, regardless of severity stage, higher
while memantine is FDA approved for use persistence, dose (approved dosages), and
in moderate and severe AD dementia. There duration of treatments are associated with
is, however, support in the literature, with better outcomes over slowing clinical decline.
differential grades/levels of evidence and
treatment effect sizes, for use of anti-AD med-
Mild Cognitive Impairment:Very Early/Mild
ications at different stages of AD. Overall, it
Alzheimers Disease
appears that the grade of evidence is higher
and the effect sizes are bigger for use of ChEI Randomized, placebo-controlled trials
monotherapy in mild and moderate AD of ChEI treatment in MCI have shown
dementia than in severe AD dementia; the mixed results; while some studies suggest
grade of evidence and effect sizes then drop treatment-related preserved cognitive func-
in very mild AD dementia and are lowest for tions (but no effects for other outcome mea-
MCI (i.e., mild and moderate > severe > very sures) (Salloway et al., 2004), other data
mild > very severe and MCI). For memantine support that ChEI treatment (donepezil)
monotherapy the overall gradient of evidence delays time to dementia diagnosis by up to
and effect sizes are as follows according to 23 years in those who carry one or more
AD dementia stage:moderate-to-severe and APOE 4 alleles (Petersen et al., 2005) or in
severe > moderate > very severe >>> mild; those who show symptoms of depression
none in MCI. Finally, for combination treat- (Lu et al., 2009). Petersen et al. found that
ment with memantine added on to baseline/ the observed relative reduction in the risk of
chronic ChEI, the overall gradient of evidence progression to Alzheimers disease of 58% at
and effect sizes are as follows according to one year and 36% at two years in the entire
AD dementia stage:moderate-to-severe and cohort is likely to be clinically significant.
414part ii The Dementias: The Major Diseases and Clinical Syndromes
However, systematic reviews of RCTs have add-on combination treatment with a ChEI.
yet to demonstrate clear efficacy for all MCI Level II grade evidence from clinical effec-
groups (Raschetti, Albanese, Vanacore, & tiveness studies in observational cohorts have
Maggini, 2007). supported that long-term clinical treatment
Heterogeneity of underlying pathology benefits are not limited to moderate and later
leading to MCI in different subjects in past stages of the disease but may be observed in
RCTs, including non-AD pathology, may con- early/mild stages of AD, increased with sus-
found results and obscure potential efficacy; tained use and time on treatment, and that
for this reason, more recent and future RCTs rates of cognitive and functional decline are
investigating MCI due to AD are starting to lower now in cohorts treated with antide-
employ AD biomarker inclusion criteria (e.g., mentia medications than in untreated con-
AD CSF profile, evidence of amyloid-PET trol or historical cohorts (Atri et al., 2008;
positivity) along with biomarkers of neuronal Gillette-Guyonnet et al., 2011; Lopez et al.,
injury (e.g., CSF tau profile, FDG-PET hypo- 2009; Rountree etal., 2009; Vellas etal., 2012;
metabolism pattern, structural MRI atro- Wallin etal., 2011; Wattmo etal., 2011).
phy pattern) to ensure a diagnosis of High For those RCTs that have specifically
Likelihood MCI due to AD according to the limited enrollment to those in the mild to
new NIA-AA criteria (Albert etal., 2011). moderate stages of AD, the ChEIs have dem-
While there are potential signals of ben- onstrated significant, if modest, benefits in
efit observed in RCT and clinical effective- terms of cognitive and global decline versus
ness studies with observational cohorts that placebo (Takeda etal., 2006; Whitehead etal.,
there may be long-term clinical treatment 2004). Even in those patients who decline
benefits even in early disease and with sus- substantially while on a ChEI, evidence sug-
tained use of antidementia medications (Atri gests that the magnitude of decline may be
et al., 2008; Petersen et al., 2005; Rountree significantly less for patients who are treated
et al., 2009), the strength of evidence does than those on placebo (Wilkinson etal., 2009).
not provide support for a clear recommen-
dation for or against the use of donepezil or Moderate Stage
other antidementia medications (memantine
and combination treatment) in persons with There is Level I and II support for monother-
MCI. The general good safety and tolerabil- apy with ChEI and memantine, and combi-
ity profile of these medications, along with nation treatment in the moderate stages of
signals of potential efficacy and effectiveness AD dementia (Atri etal., 2008; Feldman etal.,
and the generic availability of most of these 2001; Howard etal., 2012; McShane etal., 2006;
medications, could prompt a discussion Reisberg etal., 2003; Rountree etal., 2009; Tariot
between the clinician and the patient about et al., 2004). Atri, Molinuevo, and colleagues
this possibility. assessed, by meta-analysis of short-term effi-
cacy RCTs, the benefits of combination treat-
ment with memantine added to baseline
Mild Stage
donepezil and observed that treatment benefits
Level I grade evidence for the efficacy of with effect sizes in the range of 0.20.3 were
ChEI monotherapy in mild AD has been evident in moderate, as well as moderate to
established by multiple RCTs for benefits in severe, stage AD in the domains of cognition,
the domains of cognition, function, global daily function, and global status (Atri et al.,
status, and behavior. The ChEI treatment 2013).
effect sizes for cognition in short-term RCTs
appear to be small (Cohens d:0.20.3 range)
Moderate to Severe, and Severe Stages
but larger than treatment effects on functional
measures. There is no Level Igrade evidence Level Igrade evidence from short-term RCTs
to support short-term efficacy of memantine supports anti-AD medication treatment, in
monotherapy or combination treatment in monotherapy or combination therapy, in the
mild AD (Schneider etal., 2011). moderate to severe and severe stages of AD
Level II grade evidence exists for short- and (Feldman et al., 2001; McShane et al., 2006;
long-term effectiveness of ChEI monotherapy, Reisberg et al., 2003; Tariot et al., 2004; van
memantine monotherapy, and memantine Dyck et al., 2007; van de Glind et al., 2013).
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 415
Tariot and colleagues 24-week RCT (Tariot may be equivalent to expanding the span of
etal., 2004)demonstrated that the combina- the early and mid-stages of the illness up to
tion of memantine added to long-term sta- 56% or more (Rountree etal., 2009).
ble donepezil therapy has beneficial effects
on cognition, ADLs, and global function
at these stages of AD. Grossberg and col- Best Practices and Recommendations
leagues recently reported treatment benefits
of memantine add-on combination treat- The evidence supporting use of ChEIs and
ment with any baseline ChEI in multiple memantine reviewed supports, with Level
domains (Grossberg et al., 2013). Level II I evidence, initiating a ChEI in the mild
grade evidence from multiple studies sup- stages of AD and adding memantine at the
ports the long-term benefits of antidementia moderate stage. For those not diagnosed
medication treatments in multiple domains until the moderate to severe stages, either
(Atri et al., 2008; Gillette-Guyonnet et al., a ChEI or memantine can be initiated. Data
2011; Howard etal., 2012; Lopez etal., 2009; further support the added benefits of achiev-
Rountree etal., 2009; Vellas etal., 2012; Wallin ing ChEI-memantine add-on combination
etal., 2011; Wattmo etal., 2011). therapy in moderate and later stages of AD
dementia. Level II evidence or equivocal
Level Idata suggest that treatment with ChEI
Very Severe (Nursing Home) Stage
may also be significantly beneficial in very
Treatment benefits of ChEI therapy, even mild stage AD or for particular subgroups
when initiated in individuals in nursing of patients with MCI due to AD (i.e., carriers
homes with very severe stage dementia, have of APOE-e4 allele; Petersen etal., 2005; those
been demonstrated in RCTs to be of ben- with depression or depressive symptoms; Lu
efit in the domains of cognition, function/ et al., 2005). Such off-FDA label pharmaco-
ADLs (Winblad etal., 2006), and global func- therapy is not sufficiently supported by Level
tion (Black etal., 2007). Similarly, an RCT by Ievidence to warrant an unequivocal recom-
Winblad and colleagues (Winblad & Poritis, mendation for blanket use in all patients.
1999) reported that initiation of memantine However, available benefit, risk (tolerability
in late-stage nursing home patients with and safety) and cost data, individual clinical
dementia (AD dementia, vascular dementia, circumstances, and patientcaregiver dyad
or mixed dementia from both) was associated preferences warrant prompting a discussion
with significant functional improvement and between clinicians, patients, and caregivers
reduction of care dependence. about this possibility.
In practice, patients are treated differently
depending on their geographic location and
Persistence, Dose, and Duration of Treatment Are
what kind of clinician evaluates them (Iliffe,
Associated With Better Outcomes
2007; Vellas etal., 2012). While treatment rates
There is evidence that persistence in antide- with one or more antidementia medications are
mentia therapyeither ChEI monotherapy on the rise in the United States and elsewhere
or combotherapyresults in better cognitive, (Gillette-Guyonnet et al., 2011; Vellas et al.,
functional, and disease severity outcomes, 2012), regrettably, a significant percentage of
even in those with advanced dementia (Atri patients remain untreated with medications at
etal., 2008; Rountree etal., 2009). Higher doses any given stage of AD dementia, and too many
of ChEI (up to the recommended maximums), patients who are prescribed stop medications
have been shown to correlate with better within 12 years (Alzheimers-Association,
long-term cognitive, functional, and global 2013; Sun, Lai, Lu,& Chen, 2008). In the United
outcomes over 3 years of follow-up (Wallin States, patients are more likely to receive a
etal., 2011; Wattmo etal., 2011). Rountree and ChEI and/or memantine when seen in a spe-
colleagues calculated that high persistence in cialized dementia clinic than if seen in a mental
adherence to antidementia medication regi- health setting (Rattinger, Mullins, Zuckerman,
mens is of 1 point/year benefit in reducing Onukwugha, & Delisle, 2010). Among US
decline in MMSE score, and their data sug- neurologists, most routinely prescribe ChEIs
gest that incremental benefits associated with for mild to moderate AD and add memantine
greater cumulative antidementia treatment later, but some, at least at times, also prescribe
416part ii The Dementias: The Major Diseases and Clinical Syndromes
ChEIs in MCI and, less often, memantine for placebo-controlled trial performed in a
individuals with MCI or mild AD (Roberts, U.S.veterans with mild to moderate AD who
Karlawish, Uhlmann, Petersen, & Green, were already taking a cholinesterase-inhibitor
2010). Among academic Alzheimers disease further supported the benefits of high-dose
research centers, for those patients followed vitamin E (-tocopherol 1,000 international
from early disease stages for 6years, the domi- units twice daily) treatment on slowing func-
nant practice pattern was to initiate ChEIs in tional decline (Dysken et al., 2014). In this
the mild to moderate stages and memantine multiyear study, decline in activities of daily
in the moderate to severe stage (Schneider living was 19% per year slower in the group
et al., 2011). A similar pattern was observed of subjects who received vitamin E in addition
in France: Over 90% of patients were treated to their background cholinesterase-inhibitor
with anti-AD medications, with a ChEI usu- treatment, than in the group of subjects who
ally started first and then memantine added in received placebo in addition to their back-
the moderate stages (Gillette-Guyonnet etal., ground cholinesterase-inhibitor. Furthermore,
2011). all-cause mortality and safety analyses did not
suggest increased risks, compared to placebo,
of vitamin E supplementation (Dysken et al.,
Vitamins, Medical Foods, and Supplements 2014).
(Shah etal., 2013). In this study, Souvenaid uncontrolled seizures, active peptic ulcer
was, however, well tolerated in combination disease and gastrointestinal bleeding, and
with standard care anti-AD medications. unexplained syncope, ChEI therapy should
be initiated and slowly titrated over months
Other Vitamins and Supplements to a maximal clinical or tolerated dose fol-
lowing diagnosis of AD dementia (see Table
Unfortunately, large RCTs have, thus far, 16.15). For patients with moderate to severe
failed to support any significant benefit from AD, memantine can be initiated once patients
ginkgo biloba, high-dose vitamin B12/folic have received stable ChEI therapy for several
acid combinations, omega-3 fatty acid/fish months without adverse effects (Table16.15).
oil components/preparations, nonsteroidal Memantine monotherapy can be initiated
anti-inflammatory drugs, and statin medi- on-label in the United States if the patient
cations at the dementia stage of AD (Ballard has moderate or later stage AD; conversely,
etal., 2011; Tayeb etal., 2012). While epidemi- a ChEI can be added after several months of
ological and Level III/IV grade evidence has stable memantine therapy. The latter may be
suggested potential benefits associated with a particularly useful strategy in patients who
individuals who take these supplements, all are very sensitive to or experience gastroin-
efficacy RCTs in individuals with AD demen- testinal side effects with ChEIs. In the event
tia have failed to show benefit. of marked AEs, trying a very low and slow
titration (e.g., starting donepezil 2.5 mg daily
after breakfast; increasing it to 5 mg daily if
Practical Implementation of Pharmacotherapy no side effects emerge within 6 weeks) may
be helpful. In highly refractory situations,
Unless contraindicated due to conditions, switching to another ChEI at a low dose can
including unstable cardiac arrhythmias, also be tried.
Donepezil Starting dose:5 mg/day; can be increased to 10 mg/day after 46 weeks. Before
starting donepezil 23 mg/day, patients should be on donepezil 10 mg/day for at least
3months.
Rivastigmine Oral:Starting dose:1.5 mg twice daily. If well tolerated, the dose may be increased to 3
mg twice daily after 2 weeks. Subsequent increases to 4.5 and 6 mg twice daily should
be attempted after 2-week minimums at previous dose. Maximum dose:6 mg twice
daily.
Patch:Starting dose:one 4.6 mg patch once daily for a period of 24 hours
Maintenance dose:one 9.5 mg or 13.3 mg patch once daily for a period of 24 hours.
Before initiating a maintenance dose, patients should undergo a minimum of 4 weeks
of treatment at the initial dose (or at the lower patch dose of 9.5 mg) with good
tolerability.
Galantamine Extended-release:Start at 8 mg once daily for 4 weeks; increase to 16 mg once daily for
4weeks; increase to 24 mg once daily.
Generic:Start at 4 mg twice daily for 4 weeks; increase to 8 mg twice daily for 4 weeks;
increase to 12 mg twice daily.
Memantine Immediate-release:Starting dose:5 mg once daily; increase dose in 5-mg increments to a
maximum of 20 mg daily (divided doses taken twice daily) with a minimum of 1week
between dose increases. The maximum recommended dose in severe renal impairment
is 5 mg twice daily.
Extended-release:For patients new to memantine, the recommended starting dose of
memantine extended release is 7 mg once daily, and the recommended target dose is
28 mg once daily. The dose should be increased in 7 mg increments every seventh day.
The minimum recommended interval between dose increases is 1 week, and only if
the previous dose has been well tolerated. The maximum recommended dose in severe
renal impairment is 14 mg once daily.
418part ii The Dementias: The Major Diseases and Clinical Syndromes
All patients should have their vascular risk activating (e.g., stimulants) and who are also
factors managed diligently. This includes, being treated with large dosages of sedative/
in at-risk individuals, optimization of lipids hypnotics at night in order to induce sleep.
(preferably with a statin), blood pressure, and
serum glucose, and, if not contraindicated, use Antipsychotics for Treatment of Severe and
of daily enteric-coated baby aspirin (81 mg). Refractory Agitation, Aggression, and Psychosis
There should be screening and ongoing moni-
toring for anxiety and clinical depression, and Severe agitation, aggression, and psycho-
when present these should be treated with a sis are prevalent BPSDs in advancing AD
trial of an antidepressantpreferably with that can respond to atypical antipsychotics.
a selective serotonin reuptake inhibitor with However, the use of antipsychotics for BPSD
low anticholinergic load and a favorable geri- in AD dementia is off-label in the United
atric profile (e.g., citalopram, sertraline). Sleep States, and the prescribing information carries
and nutrition should be optimized, and any a FDA black box warning. Clinicians should
deficiencies (e.g., thyroid, vitamin B12) and resist starting antipsychotics in patients with
systemic conditions that can decompensate dementia and only do so when strict con-
mental functions should be treated (e.g., UTI, ditions have been met, including a careful
dehydration, hyponnatremia). Promotion of consideration of risks, benefits, side effects,
good health habits, including exercise, nutri- and alternatives. As antipsychotics can have
tion, stress management, adequate sleep, and detrimental effects on cognition, function,
social and mental engagement, should be and patient safety, they should generally be
actively promoted. reserved for a trial in selected patients who
In general, benzodiazepines (e.g., loraz- are on a multidisciplinary behavioral plan,
epam used for anxiety or as a sedative- already on stable background combination
hypnotic) and medications with high anti- therapy, and are under the supervision of a
cholinergic activity, for example, those used dementia specialist; or when there is an imme-
in the treatment of urinary incontinence, diate or impending high risk to the safety or
allergies (antihistamines), pain or sleep well-being of the patient or others.
disorders (e.g., tricyclic antidepressants, In the absence of a great immediate or
diphenhydramine), should be avoided (see impending safety risk, an alternative phar-
Table 16.8). Antipsychotics should be used macological approach that can be considered
with great caution and only under specific is a trial treatment with low-dose citalopram.
circumstances (see Chapter 24 and below). A very recently published study, the CitAD
Along with psychosocial interventions, a trial, reported that among AD patients with
trial of low-dose citalopram (starting low at clinically significant agitation who were
10 mg nightly, and increasing after 4-6 weeks, receiving psychosocial intervention, the addi-
if response is insufficient, to preferably no tion of citalopram (started at 10 mg daily and
higher than 20 mg nightly) can be consid- titrated, based on response and tolerability, to
ered in individuals with significant agitation 30 mg daily over three weeks) compared with
(see below). Stimulants are seldom indicated placebo significantly reduced agitation and
except for a trial in patients with severe and caregiver distress (Porsteinsson et al., 2014).
refractory daytime somnolence or apathy, in However, it is cautioned that potential wors-
which case low-dose modafinil may be tried. ening of cognitive functions and emergence
However, all stimulants may lower threshold of cardiac adverse effects (e.g., prolongation
for causing irritability, agitation, aggression, of QT interval) could limit the practical appli-
and dysphoria, particularly in individuals cation of citalopram at dosages as high as 30
who are susceptible. Additionally, one can mg per day. For a more detailed discussion of
avoid the common syndrome of chasing approaches to treating agitation, aggression
ones tail, which includes prescribing medi- and psychosis, see Chapter24.
cations that exacerbate a seemingly sepa-
rate condition for which another medication When to Start and Stop Anti-Alzheimers Disease
is being prescribed for as treatment. For Medications
example, it is not uncommon to come across
patients who are treated with increasing The questions of when to start and when
numbers and dosages of medications that are to stop AD medications are of utmost
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 419
importance to clinicians, patients, and fami- dressing, grooming, and bathing; and the
lies. While there is no clear consensus on elementary processes of movement, turning,
either front, the question of when to start sitting, standing, chewing, and swallowing.
anti-AD medications appears to be the sim- The benefits may also extend to reducing
pler one to address as there are FDA indica- antipsychotic usage.
tions for each drug class. Yet this presupposes In the end/terminal stages of AD when per-
that the clinician is adept at appropriately sonhood has disintegrated, and when there
staging dementia severity in all individuals is no meaningful communication or interac-
with AD, and that individuals in other stages tion, patients should only receive care (phar-
may not benefit from treatment. As the first macological or otherwise) that is directed to
caveat, there is no single measure of cogni- provide palliation and comfort. There is no
tion, function, or behavior that can, in isola- economic, moral, scientific, or ethical reason
tion, characterize AD dementia stage in every for other medications, including anti-AD
patient. Staging disease severity should also medications, statins, or for performance of
consider changes from premorbid levels and intrusive evaluations and interventions. The
the impact of the illness on family and care- health care team must focus on providing an
givers; it requires a multidimensional picture environment that promotes a good death;
of an individual and depends on a variety of one that fosters, supports, and safeguards
subjective factors. Per US FDA prescribing the dignity and integrity of the patients life-
information, clinicians may start a ChEI in long wishes regarding his or her dying pro-
mild, moderate, or severe AD, and meman- cess and also provides the necessary care,
tine in moderate or severe AD. Patients in the consideration, and comfort to the patients
moderate stages can be started with a ChEI or loved ones to prepare and assist them in this
memantine, and, ultimately, the complemen- process.
tary agent should be added to achieve com-
bination therapy. As reviewed previously,
there are data with lower grades of evidence Practical Tips for Other Therapeutic
to support potential benefits of antidementia Challenges:Sleep-Wake Disturbances,
medication in other stages of AD. Therefore, Wandering, Eating Issues, and Incontinence
based on the patientcaregiver dyad prefer-
ences and clinician comfort and expertise, an These challenges posed to caregivers and
individualized discussion may be prompted patients are myriad and often incompletely
regarding the pros and cons, cost and uncer- respond or are suboptimally addressed only
tainties of potential off-label prescription of by drug interventions (see Chapters 24, 25,
anti-AD medications. and 26 for further discussion and recommen-
There are no appropriate studies to guide dations regarding approaches to common
when anti-AD medications should be with- BPSD). Many of these conditions are also
drawn in AD dementia. In addition to other incompletely studied and clinical recommen-
stages, memantine and the ChEIs donepezil dations regarding them often fall in the realm
and rivastigmine have FDA indications in of evidenced-based opinion as opposed
severe ADstudies support their treatment to being fully supported by evidence-based
benefits even in late stages of dementia when medicine.
patients may require nursing home level of
care. It is important for clinicians, caregiv-
Sleep-Wake Dysregulation
ers, and families to appreciate that the prac-
tical benefits of anti-AD medications in very Abnormal or distorted sleep-wake patterns
severe/late-stage AD are no longer aimed at are very common in AD dementia, and they
reducing decline in memory and other higher often become worse as the illness progresses.
level cognitive functions; these functions are This can lead to significant additional strains
no longer viable. Anti-AD medications can on caregivers, such as when patients are
be maintained in late-stage AD with a goal awake or wander at night, wake up too early,
to support basic psychomotor processes; or sleep most of the day. Patients with signifi-
praxis; functional communication; behav- cant apathy who experience inactivity during
ioral responses required to assist caregiv- the day and who are not kept engaged may sit
ers to deliver basic care involving feeding, around and regularly fall asleep several times
420part ii The Dementias: The Major Diseases and Clinical Syndromes
during the day. This can produce fragmented and then be at higher risk of aspiration and
and poor quality sleep and lead to a vicious falls. Providing the individual with plenty
cycle of sleeping/napping several times dur- of engagement and activity (including exer-
ing the day and difficulty sleeping or awak- cise during the day) and a safe environment
ening during the night or very early morning. to roam (e.g., a fenced back yard, corridors
A review of systems for obstructive sleep without access to the outside) is key. The use
apnea (OSA) should be undertaken, and, if of door locks and alarms that the patient can-
positive, appropriate evaluation and treat- not disengage, and disguising routes of entry
ment of OSA should be sought, particularly and egress can also be helpful. Finally, the
early in the course of dementia. Additionally, patient who has a tendency to wander should
in some individuals ChEIs, especially if given be provided with a medical identification
at night, can adversely affect sleep by being bracelet and can be registered in a safety pro-
overly activating, delaying sleep onset, pro- gram (e.g., the Alzheimers Association Safe
ducing very vivid dreams, or affecting low Return program).
quality sleep.
First-line treatment is nonpharmacological Abnormal Eating Behaviors and Eating-Related
and involves common sleep hygiene strate- Problems
gies. These include keeping the individual
awake and physically, socially, and mentally Individuals with AD dementia can experi-
active during the day; avoiding caffeine in ence a variety of eating changes and problems
the afternoon and nicotine in the evening; that can include overeating, undereating, and
limiting naps to at most one 11.5 hour abnormal eating behaviors (Ikeda, Brown,
scheduled nap in the early afternoon; limit- Holland, Fukuhara, & Hodges, 2002). Food
ing stimulating activities, exercise, and big tastes and preferences can change along with
meals in the later evening or before bedtime; an individuals interest, mood, motivation,
ensuring that a strict sleep and wake sched- energy, appetite, and self-restraint. Changes
ule is kept and that the individual is out of in an individuals senses of taste and smell
bed and dressed in the morning; and ensur- are common, and so is a particular craving
ing the bedroom is quiet, dark, cool, devoid for sweets. In some individuals with AD or
of TV and other distractions. In refractory mixed AD dementia, especially in those with
situations, melatonin can be tried. In severely particular frontal syndromes, hyperoral-
refractory cases, pharmacological treatment ity, poor impulse control, compulsions, and
can include trials of low-dose trazodone (25 memory problems can synergize to manifest
50 mg to start; increased to 100 mg at bedtime in binging or overeating (or drinking), and
as needed); zolpidem; or quetiapine or mir- eating and tasting things that inappropri-
tazipine, particularly if these are being con- ate, inedible, or dangerous. In others, lack of
sidered for pharamacological treatment of appetite, interest, and activity, and forgetful-
coexisting severe refractory agitation, aggres- ness can lead to undereating that results in
sion, or psychosis (quetiapine), or anxiety medically significant dehydration, malnutri-
and depression (mirtazipine). tion, and frailty.
As always, a root cause analysis should
include investigation of potential biopsy-
Wandering
chosocial causes, particularly medical and
A particularly disturbing and dangerous medication-relation causes, including thy-
behavioral symptom in individuals with AD roid, diabetes and other endocrine abnor-
dementia is wandering, particularly when malities. Commonly prescribed medications
it occurs at night or when the patient strays such as antipsychotics (particularly quetiap-
outside in unhospitable conditions. The ine), antidepressants (tricyclic antidepres-
underlying etiology of wandering should be sants, SSRIs, mirtazipine), and antiepileptics
sought and treated, and it can include anxiety, (valproic acid, gabapentin) can increase appe-
confusion, lack of physical and social activ- tite and weight gain. Stimulants can have the
ity, and side effects from medications (e.g., opposite effect. Behavioral interventions and
antipsychotics). Medications are unlikely strategies usually provide the most effective
to be of benefit to safely suppress wander- approach. In binge-, compulsive-, and over-
ingthe individual can become oversedated eaters regulating access to food, drink, and
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 421
objects provides the most effective strategy. wearing adult diapers; wearing clothes that
In some cases, cabinets and refrigerators have are easy to quickly remove (and to clean);
to be locked, and in other cases, the particular facilitating easy access to the bathroom (e.g.,
food or drink that is being compulsively con- clear path and lighting); providing a uri-
sumed has to be rationed and brought into nal or bedside commode; using bed or floor
the house in limited quantities. Compulsive pads that are absorbent and easy to clean;
eating in some individuals may respond to a and using special incontinence bed sheets
trial of SSRI or carbamazepine. (rubber-like). Pelvic floor (Kegel) exercises
For individuals who are undereating, can be taught and may be of benefit to women
practical approaches such as providing and men with urge and stress incontinence or
favorite foods (particularly from childhood); urinary leakage who have sufficient cogni-
high caloric foods, drinks, and nutritional tive function. Identifying patterns, clues, and
supplements; eating with the individual triggers for incontinence can also be helpful.
(social eating); providing small portions on For example, if urinary incontinence occurs
a large plate and then replenishing it when at night, one can limit fluid and caffeinated
the portion is eaten; allowing more time for product intake in the later evening, switch a
individuals to eat; and serving meals in an diuretic dose to earlier in the day, and ensure
environment that is peaceful, uncluttered, that the individual is not oversedated due to
and devoid of distractions (e.g., is quiet but medications or supplements. Unfortunately,
has peaceful music in the background) may common medications prescribed for urinary
be effective. In more advanced stage patients, incontinence in the elderly all have anticho-
providing supervision at mealtime and fin- linergic properties (see Table16.8), effectively
ger foods; and ensuring that dental and counteract ChEIs, and can cause increased
denture problems and chewing and choking confusion in individuals with dementia. In
difficulties do not exist can also be helpful. individuals in whom prostatic hypertrophy
For individuals who are inactive, increasing can contribute to their urinary problems, a
their activity and facilitating exercise is rec- trial of low-dose tamsulosin by be tried.
ommended. If a comorbid condition such as
depression or severe agitation is also being
treated, then switching to a medication in the The Therapeutic Glue:The Caregivers, and
same class that also increases appetite, such Caring for Them
as mirtazipine or quetiapine, may be tried.
Appetite stimulants, such as megestrol and Caregivers are the glue in the clinician and
dronabinol, can be tried as a last resort. patientcaregiver dyad therapeutic relation-
ship. They are where the rubber meets the
Incontinence roadno plans for therapeutics and care,
no matter how detailed and optimized in
Urinary and, particularly, fecal incontinence theory, can be realized without the caregiv-
are very challenging for patients and care- ers. The importance of forging and maintain-
givers. When a medical assessment and ing a therapeutic alliance with caregivers in
medication review eliminates other contrib- order to provide the best care to the patient
uting causes such as a urinary tract infection, caregiver dyad cannot be understated. The
prostatic hypetrophy, or a poorly scheduled complex biopsychosocial and cultural factors
diuretic dose, then behavioral and envi- that influence patient care and their effects
ronmental strategies are the recommended on caregiver well-being and participation are
approach to management of incontinence. reviewed in Chapter 27. Caregivers require
These include optimizing the timing of food psychoeducation, support, and carethis
and fluid intake and coordinating and sched- can provide meaningful benefits to both
uling bathroom visits with meals, travel, and patient and caregivers.
sleep (e.g., reminding or taking the individu-
als to the bathroom immediately after meals,
then an hour later; before naps; and before The Medication Drift Syndrome
travel; limiting fluid intake in the evening,
particularly fluids such as caffeinated tea, The syndrome of chasing ones tail frequently
coffee, and sodas that can act as a diuretic); arises from another syndrome:the medication
422part ii The Dementias: The Major Diseases and Clinical Syndromes
drift of subtraction by addition. Many avoided and substituted when possible (see
elderly individuals unnecessarily suffer from Table16.8). This type of addition by subtrac-
this syndrome by gradually accumulating, tion can be a powerful clinical approach to
without professional review or discontinu- regain seemingly lost cognition and func-
ation when appropriate, numerous medica- tion in individuals with AD dementia, and
tions prescribed by a multitude of clinicians it should be undertaken periodically, even
and specialists for various and seemingly before anti-AD medications are prescribed.
separate, but in reality related, conditions.
Often, medications prescribed for different
conditions can have additive effects (e.g., anti- Recommendations
cholinergic load) to produce deleterious out-
comes (e.g., confusion, orthostasis, falls). In Evidence- and experience-based opinion
some cases the medications are prescribed for supports the following: (1) AD dementia
complementary or opposite conditions, such treatments should be individualized based
as excessive daytime sleep or lethargy versus upon an open discussion with the patient
inability to initiate or maintain asleep at night and caregivers regarding the prognosis,
(e.g., stimulants versus sedative-hypnotics), goals, and expectations of therapy; (2) all
and produce effects that are counteractive discussions should involve clarifying goals
(e.g., anticholinergics prescribed for urinary and expectations of treatments, make clear
incontinence and ChEIs prescribed for AD). which treatments are on-label or off-label,
A good example of this was reported by and include an honest assessment of cur-
Tsao and Heilman in the case of an elderly rent and future potential benefits, risks, side
woman who began to experience cognitive effects, costs, alternatives, and uncertainties;
and memory problems and hallucinations (3)elimination of redundant and potentially
soon after being prescribed tolterodine, an inappropriate medications; (4)initiation and
anticholinergic agent used in the treatment maintenance of anti-AD medications: Level
of urinary incontinence (Tsao & Heilman, I evidence supports short-term benefits
2003). Her primary care physician, suspect- of ChEI-memantine add-on combination
ing that the cognitive and neuropsychiatric therapy in moderate and severe AD, and
symptoms were due to dementia, then pre- long-term Level II evidence support that for
scribed the ChEI donepezil, which resulted in any individual, irrespective of AD stage, sus-
improvement of her memory problems and tained combination therapy may potentially
resolution of her hallucinations. Later, when best provide the greatest likelihood of slow-
the patient discontinued the tolterodine, her ing long-term clinical decline; (5) first-line
memory and cognitive improved further. treatment of BPSD involves psychoeducation
However, upon subsequently reintroduc- and behavioral and environmental interven-
ing the tolterodine, her memory and cogni- tions; the prescription of atypical antipsy-
tive problems re-emerged, and they did not chotics for BPSD should be reserved for a
resolve until this medication was finally dis- trial in selected highly refractory patients
continued. While this particular patient effec- who are on a multidisciplinary behavioral
tively failed the anticholinergic stress test plan, are already on stable background com-
of tolterodine and appeared to be demented, bination therapy, and are under the supervi-
and potentially may have been particularly sion of a dementia specialist; or when there is
susceptible due to a subclinical stage of AD an immediate or impending high risk to the
or another neurodegenerative dementia, she safety or well-being of the patient or others;
was, however, not demented at the time, and and (6) maintaining an open-minded, pro-
her symptoms were due to iatrogenesis. active, positive, and flexible individualized
Clinicians should, therefore, adopt a approach to compassionately caring for indi-
broad and integrative perspective regarding viduals and caregivers that utilizes thinking
medical conditions and cognitive health to and caring on the margin, which is real-
periodically review all medications and sup- istic but does not take away hope, and that
plements and to safely eliminate potentially establishes a strong therapeutic alliance that
cognitively deleterious and redundant medi- is holistic and pragmatic and involves psy-
cations. Medications that appear on Beers choeducation; behavioral and environmental
Criteria (AGS, 2012) should be particularly approaches to care; planning for current and
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 423
future care needs; and promoting vascular central cholinergic receptors impairs new
and general health, psychosocial well-being, learning and increases proactive interfer-
safety, and quality of life; and (7)care in the ence in a word paired-associate memory task.
end stages of the illness should be palliative Behavioral Neuroscience, 118(1), 223236.
Atri, A., Chang, M.S.& Strichartz, G.R. (2011).
and focus on facilitating a good death.
Cholinergic pharmacology. In D. Golan, A.
Tashjian, E. Armstrong, & A. W. Armstrong
References (Eds.), Principles of pharmacology: The patho-
physiological basis for drug therapy (3rd ed.,
Albert, M.S., DeKosky, S.T., Dickson, D., Dubois, pp. 125148. Philadelphia, PA: Lippencott &
B., Feldman, H. H., Fox, N. C.,...Phelps, Williams.
C. H. (2011). The diagnosis of mild cogni- Attems, J., Jellinger, K., Thal, D. R., & van
tive impairment due to Alzheimers dis- Nostrand, W. (2011). Review: Sporadic cere-
ease: Recommendations from the National bral amyloid angiopathy. Neuropathology and
Institute on Aging-Alzheimers Association Applied Neurobiology, 37, 7593.
workgroups on diagnostic guidelines for Bakchine, S., & Loft, H. (2008). Memantine
Alzheimers disease. Alzheimers and Dementia, treatment in patients with mild to moder-
7(3), 270279. ate Alzheimers disease: Results of a ran-
Alzheimers-Association. (2013). 2013 domised, double-blind, placebo-controlled
Alzheimers disease facts and figures. 6-month study. Journal of Alzheimers Disease,
Alzheimers and Dementia, 9(2), 208245. 13(1), 97107.
American Geriatric Society (AGS). (2012). Ballard, C., Gauthier, S., Corbett, A., Brayne, C.,
American Geriatrics Society updated Beers Aarsland, D.,& Jones, E. (2011). Alzheimers
Criteria for potentially inappropriate medica- disease. Lancet, 377(9770), 10191031.
tion use in older adults. Journal of the American Bertram, L., McQueen, M. B., Mullin, K.,
Geriatrics Society, 60(4), 616631. Blacker, D.,& Tanzi, R.E. (2007). Systematic
American Psychiatric Association (APA). meta-analyses of Alzheimer disease genetic
Diagnostic and statistical manual of mental dis- association studies: The AlzGene database.
orders (5th ed.). Washington, DC: American Nature Genetics, 39(1), 1723.
Psychiatric Publishing. Birks, J. (2006). Cholinesterase inhibitors for
Atri, A. (2011). Effective pharmacological man- Alzheimers disease. Cochrane Database of
agement of Alzheimers disease. American Systematic Reviews, (1), CD005593.
Journal of Managed Care, 17(Suppl 13), Black, S. E., Doody, R., Li, H., McRae, T.,
S346S355. Jambor, K.M., Xu, Y.,...Richardson, S. (2007).
Atri, A., Locascio, J. J., Lin, J. M., Yap, L., Donepezil preserves cognition and global
Dickerson, B. C., Grodstein, F.,...Greenberg, function in patients with severe Alzheimer
S. M. (2005). Prevalence and effects of lobar disease. Neurology, 69(5), 459469.
microhemorrhages in early-stage dementia. Blessed, G., Tomlinson, B. E., & Roth, M.
Neurodegener Dis. (6):305312. (1968). The association between quantita-
Atri, A., Molinuevo, J., Lemming, O., Wirth, Y., tive measures of dementia and of senile
Pulte, I.,& Wilkinson, D. (2013). Memantine change in the cerebral grey matter of
in patients with Alzheimers disease receiv- elderly subjects. British Journal of Psychiatry,
ing donepezil: New analyses of efficacy and 114, 797811.
safety for combination therapy. Alzheimers Bordji, K., Becerril-Ortega, J., & Buisson, A.
Research and Therapy, 5(1), 6. (2011). Synapses, NMDA receptor activity and
Atri, A., Rountree, S., Lopez, O., & Doody, R. neuronal abeta production in Alzheimers
(2012). Validity, significance, strengths, limi- disease. Reviews in the Neurosciences, 22(3),
tations, and evidentiary value of real-world 285294.
clinical data for combination therapy in Braak, H., Alafuzoff, I., Arzberger, T.,
Alzheimers disease: comparison of efficacy Kretzschmar, H., & Del Tredici, K. (2006).
and effectiveness studies. Neurodegenerative Staging of Alzheimer disease-associated
Diseases, 10(14), 170174. neurofibrillary pathology using paraffin
Atri, A., Shaughnessy, L. W., Locascio, J. J., & sections and immunocytochemistry. Acta
Growdon, J. H. (2008). Long-term course Neuropathologica, 112, 389404.
and effectiveness of combination therapy Braak, H.,& Braak, E. (1991). Neuropathological
in Alzheimer disease. Alzheimer Disease and stageing of Alzheimer-related changes. Acta
Associated Disorders, 22(3), 209221. Neuropathologica, 82(4), 239259.
Atri, A., Sherman, S., Norman, K. A., Buckner, R. L., Andrews-Hanna, J. R., &
Kirchhoff, B. A., Nicolas, M. M., Greicius, Schacter, D. L. (2008). The brains default
M. D.,...Stern, C. E. (2004). Blockade of network: Anatomy, function, and relevance
424part ii The Dementias: The Major Diseases and Clinical Syndromes
to disease. Annals of the NewYork Academy of Cummings, J.L., McRae, T.,& Zhang, R. (2006).
Sciences, 1124, 138. Effects of donepezil on neuropsychiatric
Bullock, R., Bergman, H., Touchon, J., Gambina, symptoms in patients with dementia and
G., He, Y., Nagel, J.,...Lane, R. (2006). Effect severe behavioral disorders. American Journal
of age on response to rivastigmine or done- of Geriatric Psychiatry, 14(7), 605612.
pezil in patients with Alzheimers disease. Cummings, J. L., Mega, M., Gray, K.,
Current Medical Research and Opinion, 22(3), Rosenberg-Thompson, S., Carusi, D. A., &
483494. Gornbein, J. (1994). The Neuropsychiatric
Bullock, R. (2006). Efficacy and safety of meman- Inventory: Comprehensive assessment of
tine in moderate-to-severe Alzheimer dis- psychopathology in dementia. Neurology,
ease:The evidence to date. Alzheimer Disease 44(12), 23082314.
and Associated Disorders, 20(1), 2329. Cummings, J. L., Schneider, E., Tariot, P. N., &
Bullock, R., Touchon, J., Bergman, H., Gambina, Graham, S. M. (2006). Behavioral effects of
G., He, Y., Rapatz, G., .
.
.
Lane, R. (2005). memantine in Alzheimer disease patients receiv-
Rivastigmine and donepezil treatment in ing donepezil treatment. Neurology, 67(1), 5763.
moderate to moderately-severe Alzheimers Cummings, J. L., Schneider, L., Tariot, P. N.,
disease over a 2-year period. Current Medical Kershaw, P.R.,& Yuan, W. (2004). Reduction
Research and Opinion, 21(8), 13171327. of behavioral disturbances and caregiver
Burns, A., Gauthier, S., & Perdomo, C. (2007). distress by galantamine in patients with
Efficacy and safety of donepezil over Alzheimers disease. American Journal of
3 years: An open-label, multicentre study Psychiatry, 161(3), 532538.
in patients with Alzheimers disease. Daffner, K.R. (2010). Promoting successful cog-
International Journal of Geriatric Psychiatry, nitive aging:Acomprehensive review. Journal
22(8), 806812. of Alzheimers Disease, 19(4), 11011122.
Cappell, J., Herrmann, N., Cornish, S., & Davies, P. (2000). A very incomplete comprehen-
Lanctot, K. L. (2010). The pharmacoeco- sive theory of Alzheimers disease. Annals of
nomics of cognitive enhancers in moderate the NewYork Academy of Sciences, 924, 816.
to severe Alzheimers disease. CNS Drugs, Doody, R., Geldmacher, D., Gordon, B.,
24(11), 909927. Perdomo, C., & Pratt, R. (2001). Open-label,
Choi, S. H., Park, K. W., Na, D. L., Han, H. J., multicenter, phase 3 extension study of the
Kim, E. J., Shim, Y. S., & Lee, J. H. (2011). safety and efficacy of donepezil in patients
Tolerability and efficacy of memantine with Alzheimer disease. Archives of Neurology,
add-on therapy to rivastigmine transdermal 58(3), 427433.
patches in mild to moderate Alzheimers dis- Doody, R., Wirth, Y., Schmitt, F.,& Mobius, H.J.
ease:Amulticenter, randomized, open-label, (2004). Specific functional effects of meman-
parallel-group study. Current Medical Research tine treatment in patients with moderate to
and Opinion, 27(7), 13751383. severe Alzheimers disease. Dementia and
Chou, Y.Y., Lepore, N., Avedissian, C., Madsen, Geriatric Cognitive Disorders, 18(2), 227232.
S. K., Parikshak, N., Hua, X.,...Thompson, Doody, R.S., Dunn, J.K., Clark, C.M., Farlow,
P. M. (2009). Mapping correlations between M., Foster, N. L., Liao, T.,...Massman, P.
ventricular expansion and CSF amyloid (2001). Chronic donepezil treatment is asso-
and tau biomarkers in 240 subjects with ciated with slowed cognitive decline in
Alzheimers disease, mild cognitive impair- Alzheimers disease. Dementia and Geriatric
ment and elderly controls. NeuroImage, 46(2), Cognitive Disorders, 12(4), 295300.
394410. Doody, R. S., Geldmacher, D. S., Gordon,
Corder, E. H., Saunders, A. M., Strittmatter, B., Perdomo, C. A., & Pratt, R. D. (2001).
W.J., Schmechel, D.E., Gaskell, P.C., Small, Open-label, multicenter, phase 3 extension
G. W.,...Pericak-Vance, M. A. (1993). Gene study of the safety and efficacy of donepezil
dose of apolipoprotein E type 4 allele and the in patients with Alzheimer disease. Archives
risk of Alzheimers disease in late onset fami- of Neurology, 58(3), 427433.
lies. Science, 261(5123), 921923. Dubois, B., Feldman, H., Jacova, C., DeKosky,
Courtney, C., Farrell, D., Gray, R., Hills, R., S., Barberger-Gateau, P., Cummings,
Lynch, L., Sellwood, E.,...Bentham, P. J.,...Scheltens, P. (2007). Research crite-
(2004). Long-term donepezil treatment in 565 ria for the diagnosis of Alzheimers dis-
patients with Alzheimers disease (AD2000), ease:Revising the NINCDS-ADRDA criteria.
randomised double-blind trial. Lancet, Lancet Neurology, 6(8), 734746.
363(9427), 21052115. Dubois, B., Feldman, H. H., Jacova,
Cummings, J. L. (2004). Alzheimers disease. C., Cummings, J. L., Dekosky, S. T.,
New England Journal of Medicine, 351(1), 5667. Barberger-Gateau, P.,...Scheltens, P. (2010).
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 425
Revising the definition of Alzheimers dis- Gauthier, S., Loft, H., & Cummings, J. (2008).
ease: A new lexicon. Lancet Neurology, 9(11), Improvement in behavioural symptoms in
11181127. patients with moderate to severe Alzheimers
Dysken, M.W., Sano, M., Asthana, S., Vertrees, disease by memantine:Apooled data analy-
J.E., Pallaki, M., Llorente, M.,...Guarino, P.D. sis. International Journal of Geriatric Psychiatry
(2014). Effect of Vitamin E and Memantine 2008 May;23(5), 537545.
on Functional Decline in Alzheimer Disease. Gauthier, S.,& Molinuevo, J.L. (2013). Benefits
JAMA. 311(1), 3344. of combined cholinesterase inhibitor and
Farlow, M., Anand, R., Messina, J., Jr., Hartman, memantine treatment in moderate-severe
R.,& Veach, J. (2000). A 52-week study of the Alzheimers disease. Alzheimers and Dementia,
efficacy of rivastigmine in patients with mild 9(3), 326331.
to moderately severe Alzheimers disease. Getsios, D., Blume, S., Ishak, K.J.,& Maclaine,
European Neurology, 44(4), 236241. G. D. (2010). Cost effectiveness of done-
Farlow, M.R.,& Cummings, J.L. (2007). Effective pezil in the treatment of mild to moderate
pharmacologic management of Alzheimers Alzheimers disease:AUK evaluation using
disease. American Journal of Medicine, 120(5), discrete-event simulation. PharmacoEconomics,
388397. 28(5), 411427.
Farlow, M., Veloso, F., Moline, M., Yardley, J., Gillette-Guyonnet, S., Andrieu, S., Cortes,
Brand-Schieber, E., Bibbiani, F.,...Satlin, A. F., Nourhashemi, F., Cantet, C., Ousset,
(2011). Safety and tolerability of donepezil 23 P. J.,...Vellas, B. (2006). Outcome of
mg in moderate to severe Alzheimers dis- Alzheimers disease:potential impact of cho-
ease. BMC Neurology, 11, 57. linesterase inhibitors. Journals of Gerontology
Feldman, H., Gauthier, S., Hecker, J., Vellas, B., Series A, Biological Sciences and Medical
Subbiah, P.,& Whalen, E. (2001). A 24-week, Sciences, 61(5), 516520.
randomized, double-blind study of donepe- Gillette-Guyonnet, S., Andrieu, S.,
zil in moderate to severe Alzheimers disease. Nourhashemi, F., Gardette, V., Coley, N.,
Neurology, 57, 613620. Cantet, C.,...Vellas, B. (2011). Long-term pro-
Feldman, H., Schmitt, F., & Olin, J. (2006). gression of Alzheimers disease in patients
Activities of daily living in moderate-to- under antidementia drugs. Alzheimers and
severe Alzheimer disease: An analysis Dementia, 7, 57992.
of the treatment effects of memantine in Greenberg, S. M., Tennis, M. K., Brown, L. B.,
patients receiving stable donepezil treatment. Gomez-Isla, T., Hayden, D. L., Schoenfeld,
Alzheimer Disease and Associated Disorders, 20, D.A.,...Growdon, J.H. (2000). Donepezil ther-
263268. apy in clinical practice: A randomized cross-
Feldman, H. H., Van Baelen, B., Kavanagh, over study. Archives of Neurology, 57(1), 9499.
S. M., & Torfs, K. E. (2005). Cognition, func- Grossberg, G. T., Manes, F., Allegri, R. F.,
tion, and caregiving time patterns in patients Gutierrez-Robledo, L. M., Gloger, S., Xie,
with mild-to-moderate Alzheimer dis- L.,...Graham, S.M. (2013). The safety, toler-
ease: A 12-month analysis. Alzheimer Disease ability, and efficacy of once-daily meman-
and Associated Disorders, 19(1), 2936. tine (28 mg): A multinational, randomized,
Fong, T. G., Jones, R. N., Marcantonio, E. R., double-blind, placebo-controlled trial in
Tommet, D., Gross, A. L., Habtemariam, patients with moderate-to-severe Alzheimers
D.,...Inouye, S.K. (2012). Adverse outcomes disease taking cholinesterase inhibitors. CNS
after hospitalization and delirium in persons Drugs, 27(6), 469478.
with Alzheimer disease. Annals of Internal Grossberg, G. T., Pejovic, V., Miller, M. L., &
Medicine, 156(12), 848856, W296. Graham, S.M. (2009). Memantine therapy of
Francis, P. T. (2005). The interplay of neu- behavioral symptoms in community-dwelling
rotransmitters in Alzheimers disease. CNS patients with moderate to severe Alzheimers
Spectrums, 10(11 Suppl 18), 69. disease. Dementia and Geriatric Cognitive
Fratiglioni, L., Paillard-Borg, S., & Winblad, B. Disorders, 27(2), 164172.
(2004). An active and socially integrated life- Gurland, B.J., Wilder, D.E., Lantigua, R., Stern,
style in late life might protect against demen- Y., Chen, J., Killeffer, E. H., & Mayeux, R.
tia. Lancet Neurology, 3(6), 343353. (1999). Rates of dementia in three ethnora-
Gauthier, S., Feldman, H., Hecker, J., Vellas, cial groups. International Journal of Geriatric
B., Ames, D., Subbiah, P.,...Emir, B. Psychiatry, 14(6), 481493.
(2002). Efficacy of donepezil on behavioral Haass, C., Koo, E. H., Mellon, A., Hung,
symptoms in patients with moderate to A. Y., & Selkoe, D. J. (1992). Targeting of
severe Alzheimers disease. International cell-surface beta-amyloid precursor pro-
Psychogeriatrics, 14(4), 389404. tein to lysosomes: Alternative processing
426part ii The Dementias: The Major Diseases and Clinical Syndromes
randomized, controlled trial. American Journal review of randomised trials. PLoS Medicine,
of Geriatric Psychiatry, 14(8), 704715. 4(11), e338.
Petersen, R. C., Aisen, P., Boeve, B. F., Geda, Raskind, M. A., Peskind, E. R., Truyen, L.,
Y. E., Ivnik, R. J., Knopman, D. S.,...Jack, Kershaw, P., & Damaraju, C. V. (2004). The
C. R., Jr. (2013). Criteria for mild cogni- cognitive benefits of galantamine are sus-
tive impairment due to Alzheimers dis- tained for at least 36 months: A long-term
ease in the community. Annals of Neurology. extension trial. Archives of Neurology, 61(2),
doi:10.1002/ana.23931. 252256.
Petersen, R. C., Thomas, R. G., Grundman, M., Raskind, M.A., Peskind, E.R., Wessel, T.,& Yuan,
Bennett, D., Doody, R., Ferris, S.,...Thal, L.J. W. (2000). Galantamine in AD: A 6-month
(2005). Vitamin E and donepezil for the treat- randomized, placebo-controlled trial with a
ment of mild cognitive impairment. New 6-month extension. The Galantamine USA-1
England Journal of Medicine, 352(23), 23792388. Study Group. Neurology, 54, 22612268.
Plassman, B. L., Langa, K. M., Fisher, G. G., Rattinger, G. B., Mullins, C. D., Zuckerman,
Heeringa, S. G., Weir, D. R., Ofstedal, I. H., Onukwugha, E., & Delisle, S. (2010).
M. B.,...Wallace, R. B. (2007). Prevalence Clinic visits and prescribing patterns among
of dementia in the United States: The Veterans Affairs Maryland Health Care
aging, demographics, and memory study. System dementia patients. Journal of Nutrition,
Neuroepidemiology, 29(1-2), 125132. Health and Aging, 14(8), 677683.
Porsteinsson, A. P., Grossberg, G. T., Mintzer, Reisberg, B., Doody, R., Stoffler, A., Schmitt, F.,
J.,& Olin, J.T. (2008). Memantine treatment in Ferris, S.,& Mobius, H.J. (2003). Memantine
patients with mild to moderate Alzheimers in moderate-to-severe Alzheimers disease.
disease already receiving a cholinester- New England Journal of Medicine, 348(14),
ase inhibitor: A randomized, double-blind, 13331341.
placebo-controlled trial. Current Alzheimer Reisberg, B., Doody, R., Stoffler, A., Schmitt, F.,
Research, 5(1), 8389. Ferris, S., & Mobius, H. J. (2006). A 24-week
Porsteinsson, A. P., Drye, L. T., Pollock, B. G., open-label extension study of memantine
Devanand, D. P., Frangakis, C., Ismail, in moderate to severe Alzheimer disease.
Z.,...Lyketsos,C. G.; CitAD Research Group Archives of Neurology, 63(1), 4954.
(2014). Effect of citalopram on agitation in Rentz, D.M., Locascio, J.J., Becker, J.A., Moran,
Alzheimer disease: the CitAD randomized E.K., Eng, E., Buckner, R.L.,...Johnson, K.A.
clinical trial. JAMA. 311(7), 682691. (2010). Cognition, reserve, and amyloid depo-
Potter, G. G., Plassman, B. L., Burke, J. R., sition in normal aging. Annals of Neurology,
Kabeto, M. U., Langa, K. M., Llewellyn, 67(3), 353364.
D. J.,...Steffens, D. C. (2009). Cognitive per- Riedel, G., Platt, B., & Micheau, J. (2003).
formance and informant reports in the diag- Glutamate receptor function in learning and
nosis of cognitive impairment and dementia memory. Behavioural Brain Research, 140(1-2),
in African Americans and whites. Alzheimers 147.
and Dementia, 5(6), 445453. Roberts, J.S., Karlawish, J.H., Uhlmann, W.R.,
Prince, M., Prina, M.,& Guerchet, M. (2013). The Petersen, R. C., & Green, R. C. (2010). Mild
World Alzheimer Report 2013. Journey of car- cognitive impairment in clinical care: A sur-
ing:An analysis of long-term care for demen- vey of American Academy of Neurology
tia. Alzheimers Disease International. Retrieved members. Neurology, 75(5), 425431.
March 2014, from http://www.alz.co.uk/ Rockwood, K. (2004). Size of the treatment
research/WorldAlzheimerReport2013.pdf. effect on cognition of cholinesterase inhi-
Puangthong, U.,& Hsiung, G.Y. (2009). Critical bition in Alzheimers disease. Journal of
appraisal of the long-term impact of meman- Neurology, Neurosurgery and Psychiatry, 75(5),
tine in treatment of moderate to severe 677685.
Alzheimers disease. Neuropsychiatric Disease Rogaeva, E., Meng, Y., Lee, J.H., Gu, Y., Kawarai,
and Treatment, 5, 553561. T., Zou, F.,...St George-Hyslop, P. (2007). The
Raina, P., Santaguida, P., Ismaila, A., Patterson, neuronal sortilin-related receptor SORL1 is
C., Cowan, D., Levine, M., .
.
.
Oremus, M. genetically associated with Alzheimer dis-
(2008). Effectiveness of cholinesterase inhibi- ease. Nature Genetics, 39(2), 168177.
tors and memantine for treating demen- Rogers, S., Doody, R., Pratt, R., & Ieni, J. (2000).
tia: Evidence review for a clinical practice Long-term efficacy and safety of donepezil in the
guideline. Annals of Internal Medicine, 148(5), treatment of Alzheimers disease:Final analysis
379397. of a US multicentre open-label study. European
Raschetti, R., Albanese, E., Vanacore, N., & Neuropsychopharmacology, 10(3), 195203.
Maggini, M. (2007). Cholinesterase inhibitors Rountree, S., Chan, W., Pavlik, V., Darby, E.,&
in mild cognitive impairment: A systematic Doody, R. (2012). Factors that influence
CHAPTER 16. Alzheimers Disease and Alzheimers Dementia 429
survival in a probable Alzheimer disease Scheltens, P., Twisk, J.W., Blesa, R., Scarpini, E.,
cohort. Alzheimers Research and Therapy, von Arnim, C.A., Bongers, A.,...Kamphuis,
4(3),16. P. J. (2012). Efficacy of Souvenaid in mild
Rountree, S.D., Atri, A., Lopez, O.L.,& Doody, Alzheimers disease:Results from a random-
R. S. Effectiveness of antidementia drugs in ized, controlled trial. Journal of Alzheimers
delaying Alzheimer disease progression. Disease, 31(1), 225236.
Alzheimers and Dementia, 9(3), 338345. Scherzer, C. R., Offe, K., Gearing, M., Rees,
Rountree, S.D., Chan, W., Pavlik, V.N., Darby, H. D., Fang, G., Heilman, C. J.,...Lah, J. J.
E. J., Siddiqui, S., & Doody, R. S. (2009). (2004). Loss of apolipoprotein E receptor LR11
Persistent treatment with cholinesterase in Alzheimer disease. Archives of Neurology,
inhibitors and/or memantine slows clinical 61(8), 12001205.
progression of Alzheimer disease. Alzheimers Schmitt, F.A., van Dyck, C.H., Wichems, C.H.,&
Research and Therapy, 1(2), 7. Olin, J.T. (2006). Cognitive response to meman-
Rudolph, J. L., Inouye, S. K., Jones, R. N., tine in moderate to severe Alzheimer disease
Yang, F. M., Fong, T. G., Levkoff, S. E., & patients already receiving donepezil: An
Marcantonio, E. R. (2010). Delirium: An exploratory reanalysis. Alzheimer Disease and
independent predictor of functional decline Associated Disorders, 20(4), 255262.
after cardiac surgery. Journal of the American Schneider, L.S., Dagerman, K.S., Higgins, J.P.,&
Geriatrics Society, 58(4), 643649. McShane, R. (2011). Lack of evidence for the
Rudolph, J.L., Marcantonio, E.R., Culley, D.J., efficacy of memantine in mild Alzheimer dis-
Silverstein, J. H., Rasmussen, L. S., Crosby, ease. Archives of Neurology, 68(8), 991998.
G.J.,...Inouye, S.K. (2008). Delirium is asso- Schneider, L. S., Insel, P. S., & Weiner, M. W.
ciated with early postoperative cognitive dys- (2011). Treatment with cholinesterase
function. Anaesthesia, 63(9), 941947. inhibitors and memantine of patients in
Rudolph, J.L., Salow, M.J., Angelini, M.C.,& the Alzheimers Disease Neuroimaging
McGlinchey, R.E. (2008). The anticholinergic Initiative. Archives of Neurology, 68(1), 5866.
risk scale and anticholinergic adverse effects Selkoe, D. J. (1991). Amyloid protein and
in older persons. Archives of Internal Medicine, Alzheimers disease. Scientific American,
168(5), 508513. 265(5), 6871, 46, 8.
Salloway, S., Ferris, S., Kluger, A., Goldman, R., Selkoe, D. J., Abraham, C. R., Podlisny,
Griesing, T., Kumar, D.,& Richardson, S. (2004). M. B., & Duffy, L. K. (1986). Isolation of
Efficacy of donepezil in mild cognitive impair- low-molecular-weight proteins from amyloid
ment:Arandomized placebo-controlled trial. plaque fibers in Alzheimers disease. Journal
Neurology, 63(4), 651657. of Neurochemistry, 46(6), 18201834.
Salthouse, T. A. (2009). When does age-related Seshadri, S., Wolf, P. A., Beiser, A., Au, R.,
cognitive decline begin? Neurobiology of McNulty, K., White, R., & D'Agostino,
Aging, 30(4), 507514. R. B. (1997). Lifetime risk of dementia and
Sano, M., Ernesto, C., Thomas, R. G., Klauber, Alzheimers disease. The impact of mortality
M. R., Schafer, K., Grundman, M.,...Thal, on risk estimates in the Framingham Study.
L. J. (1997). A controlled trial of selegiline, Neurology, 49(6), 14981504.
alpha-tocopherol, or both as treatment Shah, R. C., Kamphuis, P. J., Leurgans, S.,
for Alzheimers disease. The Alzheimers Swinkels, S. H., Sadowsky, C. H., Bongers,
Disease Cooperative Study. New England A.,...Bennett, D. A. (2013). The S-Connect
Journal of Medicine, 336(17), 12161222. study:Results from a randomized, controlled
Saxena, S. (2012). Dementia world report: A pub- trial of Souvenaid in mild-to-moderate
lic health priority. Geneva, Switzerland:World Alzheimers disease. Alzheimers Research and
Health Organization. Therapy, 5(6), 59.
Saxton, J., Hofbauer, R. K., Woodward, Shaw, G. (2012). Two drugs are not better than
M., Gilchrist, N. L., Potocnik, F., Hsu, one for treating moderate to severe Alzheimer
H.A.,...Perhach, J.L. (2012). Memantine and disease, British investigators report: Why
functional communication in Alzheimers some US neurologists dont agree. Neurology
disease: Results of a 12-week, international, Today, 12, 1213.
randomized clinical trial. Journal of Alzheimers Snowden, J.S., Thompson, J.C., Stopford, C.L.,
Disease, 28(1), 109118. Richardson, A.M., Gerhard, A., Neary, D.,&
Scheltens, P., Kamphuis, P.J., Verhey, F.R., Olde Mann, D.M. (2011). The clinical diagnosis of
Rikkert, M. G., Wurtman, R. J., Wilkinson, early-onset dementias: diagnostic accuracy
D.,...Kurz, A. (2010). Efficacy of a medical and clinicopathological relationships. Brain,
food in mild Alzheimers disease:Arandom- 134(Pt 9), 24782492.
ized, controlled trial. Alzheimers and Dementia, Sperling, R. A., Aisen, P. S., Beckett,
6(1), 110 e1. L. A., Bennett, D. A., Craft, S., Fagan,
430part ii The Dementias: The Major Diseases and Clinical Syndromes
patients with mild to moderate Alzheimers Winblad, B., Black, S., Homma, A., Schwam,
disease: A meta-analysis of individual E., Moline, M., Xu, Y.,...Albert, K. (2009).
patient data from randomised controlled tri- Donepezil treatment in severe Alzheimers
als. International Journal of Geriatric Psychiatry, disease:Apooled analysis of three clinical tri-
19(7), 624633. als. Current Medical Research and Opinion, 25,
Wilcock, G., Ballard, C., Cooper, J., & Loft, H. 25772587.
(2008). Memantine for agitation/aggression Winblad, B., Jones, R., Wirth, Y., Stoffler, A., &
and psychosis in moderately severe to severe Mobius, H. (2007). Memantine in moderate to
Alzheimers disease: A pooled analysis of severe Alzheimers disease: A meta-analysis
3 studies. Journal of Clinical Psychiatry, 69, of randomised clinical trials. Dementia and
341348. Geriatric Cognitive Disorders, 24, 2027.
Wilcock, G., Howe, I., Coles, H., Lilienfeld, S., Winblad, B., Kilander, L., Eriksson, S., Minthon,
Truyen, L., Zhu, Y.,...Kershaw, P. (2003). A L., Batsman, S., Wetterholm, A.L.,...Haglund,
long-term comparison of galantamine and A. (2006). Donepezil in patients with
donepezil in the treatment of Alzheimers severe Alzheimers disease: Double-blind,
disease. Drugs and Aging, 20(10), 777789. parallel-group, placebo-controlled study.
Wilkinson, D.,& Andersen, H. (2007). Analysis Lancet, 367(9516), 10571065.
of the effect of memantine in reducing the Winblad, B.,& Poritis, N. (1999). Memantine in
worsening of clinical symptoms in patients severe dementia:Results of the 9M-Best Study
with moderate to severe Alzheimers disease. (Benefit and efficacy in severely demented
Dementia and Geriatric Cognitive Disorders, 24, patients during treatment with memantine).
138145. International Journal of Geriatric Psychiatry,
Wilkinson, D., Schindler, R., Schwam, E., 14(2), 135146.
Waldemar, G., Jones, R. W., Gauthier, Wise, L. E., & Lichtman, A. H. (2007). The
S.,...Feldman, H. H. (2009). Effectiveness of uncompetitive N-methyl-D-aspartate
donepezil in reducing clinical worsening in (NMDA) receptor antagonist memantine
patients with mild-to-moderate alzheimers prolongs spatial memory in a rat delayed
disease. Dementia and Geriatric Cognitive radial-arm maze memory task. European
Disorders, 28(3), 244251. Journal of Pharmacology, 575(1-3), 98102.
Wilson, R. S., Leurgans, S. E., Boyle, P. A., & Yamada, K., Takayanagi, M., Kamei, H.,
Bennett, D. A. (2011). Cognitive decline in Nagai, T., Dohniwa, M., Kobayashi,
prodromal Alzheimer disease and mild cog- K.,...Nabeshima, T. (2005). Effects of meman-
nitive impairment. Archives of Neurology 2011 tine and donepezil on amyloid beta-induced
Mar;68(3), 351356. memory impairment in a delayed-matching
Wimo, A., & Prince, M. (2010). The World to position task in rats. Behavioural Brain
Alzheimer Report 2010: The global impact Research, 162(2), 191199.
of dementia. Alzheimers Disease International. Ziegler-Graham, K., Brookmeyer, R., Johnson,
Retrieved March 2014, from http://www.alz. E.,& Arrighi, H.M. (2008). Worldwide varia-
org/documents/national/world_alzheimer_ tion in the doubling time of Alzheimers dis-
report_2010.pdf. ease incidence rates. Alzheimers and Dementia,
Wimo, A., Winblad, B., Stoffler, A., Wirth, Y.,& 4(5), 316323.
Mobius, H.J. (2003). Resource utilisation and Zlokovic, B. V. (2011). Neurovascular path-
cost analysis of memantine in patients with ways to neurodegeneration in Alzheimers
moderate to severe Alzheimers disease. disease and other disorders. Nature Reviews
PharmacoEconomics, 21(5), 327340. Neuroscience, 12(12), 723738.
17
The field of aging and dementia is moving Scale (Reisberg et al., 1988). The construct
toward an earlier identification of symp- was limited to individuals with that partic-
tomatic subjects with the intent to identify ular degree of severity on the scale, but the
individuals as soon as possible in the patho- clinical criteria were not clearly delineated.
physiologic process of disorders such as In 1999, investigators at the Mayo Clinic
Alzheimers disease (AD), and a great deal published criteria for memory-impaired
of effort is being expended toward detect- individuals who did not meet criteria for
ing individuals early in the symptomatic dementia and called them MCI. These crite-
disease process (Petersen et al., 1999). With ria are shown in Table 17.1 and became heav-
the recent publication of sets of criteria for ily investigated in the field to determine their
individuals along the AD spectrum, demen- validity. The criteria emphasized a change in
tia is the most advanced stage while mild memory function for individuals from their
cognitive impairment (MCI) constitutes the prior level of performance, and yet other cog-
earliest manifestation of clinical symptoms. nitive domains such as language, attention,
In addition to dementia and MCI, a preclini- executive function, and visuospatial skills
cal stage was also proposed as being useful were preserved. Functionally, the individuals
for identifying individuals with the biologi- were essentially normal without the degree
cal predisposition to AD but being clinically of loss of social or occupational function con-
asymptomatic (Jack et al., 2012; Knopman sistent with dementia. These subjects were
etal., 2012; Sperling etal., 2011). followed longitudinally and were shown to
have an increased risk of developing subse-
quent dementia.
Brief History of the Mild Cognitive In 2003, an international conference was
Impairment Construct held in Stockholm to expand the construct
of MCI and determine its relevance for the
The construct of MCI has risen and become field (Petersen, 2004; Winblad et al., 2004).
popular over the past 15years (Petersen etal., At that time, MCI was divided into two
2009). Initially, investigators at New York subclasses, amnestic MCI (aMCI) and non-
University used the term MCI to charac- amnestic MCI (naMCI). The aMCI subtype
terize individuals whom they designated as essentially conformed to the 1999 criteria
being at Stage 3 on the Global Deterioration cited and characterized a set of individuals
432
CHAPTER 17. Mild Cognitive Impairment 433
TABLE17.1 Criteria for Amnestic Mild to report results in the 10%20% range, and
Cognitive Impairment1999 these figures are generally accepted (Manly
etal., 2008).
1. Cognitive concern Incidence studies for the conversion from
2. Objective impairment in memory
normal cognition to MCI have only recently
3. Relative preservation of nonmemory cognitive
functions been reported and characterize subjects who
4. Preservation of activities of daily living have been tracked from being clinically nor-
5. Not demented mal to newly diagnosed with MCI (Larrieu
etal., 2002; Roberts etal., 2012). Again, there
is a great deal of variability in this literature,
but the majority of the studies have indi-
who had a primary memory impairment
cated an annual incidence rate of from 3% to
with relative preservation of other cogni-
10% per year (Roberts etal., 2012). As such,
tive domains and function. Technically, these
the incidence rates are significant and have
individuals could also be slightly impaired
implications for aging societies around the
in other cognitive domains such as executive
world.
function, and as such, the constructs of aMCI
single domain (memory only) and multido-
main (memory plus one or more other cog- Clinical Characterization
nitive domains) were established. However,
if the individual was judged to be between
Clinical Vignette
normal cognition and dementia but not have
significant memory impairment, the naMCI
Part1
label was given with the additional qualifi-
ers of single and multiple domains. Over the A 68-year-old businesswoman with a masters
ensuing years, these entities were investi- degree began noting increasing forgetfulness for
gated quite extensively, and general support recent events. She had been having some problems
for the entity was achieved, but notable con- coming up with the names of acquaintances with
cerns were also raised. These criteria were whom she had not had contact for several months,
also used for several epidemiologic explora- but perhaps more bothersome to her was the fact
tions (Busse, Hensel, Guhne, Angermeyer, that she was occasionally missing appointments.
& Riedel-Heller, 2006; Di Carlo et al., 2007; She was quite meticulous about her daily calendar
Manly etal., 2008). but now was overlooking important appointments,
which was uncharacteristic of her. When her hus-
band was questioned about this, he indicated that
Epidemiology of Mild Cognitive Impairment he had noticed the same behaviors in her but was
not concerned about them. They both noted that
Numerous epidemiologic studies have been she continued to run her business quite well with-
conducted internationally to determine the out any problems, and those around her who had
frequency of MCI (Ganguli, Dodge, Shen, & been working closely with her had not noticed a
DeKosky, 2004; Lopez et al., 2003; Ritchie, change. On a personal level, she still handled her
Artero, & Touchon, 2001; Unverzagt et al., own finances, was driving, and showed no signs
2001; Larrieu etal., 2002). In general, the prev- of depression or anxiety. She came for a clinical
alence figures have varied from 3% to 30% in evaluation, and the history, in addition to the
the literature with most studies coalescing above, revealed that her maternal grandmother
around 15% (Ganguli etal., 2004; Lopez etal., had developed dementia in her late 70s, but oth-
2003; Petersen etal., 2010). Numerous meth- erwise, there was no other dramatic history for
odologic issues contributed to the variable cognitive impairment. She was on medications for
prevalence rates reported in the literature, hyperlipidemia and a calcium supplement. Her
including the nature of the underlying popu- clinical assessment revealed a Mini-Mental State
lation, the specific implementation of the cri- Exam score of 28, and the remainder of the neuro-
teria for MCI, and whether the studies were logic examination was normal.
performed retrospectively or prospectively. At this point, do you reassure her that she is
In recent years, prospective studies employ- manifesting signs of aging but nothing more wor-
ing MCI criteria at the outset have tended risome, or do you pursue it further?
434part ii The Dementias: The Major Diseases and Clinical Syndromes
The clinician wanted to obtain neuropsycholog- Cognitive Assessment (Nasreddine etal., 2005),
ical testing to get a more complete picture of the among others, but it should be augmented by
womans cognitive profile. The testing revealed additional tools to determine the presence and
summary scores in the area of executive function extent of cognitive impairments since the global
and attention at the 60th percentile for her age screening instruments may be insensitive, par-
and education. Comparable measures on language ticularly in individuals with a high level of
(70th percentile) and visuospatial skills (65th per- educational or occupational attainment (Lonie,
centile) were above what would be expected. Her Tierney, & Ebmeier, 2009). Neuropsychological
memory profile, however, including several mea- testing can be quite useful in this regard since
sures of delayed verbal and nonverbal recall indi- it will provide a more thorough characteriza-
cated performance at the 40th percentile. As such, tion of cognitive function in multiple domains
this clinical profile corroborated her and her hus- as well as the degree of impairment if one
bands concern and raised a suspicion of amnestic exists (Petersen et al., 2010). Preferably, neu-
mild cognitive impairment. ropsychological testing should be used in the
setting of appropriate normative data for the
patients age, education, and ethnicity. Often in
What Does the Clinician Do at This Point? the clinical setting, the individual is seen at one
time point and a diagnosis needs to be made.
Figure 17.1 depicts the general evaluation However, if longitudinal data are available,
scheme for an individual suspected of having they can be very helpful in assessing change
MCI (Petersen, 2004). Typically, a patient will for a given individual with respect to his or
present to a clinician with a concern about a her own baseline. The criteria for MCI require
new memory problem, and the clinicians obli- the clinician to assess whether or not there has
gation is to determine whether this is a mani- been a change in cognitive function over time.
festation of aging or may represent the earliest Again, if serial data exist, they can be quite
stages of a pathologic condition. As is indicated helpful; but often, the clinician has to infer this
in Figure 17.1, the clinician should start with from the history provided by the patient and
the history, preferably from the patient and someone who knows the patient well. The his-
someone who knows the patient well, and tory of a change coupled with appropriate neu-
examination in the office. This can involve a ropsychological data can be very useful for the
mental status exam such as the Mini-Mental clinician to determine whether there has been a
State Exam (Folstein, Folstein, & McHugh, substantive cognitive change.
1975), the Short Test of Mental Status (Kokmen, If the clinician determines that the patient
Naessens, & Offord, 1987), or the Montreal has experienced a change in cognition, and yet
Cognitive complaint
MCI
Single non-memory
Memory
Yes No Yes cognitive domain No
impairment only?
impaired?
MCI Subtypes
Etiology
Degen- Medical
erstive Vascular Psychiatric conditions
Single
AD Depr
domain
Amnestic
MCI
Clinical classification
Multiple
AD VaD Depr
domain
Single
FTD
Non- domain
amnestic
MCI Multiple
DLB VaD
domain
Figure17.2 Clinical classification and etiology in mild cognitive impairment (MCI). AD,
Alzheimers disease; FTD, frontotemporal dementia; LBD, dementia with Lewy bodies; VaD,
vascular dementia.
general function is well preserved, the diag- clinical picture may involve behavioral
nosis of MCI can be entertained. The next task abnormalities prior to actual cognitive
for the clinician is to determine the cause of the impairment. Similarly, in DLB, some of the
clinical syndrome. Difficulties in investigating presenting clinical features may constitute
MCI have arisen due to issues in terminology. sleep disorders, parkinsonism, or behavioral
Since the bulk of the literature on MCI has disturbances, and these may be the hallmarks
arisen in the setting of AD, some individuals of prodromal DLB (Molano etal., 2009).
assume that MCI means early AD. However, Recently, MCI has been described in the
as is evident from Figure17.1, MCI is a clini- setting of Parkinsons disease, and the condi-
cal syndrome, and there may be multiple tion known as PD-MCI has been described
etiologies. As is shown in Figure 17.2, while (Litvan etal., 2012). In this situation, patients
degenerative diseases are common causes of must first have the diagnosis of Parkinsons
MCI, especially in older patients, there can be disease, and then criteria for PD-MCI, to
other etiologies. For example, vascular insults characterize impaired cognitive function in
can produce cognitive impairment in various these individuals prior to the development
domains, and this has typically been referred of Parkinsons disease dementia, have been
to in the literature as vascular cognitive published (Emre etal., 2007).
impairment (Hachinski et al., 2006; Petersen It is important to determine the etiology of
etal., 2009). In addition, MCI can arise in the the MCI syndrome since it may be possible to
setting of certain psychiatric illnesses such as reverse or at least slow the course of some of
depression and anxiety as well as in the set- these conditions; if this is possible, the MCI syn-
ting of medical comorbidities such as diabetes, drome can improve. This has also led to some
heart failure, and chronic obstructive pulmo- misunderstanding in the literature since, when
nary disease. As such, it is incumbent upon the MCI is viewed as prodromal AD, generally,
clinician to investigate other possible causes of this is not believed to be reversible. However,
MCI or contributing factors to MCI even in the when MCI is due to other conditions, such as
setting of a degenerative disease. depression or medical comorbidities, when
Mild cognitive impairment can also arise the underlying conditions are treated, the MCI
as a prodromal state of other dementing syndrome may improve. This has led to criti-
disorders in addition to AD. There can be cism in the literature that the MCI construct is
prodromal states to frontotemporal lobar unstable when, in fact, one would expect an
degeneration (FTLD) and dementia with improvement in the symptoms if the underly-
Lewy bodies (DLB). In FTLD, the presenting ing cause is potentially reversible.
436part ii The Dementias: The Major Diseases and Clinical Syndromes
Figure17.3 Magnetic resonance imaging (MRI) in mild cognitive impairment (MCI). Coronal T1 MP
RAGE sections through the hippocampus in a cognitively normal individual (A) and individuals
with MCI (B) and dementia (C). The presence of hippocampal atrophy (long white arrows),
ventricular dilation (short white arrows), and cortical thinning (black arrows) with widening of the
sulci in MCI predicts conversion to dementia. These structural brain changes are first subtly noted
in the MCI stage (B) and rapidly increase through the dementia stage (C), when they become quite
prominent.
CHAPTER 17. Mild Cognitive Impairment 437
0 1 2 3 4
E4 carrier status had a hypometabolic pattern the progression from MCI to dementia due
on FDG-PET prior to the demonstration of to AD (Wolk et al., 2009). Again, ADNI has
any clinical symptoms (Reiman et al., 1996). been at the forefront of these studies and
This pattern was most prominent in apoli- has shown that individuals with the clinical
poprotein E4 homozygotes but also has been symptoms of MCI and having a positive amy-
seen in heterozygotes, raising the question loid imaging scan progress to the dementia
of evidence for the pathophysiologic process stage much more rapidly than MCI subjects
leading to the dementia of AD many years with a negative amyloid imaging scan (Jack
before symptoms appear (Reiman etal., 2001). et al., 2010, Landau et al., 2012) (Fig. 17.5).
More recently, there have been several studies While these data are convincing, precise pre-
documenting the utility of the temporopari- diction models have not been generated as of
etal hypometabolism pattern in MCI as being yet. There still can be a considerable time lag
indicative of increased rate of progression to for individuals with positive amyloid imag-
dementia (Chetelat et al., 2003). The ADNI ing scans with respect to their progression
has generated data in support of this position, from the MCI to the dementia stage of AD,
as well, and FDG-PET has been compared and more research needs to be done to clarify
to other indices of progression from MCI this progression pattern.
(Landau etal., 2010).
More recently, the utility of amyloid imag-
ing in characterizing patients who have MCI Cerebrospinal Fluid
has become apparent (Engler et al., 2006).
Amyloid imaging was introduced around In recent years, a great deal of data regard-
2004, using the carbon 11 Pittsburgh com- ing the utility of cerebrospinal fluid (CSF)
pound B (PiB) (Klunk et al., 2004). A great in characterizing the underlying AD patho-
deal of data have been generated over the physiology has emerged. In particular, with
past several years, suggesting the utility of a respect to MCI, numerous studies have
positive amyloid imaging scan in predicting documented that individuals with the AD
0 2 4
Figure17.5 Amyloid imaging in mild cognitive impairment (MCI). Axial section of PiB-PET scans
in a cognitively normal individual (A) and individuals with MCI (B) and dementia (C). PiB is a
positron emission tomography (PET) tracer useful for detecting amyloid deposition in the brain.
Brain areas where amyloid is absent appear blue; brain areas with the greatest tracer uptake appear
red, while areas with less tracer uptake appear green or yellow. Amyloid deposition of the white
matter, but not gray matter, is seen in cognitively normal individuals, creating a clear contrast in
radioactivity between gray and white matter (A, short arrow). When amyloid is deposited in the
cortices, as occurs in MCI (B, long arrow) and dementia (C, long arrow) due to Alzheimers disease,
diffuse reduction or loss of the normal gray-white contrast is noted. Amyloid deposition occurs
early in the pathological cascade and before development of symptoms, creating relatively similar
distribution and concentration of deposition between the MCI and dementia subjects. (See color
plate section)
CHAPTER 17. Mild Cognitive Impairment 439
pathophysiologic fingerprint (i.e., low amy- this presents a problem for the practicing
loid beta 42 levels and elevated total tau or clinician. Nevertheless, CSF is likely to be
phospho-tau levels) predict a more rapid very useful in characterizing the underlying
progression (Shaw etal., 2009). Agreat deal pathophysiologic nature of clinical symp-
of this work has been done in Europe, and toms found in MCI.
there are several review studies indicat-
ing that combining samples from several
medical centers have demonstrated that Theoretical Foundation for
the low Abeta 42 and elevated tau or p-tau Biomarkers
ratios can also be quite suggestive (Hansson
et al., 2006). Investigators from ADNI have A great deal of work has been completed
also demonstrated the utility of CSF in pre- and is undergoing regarding the establish-
dicting progression from MCI to dementia ment of the utility of the variety of fluid and
(Shaw et al., 2009). While these data have biomarkers in characterizing the AD patho-
been intriguing and likely to be quite useful physiologic process. Jack and colleagues pre-
in assisting clinicians, there has been a great sented convincing data in a very influential
deal of difficulty encountered in standardiz- paper in 2010, setting forth the hypothetical
ing CSF assays around the world (Mattsson sequence of events that occurs as the AD pro-
et al., 2009). Currently, there is an interna- cess unfolds (Jack etal., 2010). As is seen in
tional standardization exercise under way Figure 17.6, the initiating process in the AD
sponsored by the Alzheimers Association to cascade involves the deposition of amyloid
bring multiple laboratories together to stan- in the brain typically during the asymptom-
dardize the methodology for CSF collection atic stage. The precise timing of this relative
and the assays themselves. While this work to the subsequent presentation of clinical
is progressing, there is currently not a stan- symptoms is not known, and the shape of
dard cutoff threshold for CSF measures, and the deposition curve needs to be elucidated,
Abnormal A
Tau-mediated neuron injury and dysfunction
Brain structure
Memory
Clinical function
Biomarker magnitude
Cut points
Normal
Cognitively normal MCI Dementia
Clinical disease stage
Figure17.6 The evolution of biomarkers in the Alzheimers pathological cascade. With the early
deposition of amyloid in the pathological cascade, corresponding biomarkers (low cerebrospinal
fluid [CSF], A declines, and positive amyloid imaging) are detected before the development of
clinical symptoms. Following this, there is a sequence of events characterizing neurodegeneration
where evidence of brain dysfunction can be measured through CSF tau levels or fludeoxyglucose
positron emission tomography (FDG-PET). As memory and clinical function decline, structural
changes of the brain are noted on magnetic resonance imaging (MRI). MCI, mild cognitive
impairment. (Reprinted from The Lancet Neurology, Vol. number 9, Clifford R Jack, David S
Knopman, William J Jagust, Leslie M Shaw, Paul S Aisen, Michael W Weiner, Ronald C Petersen,
John Q Trojanowski. Hypothetical model of dynamic biomarkers of the Alzheimers pathological
cascade, pages 119128. Copyright (2010), with permission from Elsevier) (See color plate section)
440part ii The Dementias: The Major Diseases and Clinical Syndromes
but the construct of the initiating event being in the chapter, this model also serves as the
amyloid deposition is well documented framework for the revised criteria for the AD
(Hardy & Selkoe, 2002). Following the depo- spectrum.
sition of amyloid, there is a sequence of
events characterizing neurodegeneration.
One of the early events may be the devel- New Criteria for the Alzheimers
opment of an abnormal pattern of glucose DiseaseSpectrum
metabolism on FDG-PET scanning. There is
some evidence that this may occur quite early In 2011, the National Institute on Aging and
in the pathophysiologic process but at pres- the Alzheimers Association published the
ent is being characterized as occurring after results of several expert groups who had
the deposition of amyloid. Another event been working on a revision of the criteria for
that occurs to index neurodegeneration is Alzheimers disease (Jack et al., 2011). The
depicted by the abnormal processing of the previously published criteria from 1984 were
tau protein (Buerger etal., 2006). In general, updated and expanded to reflect all of the
when tau becomes hyperphosphorylated, activity in the field over the intervening two
it reflects underlying neurodegeneration, and a half decades. There were two major
and this can be an early event in the neuro- changes to the overall conceptualization of
degeneration process. The model then indi- the criteria. First, the notion of Alzheimers
cates that, after these events have occurred, disease being a clinical-pathologic entity
one is likely to see structural changes on was discarded. Since the clinical spectrum
magnetic resonance imaging (MRI) such as can vary according to disease severity, it was
hippocampal atrophy, whole-brain atrophy, believed that the clinical aspects of the dis-
ventricular dilatation, and cortical thinning ease should be characterized from the most
(Dickerson et al., 2009; Fox, Warrington, & severe state being dementia back through
Rossor, 1999; Jack et al., 2004; Kaye et al., the intermediate state of MCI and ultimately
1997). As such, quantitative measures of to a preclinical state, which is the point at
MRI can be very useful but are likely most which individuals are clinically normal but
dynamic during the symptomatic stage of may harbor the underlying pathophysiologi-
the process such as that seen during MCI. cal characteristics of Alzheimers disease.
As is depicted in Figure17.2, it is only after Correspondingly, there is a pathological
these events take place that clinical symp- spectrum for Alzheimers disease stretch-
toms evolve. Typically, memory impairment ing backward from the most severe stage of
is the first hallmark characterized during well-established neuritic plaques and neu-
the MCI stage, and as that progresses and rofibrillary tangles to stages of much lesser
other cognitive domains become impaired pathophysiology, yet believed to be on the
and daily function is compromised, then one pathology spectrum. Secondly, as indicated
crosses the threshold for dementia. previously, the disease was now being char-
This model, which was recently revised acterized as a full spectrum and not just at
(Jack etal., 2013), has proved to be extremely the dementia stage. Relevant to our current
useful for the field of aging and dementia at discussion, the MCI stage is now called MCI
characterizing putative pathologic processes due to AD. This stage is meant to reflect the
and their consequences. However, as indi- fact that a person may be minimally symp-
cated previously, the precise temporal order- tomatic, demonstrating a mild episodic
ing of these events, the shapes of the curves, memory deficit, but has underlying features
and the thresholds for normal and abnor- of Alzheimers disease pathophysiology.
mal on each of these markers are largely To implement this thinking in the criteria,
unknown. Awealth of research is being done biomarkers become an essential component.
to elucidate these processes further, but the As mentioned previously, the theoretical model
specific calibration of the various biomark- characterizing the evolution of Alzheimers
ers remains to be done. However, this basic disease pathophysiology and clinical symp-
formulation of pathological events provides toms was outlined by Jack and colleagues
the backdrop for the use of individual bio- (Jack et al., 2010). This model implies that
markers in characterizing individuals across the deposition of amyloid was the initiating
the AD spectrum. As will be discussed later event followed by neurodegeneration and
CHAPTER 17. Mild Cognitive Impairment 441
AD, Alzheimers disease; CSF, cerebrospinal fluid; PET, positron emission tomography.
then clinical manifestations. With this model of certainty that the MCI syndrome is due
in mind, the MCI-due-to-AD stage is charac- to underlying Alzheimers disease patho-
terized as a state in which the subjects have physiology is achieved when the clinical
minimal clinical symptoms, usually mild syndrome is present and is accompanied by
memory impairment, but are otherwise func- evidence for amyloid deposition and neuro-
tioning reasonably normal. The subjects may degeneration. For completeness, a low level
have some inefficiency in conducting their of certainty is also demonstrated when the
daily activities but are able to do them with- clinical syndrome is present and biomarkers
out any assistance. The subjects may have a are available, but they are negative for under-
memory impairment (aMCI) or, less com- lying Alzheimers disease pathophysiology.
monly, mild impairments in nonmemory cog-
nitive domains (naMCI). However, the new
criteria for MCI due to AD do not distinguish Clinical Vignette
between aMCI and naMCI, but this remains
an area of investigation. Part2
To enhance the clinicians suspicion that Resumption of Evaluation of Clinical Case
the clinical syndrome of MCI is due to
Alzheimers disease, biomarkers must be Due to the concern about possible aMCI, the cli-
invoked. As is shown in Table 17.3, the first nician decided to obtain additional measures. An
level of certainty is reflected in just the clini- MRI scan was performed, which showed only
cal syndrome alone. That is, in addition to slight atrophy in the medial temporal lobe, most
the MCI diagnostic criteria being fulfilled, notably in the hippocampal formations, but was
the clinician does not have any information judged to be within normal limits for age. Afunc-
regarding the underlying biomarker status tional imaging test involving FDG-PET also was
for a given person. The next level of certainty, equivocal. There was a suggestion of temporopa-
which is called intermediate, is higher with rietal hypometabolism on the left, but it was of
respect to the likelihood of the clinical syn- insufficient severity to be judged as abnormal.
drome being due to underlying Alzheimers However, an amyloid imaging study was per-
disease, and this can be achieved by either formed, and this was positive. The patient was
having evidence for amyloid deposition, entered into a research protocol, and a lumbar
via amyloid PET or CSF Abeta, or evidence puncture was performed, and the cerebrospinal
for neurodegeneration, as indicated by an fluid measure for Abeta 42 was low, and the indi-
abnormal FDG-PET scan, CSF tau levels, or ces for total tau and p-tau were elevated.
atrophy on MRI. The criteria do not weight
one set of biological markers as being more
important than the other at this point in time Conclusion
due to insufficient data. However, as the field
evolves, it is likely that these biomarkers will It appears that this woman had a gradual onset
be rank ordered. Finally, the highest level of a memory difficulty which by evaluation was
442part ii The Dementias: The Major Diseases and Clinical Syndromes
judged to be beyond what one would expect for These data are beginning to emerge, and their
age. The neuropsychological testing profile con- implication for the application of the new cri-
firmed her suspicions of a decrement in memory, teria remains to be determined.
and by history, one can infer that this is a change
in performance for her. As such, the diagnosis
of aMCI was established, but the etiology was Diagnostic and Statistical Manual for
uncertain. Since the woman was relatively young, Mental Disorders, Fifth Edition
additional imaging studies were performed, and
the structural imaging MRI and functional imag- In conjunction with the National Institute
ing FDG-PET scan were equivocal. However, the on Aging/Alzheimers Association criteria
more definitive molecular neuroimaging mea- for the Alzheimers disease spectrum, the
sures, as determined by amyloid PET imaging Diagnostic and Statistical Manual for Mental
and CSF, did, in fact, indicate that she had the Disorders (fifth ed.) (DSM-5) was recently final-
presence of amyloid in the brain, and the suspicion ized and published (Ganguli etal., 2011). The
is that this is now MCI due to AD with a high construct of MCI is included in the section
likelihood, according to the new criteria. dealing with neurocognitive disorders. This
At this point, these criteria are for research area of neurocognitive disorders is labeled
purposes, and a great deal of additional data minor neurocognitive disorders and essen-
needs to be developed. In particular, as men- tially captures the clinical criteria of MCI, as
tioned previously, we need to determine discussed here. The construct of neurocog-
whether markers for amyloid deposition nitive disorders for DSM-5 is broader than
carry more weight than those of neurodegen- just Alzheimers disease, and consequently,
eration with respect to Alzheimers disease the criteria must be more flexible to encom-
pathophysiology specificity. One would sus- pass other disorders such as frontotemporal
pect that this is the case given that amyloid is a lobar degeneration, dementia with Lewy
sine qua non for the diagnosis of Alzheimers bodies, Parkinsons diseasemild cogni-
disease pathophysiologically. That is, one tive impairment, vascular cognitive impair-
must have evidence of amyloid deposition ment, HIV, AIDS, neurocognitive disorders,
in the brain to make the pathophysiologic and traumatic brain injury. Nevertheless, the
diagnosis of Alzheimers disease, and hence, construct of a predementia clinical state has
a biomarker reflecting that pathologic charac- officially been recognized in DSM-5, and this
teristic would be quite reasonable. will coincide with MCI due to Alzheimers
There is also a variable degree of specific- disease, as discussed previously.
ity of the biomarkers. As indicated, the amy-
loid biomarkers reflect underlying amyloid
pathology, as has been demonstrated in amy- Clinical Acceptance
loid PET pathology correlations, whereas
biomarker measures of neurodegeneration In summary, the construct of MCI has been
are relatively nonspecific. One can see atro- intensely investigated over the past 10 to
phy on an MRI from a variety of pathologic 15 years. While there is not complete agree-
entities, including neurodegeneration, vascu- ment on the clinical characterization, it has
lar disease, or combinations of them (Barber, been adopted in clinical practice. A study
Ballard, McKeith, Gholkar, & OBrien, 2000, published in Neurology reflecting the opin-
OBrien etal., 2001). Similarly, CSF tau can be ions of practicing neurologists with respect
elevated in a variety of neurologic conditions, to the construct of MCI was quite illuminat-
such as stroke, traumatic brain injury, or ing (Roberts, Karlawish, Uhlmann, Petersen,
Creutzfeldt-Jakob disease (Hesse etal., 2001; & Green, 2010). This study indicated that
Ost etal., 2006; Otto etal., 2002). In addition, most practicing neurologists see patients
research needs to be done to characterize with this intermediate degree of cognitive
the outcome of subjects whose biomarkers impairment and prefer to use the term MCI
do not agree. That is, how does one classify to other nomenclatures. The neurologists
an individual who may have evidence for indicated that MCI is a useful term for them,
amyloid deposition but no degeneration? and in spite of the challenges of making the
What about the subject who has evidence for diagnosis at times, they find it quite useful.
neurodegeneration but is amyloid negative? They prefer to use MCI rather than other
CHAPTER 17. Mild Cognitive Impairment 443
and problems on the road to therapeutics. and magnetic resonance imaging atrophy
Science, 297(5580), 353356. both predict time-to-progression from mild
Hesse, C., Rosengren, L., Andreasen, cognitive impairment to Alzheimers disease.
N., Davidsson, P., Vanderstichele, H., Brain, 133(11), 33363348.
Vanmechelen, E., & Blennow, K. (2001). Jean, L., Bergeron, M.E., Thivierge, S., & Simard,
Transient increase in total tau but not M. (2010). Cognitive intervention programs
phospho-tau in human cerebrospinal fluid for individuals with mild cognitive impair-
after acute stroke. Neuroscience Letters, 297(3), ment: Systematic review of the literature.
187190. American Journal of Geriatric Psychiatry, 18(4),
Jack, C., Barkhof, F., Bernstein, M., Cantillon, 281296.
M., Cole, P., DeCarli, C.,...Foster, N.L. (2011). Kaye, J.A., Swihart, T., Howieson, D., Dame, A.,
Steps to standardization and validation of Moore, M.M., Karnos, T.,...Sexton, G. (1997).
hippocampal volumetry as a biomarker Volume loss of the hippocampus and tempo-
in clinical trials and diagnostic criteria for ral lobe in healthy elderly persons destined to
Alzheimers disease. Alzheimer Dementia, 7(4), develop dementia. Neurology, 48, 12971304.
474485. Klunk, W. E., Engler, H., Nordberg, A., Wang,
Jack, C., Knopman, D., Jagust, W., Shaw, L.M., Y., Blomqvist, G., Holt, D.P.,...Lngstrm, B.
Aisen, P. S., Weiner, M.,...Trojanowski, J. Q. (2004). Imaging brain amyloid in Alzheimers
(2010). Hypothetical model of dynamic bio- disease with Pittsburgh Compound-B. Annals
markers of the Alzheimers pathological cas- of Neurology, 55(3), 306319.
cade. Lancet, 9(1), 119128. Knopman, D. S., Jack, C. R., Jr., Wiste,
Jack, C. R., Albert, M. S., Knopman, D. S., H. J., Weigand, S. D., Vemuri, P., Lowe,
McKhann, G. M., Sperling, R. A., Carillo, V.,...Petersen, R. C. (2012). Short-term clini-
M.,...Phelps, C. H. (2011). Introduction to cal outcomes for stages of NIA-AA preclini-
the recommendations from the National cal Alzheimer disease. Neurology, 78(20),
Institute on Aging-Alzheimers Association 15761582.
workgroups on diagnostic guidelines for Kokmen, E., Naessens, J. M., & Offord,
Alzheimers disease. Alzheimers Dementia, K. P. (1987). A short test of mental sta-
7(3), 257262. tus: Description and preliminary results.
Jack, C. R., Knopman, D. S., Jagust, W. J., Mayo Clinic Proceedings, 62(4), 281288.
Petersen, R. C., Weiner, M. W., Aisen, Landau, S. M., Harvey, D., Madison, C. M.,
P. S.,...Trojanowski, J. Q. (2013). Tracking Reiman, E. M., Foster, N. L., Aisen,
pathophysiological processes in Alzheimer's P. S.,...Jagust, W. J. (2010). Comparing pre-
disease: an updated hypothetical model of dictors of conversion and decline in mild cog-
dynamic biomarkers. Lancet Neurology, 12(2), nitive impairment. Neurology, 75(3), 230238.
207216. Landau, S.M., Mintun, M.A., Joshi, A.D., Koeppe,
Jack, C. R., Knopman, D. S., Weigand, S. D., R. A., Petersen, R. C., Aisen, P. S.,...Jagust,
Wiste, H.J., Vemuri, P., Lowe, V.,...Petersen, W. J. (2012). Amyloid deposition, hypome-
R. C. (2012). An operational approach to tabolism, and longitutdinal cognitive decline.
NIA-AA crtiteria for preclinical Alzheimers Annals of Neurology, 72(4), 578586.
disease. Annals of Neurology, 71(6), 765775. Larrieu, S., Letenneur, L., Orgogozo, J. M.,
Jack, C. R., Petersen, R. C., Xu, Y. C., OBrien, Fabrigoule, C., Amieva, H., Le Carret,
P.C., Smith, G.E., Ivnik, R.J.,...Kokmen, E. N.,...Dartigues, J. F. (2002). Incidence and
(1999). Prediction of AD with MRI-based hip- outcome of mild cognitive impairment in
pocampal volume in mild cognitive impair- a population-based prospective cohort.
ment. Neurology, 52(7), 13971403. Neurology, 59(10), 15941599.
Jack, C. R., Shiung, M. M., Gunter, J. L., Lautenschlager, N. T., Cox, K. L., Flicker, L.,
OBrien, P. C., Weigand, S. D., Knopman, Foster, J. K., van Bockxmeer, F. M., Xiao,
D. S.,...Petersen, R. C. (2004). Comparison J.,...Almedia, O. P. (2008). Effect of physi-
of different MRI brain atrophy rate mea- cal activity on cognitive function in older
sures with clinical disease progression in AD. adults at risk for Alzheimer disease: A ran-
Neurology, 62(4), 591600. domized trial. Journal of the American Medical
Jack, C. R., Weigand, S. D., Shiung, M. M., Association, 300(9), 10271037.
Przybelski, S. A., OBrien, P. C., Gunter, Litvan, I., Goldman, J. G., Troster, A. I.,
J. L.,...Petersen, R. C. (2008). Atrophy rates Schmand, B. A., Weintraub, D., Petersen,
accelerate in amnestic mild cognitive impair- R. C.,...Emre, M. (2012). Diagnostic criteria
ment. Neurology, 70(19 Pt 2), 17401752. for mild cognitive impairment in Parkinsons
Jack, C. R., Wiste, H. J., Vemuri, P., Weigand, disease: Movement Disorder Society Task
S. D., Senjem, M. L., Zeng, G.,...Knopman, Force guidelines. Movement Disorders, 27(3),
D. S. (2010). Brain beta-amyloid measures 349356.
446part ii The Dementias: The Major Diseases and Clinical Syndromes
Lonie, J. A., Tierney, K. M., & Ebmeier, K. P. Petersen, R. C., Aisen, P. S., Beckett, L. A.,
(2009). Screening for mild cognitive impair- Donohue, M. C., Gamst, A. C., Harvey,
ment: A systematic review. International D. J.,...Weiner, M. W. (2010). Alzheimers
Journal of Geriatric Psychiatry, 24(9), 902915. Disease Neuroimaging Initiative
Lopez, O. L., Jagust, W. J., DeKosky, S. T., (ADNI): Clinical characterization. Neurology,
Becker, J. T., Fitzpatrick, A., Dulberg, 74(3), 201209.
C.,...Kuller, J.H. (2003). Prevalence and clas- Petersen, R. C., Roberts, R. O., Knopman,
sification of mild cognitive impairment in D. S., Geda, Y. E., Cha, R. H., Pankratz,
the Cardiovascular Health Study Cognition V. S.,...Rocca, W. A. (2010). Prevalence of
Study: Part 1. Archives of Neurology, 60(10), mild cognitive impairment is higher in men.
13851389. The Mayo Clinic Study of Aging. Neurology,
Manly, J. J., Tang, M. X., Schupf, N., Stern, Y., 75(10), 889897.
Vonsattel, J.P., & Mayeux, R. (2008). Frequency Petersen, R.C., Smith, G.E., Waring, S.C., Ivnik,
and course of mild cognitive impairment in a R. J., Tangalos, E. G., & Kokmen, E. (1999).
multiethnic community. Annals of Neurology, Mild cognitive impairment: Clinical charac-
63(4), 494506. terization and outcome. Archives of Neurology,
Mattsson, N., Zetterberg, H., Hansson, O., 56, 303308.
Andreasen, N., Parnetti, L., Jonsson, Petersen, R.C., Thomas, R.G., Grundman, M.,
M.,...Blennow, K. (2009). CSF biomarkers Bennett, D., Doody, R., Ferris, S.,...Thal, L.J.
and incipient Alzheimer disease in patients (2005). Donepezil and vitamin E in the treat-
with mild cognitive impairment. Journal of the ment of mild cognitive impairment. New
American Medical Association, 302(4), 385393. England Journal of Medicine, 352, 23792388.
Molano, J., Boeve, B., Ferman, T., Smith, G., Parisi, Reiman, E.M., Caselli, R.J., Chen, K., Alexander,
J., Dickson, D.,...Petersen, R. (2009). Mild cog- G.E., Bandy, D., & Frost, J. (2001). Declining
nitive impairment associated with limbic and brain activity in cognitively normal apolipo-
neocortical lewy body disease:Aclinicopatho- protein E epsilon 4 heterozygotes:Afounda-
logical study. Brain, 133, 540556. tion for using positron emission tomography
Nasreddine, Z. S., Phillips, N. A., Bedirian, to efficiently test treatments to prevent
V., Charbonneau, S., Whitehead, V., Collin, Alzheimers disease. Proceedings of the National
I.,...Chertkow, H. (2005). The Montreal Academy of Sciences USA, 98(6), 33343339.
Cognitive Assessment (MoCA): A brief Reiman, E.M., Caselli, R.J., Lang, S., Yun, M.S.,
screening tool for mild cognitive impairment. Chen, K., Bandy, D.,...Greicius, M.D. (1996).
Journal of the American Geriatric Society, 53, Preclinical evidence of Alzheimers disease
695699. in persons homozygous for the E4 allele for
OBrien, J. T., Paling, S., Barber, R., Williams, apolipoprotein E. New England Journal of
E.D., Ballard, C., McKeith, I.G.,...Fox, N.C. Medicine, 334, 752758.
(2001). Progressive brain atrophy on serial Reisberg, B., Ferris, S., & de Leon, M.J. (1988).
MRI in dementia with Lewy bodies, AD, Stage-specific behavioral, cognitive, and in
and vascular dementia. Neurology, 56(10), vivo changes in community residing subjects
13861388. with age-associated memory impairment
Ost, M., Nylen, K., Csajbok, L., Ohrfelt, A. O., and primary degenerative dementia of the
Tullberg, M., Wikkelso, C.,...Nellgrd, B. Alzheimer type. Drug Development Research,
(2006). Initial CSF total tau correlates with 15(2-3), 101114.
1-year outcome in patients with traumatic Ritchie, K., Artero, S., & Touchon, J. (2001).
brain injury. Neurology, 67(9), 16001604. Classification criteria for mild cognitive
Otto, M., Wiltfang, J., Cepek, L., Neumann, M., impairment: A population-based validation
Mollenhauer, B., Steinacker, P.,...Poser, S. study. Neurology, 56, 3742.
(2002). Tau protein and 14-3-3 protein in the Roberts, J.S., Karlawish, J.H., Uhlmann, W.R.,
differential diagnosis of CreutzfeldtJakob Petersen, R. C., & Green, R. C. (2010). Mild
disease. Neurology, 58(2), 192197. cognitive impairment in clinical care: A sur-
Petersen, R., Knopman, D., Boeve, B., Geda, Y., vey of American Academy of Neurology
Ivnik, R., Smith, G., & Jack, C. R., Jr. (2009). members. Neurology, 75(5), 425431.
Mild cognitive impairment: Ten years later. Roberts, R.O., Geda, Y.E., Knopman, D.S., Cha,
Archives of Neurology, 66(22), 14471455. R.H., Pankratz, V.S., Boeve, B.F.,...Petersen,
Petersen, R. C. (2004). Mild cognitive impair- R. C. (2012). The incidence of MCI differs
ment as a diagnostic entity. Journal of Internal by subtype and is higher in men:The Mayo
Medicine, 256(3), 183194. Clinic Study of Aging. Neurology, 78(5),
Petersen, R. C. (2011). Clinical practice. Mild 342351.
cognitive impairment. New England Journal of Shaw, L. M., Vanderstichele, H., Knapik-
Medicine, 364(23), 22272234. Czajka, M., Clark, C. M., Aisen, P. S.,
CHAPTER 17. Mild Cognitive Impairment 447
Petersen, R. C.,...Trojanowski, J. Q. (2009). van de Pol, L. A., van der Flier, W. M., Korf,
Cerebrospinal fluid biomarker signature E. S., Fox, N. C., Barkhof, F., & Scheltens, P.
in Alzheimers disease neuroimaging ini- (2007). Baseline predictors of rates of hip-
tiative subjects. Annals of Neurology, 65(4), pocampal atrophy in mild cognitive impair-
403413. ment. Neurology, 69(15), 14911497.
Sperling, R. A., Aisen, P. S., Beckett, Visser, P.J., Scheltens, P., Verhey, F.R., Schmand,
L. A., Bennett, D. A., Craft, S., Fagan, B., Launer, L.J., Jolles, J., & Jonker, C. (1999).
A. M.,...Phelps, C. H. (2011). Toward defin- Medial temporal lobe atrophy and memory
ing the preclinical stages of Alzheimers dis- dysfunction as predictors for dementia in
ease: Recommendations from the National subjects with mild cognitive impairment.
Institute on Aging-Alzheimers Assocation Journal of Neurology, 246(6), 477485.
workgroups on diagnostic guidelines for Winblad, B., Gauthier, S., Scinto, L., Feldman,
Alzheimers disease. Alzheimers Dementia, H., Wilcock, G. K., Truyen, L.,...Nye, J. S.
7(3), 280292. (2008). Safety and efficacy of galantamine
Thal, L.J., Ferris, S.H., Kirby, L., Block, G.A., in subjects with mild cognitive impairment.
Lines, C.R., Yuen, E.,...Reines, S.A. (2005). A Neurology, 70(22), 20242035.
randomized, double-blind, study of rofecoxib Winblad, B., Palmer, K., Kivipelto, M., Jelic, V.,
in patients with mild cognitive impairment. Fratiglioni, L., Wahlund, L-O.,...Petersen,
Neuropsychopharmacology, 30, 12041215. R. C. (2004). Mild cognitive impairment
Unverzagt, F. W., Gao, S., Baiyewu, O., beyond controversies, towards a consensus.
Ogunniyyi, A. O., Gureje, O., Perkins, Journal of Internal Medicine, 256, 240246.
A.,...Hendrie, H. C. (2001). Prevalence Wolk, D., Price, J., Saxton, J., Snitz, B., James, J.,
of cognitive impairment: Data from the Lopez, O.,...De-Kosky, S.T. (2009). Amyloid
Indianapolis Study of Health and Aging. imaging in mild cognitive impairment sub-
Neurology, 57(9), 16551662. types. Annals of Neurology, 65(5), 557568.
18
In 2010, more than a quarter of a century after Moreover, the presence of A markers in
the original clinical criteria for Alzheimers these asymptomatic individuals was often
disease (AD) were published (McKhann associated with functional and structural
etal., 1984), the National Institute on Aging brain alterations, consistent with the patterns
and the Alzheimers Association convened of abnormality seen in patients with mild
three working groups to develop recom- cognitive impairment (MCI) and dementia
mendations for updated diagnostic criteria due to AD. In addition, longitudinal stud-
for AD. One of the workgroups was charged ies suggest that are very subtle alterations
with exploring the border zone between in cognition and behavior that are detectable
normal aging and the earliest stages of AD. in these normal individuals years prior
After much discussion and debate, this work- to meeting criteria for MCI and AD demen-
group suggested the term preclinical AD to tia. Thus, it is increasingly evident that AD
connote the stage when the pathophysiologi- represents a disease continuum, beginning
cal process of AD has begun in the brain but with a preclinical phase that may gradually
clinically evident symptoms of AD are not progress toward the earliest symptomatic
yet clearly manifest. stages of AD, through MCI due to AD and
Converging evidence from studies of ultimately to AD dementia.
clinically normal elders and genetic at-risk It is also clear, however, that some clini-
cohorts strongly suggests that the AD patho- cally normal older individuals with bio-
physiological process begins years, perhaps marker evidence of AD may not become
decades, prior to the diagnosis of clinical symptomatic during their lifetime. The moni-
dementia. Recent advances in neuroimaging, ker preclinical AD does not suppose that
cerebrospinal fluid (CSF) assays, and other all individuals with evidence of preclinical
biomarkers now allow the in vivo detection AD will progress to AD dementiamerely
of AD pathology. As data began to accumu- that the pathophysiological process of AD is
late from large cohorts of cognitively normal present prior to clinically evident symptoms
older individuals and asymptomatic autoso- of AD. Currently, there are insufficient data
mal dominant mutation carriers, it became to predict the likelihood of clinical decline
clear that a substantial proportion of these on an individual basis. Thus, the workgroup
individuals harbored biomarker or imaging recommendations for defining the preclinical
evidence of amyloid- (A) accumulation. stages of AD are intended only for research
448
CHAPTER 18. Preclinical Alzheimers Disease 449
purposes and have no clinical utility at this measures to identify individuals at high risk
point. for cognitive decline
It is likely that even the preclinical stage of
AD represents a continuum from completely
Redefining the Earliest Stages asymptomatic individuals with biomarker
ofAlzheimersDisease evidence of AD to biomarker positive indi-
viduals who are already demonstrating very
To facilitate the possibility of presymp- subtle decline but whom do not yet meeting
tomatic treatment of AD in the future, the standardized criteria for MCI (see Fig.18.1).
NIA-AA workgroup felt it was important It is for this reason that the NIA-AA work-
to define AD as including the underly- group chose the term preclinical AD rather
ing pathophysiological disease process, as than asymptomatic or presymptomatic, as it
opposed to having AD connote only the is clear that there is evidence of decline from
clinical stages of the disease as suggested baseline and very subtle symptoms that are
by other criteria (Dubois etal., 2010). In par- detectable prior to the stage of MCI or pro-
ticular, emerging evidence from both genetic dromal AD. The continuum of preclinical AD
at-risk and aging cohorts suggests that also encompasses:(1)individuals who carry
there may be a time lag of a decade or more one or more apolipoprotein E (APOE) 4
between the beginning of the pathological alleles who are known to have an increased
cascade of AD and the onset of clinically risk of developing AD dementia, at the point
evident impairment. The extent to which they are biomarker positive, and (2)carriers
biomarkers of AD predict a cognitively nor- of autosomal dominant mutations, who are
mal individuals subsequent clinical course in the presymptomatic biomarker positive
remain to be elucidated, and it is likely that stage of their illness, and who will almost cer-
some of individuals with biomarker evi- tainly manifest clinical symptoms and prog-
dence of AD will never manifest clinical ress to dementia.
symptoms in their lifetime. Thus, it is criti-
cal to determine the factors that best predict
the emergence of clinical impairment and Models of the Pathophysiological
progression to eventual AD dementia, and Sequence of Alzheimers Disease
to identify individuals most likely to benefit
from early intervention. The majority of biological models of AD con-
Although the concept of a preclinical tinue to suggest that abnormal accumulation
stage of AD has been somewhat controver- of A42 is an early event in the pathophysi-
sial, this notion should not be too foreign, as ologic cascade. All of the known autoso-
medical professionals readily acknowledge mal dominant, early-onset forms of AD are
that cancer can be detected at the stage of thought to be due, at least in part, to altera-
carcinoma in situ and that hypercholester- tions in amyloid precursor protein (APP)
olemia and atherosclerosis can result in nar- production or enzymatic cleavage (preseni-
rowing of coronary arteries that is detectable lin 1 and 2). Similarly, trisomy-21 invariably
prior to myocardial infarction. In most areas results in AD pathology in individuals who
of medicine, symptoms are not required have three intact copies of the APP coding
to diagnose human disease. Type II diabe- region located on chromosome 21. Finally,
tes, hypertension, renal insufficiency, and apolipoprotein E (APOE), the major genetic
osteoporosis are primarily detected through risk factor for late-onset AD, has been impli-
laboratory tests (i.e., biomarkers), and effec- cated in amyloid trafficking and plaque
tive treatment can prevent the emergence of clearance. Both autopsy and biomarker stud-
symptoms. The field of AD has not yet firmly ies suggest that A42 accumulation increases
established the link between the appearance with advanced aging, the greatest risk factor
of any specific biomarker in asymptomatic for developing AD. There remains significant
individuals and the subsequent emergence of debate in the field as to whether abnormal
clinical symptomatology; however, accumu- processing or clearance of A42 is actually
lating data suggest that we will someday be an etiologic event in sporadic, late-onset AD
able to utilize a combination of biomarkers, (Mawuenyega et al., 2010), and some inves-
genetics, and sensitive neuropsychological tigators have suggested that sequestration
450part ii The Dementias: The Major Diseases and Clinical Syndromes
Healthy Aging
Aysmptomatic
Subtle decline
Cognitive
function Preclinical AD
MCI due to AD
(Prodromal AD)
AD Dementia
Mild
Moderate
Severe
Years
Figure18.1 The continuum of Alzheimers disease (AD). The stage of preclinical AD precedes mild
cognitive impairment (MCI) and encompasses the spectrum of asymptomatic biomarker-positive
older individuals at risk for progression to MCI due to AD and AD dementia, as well as
biomarker-positive individuals who have demonstrated subtle decline from their own baseline
that exceeds that expected in typical aging but would not yet meet criteria for MCI. Preclinical AD
also encompasses individuals at genetic risk for AD, both presymptomatic autosomal dominant
mutation carriers and asymptomatic APOE 4 carriers at the point they begin to demonstrate
abnormalities on AD biomarkers.
of A into fibrillar forms may even serve Fig.18.2). Figure18.2 was adapted from the
as a protective mechanism (Lee et al., 2004; original graph proposed by Jack (Jack etal.,
Shankar etal., 2008). 2010), which has recently been revised, to
It is also clear that intracellular hyper- expand the preclinical phase. This biomarker
phosphorylated forms of tau, synaptic, and model parallels the hypothetical pathophysi-
neuronal loss invariably occur in AD. Thus ological sequence of AD and is particularly
far, markers of synaptic and neuronal injury relevant to tracking the preclinical stages of
appear to correlate better than A plaque AD. Biomarkers of brain A amyloidosis are
burden with clinical status. Although over- reductions in CSF A42 and increased amy-
production of A due to autosomal dominant loid positron emission tomography (PET)
mutations appear to result in downstream tracer retention. Elevated CSF tau is thought
neuronal pathology (Bateman etal., 2012), it to be a biomarker of neuronal injury but is
remains to be proven whether A accumu- not specific to AD, whereas increased CSF
lation is sufficient to incite the downstream phospho-tau may reflect ongoing injury and
pathological cascade of AD in late-onset AD. make be somewhat more specific. Decreased
Furthermore, it is not yet clear whether the fludeoxyglucose (FDG) uptake on PET in
associated neurodegenerative processes a characteristic temporal-parietal pattern
are related to direct synaptic toxicity from is thought to reflect AD-related synaptic
oligomeric forms of A, disruption of axo- dysfunction. More recently, resting state or
nal trajectories from fibrillar forms of A, or task-free functional connectivity magnetic
a second hit (another X factor) that leads resonance imaging (MRI) has also demon-
to synaptic dysfunction, neurofibrillary tan- strated a similar pattern of dysfunction in
gle formation, neurodegeneration, and ulti- early AD. Note that biomarkers of synaptic
mately neuronal loss. dysfunction may demonstrate abnormalities
very early, particularly in apolipoprotein E
(APOE) 4 allele and autosomal dominant
Biomarker Model of the Preclinical mutation carriers, who may manifest func-
Stage of Alzheimers Disease tional abnormalities prior to detectable A
deposition (Filippini et al., 2009; Reiman
Jack and colleagues proposed a hypothetical et al., 2004, 2012; Sheline et al., 2010). Brain
model in which the most widely validated atrophy on structural MRI in a characteristic
biomarkers of AD become increasingly abnor- pattern involving medial temporal regions
mal in an ordered manner (Jack etal., 2010; see and thinning of temporo-parietal cortices
CHAPTER 18. Preclinical Alzheimers Disease 451
Abnormal
Amyloid- accumulation (CSF/PET)
Synaptic dysfunction (FDG-PET/fMRI)
Tau-mediated neuronal injury (CSF)
Brain structure (volumetric MRI)
Cognition
Clinical function
Normal
Preclinical MCI Dementia
are later biomarkers of AD-related neuro- pathologic insult, perhaps due to greater
degeneration that may also become subtly synaptic density or larger number of healthy
abnormal even before clinical symptoms are neurons, such that sufficient neural substrate
evident. remains to support normal function. It is not
The temporal lag between the earliest posi- clear, however, that the data support a clear
tivity on AD biomarkers and the emergence demarcation between these two concepts, as
of clinical symptoms also may be altered by many factors, such as higher socioeconomic
factors such as brain or cognitive reserve status or engagement in cognitively stimulat-
(Stern, 2009). The concept of reserve was ing activities, may contribute to both types
originally invoked to account for the obser- of reserve. Recent studies suggest that high
vation that the extent of AD histopathologic reserve may primarily influence the capa-
changes at autopsy was not tightly corre- bility of individuals to tolerate occult AD
lated with the degree of clinical impairment. pathology without evidence of subtle cogni-
Reserve can be conceptualized as the ability tive signs (Rentz etal., 2010; Roe etal., 2008),
to tolerate higher levels of brain injury with- but it may be associated with rapid decline
out exhibiting clinical symptoms. Cognitive once the tipping point is reached and com-
reserve is thought to represent the ability to pensatory mechanisms begin to fail (Fotenos,
engage alternate brain networks or cognitive Mintun, Snyder, Morris, & Buckner, 2008;
strategies to cope with the effects of encroach- Wilson etal., 2010).
ing pathology, whereas brain reserve refers Epidemiological studies suggest there are
to the capacity of the brain to withstand factors that may significantly modulate the
452part ii The Dementias: The Major Diseases and Clinical Syndromes
2010; Storandt, Mintun, Head, & Morris, 2009; individuals at increasing risk of progression
Villemagne et al., 2008). Additional longitu- toward MCI and dementia (Sperling, Jack, &
dinal studies are clearly needed to confirm Aisen, 2011). Table18.1 summarizes the cat-
these findings and to elucidate the combina- egorization of biomarkers across the stages
tion of factors or biomarkers that best predict of preclinical AD. Stage 1 is characterized as
likelihood and rate of decline, and to better asymptomatic cerebral amyloidosis; Stage
understand individual differences in risk for 2 is amyloidosis plus neurodegeneration;
decline. and Stage 3 is amyloidosis, neurodegenera-
In addition to the aforementioned longi- tion, and evidence of very subtle change in
tudinal studies in older at-risk populations, cognition, including subjective cognitive
researchers continue to investigate the bio- concern, or behavior that is insufficient to
marker changes associated with genetic risk be diagnosed with MCI. Cliff Jack and col-
for AD. To date, the best established genetic leagues from the Mayo Clinic added two
risk factors for AD include common allelic additional categories that may be useful in
variants of APOE, the major late-onset AD capturing the full spectrum of the clinically
susceptibility gene, uncommon early-onset normal populations: (1) Stage 0 to connote
AD-causing mutations in the presenilin 1 older individuals without any biomarker
(PSEN1), presenilin 2 (PSEN2), and amyloid evidence of AD pathology and (2)Suspected
precursor protein (APP) genes, and Trisomy non-Alzheimers pathology (SNAP) to cat-
21 (Down syndrome). Biomarker studies in egorize individuals who do not have bio-
presymptomatic carriers of autosomal domi- marker evidence of amyloid pathology but
nant mutations have revealed evidence of A who demonstrate abnormalities on markers
accumulation on CSF and PET amyloid imag- of neuronal injury or subtle cognitive abnor-
ing more than 20years prior to the expected malities (Jack et al., 2012). Additional work
age of dementia onset in their families, as is required to determine the utility of such a
well as FDG-PET hypometabolism, func- staging framework; however, initial results
tional MRI abnormalities, and brain atrophy suggest that individuals in preclinical Stage
that may also precede symptoms by more 2 or 3 are indeed at increased risk of progres-
than a decade (Bateman etal., 2012; Reiman sion to MCI and AD dementia (Knopman
etal., 2012). etal., 2012).
The definitive studies to determine
whether the majority of asymptomatic indi-
A Conceptual Framework for Staging viduals with A accumulation are indeed
Preclinical Alzheimers Disease destined to develop AD dementia, and to
elucidate the biomarker and/or cognitive
Based on the available data in 2010 and the endophenotype that is most predictive of
biomarker framework utilized by the MCI cognitive decline will likely take more than
and AD dementia workgroups, the NIA-AA a decade to fully accomplish. Even if all of
preclinical workgroup proposed a three-stage the postulates mentioned previously prove
model for preclinical AD to characterize to be correct, a number of challenges remain
before these research recommendations can would reduce the lifetime risk for AD demen-
be translated into clinical practice (Sperling tia for a 65-year-old from 10.5% to 5.7%.
etal., 2013). The ethical and practical implica- The recognition that the pathophysiologi-
tions of future implementation of making a cal process of AD is already well under way
diagnosis of AD at a preclinical stage need prior to the stage of clinically evident symp-
to be carefully studied before any of these toms has already spurred plans for very
diagnostic tests are offered to clinically nor- early intervention trials. These studies might
mal older individuals. In particular, the poi- be thought of as secondary prevention to
gnant question of Why would individuals delay the onset of the clinical syndrome in
want to know they have AD a decade before individuals in whom the brain disease has
they might develop symptoms, if there is already begun. The Alzheimers Prevention
nothing they can do about it? needs to be Initiative (API) (Reiman et al., 2011) and
carefully considered well before any results Dominantly Inherited Alzheimer Network
from research is translated into clinical prac- (DIAN) (Bateman et al., 2012) clinical trials
tice. There may be important reasons, includ- will enroll asymptomatic individuals from
ing social and financial planning, that some families with autosomal dominant mutations
individuals would want to know their like- with two monoclonal antibodies against A
lihood of developing AD dementia within (solanezumab and gantanerumab). The A4
the next decade, even in the absence of an Anti-Amyloid Treatment of Asymptomatic
available disease-modifying therapy. It is Alzheimers disease trial will enroll clini-
our hope, however, that the advances in pre- cally normal older individuals with evi-
clinical detection of AD will enable earlier, dence of amyloid pathology on PET amyloid
more effective treatment, just as nearly all of imaging and treat with a monoclonal anti-
therapeutic gains in cancer, cardiovascular body against A (solanezumab) for 3 years
disease, osteoporosis, and diabetes involve in a placebo-controlled trial. Additional
treatment before significant clinical symp- anti-amyloid trials in preclinical AD popu-
toms are present. lations are currently in the planning stages.
The results from these studies will provide
important information regarding the role of
Why Would We Want to Detect Alzheimers amyloid in early cognitive decline in AD.
Disease a Decade Before Dementia? The success of these prevention trials, how-
ever, does not require that amyloid is the
The long preclinical phase of AD provides cause of AD, merely that amyloid is a criti-
a critical opportunity for potential interven- cal factor in the pathway that can be treated at
tion with disease-modifying therapy, if we the right stage of AD. A useful analogy may
are able to elucidate the link between the be cholesterol lowering in cardiac disease.
presence of AD biomarkers in asymptom- Many individuals with high cholesterol never
atic individuals and the emergence of the experience a myocardial infarction (MI), but
clinical syndrome. As our population ages, lowering cholesterol at the population level
with 10,000 baby boomers turning age 65 has substantially decreased cardiac morbid-
every day in the United States and entering ity and mortality over the past decade. The
the age of increased risk for AD, early detec- relationship between cholesterol and cardiac
tion and intervention is increasingly impera- disease took many years to establish, requir-
tive. Recent analyses by the Alzheimers ing both large natural history studies, such as
Association suggest that a hypothetical the Framingham study, and multiple preven-
intervention that delayed the onset of AD tion trials in familial hypercholesterolemia,
dementia by just 5 years would result in a individuals with early symptoms of ischemic
57% reduction in the number of AD dementia hear disease, and ultimately in healthy indi-
patients and reduce the projected Medicare viduals at high risk for coronary heart disease.
costs of AD from $627 to $344 billion (http:// Lowering cholesterol may be very helpful in
www.alz.org/alzheimers_disease_trajectory. reducing an individuals risk prior to any car-
asp). These models suggest that a screening diac symptoms, and even after a single MI, but
instrument for the presence of AD pathology is unlikely to improve cardiac function at the
(with 90% sensitivity and specificity), and end stage of ischemic heart failure. Similarly,
a treatment that slows progression by 50%, it is likely that we may need to intervene with
CHAPTER 18. Preclinical Alzheimers Disease 455
anti-amyloid therapies at a much earlier stage thinning in clinically normal elderly. Annals
of AD to maximally impact the clinical course of Neurology, 69(6), 10321042.
of the disease (Sperling et al., 2011). Studies Bennett, D., Schneider, J., Arvanitakis, Z., Kelly, J.,
with transgenic mouse models strongly sug- Aggarwal, N., Shah, R., & Wilson, R.S. (2006).
Neuropathology of older persons without cog-
gest that A-modifying therapies may have
nitive impairment from two community-based
limited impact once neuronal degeneration
studies. Neurology, 66, 18371844.
has begun (Oddo, Billings, Kesslak, Cribbs, Chtelat, G., Villemagne, V. L., Pike, K., Ellis,
& LaFerla, 2004). Disappointing results from K., Bourgeat, P., Jones, G.,...Rowe, C. C.
Phase 3 studies of anti-A monoclonal anti- (2011). Independent contribution of tempo-
bodies at the stage of dementia, despite evi- ral b-Amyloid deposition to memory decline
dence of biological activity, also support in non-demented elderly. Brain, 134(Pt 3),
the need for earlier intervention. Although 798807.
secondary prevention trials at the stage of Chetelat, G., Villemagne, V.L., Villain, N., Jones,
preclinical AD will be long, expensive, and G., Ellis, K. A., Ames, D.,...Rowe, C. C.
(2012). Accelerated cortical atrophy in cogni-
challenging to execute, the potential public
tively normal elderly with high beta-amyloid
health impact is tremendous.
deposition. Neurology, 78(7), 477484.
Craft, S. (2009). The role of metabolic disor-
ders in Alzheimer disease and vascular
Acknowledgments dementia: Two roads converged. Archives of
Neurology, 66(3), 300305.
The author wishes to acknowledge the invalu- De Meyer, G., Shapiro, F., Vanderstichele,
able contributions of the NIA-AA Workgroup H., Vanmechelen, E., Engelborghs, S., De
on Preclinical Alzheimers disease. Deyn, P. P.,...Trojanowski, J. Q. (2011).
Diagnosis-independent Alzheimer disease
biomarker signature in cognitively normal
References elderly people. Archives of Neurology, 67(8),
949956.
Aizenstein, H. J., Nebes, R. D., Saxton, J. A., Desikan, R.S., Sabuncu, M.R., Schmansky, N.J.,
Price, J. C., Mathis, C. A., Tsopelas, N. D.,... Reuter, M., Cabral, H.J., Hess, C.P.,...Fischl,
Klunk, W.E (2008). Frequent amyloid depo- B. (2010). Selective disruption of the cerebral
sition without significant cognitive impair- neocortex in Alzheimers disease. PLoS One,
ment among the elderly. Archives of Neurology, 5(9), e12853.
65(11), 15091517. Dickerson, B.C., Bakkour, A., Salat, D.H., Feczko,
Amariglio, R. E., Becker, J. A., Carmasin, J., E., Pacheco, J., Greve, D.N.,...Buckner, R.L.
Wadsworth, L. P., Lorius, N., Sullivan, (2009). The cortical signature of Alzheimers
C.,...Rentz, D. M. (2012). Subjective cog- disease: Regionally specific cortical thinning
nitive complaints and amyloid burden relates to symptom severity in very mild
in cognitively normal older individuals. to mild AD dementia and is detectable in
Neuropsychologia, 50(12), 28802886. asymptomatic amyloid-positive individuals.
Arriagada, P. V., Marzloff, K., & Hyman, B. T. Cereb Cortex, 19(3), 497510.
(1992). Distribution of Alzheimer-type patho- Doraiswamy PM, Sperling RA, Coleman
logic changes in nondemented elderly indi- RE, Johnson KA, Reiman EM, Davis
viduals matches the pattern in Alzheimers MD,...Pontecorvo, M.J. (2012). Amyloid-beta
disease. Neurology 1992;42(9), 16811688. assessed by florbetapir F 18 PET and
Arvanitakis, Z., Wilson, R. S., Bienias, J. L., 18-month cognitive decline: A multicenter
Evans, D.A., & Bennett, D.A. (2004). Diabetes study. Neurology, 79(16), 16361644.
mellitus and risk of Alzheimer disease and Dubois, B., Feldman, H. H., Jacova,
decline in cognitive function. Archives of C., Cummings, J. L., Dekosky, S. T.,
Neurology, 61(5), 661666. Barberger-Gateau, P.,...Scheltens, P. (2010).
Bateman, R. J., Xiong, C., Benzinger, T. L., Revising the definition of Alzheimers dis-
Fagan, A.M., Goate, A., Fox, N.C.,...Morris, ease: A new lexicon. Lancet Neurology, 9(11),
J. C. (2012). Clinical and biomarker changes 11181127.
in dominantly inherited Alzheimers dis- Fagan, A. M., Roe, C. M., Xiong, C., Mintun,
ease. New England Journal of Medicine, 367(9), M.A., Morris, J.C., & Holtzman, D.M. (2007).
795804. Cerebrospinal fluid tau/beta-amyloid(42)
Becker, J. A., Hedden, T., Carmasin, J., Maye, ratio as a prediction of cognitive decline
J., Rentz, D.M., Putcha, D.,...Johnson, K.A. in nondemented older adults. Archives of
(2011). Amyloid-beta associated cortical Neurology, 64(3), 343349.
456part ii The Dementias: The Major Diseases and Clinical Syndromes
Filippini, N., MacIntosh, B. J., Hough, M. G., Klunk, W.E., Price, J.C., Mathis, C.A., Tsopelas,
Goodwin, G. M., Frisoni, G. B., Smith, N.D., Lopresti, B.J., Ziolko, S.K.,...DeKosky,
S. M.,...Mackay, C. E. (2009). Distinct pat- S. T. (2007). Amyloid deposition begins in
terns of brain activity in young carriers of the striatum of presenilin-1 mutation carri-
the APOE-epsilon4 allele. Proceedings of the ers from two unrelated pedigrees. Journal of
National Academy of Science USA, 106(17), Neuroscience, 27(23), 61746184.
72097214. Knopman, D. S., Jack, C. R., Jr., Wiste,
Fjell, A.M., Walhovd, K.B., Fennema-Notestine, H. J., Weigand, S. D., Vemuri, P., Lowe,
C., McEvoy, L. K., Hagler, D. J., Holland, V.,...Petersen, R. C. (2012). Short-term clini-
D.,...Dale, A. M. (2010). Brain atrophy in cal outcomes for stages of NIA-AA preclini-
healthy aging is related to CSF levels of cal Alzheimer disease. Neurology, 78(20),
Abeta1-42. Cerebral Cortex, 20(9), 20692079. 15761582.
Fotenos, A. F., Mintun, M. A., Snyder, A. Z., Landau, S. M., Marks, S. M., Mormino,
Morris, J. C., & Buckner, R. L. (2008). Brain E. C., Rabinovici, G. D., Oh, H., ONeil,
volume decline in aging:Evidence for a rela- J. P.,...Jagust, W. J. (2012). Association
tion between socioeconomic status, preclini- of lifetime cognitive engagement and
cal Alzheimer disease, and reserve. Archives low beta-amyloid deposition. Archives of
of Neurology, 65(1), 113120. Neurology, 69(5), 623629.
Gomperts, S.N., Rentz, D.M., Moran, E., Becker, Lee, H.G., Casadesus, G., Zhu, X., Takeda, A.,
J. A., Locascio, J. J., Klunk, W. E.,...Johnson, Perry, G., & Smith, M.A. (2004). Challenging
K. A. (2008). Imaging amyloid deposition in the amyloid cascade hypothesis: Senile
Lewy body diseases. Neurology, 71(12), 903910. plaques and amyloid-beta as protective adap-
Hedden, T., Mormino, E. C., Amariglio, tations to Alzheimer disease. Annals of the
R. E., Younger, A. P., Schultz, A. P., Becker, NewYork Academy of Sciences, 1019, 14.
J. A.,...Rentz, D. M. (2012). Cognitive Li, G., Sokal, I., Quinn, J. F., Leverenz, J. B.,
profile of amyloid burden and white mat- Brodey, M., Schellenberg, G. D.,...Montine,
ter hyperintensities in cognitively normal T. J. (2007). CSF tau/Abeta42 ratio for
older adults. Journal of Neuroscience, 32(46), increased risk of mild cognitive impair-
1623316242. ment: A follow-up study. Neurology, 69(7),
Hedden, T., Van Dijk, K.R., Becker, J.A., Mehta, 631639.
A., Sperling, R.A., Johnson, K.A., & Buckner, Lim, Y. Y., Pietrzak, R. H., Ellis, K. A., Jaeger,
R.L. (2009). Disruption of functional connec- J., Harrington, K., Ashwood, T.,...Maruff, P.
tivity in clinically normal older adults harbor- (2013). Rapid decline in episodic memory in
ing amyloid burden. Journal of Neuroscience, healthy older adults with high amyloid-beta.
29(40), 1268612694. Journal of Alzheimers Disease, 33(3), 675679.
Jack, C. R., Jr., Knopman, D. S., Jagust, Mawuenyega, K. G., Sigurdson, W., Ovod,
W. J., Shaw, L. M., Aisen, P. S., Weiner, V., Munsell, L., Kasten, T., Morris,
M. W.,...Trojanowski, J. Q. (2010). J.C.,...Bateman, R.J. (2010). Decreased clear-
Hypothetical model of dynamic biomark- ance of CNS beta-amyloid in Alzheimers dis-
ers of the Alzheimers pathological cascade. ease. Science, 330(6012), 1774.
Lancet Neurology, 9(1), 119128. McKhann, G., Drachman, D., Folstein, M.,
Jack, C.R., Jr., Knopman, D.S., Weigand, S.D., Katzman, R., Price, D., & Stadlan, E. M.
Wiste, H.J., Vemuri, P., Lowe, V.,...Petersen, (1984). Clinical diagnosis of Alzheimers dis-
R. C. (2012). An operational approach to ease: Report of the NINCDS-ADRDA Work
National Institute on Aging-Alzheimers Group under the auspices of Department
Association criteria for preclinical Alzheimer of Health and Human Services Task Force
disease. Annals of Neurology, 71(6), 765775. on Alzheimers Disease. Neurology, 34(7),
Jack, C.R., Jr., Lowe, V.J., Senjem, M.L., Weigand, 939944.
S.D., Kemp, B.J., Shiung, M.M.,...Petersen, Mintun, M. A., Larossa, G. N., Sheline, Y. I.,
R.C. (2008). 11C PiB and structural MRI pro- Dence, C.S., Lee, S.Y., Mach, R.H.,...Morris,
vide complementary information in imag- J. C. (2006). [11C]PIB in a nondemented
ing of Alzheimers disease and amnestic population: Potential antecedent marker of
mild cognitive impairment. Brain, 131(Pt 3), Alzheimer disease. Neurology, 67(3), 446452.
665680. Montine, T. J., Peskind, E. R., Quinn, J. F.,
Kennedy, K. M., Rodrigue, K. M., Devous, M. Wilson, A. M., Montine, K. S., & Galasko,
D., Sr., Hebrank, A.C., Bischof, G.N., & Park, D. (2011). Increased cerebrospinal fluid
D.C. (2012). Effects of beta-amyloid accumu- F(2)-isoprostanes are associated with aging
lation on neural function during encoding and latent Alzheimers disease as identi-
across the adult lifespan. Neuroimage, 62(1), fied by biomarkers. Neuromolecular Medicine,
18. 13(1), 3743.
CHAPTER 18. Preclinical Alzheimers Disease 457
Moonis, M., Swearer, J. M., Dayaw, M. P., St amyloid-beta burden in cognitively nor-
George-Hyslop, P., Rogaeva, E., Kawarai, mal people at 3 levels of genetic risk for
T.,...Pollen, D.A. (2005). Familial Alzheimer Alzheimers disease. Proceedings of the
disease: Decreases in CSF Abeta42 levels National Academy of Science USA, 106(16),
precede cognitive decline. Neurology, 65(2), 68206825.
323325. Reiman, E. M., Langbaum, J. B., Fleisher,
Mormino, E. C., Kluth, J. T., Madison, C. M., A. S., Caselli, R. J., Chen, K., Ayutyanont,
Rabinovici, G. D., Baker, S. L., Miller, B. L., N.,...Tariot, P. N. (2011). Alzheimers
(2009). Episodic memory loss is related Prevention Initiative:Aplan to accelerate the
to hippocampal-mediated {beta}-amyloid evaluation of presymptomatic treatments.
deposition in elderly subjects. Brain, 132(5), Journal of Alzheimers Disease, 26(Suppl 3),
13101323. 321329.
Mormino, E. C., Smiljic, A., Hayenga, A. O., Reiman, E. M., Quiroz, Y. T., Fleisher, A. S.,
Onami, S. H., Greicius, M. D., Rabinovici, Chen, K., Velez-Pardo, C., Jimenez-Del-Rio,
G. D.,...Jagust, W. J. (2011). Relationships M.,...Lopera, F. (2012). Brain imaging and
between beta-amyloid and functional con- fluid biomarker analysis in young adults
nectivity in different components of the at genetic risk for autosomal dominant
default mode network in aging. Cerebral Alzheimers disease in the presenilin 1
Cortex, 21(10), 23992407. E280A kindred: A case-control study. Lancet
Morris, J.C., Roe, C.M., Grant, E.A., Head, D., Neurology, 11(12), 10481056.
Storandt, M., Goate, A. M.,...Mintun, M. A. Rentz, D.M., Locascio, J.J., Becker, J.A., Moran,
(2009). Pittsburgh Compound B imaging and E.K., Eng, E., Buckner, R.L.,...Johnson, K.A.
prediction of progression from cognitive nor- (2010). Cognition, reserve, and amyloid depo-
mality to symptomatic Alzheimer disease. sition in normal aging. Annals of Neurology,
Archives of Neurology, 66(12), 14691475. 67(3), 353364.
Morris, J. C., Storandt, M., McKeel, D. W., Jr., Resnick, S. M., Sojkova, J., Zhou, Y., An, Y.,
Rubin, E.H., Price, J.L., Grant, E.A., & Berg, L. Ye, W., Holt, D. P.,...Wong, D. F. (2010).
(1996). Cerebral amyloid deposition and dif- Longitudinal cognitive decline is associated
fuse plaques in normal aging:Evidence for with fibrillar amyloid-beta measured by
presymptomatic and very mild Alzheimers [11C]PiB. Neurology, 74(10), 807815.
disease. Neurology, 46(3), 707719. Ringman, J. M., Younkin, S. G., Pratico,
Oddo, S., Billings, L., Kesslak, J. P., Cribbs, D., Seltzer, W., Cole, G. M., Geschwind,
D. H., & LaFerla, F. M. (2004). Abeta immu- D.H.,...Cummings, J.L. (2008). Biochemical
notherapy leads to clearance of early, but not markers in persons with preclinical familial
late, hyperphosphorylated tau aggregates via Alzheimer disease. Neurology, 71(2), 8592.
the proteasome. Neuron, 43(3), 321332. Roe, C.M., Mintun, M.A., DAngelo, G., Xiong, C.,
Oh, H., Mormino, E.C., Madison, C., Hayenga, Grant, E.A., & Morris, J.C. (2008). Alzheimer
A., Smiljic, A., & Jagust, W. J. beta-Amyloid disease and cognitive reserve: Variation
affects frontal and posterior brain networks in of education effect with carbon 11-labeled
normal aging. Neuroimage, 54(3), 18871895. Pittsburgh Compound B uptake. Archives of
Perrotin, A., Mormino, E. C., Madison, C. M., Neurology, 65(11), 14671471.
Hayenga, A.O., & Jagust, W.J. (2012). Subjective Rowe, C.C., Ellis, K.A., Rimajova, M., Bourgeat,
cognition and amyloid deposition imaging: P., Pike, K. E., Jones, G.,...Villemagne, V. L.
A Pittsburgh compound B positron emission (2010). Amyloid imaging results from the
tomography study in normal elderly individu- Australian Imaging, Biomarkers and Lifestyle
als. Archives of Neurology, 69(2), 223229. (AIBL) study of aging. Neurobiology of Aging,
Pike, K. E., Savage, G., Villemagne, V. L., Ng, 31(8), 12751283.
S., Moss, S. A., Maruff, P.,...Rowe, C. C. Rowe, C. C., Ng, S., Gong, S. J., Ackermann,
(2007). Beta-amyloid imaging and memory in W., Pike, K., Savage, G., (2006). C-11 PIB
non-demented individuals:Evidence for pre- PET amyloid imaging in ageing and demen-
clinical Alzheimers disease. Brain, 130(Pt 11), tia. Presentation at the Alzheimer Imaging
28372844. Consortium, International Conference on
Reiman, E.M., Chen, K., Alexander, G.E., Caselli, Alzheimers Disease, Madrid, Spain.
R.J., Bandy, D., Osborne, D.,...Hardy, J. (2004). Sabuncu, M. R., Desikan, R. S., Sepulcre, J.,
Functional brain abnormalities in young Yeo, B.T., Liu, H., Schmansky, N.J.,...Fischl,
adults at genetic risk for late-onset Alzheimers B. (2011). The dynamics of cortical and hip-
dementia. Proceedings of the National Academy of pocampal atrophy in Alzheimer disease.
Science USA, 101(1), 284289. Archives of Neurology, 68(8), 10401048.
Reiman, E.M., Chen, K., Liu, X., Bandy, D., Yu, Schott, J.M., Bartlett, J.W., Fox, N.C., & Barnes,
M., Lee, W.,...Caselli, R. J. (2009). Fibrillar J. (2010). Increased brain atrophy rates in
458part ii The Dementias: The Major Diseases and Clinical Syndromes
cognitively normal older adults with low challenges ahead. Nature Reviews Neurology,
cerebrospinal fluid Abeta1-42. Annals of 9(1), 5458.
Neurology, 68(6), 825834. Sperling, R. A., Laviolette, P. S., OKeefe,
Shankar, G. M., Li, S., Mehta, T. H., K., OBrien, J., Rentz, D. M., Pihlajamaki,
Garcia-Munoz, A., Shepardson, N.E., Smith, M.,...Johnson, K. A. (2009). Amyloid depo-
I.,...Selkoe, D.J. (2008). Amyloid-beta protein sition is associated with impaired default
dimers isolated directly from Alzheimers network function in older persons without
brains impair synaptic plasticity and mem- dementia. Neuron, 63(2), 178188.
ory. Nature Medicine, 14(8), 837842. Stern, Y. (2009). Cognitive reserve.
Sheline, Y.I., Morris, J.C., Snyder, A.Z., Price, Neuropsychologia, 47(10), 20152028.
J.L., Yan, Z., DAngelo, G.,...Mintun, M.A. Storandt, M., Mintun, M. A., Head, D., &
(2010). APOE4 allele disrupts resting state Morris, J. C. (2009). Cognitive decline and
fMRI connectivity in the absence of amyloid brain volume loss as signatures of cerebral
plaques or decreased CSF Abeta42. Journal of amyloid-beta peptide deposition identified
Neuroscience, 30(50), 1703517040. with Pittsburgh compound B: Cognitive
Sheline, Y. I., Raichle, M. E., Snyder, A. Z., decline associated with Abeta deposition.
Morris, J. C., Head, D., Wang, S., & Mintun, Archives of Neurology, 66(12), 14761481.
M. A. (2009). Amyloid plaques disrupt rest- Vidoni, E.D., Van Sciver, A., Johnson, D.K., He,
ing state default mode network connectiv- J., Honea, R., Haines, B.,...Burns, J.M. (2012).
ity in cognitively normal elderly. Biological A community-based approach to trials of aero-
Psychiatry, 67(6), 584587. bic exercise in aging and Alzheimers disease.
Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett, Contemporary Clinical Trials, 33(6), 11051116.
D.A., Craft, S., Fagan, A.M.,...Phelps, C.H. Villemagne, V.L., Pike, K.E., Darby, D., Maruff,
(2011). Toward defining the preclinical stages of P., Savage, G., Ng, S.,...Rowe, C. C. (2008).
Alzheimers disease:Recommendations from Abeta deposits in older non-demented indi-
the National Institute on Aging-Alzheimers viduals with cognitive decline are indica-
Association workgroups on diagnostic guide- tive of preclinical Alzheimers disease.
lines for Alzheimers disease. Alzheimers Neuropsychologia, 46(6), 16881697.
Dementia, 7(3), 280292. Wilson, R. S., Barnes, L. L., Aggarwal, N. T.,
Sperling, R. A., Jack, C. R., Jr., & Aisen, P. S. Boyle, P. A., Hebert, L. E., Mendes de Leon,
(2011). Testing the right target and right C.F., & Evans, D.A. (2010). Cognitive activ-
drug at the right stage. Science Translational ity and the cognitive morbidity of Alzheimer
Medicine, 3(111), 111cm33. disease. Neurology, 75(11), 990996.
Sperling, R. A., Johnson, K. A., Doraiswamy, Wilson, R.S., Scherr, P.A., Schneider, J.A., Tang,
P.M., Reiman, E.M., Fleisher, A.S., Sabbagh, Y., & Bennett, D.A. (2007). Relation of cogni-
M. N.,...Pontecorvo, M. J. (2013). Amyloid tive activity to risk of developing Alzheimer
deposition detected with florbetapir F 18 disease. Neurology, 69(20), 19111920.
((18)F-AV-45) is related to lower episodic Yaffe, K., Fiocco, A. J., Lindquist, K.,
memory performance in clinically normal Vittinghoff, E., Simonsick, E. M., Newman,
older individuals. Neurobiology of Aging, A. B.,...Harris, T. B. (2009). Predictors of
34(3), 822831. maintaining cognitive function in older
Sperling, R.A., Karlawish, J., & Johnson, K.A. adults: The Health ABC study. Neurology,
(2013). Preclinical Alzheimer disease-the 72(23), 20292035.
Part III
461
462 part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
presentation of each patient. For example, if to other cognitive domains if the presenting
it becomes clear upon initial introductions symptoms differ (e.g., if a patient presents
that a patient is extremely disinhibited (e.g., with language or visuospatial symptoms).
making inappropriate sexual comments), a
mental status examination with more elabo-
rate assessment of executive and frontal lobe Qualitative Evaluation by Domain
functioning would be warranted, whereas
memory function might be more of a focus Many behaviors can be informally assessed
if the patient has trouble recalling details of through careful behavioral observations of
her recent personal history. Before and while the patient. While some clinicians prefer to
meeting with a patient, consider the fol- do this assessment in an unstructured for-
lowing questions to form a hypothesis and mat, others benefit from having the struc-
appropriate plan of action: ture of a checklist, outline, or standardized
tool for answering basic questions about the
What is the purpose of this examination? patients presentation. We will first provide
What is the primary presenting symptom, an overview of the domains that are typically
complaint, or problem? assessed in a mental status examination and
What is/has been the most salient symp- provide examples of observations or tasks
tom, complaint, or problem? that illustrate or assess each. Next, we will
What is the pace of progression of symp- review some of the most common and empir-
toms or problems? ically supported standardized tools for the
Are there any unusual associated features brief evaluation of mental status. Whenever
or temporal associations? possible, we recommend use of a standard-
What diagnoses may be considered in this ized tool in addition to informal observations.
case?
What particular aspects of cognition or
psychological function may be affected? Appearance and Indicators
How should the testing and interpre- ofFunctional Status
tation of the results be adjusted to the
patients level of education, intelligence, Basic observations regarding the patients
and estimated previous intellectual and physical characteristics, such as the patients
functional capacities? sex, age, race, dress, posture, hygiene,
Are there cultural, ethnic, or primary grooming, and social interactions are essen-
language considerations that should be tial to consider and describe in the office
made while testing and interpreting the report. Functional status is a term used
results? to describe ones ability to carry out basic
activities of daily living (BADLs; e.g., dress-
In the context of performing mental status ing, bathing) and instrumental activities of
examinations where dementia diagnosis is daily living (IADLs; e.g., grocery shopping,
at the forefront of the differential diagnosis, financial management) (Lawton & Brody,
appropriate consideration of the base rates 1969; Njegovan, Hing, Mitchell, & Molnar,
of different forms of dementia is warranted. 2001; Weintraub, 1986). While not always a
Specifically, as Alzheimers dementia is the standard component of a mental status exam
most common form of dementia (Hebert, with all patient populations, assessment
Weuve, Scherr, & Evans, 2013), and changes of functional status is an essential aspect
in memory function tend to be the first clini- of dementia diagnosis (Mckhann et al.,
cally observable signs in the Alzheimers 2011) and is thus an essential component of
disease (AD) spectrum (Albert et al., 2011; the mental status examination with geriatric
Mckhann et al., 2011; Petersen et al., 1999; patients. Regardless of the consideration of a
Sperling et al., 2011), evaluation of memory dementia diagnosis, it is important to assess
is almost always an essential aspect, if not functional status of older adults, as impair-
the central focus, of a mental status examina- ment in daily functioning puts patients at
tion in this context. Despite this point related risk for many detrimental outcomes, such as
to prior probability, this primary focus on car accidents (OConnor, Kapust, & Hollis,
memory function should be flexibly shifted 2008); falls (Lakhan, Jones, Wilson, & Gray,
CHAPTER 19. Dementia Screening and Mental Status Examination in Clinical Practice 463
reverse order (e.g., counting back from 20 to flexibility. Formal assessment of elements of
1; spelling world or sailor forward and executive function can be done by asking the
backward), to repeatedly do fixed subtrac- patient to alternate between reciting or draw-
tions from starting number (e.g., subtracting ing lines on a piece of paper between two
7s starting from 100, subtracting 3s starting sequences (e.g., alternating between count-
at 20), or to rearrange a sequence according ing by 7s and reciting the months of the year;
to a certain rule (e.g., reordering the alpha- alternating between stating the letters of the
numeric sequence:8, A, 3, L, 6, I presented alphabet starting at A and ending at Z and
at one number/letter per second into ascend- counting numbers from 1 to 26; alternate
ing alphabetic and numerical order as A, I, between connecting numbers and letters on a
L, 3, 6, 8). These tasks all have the common page as in the trails B test (Reitan & Wolfson,
component of asking a patient to attend to a 1985). There are a diverse array of formal
verbal instruction set and to mentally hold and informal measures of many aspects of
and manipulate a set of information to pro- executive function that have been developed;
vide accurate responses. some provide qualitative information regard-
Many patients with mild Alzheimers ing a patients approach to problem solving,
dementia can display relatively preserved and some have systematic scoring criteria
attention but may show subtle deficits in for objective quantification of performance.
speed or psychomotor function. In dementias Several commonly used screening measures
that have more subcortical or diffuse white include items specifically designed to assess
matter involvement, such as Parkinsonian executive function (e.g., MoCA, ACE-R),
dementias or vascular dementia, more nota- while there are also domain-specific screen-
ble difficulties with speed and motor func- ing measures, such as the Clock Drawing Test
tion are often evident (Cherrier et al., 1997; (see later for a review of several variants on
OBrien etal., 2002). At the outset of any clini- this task). Importantly, the Mini Mental State
cal office visit, motor function can be assessed Examination provides very limited assess-
by informally observing the patients gait, ment of executive functioning through spell-
posture, stability, facial movements (e.g., ing of the word world backward. Other
blink rate), and the speed of performing basic bedside tasks to assess executive function
motor functions and overall movements (e.g., include performance of Luria-type motor
rising from sitting to standing). Processing programming sequences to test ordering,
speed can also be informally observed by set-maintenance/shifting, and persevera-
the patients response latency to questioning tion, and the visual pattern completion test.
during the interview. For example, Weiner and colleagues (2011)
devised a more difficult Luria-type task
by modifying the original Luria three-step
Executive Function sequence task of fist-cut-slap by asking the
patient to first mimic the examiner and then
Executive function, a term often used to to perform several cycles of a hand motor
refer to the cognitive tasks primarily con- sequence of cut, fist, slap (Weiner, Hynan,
trolled by the frontal lobes or frontal systems Rossetti, & Falkowski, 2011)with the knuck-
of the brain, includes cognitive abilities such les pointing down during the formation of a
as planning, organization, inhibition, shift- fist (see Fig. 19.1). An example of the visual
ing from one task to another, fluency, and pattern completion task involves asking the
abstract reasoning (Stuss & Alexander, 2000). patient to extend an alternating pattern of
Informal assessment of executive functions connected open-square and triangular shapes
can be obtained by observing for signs of (i.e., ramparts; see Fig.19.2).
disinhibition, such as frequently interrupt- Another aspect of executive functioning
ing or making socially inappropriate com- is the ability to generate responses, either
ments. Patients with executive dysfunction verbally or nonverbally. Verbal fluency is
also commonly have difficulty shifting from discussed later in the language section, but
one task to another; this can be observed the executive component of these types of
during interview if the patient exhibits diffi- tasks is that they require the examinee to
culty when the topic of conversation or task generate novel responses according to a set
changes, is perseverative, or has poor mental of rules (e.g., to say or write words following
466 part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
1 2 3
1 2 3
Figure19.1 Demonstration of the original Luria motor sequencing test (top) and the modified,
slightly more challenging motor sequence (bottom) used by Weiner etal. (2011).
grocery store?) or the route the patient trav- Assessment of recent episodic memory
eled to come to the office visit; the latter task can be evaluated informally while inter-
also makes demands on episodic memory viewing the patient by asking questions
function. Mental visualization may also be about recent events in the news. Ideally, this
tested by asking the patient to perform men- is done after obtaining some information
tal rotations, spatial navigation, or by the about the patients interests (e.g., a particu-
clock visualization and projection (CVP) task. lar sports team; a current political issue) and
During this multimodal screening task, which asking questions specific to those interests
also requires good attention, comprehension, (e.g., details and the score of the last game he
and working memory, the patient is asked to watched) that can be verified. Alternatively,
close her eyes and to visualize a clock face; if a family member is available to provide the
the patient is then instructed to imagine the clinician with details about a recent family
short-hand of the clock is pointing to three event, the clinician can ask questions about
and the long-hand is pointing to five. What the patients recent personal history. If such
time will the clock show in half-an-hour? It information is not readily available, one can
is possible, however, to use alternative strate- assess nonpersonal semantic memory by ask-
gies, such as using semantic knowledge and ing the patient to name, for example, the cur-
working memory without utilizing mental rent president (prime minister or monarch),
imagery, to solve the CVP task. vice president, state governor or senator,
Visuospatial function can be impaired early the mayor of the patients town, the name
in several conditions, including dementia of the US President who was assassinated
with Lewy bodies, vascular cognitive impair- in the 1960s (and what city he was in), or
ment, corticobasal syndrome, or the posterior naming the US Presidents in reverse tempo-
cortical atrophy syndrome. A patient who ral order starting with the current president.
reports abnormalities in perception, such as Often the last type of memory to be affected
detailed visual hallucinations or subtle per- is personal or autobiographic memory such
ceptual distortions, should be referred for as the patients current age, date and place of
further subspecialty evaluation. Visual hallu- birth, her profession and names and places
cinations can also be due to a medication side of past major employment, names of schools
effect in susceptible individuals, such as in attended, and names of family members.
patients with Parkinsons disease prescribed All of the cognitive screening tools dis-
dopamine-enhancing medications. cussed later provide objective assessment
of memory and include tasks on which the
patient is asked to learn and recall (or rec-
Memory Function ognize), after a delay in which the patient
is mentally engaged and not allowed to
Memory is the capacity to store, retain, and rehearse the presented materials, a verbally
recall information and experiences (see presented word list or story, or to redraw a
Chapter 1 for review of memory systems). previously copied figure. When expressive
The aspect of cognition most affected by language function can significantly interfere
Alzheimers disease in its earliest stages with verbal recall during memory testing,
is episodic memory, and the difficulty lies other alternatives to redrawing previously
with the formation of new memories. This copied figures include testing recognition
can often translate to a patient with early memory through presenting lists of words,
Alzheimers disease who may have an excel- patterns, or pictures, or to hide objects in par-
lent memory for information learned and ticular locations in the exam room and ask
events that occurred in their remote past the patient to remember and later show you
(e.g., many lines of poetry, autobiographical their locations.
information such as where she went to grade It is important to always assess that the
school) but may have less ability to learn patient has been able to immediately register
new information or form detailed memories or encode the material, as well as to ensure
for more recent events (e.g., names of new that the patients hearing is intact, by ask-
coworkers, details of current events, what ing the patient to first repeat the presented
restaurant she went to last week, what meal items (at least once, and preferably twice or
she ate last night). more when a greater learning load is being
CHAPTER 19. Dementia Screening and Mental Status Examination in Clinical Practice 469
demanded). If the patient is unable to ade- Simple reasoning and problem solving can
quately register this material (e.g., because be tested in a variety of ways, including ask-
of an attentional, learning, or severe hear- ing the patient to address a simple life sce-
ing problem) then subsequent assessment nario such as What would you do if you
of memory storage capacity may not be found a stamped and addressed envelope on
completely made. After a delay, ideally of at the street? or You find water pouring out
least 5 minutes, when the patient has been from a cracked pipe in your bathroom; what
mentally engaged with other tasks that do do you do?
not require substantial learning and remem- Abstraction can be assessed by asking for
bering of material that can interfere with this the meaning of common proverbs as well as
material/information, the patient is asked to asking the patient to delineate the similar-
recall the specific information he was asked ity (e.g., In the most general sense, how are
to remember. Any items the patient cannot bicycle and train similar?) and difference
recall can be first cued by category (e.g., a cat- between two things (e.g., What is the differ-
egory cue of building for the learned item ence between a lie and a mistake?).
of church) and then by multiple-choice Agnosia, derived from a-gnosis or
recognition (e.g., Was it school, church, non-knowledge, is the loss of ability to rec-
hospital, or train station?). The hallmark of ognize objects, persons, sounds, shapes, or
patients with early to mid-stage Alzheimers smells while the specific sense is not defec-
dementia is a relatively preserved ability to tive. Anosognosia is the lack of awareness of
immediately register new information but or denial of the existence of a deficit or handi-
significant storage loss for this information cap (Greek: nosos or disease and gnosis or
when tested after an adequate delay that is knowledge) and is a common (but not nec-
not substantially amenable to cues or recog- essary), and relatively early, feature of sev-
nition by multiple/forced-choice testing. eral dementias, particularly AD and bvFTD.
It is important to gauge anosognosia, and the
patients overall insight, for several reasons,
Specialized Mental Functions and Multimodal including to advise the caregivers about the
Cognitive Operations best approaches to the patients care and
safety considerations (including driving,
While not necessary to evaluate these func- guns, cooking). Anosognosia can be assessed
tions during all screening MSEs in the pri- by comparing actual facts to the patients
mary care setting, some tests of specialized insight, perception, and understanding of her
cognitive functions can be included in certain condition (deficits, disabilities, and behav-
primary care situations and should be often iors, and their impact on others), current
included in screening MSEs by subspecial- station in life, and the reason and context of
ists. These include assessment of calculations, the medical evaluation. Patients with simul-
reasoning and problem solving, abstrac- tanagnosia can recognize objects or details in
tion, agnosia, neglect, praxis (see Chapter1), their visual field, but only one at a time. They
insight, and judgment (see Table19.1). cannot make out the scene they belong to or
Complexity of calculations should be make out a whole image out of the details
adjusted to the patients level of education or they literally cannot see the forest for the
highest function. This can range from simple trees. Simultanagnosia can be tested using
arithmetic (e.g., What is 9 plus 14?) to cal- scenes (e.g., The Cookie Theft Picture) or
culations involving money (e.g., How many asking the patient to identify specific targets
nickels are there in 65 cents?), to making of various sizes such as letters, numbers, or
change (e.g., If you bought something that shapes on a pageaffected patients may be
cost $3.73 and you paid with a $5 bill, how able to identify smaller individual targets but
much change should you receive back?), to not larger ones (e.g., the patient can circle all
calculating more complex bills involving per- small As on a page with an array of small
centages (e.g., If you went to a restaurant and large letters, but not the very large As)
and the bill came to $120, how much total or ones that are produced by smaller shapes
money would you leave if you wanted to (see Fig.19.3).
also include a 15% tip?), and to solving more Hemispatial neglect (also known as uni-
complex word problems. lateral neglect, spatial neglect, or neglect
470 part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
TABLE19.1Continued
Anosognosia Describe his or her understanding of the reasons why a given safety measure has been
taken or restriction has been made (e.g., if the patients drivers license has been
revoked) and compare his or her provided reasons to known facts (e.g., the patient
has a recent history of several minor car accidents).
Simultanagnosia Describe a complex scene (e.g., the Boston Cookie Theft picture) or identify a large
object that is made up of smaller shapes (e.g., an Amade on a page with small As)
Neglect Bisect a line drawn on a page
Apraxia Show you how he or she would cut with scissors; sweep with a broom; strike a match
syndrome) is broadly defined when a deficit is touched simultaneously on the right and
in attention to the opposite side of space is left). While the sequelae of large right middle
observed. When florid, it will be symptom cerebral artery stroke is the most common
described by the informant, which can be cause of hemispatial neglect, traumatic brain
observed during the examination by notic- injury, brain tumors, and neurodegenerative
ing that the patient has not shaved, applied conditions such as corticobasal degeneration
makeup, or brushed the hair on the left side (CBD) and Creutzfeldt-Jakob disease may
of her body. When more subtle, it can be also cause this condition.
assessed by asking the patient to bisect a Apraxia can be broadly defined as the loss
horizontal line, cross out a target letter on a of the ability to execute or carry out learned
page of randomly placed letters, copy a geo- purposeful movements, despite having the
metric figure, describe the examination room, desire and the physical ability to perform
or a picture presented to her (see Fig. 19.4 the movements (see Chapter 1). Ideomotor
for an example task). When the primary praxis, the ability to correctly form the nec-
modality is intact, extinction to double-sided essary postures and movements to perform
stimulation in any modality (e.g., visual, a task using a tool, can be tested by asking
tactile) can also indicate neglect (e.g., with the patient to pretend by showing you how
eyes closed the patient indicates the light
touch by the examiner on the left and right
side of his body when touched in sequence, S
M C O F A R
but not when touched at the same timein A S A B A
left-sided neglect he would only indicate A C
X T G X Q
being touched on his right side though he A F A T A J
H F A
R N
A N I
B A A U O
A A S U F
B L
D
A A A F F A R
E F
A A A A A
M X S A Q
A A B A R G
K A
A A A L
Y T A
AAAAAAAA A Q A L P S Z
A A
Figure19.4 Example of a task that evaluates
A A
visual field perception and hemifield attention.
A A The patient can be shown such an array of
A A letters or objects on a page and be instructed
A A to cross out all of the As on the page. People
Figure19.3 Asample of a hierarchical figure with visual neglect (typically left) will have a
in which the smaller letters make up a larger high rate of omissions on the left side of the
letter. In patients with simultagnosia (seen in page. Similarly, when asked to bisect a line by
Balints syndrome), there would be difficulty in marking the center of the line, patients with
seeing the larger letter (H)below. neglect will mark the line to the right of center.
472 part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
she would scramble an egg with a fork (a and traveling independently. Each item on
transitive task) or by asking her to show you the FAQ is rated on a scale of 03, with a rat-
how she would salute (a nontransitive task). ing of 0 indicating complete independence
Ideational praxis, the ability to correctly tem- and a score of 3 indicating complete reliance
porally sequence independent actions/task on caregivers. The FAQ is helpful as a screen-
components to perform a goal, can be tested ing tool, as any score greater than 0 would
by asking the patient to verbalize, step by indicate some level of functional impairment
step, how she would make a sandwich. and would thus represent a red flag for fur-
An overall general estimate of the patients ther evaluation of dementia. As suggested by
insight and judgment can be made after the Alzheimers Association recommenda-
obtaining a complete history (from patient tions for primary care clinicians conducting
and informant), performing the assess- the Medicare Annual Wellness Visit (Cordell
ment discussed previously, and gauging etal., 2013), a questionnaire such as the FAQ
the patients understanding, response, and to screen for functional impairment should be
receptiveness to the clinical impression and used in conjunction with a screening tool for
recommendations made by the clinician. cognitive function, such as those described
later. This recommendation is made because
subtle changes in cognition often predate
Review of Common Standardized Mental overt problems with daily function (Petersen
Status Examination Tools etal., 1999).
participants and found to have a sensitivity probable dementia (n = 132). Using the cut-
of.74 (ROC AUC = .83) when using a cutoff off of 4 on the GPCOG Informant Interview
of AD8 2 to distinguish between nonde- had a sensitivity of.89 (ROC AUC = .84),
mented participants (CDR=0, n=112) and and when combined with the cognitive test-
participants with questionable or very mild ing portion (GPCOG Patient Examination
dementia (CDR = 0.5, n = 68), while sensi- discussed later), the total scale had a sensi-
tivity improved to.85 (receiver operating tivity of 0.82 (ROC AUC = .91). These sen-
characteristic area under the curve, ROC sitivities were significantly higher than the
AUC = .90) when using the same cutoff to Abbreviated Mental Test (AMT; Hodkinson,
distinguish between the nondemented group 2012; sensitivity=.42; ROC AUC=.78) and
and participants at all levels of dementia were higher (although not significantly
(CDR 0.5, n = 124). Replication studies higher) than the MMSE (sensitivity = .81,
have further supported the validity and reli- ROC AUC=.85).
ability of the AD8. In 225 patientcaregiver A benefit of the GPCOG is that it integrates
dyads, the AD8 was found to have very good both objective cognitive testing and caregiver
interrater reliability (intraclass correlation report into one comprehensive summary
coefficient=0.80, 95% CI 0.55 to 0.92) and a score, and also allows the clinician to choose
ROC AUC of 0.92 (95% CI 0.88 to 0.95) that to administer either or both sections based on
suggests excellent discrimination between the clinical situation at hand. Furthermore,
nondemented individuals and those with in the initial validation paper of the GPCOG,
cognitive impairment regardless of etiology both individual components had higher spec-
(Galvin, Roe, Xiong, & Morris, 2006). The ificity values compared to the MMSE, provid-
AD8 is estimated to only take 3 minutes to ing support for potentially using one of these
complete and can be used alone or in con- subtests in lieu of the MMSE. However, as
junction with a brief cognitive screening tool, is the case with the MMSE, the sensitivity
as is recommended by the measures authors. to detect decline in the earlier stage of mild
Finally, the AD8 is freely available for general cognitive impairment (MCI) has not been
clinical use at: http://alzheimer.wustl.edu/ established. The Informant Interview por-
About_Us/PDFs/AD8form2005.pdf. tion of the GPCOG is extremely brief, taking
approximately 13 minutes to administer.
General Practitioner Assessment of Cognition
Informant Interview Relevant Outcome Scale for Alzheimers Disease
The General Practitioner Assessment of The Relevant Outcome Scale for
Cognition (GPCOG) is a dementia screen- Alzheimers Disease (ROSA) is a 16-item,
ing tool that includes both a brief informant clinician-administered questionnaire that is
interview (GPCOG Informant Interview; ideally administered to a patient caregiver,
Brodaty et al., 2002), discussed here, and a although it can be administered to the patient
brief cognitive screening test for the patient in early stages of dementia. As opposed to
(GPCOG Patient Examination), discussed in the other measures mentioned in this sec-
the cognitive screening tool section discussed tion, which were primarily developed to
later. The informant interview consists of six detect the first signs of dementia, the ROSA
questions, rated dichotomously regarding the was designed to track the progression of
patients current cognitive or daily function symptoms of dementia over time, and thus
relative to his level of function a few years includes items that are largely inapplicable
prior (e.g., Does the patient have more trou- to many patients in the earliest stages of AD
ble remembering things that have happened (e.g., experiencing delusions or becoming dis-
recently?). Each item with a yes response oriented). However, the ROSA does include
is given a score of 1, and a total score 4 is several items relevant to early-stage AD (e.g.,
recommended as the cutoff for impairment. difficulties remembering details of recent
In the original validation study for the events), and the rating of each item on the
GPCOG (Brodaty etal., 2002), both informant ROSA is on a scale of 010, with 0 indicating
and patient sections were administered to 283 the most difficulty and 10 indicating no dif-
older adults and divided into a nondemented ficulty. Thus, the ROSA offers the benefit of a
group (n=151) and a group with possible or wider range of scores on each item and can
474 part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
to many types of cognitive impairment and Clock Drawing Test and Its Variants
should not be used as standalone measures
to attribute cause and diagnose dementia. The Clock Drawing Test (CDT) has the ben-
An ideal screening tool for dementia would efit of being an extremely short measure
correctly classify all patients with dementia (approximately 1 minute) that taps multiple
as having dementia (i.e., 100% sensitivity) cognitive abilities, including visuospatial,
and all those without as normal (i.e., 100% memory, and executive functions. While the
specificity). Of course, such a perfect screen- brevity and complexity of the task make it a
ing test does not yet exist, sensitivity and very good screening tool, it is important to
specificity trade-offs have to be considered note that the sensitivity of the test comes at a
for all tests, and there are multiple factors, cost to specificity; there are many underlying
such as education level, cultural and lan- cognitive problems that can lead to impaired
guage barriers, and premorbid level of cog- clock drawing, and the CDT does not test
nitive function that influence performance learning and remembering of new infor-
on even the most basic screens of cognitive mation (including episodic memory), thus
function (Crum, Anthony, Bassett, & Folstein, underscoring the importance of viewing this
1993). The threshold for a score on a screening task as a limited screening tool when used in
tool to be flagged as abnormal is typically isolation.
determined by choosing a cutoff score that In the most common variant of this task,
minimizes the change of a false negative (i.e., the patient is given a blank sheet of paper
sensitivity:incorrectly classifying a dementia and given the verbal instructions to Draw
patient as not demented), the idea being that the face of a clock, place all of the numbers on
it would be less desirable to miss a diagno- the clock face, and set the hands to ten after
sis of dementia than to have a false alarm eleven. There has been an entire literature
(i.e., incorrectly classifying a nondemented on this task and its variants (Cahn-Weiner
individual as demented). Thus, the screen- et al., 1999; Royall, Cordes, & Polk, 1998),
ing should be framed to the patient as part and there have been many different pro-
of a procedure (answering some questions) posed scoring criteria (Libon, Swenson,
that can help to determine whether further Barnoski, & Sands, 1993; Storey, Rowland,
evaluation may be helpful, and performance Basic, & Conforti, 2001; Sunderland et al.,
should never be presented or interpreted as a 1989)and classic signs of impairment that
definitive pass or fail on a test. are exhibited on the task. To highlight a few
With these points in mind, the follow- of the main considerations that a clinician
ing review considers the main aspects of should look for in this task, there are several
test comparison for the clinician to con- types of errors reflecting different cognitive
sider: (1) test length; (2) ease of obtaining problems, including graphomotor difficul-
test materials and appropriate training; ties, perseverative errors, stimulus-bound
(3)complexity of administration and scoring responses, errors in conceptualization, and
procedures; and (4) evidence of a tests sen- problems with planning and spatial orga-
sitivity to detect mild cognitive impairment nization (Eknoyan, Hurley, & Taber, 2012).
(versus more advanced stages of dementia). Graphomotor problems (e.g., imprecise lines,
Aspects of screening tests that we regard distorted or illegible numbers, micrographia)
with less emphasis in this review include the reflect underlying problems with motor func-
availability of alternate test forms for serial tioning and are more common in subcortical
evaluations, development and availability dementias (e.g., Parkinsons disease, vascular
of translated versions for international clini- dementia) than in early stages of Alzheimers
cal or research use, and evidence for a tests disease (Kitabayashi et al., 2001; Rouleau,
specificity (i.e., the ability of a test to distin- Salmon, Butters, Kennedy, & Mcguire, 1992).
guish between different forms of cognitive Planning ability can be assessed by observ-
impairment or diagnostic groups, including ing the approach the examinee takes to draw-
false positives in nondemented individu- ing the clock, with a planful approach being
als). While all of the following are considered characterized by anchoring, or first plac-
brief screening measures, they are presented ing the numbers 12, 3, 6, and 9 on the clock
in order of estimated administration time face, and then filling in the other numbers
from the shortest to longest (see Table19.2). appropriately. Aclassic example of a poorly
476 part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Clock Drawing 1 Varies by scoring system Very brief; taps Low specificity; many
multiple cognitive scoring systems
functions in a single
task
Mini-Cog 24 03 See decision rules in Simple scoring Limited evidence for
text algorithm sensitivity to MCI
Memory 4 08 See decision rules in Better sensitivity than Only assesses memory
Impairment text three-word recall
Screen (MIS) from MMSE
General 25 09 7 indicates Has accompanying Limited evidence for
Practitioner impairment informant interview sensitivity to MCI
Assessment questions
of Cognition
(GPCOG)
Patient Version
St. Louis 7 030 Varies by education Evidence for Largely studied in VA
University level: sensitivity to clinical settings
Mental Status 26 for those with predementia
(SLUMS) 12+ years cognitive
examination 24 for those with impairment
<12
7-minute Screen 712 Requires use of scoring Multidomain tool Original validation
(7MS) calculator availableat study had small
memorydoc.org sample size; Limited
evidence for
sensitivity to MCI
Mini Mental State 710 030 <24 indicates Widely known, Limited evidence for
Examination impairment, allowing for ease sensitivity to MCI
(MMSE) but use of available of communication
normative data among clinicians
recommended
(Crum etal., 1993)
The Modified Mini 10 0100 <77 generally Generates MMSE Limited evidence for
Mental Sate indicates and 3MS score sensitivity to MCI
Examination impairment, from a single
(3MS) but use of available administration;
normative data verbal fluency item
recommended improves sensitivity
(Tombaugh etal., of original MMSE
1996)
Blessed 10 037 >3 errors generally Ideal for tracking Limited evidence for
Dementia Scale indicates global impairment sensitivity to MCI
Information- impairment in established
Memory- 410 errors:suggests dementia cases
Concentration mildAD
(BDS-IMC) 1116 errors:suggests
moderateAD
1737 errors:suggests
advanced AD
6-Item Impairment 46 016 >7 errors indicates Superior sensitivity to Limited sensitivity
Test (6CIT) impairment MMSE with shorter toMCI
administration time
(continued)
CHAPTER 19. Dementia Screening and Mental Status Examination in Clinical Practice 477
TABLE19.2Continued
planned clock draw would be one in which is scored on a scale of 03 with 0 indicat-
the numbers are drawn in numeric order and ing no impairment and 3 indicating severe
poorly spaced, such that the examinee runs impairment according to the Consortium to
out of room for the last few numbers on the Establish a Registry for Alzheimers Disease
clock. (CERAD) scoring criteria (Morris etal., 1989).
Several different scoring criteria have been These scores were reduced to a dichoto-
proposed for the CDT, ranging from dichoto- mous scale (0 = normal, 13 = abnormal) to
mous scoring for normal versus abnormal evaluate the Mini-Cogs diagnostic accu-
performance, to detailed scoring of each racy (Borson et al., 2000). Words recalled
aspect of the clock drawing. Generally, scor- (after a filled delay during which the CDT
ing systems include consideration for the is completed) are scored on a scale of 03.
general shape or contour of the clock face The scoring algorithm specifies that one
(i.e., specifying that the clock face is approxi- would arrive at a dementia classification in
mately circular in shape), accurate placement one of two ways: (1) 3-Item Recall = 0, or
and sequencing of the numbers on the clock (2) 3-Item Recall = 12 and CDT is abnor-
face (i.e., all numbers present and spaced mal. Conversely, a nondemented classifica-
approximately evenly around the entire tion would be given if 3-Item recall=3, or if
inner circle of the clock face), and accurate 3-Item recall = 12 and CDT is normal. The
placement of clock hands (i.e., pointing to the Mini-Cog has been reported to have higher
correct numbers with a clear differentiation sensitivity than the Mini Mental State Exam
in the lengths of the hour and minute clock (MMSE;.99 versus.91) when distinguishing
hands). Overall, the CDT, when scored on between older adults with normal cogni-
10-point scale, has been found to have good tion (n = 120) versus those with dementia
interrater reliability and sensitivity in distin- (n=129). The Mini-Cog has the added benefit
guishing patients with mild AD from cogni- over the MMSE of having a shorter admin-
tively normal older individuals (Nair et al., istration time (approximately 3 versus 10
2010). minutes). However, in contrast to some of the
tools listed later (e.g., the MoCA and ACE-R),
Mini-Cog the diagnostic accuracy of the Mini-Cog has
not been well characterized in distinguishing
The Mini-Cog consists of a combination of between normal aging and MCI.
a clock drawing task and a three-item word
list recall (Borson, Scanlan, Brush, Vitaliano,
Memory Impairment Screen
& Dokmak, 2000). Scoring for the Mini-Cog
consists of numbered scores for each item as The Memory Impairment Screen (MIS;
well as a scoring algorithm to classify exam- Buschke et al., 1999) is a screening tool
inees as demented or nondemented. The designed to detect memory impairment at the
clock drawing test (CDT) for the Mini-Cog exclusion of any other cognitive difficulties
478 part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
and is thus designed to better detect AD Using the cutoff of 7 on the GPCOG Patient
dementia compared to other forms of demen- Examination, the measure had a sensitivity
tia. The MIS is estimated to take approxi- of.82 (ROC AUC = .86), while the total scale
mately 4 minutes to administer and consists had a sensitivity of 0.82 (ROC AUC=.91), both
of a 4-item learning and memory task during of which were higher than the sensitivities
which the examinee is presented with a page observed for the AMT or MMSE. An advan-
and asked to read the four printed words on tage of the GPCOG is short time of adminis-
the page. Next, the examinee is asked to state tration as it is estimated to take approximately
the word on the page associated with a given 25 minutes to administer. The main limita-
semantic category (e.g., the examiner says, tion of the GPCOG Patient Examination is that
Which word is a type of fruit? to which there is limited evidence of its sensitivity to
the examinee would respond, Orange). distinguish between older adults with normal
After these semantic associations are made versus mildly impaired cognitive function.
for all words, the examinee engages in a dif- The GPCOG is freely available in multiple lan-
ferent mentally occupying task for 23 min- guages for general clinical use on the authors
utes and is then asked to freely recall the four Web site:http://www.gpcog.com.au
words. The examiner provides semantic cues
for those items not freely recalled, and the St. Louis University Mental Status Examination
total score on the MIS is represented by dou-
bling the number of items freely recalled and The St. Louis University Mental Status
adding that number to the number of items (SLUMS; Tariq, Tumosa, Chibnall, Perry,
recalled with semantic cueing (MIS = (free & Morley, 2006) is a screening tool that has
recall X 2) + cued recall), generating a sum- been largely studied in a VA geriatric clinic
mary score ranging from 0 to 8 with higher setting that takes approximately 7 minutes to
scores indicating better performance. The administer. Similar to the MMSE and MoCA,
MIS has been compared to the 3-word recall SLUMS scores range from 0 to 30, with higher
from the MMSE and found to have higher scores indicating better performance. As is
sensitivity than the 3-word recall MMSE the case with the MoCA, the SLUMS pro-
item at detecting dementia (sensitivities=.86 vides normative score ranges for older adults
and.65, respectively). Limitations of the MIS at two education levels (12+ years versus less
include that it only assesses memory function than 12 years), and three different levels of
and has not been demonstrated to be sensi- cognitive impairment (normal, mild neuro-
tive to detecting MCI. cognitive disorder or MNCD, and demen-
tia). Also similar to the MoCA, the SLUMS
includes items that assess a broader range of
General Practitioner Assessment of Cognition,
cognitive domains compared to other screen-
Patient Version
ing measures, including items to assess ori-
The General Practitioner Assessment of entation, memory, attention, and executive
Cognition (GPCOG; Brodaty et al., 2002) function. Items for each of these domains
Patient Examination is one of two subtests are also more difficult than the comparable
that comprise the GPCOG and includes six items on the MMSE (e.g., the SLUMS, like
clinician-administered items assessing mem- the MoCA, as a five-word list learning task
ory (recall of a previously repeated name and as opposed to the MMSEs three-word item).
address), orientation (to exact date), informa- In the original validation study (Tariq etal.,
tion (ability to provide examiner with a news 2006), sensitivity of the SLUMS to detect
item occurring in the last week), and execu- mild neurocognitive disorder (MCND) and
tive, and visuospatial function (clock drawing dementia were compared with the MMSE
test). Scores on the GPCOG range from 0 to in a sample of older veterans (n=702), who
9 with higher scores indicating more impair- were classified into three groups: normal
ment. In the original validation study for the cognition (n = 440), MCND (n = 180), and
GPCOG (Brodaty et al., 2002), both infor- dementia (n = 82). Using different cutoff
mant and patient sections were administered scores for those with <12 versus 12+ years of
to 283 older adults who were divided into a education, the SLUMS was consistently more
nondemented group (n = 151) and a group sensitive than the MMSE at detecting MCND
with possible or probable dementia (n=132). from normal cognition. Specifically, in the
CHAPTER 19. Dementia Screening and Mental Status Examination in Clinical Practice 479
<12-year education group, using the optimal assessment capable of distinguishing between
SLUMS cutoff score of 23.5, sensitivity was.92 cognitively healthy older adults and those
(ROC AUC=.93), while the optimal cutoff for with AD. The measure is comprised of four
the MMSE was 28.5 with a sensitivity of.60 previously developed tests, each with slight
(ROC AUC = .67). Similarly, in the 12+ year modifications, including a modified version
education group, using a SLUMS cutoff score of the Free and Cued Selective Reminding
of 25.5, sensitivity was.95 (ROC AUC=.94), Test (Grober & Buschke, 1987), a 60-second
while the optimal cutoff for the MMSE was trial of semantic verbal fluency (animal nam-
29.5 with a sensitivity of.75 (ROC AUC=.64). ing), the Benton Temporal Orientation Test
Both SLUMS and MMSE did an acceptable (Benton, Sivan, Hamsher, Varney, & Spreen,
job at detecting dementia from normal cog- 1994), and a variant of the clock drawing test
nition across education groups, although (with instructions to set the hands to seven
the sensitivity and ROC AUC values for the to four and use of a 7-point scoring system
SLUMS in these analyses were consistently originally developed by Freedman and col-
higher than the MMSE. Detailed information leagues (Freedman etal., 1994).
on all recommended cutoff scores for each The original validation study for
diagnostic distinction and education level the 7MS compared performance in 60
can be found in the original SLUMS valida- community-dwelling older adults to a demo-
tion paper (Tariq etal., 2006). graphically comparable clinical sample of
The SLUMS shows clear superiority to older adults with probable AD diagnoses.
the MMSE at detecting mild neurocognitive It reported the 7MS to have extremely high
disorder, but more research is needed on sensitivity in the overall sample (1.0), and
the sensitivity of the SLUMS to detect MCI. when repeatedly testing sensitivity on 1,000
The diagnosis of MCND is based on a set of random samples of 30 AD and 30 control
suggested research criteria set forth in the subjects, sensitivity was found to have an
Diagnostic and Statistical Manual of Mental average value of.92. Strengths of the 7MS
Disorders, 4th edition (DSM-IV, American include its relative brevity, while still provid-
Psychiatric Association, 2000), which essen- ing a more detailed assessment of memory
tially defines MCND as impaired function function than most screening measures, and
in two or more cognitive domains that cause its high sensitivity. Limitations of the 7MS
impaired daily function for at least 2 weeks include the small sample size with which it
and is accompanied by medical evidence was developed and validated, and its admin-
(e.g., neurologic exam or imaging) thought to istration and scoring, which require slightly
be related to the cognitive change. Essentially, more training than some of the more widely
the main difference between the criteria for used measures. Finally, the 7MS has not
MCND and frank dementia in the DSM-IV been well studied in distinguishing between
definition is the description of the cognitive groups of older adults with normal cognition
symptoms in dementia gradually worsening versus patients with MCI.
over time. Thus, MCND as a diagnostic entity
is much closer on the continuum to the diag-
nosis of dementia than the diagnosis MCI, Mini Mental State Examination
as it includes individuals with two domains
of impaired cognition with associated func- Historically, the Mini Mental State
tional impairment. While the SLUMS holds Examination (MMSE; Folstein, Robins, &
promise as a dementia screening instrument, Helzer, 1983)has been the most widely used
it needs further validation at detecting subtle and recognized of standardized mental status
cognitive problems in patients with MCI and measures, which greatly increases the ease of
validation in nonveteran patient populations. communication among clinicians regarding
The SLUMS is freely available for general scores and specific test items. The test takes
clinical use at http://aging.slu.edu approximately 10 minutes to administer and
generates a summary score ranging from 0 to
30, including items assessing orientation to
7-Minute Screen
time and place (10 points), repetition of three
The 7-Minute Screen (7MS; Solomon et al., words (3 points), attention and mental con-
1998) was developed to provide a rapid trol (5 points), recall of three words following
480 part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
a 3-minute delay (3 points), language abili- of the MMSE is that it is not free but copy-
ties (8 points), and visuoconstruction (1 righted; it can be purchased for general clini-
point). The original validation study for the cal use at http://www.minimental.com
MMSE suggested use of a cutoff score of 24
(Folstein, Folstein, & Mchugh, 1975), but sen-
The Modified Mini-Mental State Examination
sitivity of the MMSE using cutoff scores alone
has been shown to be highly dependent on The Modified Mini-Mental State Examina
the sample with which its accuracy is tested. tion (3MS; Teng & Chui, 1987)is a modifica-
Specifically, as a broad-based screening mea- tion of the MMSE that was developed upon
sure in a general population, the MMSE on the concept that adding a few additional
has limited utility in providing distinctions items to the original MMSE and chang-
between older adults with normal cognition ing the scoring to create a broader range of
versus MCI (Lonie, Tierney, & Ebmeier, 2009), scores (030 versus 0100) would increase
while it generally distinguishes older adults the sensitivity of the screening tool while
with normal cognition from those with more still allowing for the provision of an original
advanced stages of dementia (Folstein etal., MMSE score. The benefit of this approach is
1975). that the full 3MS expands on the original,
Despite its limitations, the MMSE is still while still allowing clinicians familiar with
often considered a corner stone standardized the original MMSE to reference the 0100
test to include in dementia clinical trials; this scale performance to a 030 MMSE score.
is likely a function of its long history of use The original paper presenting the 3MS
(first published in 1975), and its wide use in (Teng & Chui, 1987)offers a full description
clinical and research settings to detect and of the changes in scoring from the original
track cognitive impairment (Cullen, Oneill, MMSE to the 3MS and includes side-by-side
Evans, Coen, & Lawlor, 2007; Tangalos administration and scoring protocols for
etal., 1996), in epidemiologic studies (Crum both the 3MS and MMSE. Briefly, the 3MS
et al., 1993), in clinical trials as a tool for includes additional items assessing orien-
operationalizing inclusion/exclusion crite- tation (year, month, day, town, and state of
ria based on level of cognitive impairment birth), more unusual words for the 3-item
(Raskind, Peskind, Wessel, & Yuan, 2000), registration and recall, standardized seman-
and as a cognitive outcome measure to track tic and multiple-choice cueing for 3-item
response to treatment (Wallin, Wattmo, & recall, finer gradation of scoring for existing
Minthon, 2011). Given its ubiquity, it is fre- MMSE items (e.g., a 10-point scoring system
quently used as a reference for comparison for overlapping pentagon copy versus the
for newer mental status exams and cognitive dichotomous 0 vs. 1 scoring on the original
screening measures and has generally been MMSE), additional naming items, a brief
shown to stand the test of time as a tool for (30-second) test of semantic verbal fluency,
detecting and tracking moderate to severe several word similarity items, and a sec-
levels of cognitive impairment. However, ond 3-word recall trial at the end of the test,
the MMSE does not perform as well as sev- allowing for additional memory testing.
eral newer screening tools (e.g., the Montreal In a study comparing sensitivity of the 3MS
Cognitive Assessment) at detecting the more to MMSE in a sample of cognitively healthy
subtle changes in cognitive function seen in older adults (n = 406) versus those with
MCI (Freitas, Simoes, Alves, & Santana, 2013; Alzheimers disease (n=119), Tombaugh and
Nasreddine et al., 2005). Additionally, using colleagues (1996) found that the 3MS was
traditional cutoffs, the MMSE has been par- more sensitive than the MMSE overall (.926
ticularly criticized for having low sensitivity versus.905), and that this difference was more
to detect cognitive impairment and dementia pronounced in a subsample of individuals
in individuals with high education or intel- with lower (08 years) education (.901 ver-
ligence (Alves, Simoes, Martins, Freitas, & sus.848). While these differences in sensitivity
Santana, 2013; Christensen & Jorm, 1992). were not statistically significant, the authors
As is reflected in the reviews of these other suggest that the addition of a verbal fluency
screening tools, there are several alternatives test to the MMSE would increase its sensitiv-
to the MMSE that have higher sensitivity for ity (Tombaugh, Mcdowell, Kristjansson, &
this diagnostic distinction. Afinal limitation Hubley, 1996).
CHAPTER 19. Dementia Screening and Mental Status Examination in Clinical Practice 481
Blessed Dementia Scale shown in the same study to have superior sen-
Information-Memory-Concentration sitivity to the MMSE (using a cutoff of 23)in
this sample at distinguishing between those
The Blessed Dementia Scale Information-
with normal cognition versus mild dementia
Memory-Concentration (BDS-IMC; Blessed,
(MMSE sensitivity = .51 versus 6CIT = .79).
Tomlinson, & Roth, 1968) was originally
The sensitivity of the MMSE improved to
designed to track cognitive impairment in
.79 when distinguishing the control group
patients with established dementia diagnoses
from the entire dementia group, while 6CIT
and thus contains a number of test items that
sensitivity improved to.90. With superior
have ceiling effects in less impaired patients
sensitivity and shorter administration time
and may be less sensitive at detecting early,
(approximately 46 minutes), the 6CIT also
subtle signs of cognitive impairment seen
appears to be superior to the MMSE for
in MCI. While the BDS is heavily weighted
detecting dementia, but again it has limited
toward a continuum of memory and orien-
empirical support at distinguishing between
tation items of easy to moderate difficulty, it
normal cognition and MCI.
also includes several items that assess work-
ing memory and executive function (e.g., Montreal Cognitive Assessment
reciting the months of the year in reverse
order; counting backward from 20 to 1). The The Montreal Cognitive Assessment (MoCA;
BDS is scored on a scale of 037, with higher Nasreddine etal., 2005)is a mental status test
scores indicating more errors and more cog- that was specifically designed as a screen-
nitive impairment. The generally accepted ing tool for MCI, and thus it includes sev-
cutoff score for dementia-level cognitive eral test items that are intentionally more
impairment on the BDS is >3 errors, and non- difficult than comparable test items on the
adjusted (e.g., for age, education, premorbid MMSE. It additionally includes more items
IQ) error score ranges for mild, moderate, that assess executive and visuospatial func-
and severe impairments in patients with AD tions than many of the other screening tools;
are reported as 410, 1116, and 1737 errors, these include an abbreviated version of the
respectively (Locascio, Growdon, & Corkin, Trails B test (Reitan & Wolfson, 1985), a cube
1995). While neuropsychological testing copy, and a clock drawing task. In addition
plays an important role in detecting, verify- to these items that assess combined visuospa-
ing, and delineating patterns of cognitive tial and executive functions, the MoCA has a
dysfunction in AD, the BDS, due to its range, two-item word similarities task that requires
has been shown to be superior to cognitive abstract reasoning and several items each
test domains in staging and tracking demen- to assess the domains of language (3-item
tia severity in patients with AD. confrontation naming, 2-item sentence repe-
The BDS-IMC has been adapted to create a tition, and a single verbal fluency trial), atten-
shorter, 6-item version that is more amenable tion (2-item digit span, an item assessing
for use as a screening tool; this was originally vigilance, and serial 7s subtraction from 100),
named the 6-Item Cognitive Impairment Test memory (5-word list learning, free recall, and
(6CIT) (Katzman et al., 1983) but has also recall with semantic and multiple-choice cue-
been referred to in the literature as the 6-Item ing), and orientation (date, month, year, day,
or Short Orientation-Memory-Concentration place, city). Similar to the MMSE, the MoCA
Test (6OMCT), or the Short Blessed Test (SBT) generates a summary score ranging from 0
(Brooke & Bullock, 1999). Scoring from the to 30. In contrast to the MMSE, however, the
original BDS-IMC was modified in the 6CIT MoCA has an adjustment for lower educa-
to include a broader range of scores and to tion (an additional point is added to the total
weight some items more than others to yield score if the examinee has 12 or fewer years
a total score range of 016, with higher scores of education) and a relatively higher cutoff
indicating more impairment. The 6CIT has score of 26 or greater has been recommended
demonstrated a strong correlation to MMSE as a general guideline to indicate perfor-
(r=.91) in a sample of 287 older adults rang- mance in the normal range. In a direct com-
ing from normal cognitive function to severe parison of the sensitivity of both measures
dementia (Brooke & Bullock, 1999). Using a at distinguishing between a sample of older
cutoff score of 8 or more on the 6CIT, it was adults with MCI (n=94) and those who were
482 part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
cognitively healthy (n = 90), the MoCA was (Ahmed et al., 2012). Given the MoCA is
found to be significantly more sensitive than shorter in administration time (1012 versus
the MMSE (.90 versus .18) (Nasreddine etal., approximately 1225 minutes), it can present
2005). Subsequently, the superiority of the a more attractive choice than the ACE-R for
MoCA to the MMSE in regards to sensitivity, use in the primary care setting. A potential
specificity, positive predictive value, negative benefit of the ACE-R over the MoCA, how-
predictive value, and classification accuracy ever, is that it provides cognitive domain
between normal cognition, MCI, and AD has scores, for which normative ranges have been
been shown at different cutoffs (i.e., cutoff provided for general clinical use, thus allow-
of 17 for MCI and 22 for AD) (Freitas et al., ing for a more detailed summary of cogni-
2013). tive functioning. The ACE-R has been used
Advantages of the MoCA over other extensively in AD clinical trials in England
screening tools include its increased sensi- and worldwide, and it is available in many
tivity at distinguishing normal aging from languages and alternate test forms that are all
MCI, the ease of obtaining test materials, its freely available to the public by request to the
relative ease of administration, and strong tests authors.
evidence for its acceptance by general prac-
titioners. It is additionally available in many
different languages, and the English version Conclusion
is available in alternate, co-normed test forms
helpful for serial evaluations. Administration The mental status examination can be used
time for the MoCA is estimated to be approx- in a succinct form for screening for demen-
imately 1012 minutes, making it a slightly tia or in an extended form to evaluate the
longer test to administer than the MMSE. The type and severity of cognitive impairment
MoCA and its alternate versions in English or dementia. In addition to the informal and
and several languages are freely available at qualitative descriptions of mental status that
http://www.mocatest.org are routinely performed by geriatricians,
primary care physicians, neurologists, and
psychiatrists, incorporating a standardized
Addenbrookes Cognitive Examination, Revised
screening tool into routine clinical practice is
The original Addenbrookes Cognitive recommended. The relative objectivity and
Examina tion (ACE) was developed as a consistency with which these measures are
screening tool to detect early dementia and administered and interpreted reduces the
distinguish between AD and other forms subjectivity of clinical judgment and pro-
of dementia (Mathuranath, Nestor, Berrios, vides a quantifiable metric of a patients cur-
Rakowicz, & Hodges, 2000). Several modifica- rent cognitive function and any change from
tions were made in the revised version, which the patients own baseline.
includes the full test items for the MMSE in
addition to a number of additional items to
assess attention, orientation, memory, verbal References
fluency, language, and visuospatial func- Ahmed, S., de Jager, C., & Wilcock, G. (2012).
tions (Ahmed, De Jager, & Wilcock, 2012). A comparison of screening tools for the
In addition to generating an MMSE score, assessment of mild cognitive impair-
the Addenbrookes Cognitive Examination, ment: Preliminary findings. Neurocase, 18(4),
Revised (ACE-R; Mioshi, Dawson, Mitchell, 336351.
Arnold, & Hodges, 2006) generates a global Albert, M.S., DeKosky, S.T., Dickson, D., Dubois,
score ranging from 0 to 100, subscores for each B., Feldman, H. H., Fox, N. C.,...Phelps,
of the aforementioned cognitive domains, C. H. (2011). The diagnosis of mild cogni-
tive impairment due to alzheimers dis-
and a formula for distinguishing between AD
ease: Recommendations from the national
and frontotemporal dementia. institute on aging-alzheimers association
Using the generally recommended cutoff workgroups on diagnostic guidelines for
score of 82/100, the ACE-R has been shown alzheimers disease. Alzheimers and Dementia,
to have roughly equivalent sensitivity to the 7(3), 270279.
MoCA (both approximately .90) at distin- Alves, L., Simoes, M. R., Martins, C., Freitas,
guishing between healthy aging and MCI S.,& Santana, I. (2013). Premorbid iq influence
CHAPTER 19. Dementia Screening and Mental Status Examination in Clinical Practice 483
on screening tests scores in healthy patients on mental status examination. Journal of the
and patients with cognitive impairment. American Geriatric Society, 45(5), 579583.
Journal of Geriatric Psychiatry and Neurology, Christensen, H., & Jorm, A. F. (1992). Short
26(2), 117126. report:Effect of premorbid intelligence on the
Barnes, D. E., Yaffe, K., Byers, A. L., mini-mental state and iqcode. International
McCormick, M., Schaefer, C., & Whitmer, Journal of Geriatric Psychiatry, 7(3), 159160.
R.A. (2012). Midlife vs late-life depressive Cordell, C.B., Borson, S., Boustani, M., Chodosh,
symptoms and risk of dementia:Differential J., Reuben, D., Verghese, J.,...Fried, L. B.
effects for alzheimer disease and vascular (2013). Alzheimers association recommen-
dementia. Archives of General Psychiatry, dations for operationalizing the detection of
69(5), 493498. cognitive impairment during the medicare
Beck, A. T., Ward, C. D. H., Mendelson, M., annual wellness visit in a primary care set-
Mock, J.,& Erbaugh, J. (1961). An inventory ting. Alzheimers Dementia, 9(2), 141150.
for measuring depression. Archives of General Crum, R. M., Anthony, J. C., Bassett, S. S., &
Psychiatry, 4, 561571. Folstein, M.F. (1993). Population-based norms
Benton, A. L., Sivan, A. B., Hamsher, K. D., for the mini-mental state examination by age
Varney, N. R., & Spreen, O. (1994). and educational level. Journal of the American
Contributions to neuropsychological assessment. Medical Association, 269(18), 23862391.
NewYork, NY:Oxford University Press. Cullen, B., ONeill, B., Evans, J.J., Coen, R.F.,&
Blessed, G., Tomlinson, B.E.,& Roth, M. (1968). Lawlor, B. A. (2007). A review of screening
The association between quantitative mea- tests for cognitive impairment. Journal of
sures of dementia and of senile change in Neurology, Neurosurgery, and Psychiatry, 78(8),
the cerebral grey matter of elderly subjects. 790799.
British Journal of Psychiatry, 114, 797811. Edelberg, H. K., Shallenberger, E., Hausdorff,
Borson, S., Scanlan, J., Brush, M., Vitaliano, P.,& J.M.,& Wei, J.Y. (2000). One-year follow-up
Dokmak, A. (2000). The mini-cog:Acognitive of medication management capacity in highly
vital signs measure for dementia screening functioning older adults. Journal of Gerontology
in multi-lingual elderly. International Journal A Biological Science Medical Science, 55(10),
of Geriatric Psychiatry, 15(11), 10211027. M550553.
Boustani, M., Peterson, B., Hanson, L., Harris, Edelberg, H. K., Shallenberger, E., & Wei, J. Y.
R.,& Lohr, K.N. (2003). Screening for demen- (1999). Medication management capacity in
tia in primary care: A summary of the evi- highly functioning community-living older
dence for the u.S. Preventive services task adults: Detection of early deficits. Journal of
force. Ann Intern Med, 138(11), 927937. the American Geriatric Society, 47(5), 592596.
Brodaty, H., Pond, D., Kemp, N.M., Luscombe, Edelstein, B., Lichtenberg, P., Marson, D.,
G., Harding, L., Berman, K.,& Huppert, F.A. Moye, J., Powers, D., Sabatino, C.,...Moye,
(2002). The gpcog: A new screening test for J. (2008). Assessment of older adults with
dementia designed for general practice. dimished capacity: A handbook for psy-
Journal of the American Geriatric Society, 50(3), chologists. American Bar Association and
530534. American Psychological Association.
Brooke, P.,& Bullock, R. (1999). Validation of a Retrieved March 2014, from http://www.
6 item cognitive impairment test with a view apa.org/pi/aging/programs/assessment/
to primary care usage. International Journal of capacity-psychologist-handbook.pdf.
Geriatric Psychiatry, 14(11), 936940. Eknoyan, D., Hurley, R. A., & Taber, K. H.
Buschke, H., Kuslansky, G., Katz, M., Stewart, (2012). The clock drawing task: Common
W. F., Sliwinski, M. J., Eckholdt, H. M., & errors and functional neuroanatomy. Journal
Lipton, R. B. (1999). Screening for demen- of Neuropsychiatry and Clinical Neuroscience,
tia with the memory impairment screen. 24(3), 260265.
Neurology, 52(2), 231238. Folstein, M. F., Folstein, S. E., & McHugh,
Cahn-Weiner, D. A., Sullivan, E. V., Shear, P. R. (1975). Mini-mental state. A practi-
P. K., Fama, R., Lim, K. O., Yesavage, cal method for grading the cognitive state of
J. A.,...Pfefferbaum, A. (1999). Brain struc- patients for the clinician. Journal of Psychiatric
tural and cognitive correlates of clock draw- Research, 12(3), 189198.
ing performance in Alzheimers disease. Folstein, M. F., Robins, L. N., & Helzer, J. E.
Journal of the International Neuropsychological (1983). The mini-mental state examination.
Society, 5(6), 502509. Archives of General Psychiatry, 40(7), 812.
Cherrier, M.M., Mendez, M.F., Perryman, K.M., Freedman, M., Leach, L., Kaplan, E., Winocur,
Pachana, N. A., Miller, B. L., & Cummings, G., Shulman, K. I., & Delis, D. (1994). Clock
J. L. (1997). Frontotemporal dementia ver- drawing: A neuropsychological analysis.
sus vascular dementia: Differential features NewYork, NY:Oxford University Press.
484 part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Freitas, S., Simoes, M.R., Alves, L.,& Santana, Libon, D. J., Swenson, R. A., Barnoski, E. J., &
I. (2013). Montreal cognitive assess- Sands, L. P. (1993). Clock drawing as an
ment: Validation study for mild cognitive assessment tool for dementia. Archives of
impairment and alzheimer disease. Alzheimer Clinical Neuropsychology, 8(5), 405415.
Disease and Associated Disorders, 27(1), 3743. Locascio, J. J., Growdon, J. H., & Corkin, S.
Galvin, J.E., Roe, C.M., Powlishta, K.K., Coats, (1995). Cognitive test performance in detect-
M. A., Muich, S. J., Grant, E.,...Morris, J. C. ing, staging, and tracking Alzheimers dis-
(2005). The ad8:Abrief informant interview ease. Archives of Neurology, 52(11), 10871099.
to detect dementia. Neurology, 65(4), 559564. Lonie, J. A., Tierney, K. M., & Ebmeier, K. P.
Galvin, J. E., Roe, C. M., Xiong, C., & Morris, (2009). Screening for mild cognitive impair-
J.C. (2006). Validity and reliability of the ad8 ment: A systematic review. International
informant interview in dementia. Neurology, Journal of Geriatric Psychiatry, 24(9), 902915.
67(11), 19421948. Mathuranath, P. S., Nestor, P. J., Berrios, G. E.,
Grober, E., & Buschke, H. (1987). Genuine Rakowicz, W., & Hodges, J. R. (2000). A
memory deficits in dementia. Developmental brief cognitive test battery to differentiate
Neuropsychology, 3, 1336. Alzheimers disease and frontotemporal
Hardy, J., Momeni, P., & Traynor, B. J. (2006). dementia. Neurology, 55(11), 16131620.
Frontal temporal dementia: Dissecting the McKhann, G. M., Knopman, D. S., Chertkow,
aetiology and pathogenesis. Brain, 129(Pt 4), H., Hyman, B. T., Jack, C. R., Jr., Kawas,
830831. C. H.,...Phelps, C. H. (2011). The diag-
Hebert, L.E., Weuve, J., Scherr, P.A.,& Evans, nosis of dementia due to alzheimers dis-
D.A. (2013). Alzheimer disease in the united ease: Recommendations from the national
states (2010-2050) estimated using the 2010 institute on aging-Alzheimers association
census. Neurology, 80(19), 17781783. workgroups on diagnostic guidelines for
Hodkinson, H.M. (2012). Evaluation of a men- Alzheimers disease. Alzheimers and Dementia,
tal test score for assessment of mental impair- 7(3), 263269.
ment in the elderly. 1972. Age and Ageing, Mioshi, E., Dawson, K., Mitchell, J., Arnold, R.,&
41(Suppl 3), iii3540. Hodges, J.R. (2006). The Addenbrookes cog-
James, W. (1890). Principles of psychology. Boston, nitive examination revised (ACE-R): A brief
MA:Harvard University Press. cognitive test battery for dementia screening.
Jost, B.C.,& Grossberg, G.T. (1996). The evolu- International Journal of Geriatric Psychiatry,
tion of psychiatric symptoms in alzheimers 21(11), 10781085.
disease:Anatural history study. Journal of the Morris, J. C. (1993). The clinical dementia rat-
American Geriatric Society, 44(9), 10781081. ing (CDR):Current version and scoring rules.
Katzman, R., Brown, T., Fuld, P., Peck, A., Neurology, 43(11), 24122414.
Schechter, R.,& Schimmel, H. (1983). Validation Morris, J.C., Heyman, A., Mohs, R.C., Hughes,
of a short orientation-memory-concentration J. P., van Belle, G., Fillenbaum, G.,...Clark,
test of cognitive impairment. American Journal C. (1989). The Consortium to Establish a
of Psychiatry, 140(6), 734739. Registry for Alzheimers disease (CERAD).
Kaufer, D.I., Cummings, J.L., Ketchel, P., Smith, Part I. Clinical and neuropsychological
V., MacMillan, A., Shelley, T.,...Dekosky, assessment of Alzheimers disease. Neurology,
S. T. (2000). Validation of the npi-q, a brief 39(9), 11591165.
clinical form of the neuropsychiatric inven- Nair, A.K., Gavett, B.E., Damman, M., Dekker,
tory. Journal of Neuropsychiatry and Clinical W., Green, R. C., Mandel, A.,...Stern, R. A.
Neuroscience, 12(2), 233239. (2010). Clock drawing test ratings by demen-
Kitabayashi, Y., Ueda, H., Narumoto, J., tia specialists:Interrater reliability and diag-
Nakamura, K., Kita, H., & Fukui, K. (2001). nostic accuracy. Journal of Neuropsychiatry and
Qualitative analyses of clock drawings in Clinical Neuroscience, 22(1), 8592.
Alzheimers disease and vascular dementia. Nasreddine, Z. S., Phillips, N. A., Bdirian,
Psychiatry and Clinical Neuroscience, 55(5), V., Charbonneau, S., Whitehead, V., Collin,
485491. I.,...Chertkow, H. (2005). The montreal cog-
Lakhan, P., Jones, M., Wilson, A.,& Gray, L.C. nitive assessment, moca: A brief screening
(2012). The decline in activities of daily liv- tool for mild cognitive impairment. Journal of
ing at discharge (dadld) index: Stratifying the American Geriatric Society, 53(4), 695699.
patients at lower and higher risk. Journal of Njegovan, V., Hing, M. M., Mitchell, S. L., &
Nutrition, Health and Aging, 16(10), 919924. Molnar, F. J. (2001). The hierarchy of func-
Lawton, M.P.,& Brody, E.M. (1969). Assessment tional loss associated with cognitive decline
of older people:Self-maintaining and instru- in older persons. Journal of Gerontology
mental activities of daily living. Gerontologist, A Biological Science Medical Science, 56(10),
9, 179186. M638643.
CHAPTER 19. Dementia Screening and Mental Status Examination in Clinical Practice 485
OBrien, J.T., Wiseman, R., Burton, E.J., Barber, Salthouse, T. A. (2010). Selective review of
B., Wesnes, K., Saxby, B.,& Ford, G.A. (2002). cognitive aging. [Review]. Journal of the
Cognitive associations of subcortical white International Neuropsychological Society, 16(05),
matter lesions in older people. Annlas of the 754760.
NewYork Academy of Sciences, 977, 436444. Sheikh, J. I., & Yesavage, J. A. (1986). Geriatric
OConnor, M.G., Kapust, L.R.,& Hollis, A.M. depression scale (GDS):Recent evidence and
(2008). Drivewise: An interdisciplinary development of a shorter version. In Terry
hospital-based driving assessment program. L. Brink (Ed.) Clinical Gerontology: A guide
Gerontology and Geriatric Education, 29(4), to assessment and intervention (pp. 165173).
351362. NewYork:Haworth Press.
Petersen, R.C., Smith, G.E., Waring, S.C., Ivnik, Slachevsky, A., Munoz-Neira, C., Nunez-Huasaf,
R. J., Tangalos, E. G., & Kokmen, E. (1999). J., Stern, T.A., Blesius, C.R.,& Atri, A. (2011).
Mild cognitive impairment: Clinical charac- Late-onset cinephilia and compulsive behav-
terization and outcome. Archives of Neurology, iors:Harbingers of frontotemporal dementia.
56(3), 303308. Primary Care Companion CNS Disorders, 13(3).
Pfeffer, R. I., Kurosaki, T. T., Harrah, C. H., Jr., pii:PCC.10f01115.
Chance, J.M.,& Filos, S. (1982). Measurement Solomon, P. R., Hirschoff, A., Kelly, B., Relin,
of functional activities in older adults in the M., Brush, M., DeVeaux, R.D.,& Pendlebury,
community. Journal of Gerontology, 37(3), W. W. (1998). A 7 minute neurocogni-
323329. tive screening battery highly sensitive to
Rascovsky, K., Hodges, J. R., Knopman, D., Alzheimers disease. Archives of Neurology,
Mendez, M. F., Kramer, J. H., Neuhaus, 55(3), 349355.
J.,...Miller, B.L. (2011). Sensitivity of revised Sperling, R.A., Aisen, P.S., Beckett, L.A., Bennett,
diagnostic criteria for the behavioural variant D. A., Craft, S., Fagan, A. M., et al. (2011).
of frontotemporal dementia. Brain, 134(Pt 9), Toward defining the preclinical stages of
24562477. Alzheimers disease:Recommendations from
Raskind, M.A., Peskind, E.R., Wessel, T.,& Yuan, the national institute on aging-Alzheimers
W. (2000). Galantamine in ad: A 6-month association workgroups on diagnostic guide-
randomized, placebo-controlled trial with a lines for Alzheimers disease. Alzheimers and
6-month extension. The galantamine USA-1 Dementia, 7(3), 280292.
study group. Neurology, 54, 22612268. Storey, J.E., Rowland, J.T., Basic, D.,& Conforti,
Reger, M. A., Welsh, R. K., Watson, G. S., D.A. (2001). A comparison of five clock scor-
Cholerton, B., Baker, L.D.,& Craft, S. (2004). ing methods using ROC (receiver operating
The relationship between neuropsychologi- characteristic) curve analysis. International
cal functioning and driving ability in demen- Journal of Geriatric Psychiatry, 16(4), 394399.
tia: A meta-analysis. Neuropsychology, 18(1), Stuss, D.T.,& Alexander, M.P. (2000). Executive
8593. functions and the frontal lobes:Aconceptual
Reitan, R. M., & Wolfson, D. (1985). The view. Psychological Research, 63(34), 289298.
halstead-reitan neuropsychological test battery Sunderland, T., Hill, J. L., Mellow, A. M.,
(2nd ed.). Tucson, AZ:Neuropsychology Press. Lawlor, B.A., Gundersheimer, J., Newhouse,
Robitaille, A., Piccinin, A. M., Muniz-Terrera, P. A., & Grafman, J. H. (1989). Clock draw-
G., Hoffman, L., Johansson, B., Deeg, ing in Alzheimers disease. Anovel measure
D. J.,...Hofer, S. M. (2013). Longitudinal of dementia severity. Journal of the American
mediation of processing speed on age-related Geriatric Society, 37(8), 725729.
change in memory and fluid intelligence. Tangalos, E.G., Smith, G.E., Ivnik, R.J., Petersen,
Psychology of Aging, 28(4), 887901. R. C., Kokmen, E., Kurland, L. T.,...Parisi,
Rouleau, I., Salmon, D.P., Butters, N., Kennedy, J. E. (1996). The mini-mental state examina-
C., & McGuire, K. (1992). Quantitative and tion in general medical practice:Clinical util-
qualitative analyses of clock drawings in ity and acceptance. Mayo Clinic Proceedings,
Alzheimers and Huntingtons disease. Brain 71(9), 829837.
and Cognition, 18(1), 7087. Tariq, S. H., Tumosa, N., Chibnall, J. T., Perry,
Royall, D. R., Cordes, J. A., & Polk, M. (1998). M.H., III,& Morley, J.E. (2006). Comparison
Clox:An executive clock drawing task. Journal of the Saint Louis University mental status
of Neurology, Neurosurgery and Psychiatry, examination and the mini-mental state exam-
64(5), 588594. ination for detecting dementia and mild neu-
Rudolph, J.L., Marcantonio, E.R., Culley, D.J., rocognitive disorder--a pilot study. American
Silverstein, J. H., Rasmussen, L. S., Crosby, Journal of Geriatric Psychiatry, 14(11), 900910.
G.J.,...Inouye, S.K. (2008). Delirium is asso- Teng, E.L.,& Chui, H.C. (1987). The modified
ciated with early postoperative cognitive dys- mini-mental state (3MS) examination. Journal
function. Anaesthesia, 63(9), 941947. of Clinical Psychiatry, 48(8), 314318.
486 part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Tombaugh, T. N., McDowell, I., Kristjansson, test: What is it and what does it tell us?
B.,& Hubley, A.M. (1996). Mini-mental state International Psychogeriatrics, 23(10), 16021606.
examination (MMSE) and the modified mmse Weintraub, S. (1986). The record of independent
(3MS): A psychometric comparison and nor- living. An informant-completed measure of
mative data. Psychological Assessment, 8(1), activities of daily living and behaviour in
4859. elderly patients with cognitive impairment.
Wallin, A.K., Wattmo, C.,& Minthon, L. (2011). American Journal of Alzheimer Care and Related
Galantamine treatment in Alzheimers dis- Disorders, Spring, 3539.
ease: Response and long-term outcome in Yesavage, J. A., Brink, T. L., Rolse, T. L., Lum,
a routine clinical setting. Neuropsychiatric O., Huang, V., Adey, M., & Leirer, V. O.
Disease Treatment, 7, 565576. (1983). Development and validity of a geri-
Weiner, M. F., Hynan, L. S., Rossetti, H., & atric depression scale: A preliminary report.
Falkowski, J. (2011). Lurias three-step Journal of Psychiatric Research, 17, 3749.
20
Sandra Weintraub
This chapter presents a model for the neu- etal., 2011). Recognition of this slow evolution
ropsychological assessment of dementia makes it imperative to detect disease early, at
based on a large-scale neurocognitive net- a time when the neuropathologic change is
work approach. For most of the last cen- not advanced and there is the potential for
tury, the neurodegenerative dementias had treatment or prevention. In the very earliest
been clinically characterized as conditions stages of cognitive decline and dementia,
in which cognitive deficits are widespread, deficits can be quite focal, that is, clinically
and associated brain pathology diffuse. It is restricted to a single cognitive domain or
now understood, however, that clinical and process. This focality of symptoms mirrors
neuropathologic changes are not widespread the neuroanatomical specificity of the earliest
until the later stages of illness, when much neuropathologic and physiologic changes.
of the cerebral cortex associated with cog- For reasons still not well understood, these
nition has been ravaged by the cellular and diseases target portions of large-scale distrib-
molecular abnormalities that mark each dis- uted neurocognitive networks, disrupting
ease and that cause neuronal cell death and anatomical and functional connectivity, and
synaptic dysfunction. Most recently, revision affecting specific cognitive domains, such as
of the criteria for the diagnosis of dementia episodic memory, visuospatial function, and
due to Alzheimers disease (AD) (Jack etal., executive function and language, which are
2011)has taken into consideration the notion subserved by these networks (Weintraub &
that there are stages of disease that include Mesulam, 1996). Most recently, this principle
a biomarker-positive but symptom-negative has been further supported by the work of
period, the so-called preclinical stage Seeley and colleagues (2009).
(Sperling et al., 2011); a period where mild This chapter focuses on the neuropsy-
symptoms are evident but not incompatible chological evaluation of the patient with
with independent living, the so-called mild neurodegenerative dementia for purposes
cognitive impairment stage (Albert et al., of differential diagnosis and also for recom-
2011); and, finally, the stage of dementia mending management. Vascular dementia
marked by cognitive and disease progression and syndromes of progressive cognitive
as well as functional impairment (McKhann decline related to nonneurodegenerative
487
488 part iiiAssessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
etiologies (e.g., normal pressure hydroceph- a dementia-like picture. Figure 20.1 shows
alus, brain tumors, toxic/metabolic enceph- classes of cognitive decline based on their
alopathy, and others) are not covered in mode of onset.
detail. However, the conceptual framework The DSM-IV (American Psychiatric
presented here can also be used to derive a Association, 1994) criteria for the diagnosis
neuropsychological profile for these disease of dementia were recently revised in part
entities, with the diagnosis resting addition- because memory loss need not be the present-
ally on the history, neurologic examination, ing, or even predominant, symptom in many
and diagnostic testing. Tests and strategies forms of dementia (which was required in the
for screening for dementia; gauging demen- DSM-IV criteria). The newly proposed crite-
tia severity; and evaluating the domains of ria for the diagnosis of dementia due to AD
attention, mood, language, visual percep- also have recognized that while amnesia is
tion, episodic memory, reasoning, executive a hallmark symptom of AD, other domains
functions, and social cognition are sug- can be affected first (McKhann et al., 2011).
gested. Red flags that should alert clini- This chapter uses the following definition of
cians, especially the primary care physician, dementia:
to the possibility of dementia are high-
lighted, with emphasis on the more atypi- The decline and progressive worsening
cal presentations of AD and the class of of one or more cognitive functions (e.g.,
diseases under the umbrella of frontotem- memory, attention, language, visual per-
poral lobar degeneration (FTLD) in which ception, reasoning) and/or comportment
language deficits, behavioral changes, and (e.g., characteristic personality traits,
motor disorders, rather than memory loss, insight, judgment, social cognition), from a
characterize onset. Finally, there is a brief prior, customary level of functioning, to the
discussion of the need to establish metrics point where usual activities of daily living
of brain health throughout the life span are negatively affected; caused by irrevers-
for purposes of early identification and ible brain disease. (Wicklund & Weintraub,
intervention. 2005, p.568)
Neurodegenerative
Alzheimers
Non Alzheimers Disease Disease
predict the underlying etiology of the demen- neuroimaging (magnetic resonance imaging,
tia. The state-of-the-art dementia evaluation, amyloid imaging, positron emission tomogra-
which may not be available in some settings, phy [PET], single-photon emission computed
performed at major research medical centers tomography [SPECT], and electroencephalog-
includes a specialized clinical examination raphy [EEG]) may be ordered to further evalu-
and testing often coordinated by a behavioral ate the patient. Cerebrospinal fluid may be
neurologist, geriatrician, and/or neuropsychi- obtained for routine or specialized assessment,
atrist. In the initial examination, the major clin- including possibly to measure levels of tau and
ical characteristics of the patients syndrome amyloid (Jack etal., 2010)(see Chapter22).
are determined through history and exami-
nation and provide information about the
types and severity of cognitive, affective, and Screening for Dementia
motor symptoms and other clinical features
that help the specialist narrow the differential Most of the current pharmacologic treatments
diagnosis. Depending on the patients clinical for neurodegenerative dementia aim to treat
characteristics, blood tests may be obtained symptoms or slow the rate of progression.
to evaluate for systemic illness that could be Thus, early detection is essential. In some set-
contributing to or accounting for mental state tings, however, neuropsychological assess-
changes (e.g., thyroid dysfunction, conges- ment may not be available. In this instance, the
tive heart failure, paraneoplastic syndromes, clinician can use brief mental state screening
lupus, etc.). Neuropsychological assessment is tests to identify symptoms. The Mini Mental
often recommended. Structural and functional State Examination (MMSE) (Folstein, Folstein,
490 part iiiAssessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
& McHugh, 1975) is commonly used in clinical screening examination. At the least, a com-
practice and clinical trials but is not sensitive prehensive evaluation serves the purpose of
to very mild decline and does not cover all rel- providing a baseline against which future
evant domains. Measures such as the Montreal development of symptoms can be measured.
Cognitive Assessment (MoCA) (Nasreddine Table 20.1 provides some rules of thumb
et al., 2005) and the Addenbrookes Cognitive regarding complaints that are more likely
Examination (ACE) (Mathuranath, Nestor, to be more representative of dementia than
Berrios, Rakowicz, & Hodges, 2000) are more of normal, age-related decline. However,
sensitive to a wider range of impairment at these guidelines are not steadfast.
very mild levels (Pendlebury, Mariz, Bull,
Mehta, & Rothwell, 2012; Smith, Gildeh, &
Holmes, 2007), although the ACE does require The Neuropsychological Examination
slightly more time than the MMSE or MoCA. of Mental State
It has been suggested that the MoCA should
be interpreted with caution in an ethnically Unlike a mental status examination in the
diverse sample where different cutoff scores neurologists office, where a particular behav-
may need to be employed to reflect a range ior may be briefly sampled, the neuropsycho-
of demographic variables (Rossetti, Lacritz, logical assessment requires multiple items to
Cullum, & Weiner, 2011). Recent revisions assess each domain in order to derive a reli-
of the MoCA introduce a scoring system that able score that can be compared with norma-
groups items into different domains and also tive values. Thus, the full examination can
that allows for more sensitive scoring of the take from 24 hours of face-to-face contact
word learning portion (Julayanont et al., 2014). with the patient and caregiver, depending
The clinician should keep in mind that on the level of symptoms and the patients
some dementias do not affect memory in the former level of ability. More extensive testing
early stages and that screening tests may may be necessary in the patient who is still
miss these disorders. The group of disorders gainfully employed, where symptoms are
caused by FTLD presents with changes in subtle or noncognitive in nature. The compo-
personality, reasoning, and executive func- nents of the comprehensive neuropsycholog-
tions, or with aphasia, most of which are not ical examination for dementia are as follows.
suitably measured with screening tests. This First, conduct a careful history. A clinical
class of diseases may also present with motor diagnostic interview should be conducted
symptoms. Since the screening examinations with the patient and an informant, ide-
have drawbacks from the standpoint of dif- ally independently. Gathering information
ferential diagnosis and care planning, formal from a reliable informant is critical since
neuropsychological assessment is the most many individuals with cognitive decline
desirable way to demonstrate the deficits in may not be aware of or may minimize their
mental state at a time when other diagnostics symptoms (Cacchione, Powlishta, Grant,
may be normal or unremarkable. Buckles, & Morris, 2003; Gavett, Stern, Cantu,
Individuals with previously high levels of Nowinski,& McKee, 2010). All of these factors
intellectual ability may subjectively experi- will influence the clinicians interpretation of
ence symptoms despite normal performance test performance and, ultimately, the differ-
on screening and other tests of mental state. ential diagnosis. As part of the history, the
The significance of subjective cognitive following information should be obtained.
complaints for the subsequent diagnosis of The nature of the onset (abrupt, subacute,
dementia has been debated, but most recent insidious, and gradual), duration, and course
evidence suggests that cognitively normal (worsening, static, fluctuating) of symptoms
individuals with cognitive complaints show is critically important. Information regarding
biological evidence of hippocampal vol- prior medical, neurological, and psychiatric
ume reduction on structural neuroimaging history, with special emphasis on factors that
in comparison with noncomplaining adults could contribute to cognitive deficits (e.g.,
(Saykin et al., 2006). It is, therefore, recom- sleep apnea, thyroid dysfunction, diabetes,
mended that neuropsychological evalua- history of or current substance dependency/
tion be considered for patients who have abuse, etc.). The list of current medications
subjective complaints but pass the standard should be reviewed. It is critical to obtain
CHAPTER 20. Neuropsychological Assessment of Dementia 491
details about the patients educational and or civic duties may yield a better estimate of
psychosocial history and current functional prior cognitive ability.
status. Is there is history of pre-existing cog- Next, obtain a general measure of demen-
nitive dysfunction (e.g., learning disabilities, tia severity. The MMSE, Blessed Dementia
developmental disorders, prior head trauma, Scale (BDS), or MOCA scores can be used
etc.?). Finally, the clinician should carefully for this purpose and/or to follow the patient
review the family history for medical, neu- over time. These tests are especially useful in
rologic, or psychiatric disorders that might later stages of illness when other neuropsy-
inform the differential diagnosis. chological tests are too difficult. Several ques-
Next, the neuropsychologist should esti- tionnaires (e.g., the FAST (Reisberg, 1988)are
mate the patients premorbid level of func- also available for patients in the severe stages
tioning against which to compare current test of illness. For patients in the milder stages of
scores. Some tests, for example the AMNART dementia, the Dementia Rating Scale (DRS)
(Grober & Sliwinski, 1991) can be used to (Mattis, 2001) is more sensitive to change
derive an estimated IQ since most individuals over time (Salmon, Thal, Butters, & Heindel,
have never had detailed cognitive testing prior 1990) and has normative data for individu-
to the onset of dementia. Estimates also can be als over 89 years of age (Lucas et al., 1998;
derived from demographic variables (Barona, Schmidt et al., 1994). The mean score for
Reynolds, & Chastain, 1984). The Vocabulary high-school educated individuals over 70
subtest of the Wechsler Adult Intelligence is 27/30 on the MMSE, 34/37 on the BDS,
Scale-III (WAIS-IIII) (Wechsler, 1998)is robust and 137/144 on the DRS (Spreen & Strauss,
in the face of brain damage and can be used 1998). These scores need to be adjusted for
for this purpose, especially in the absence of education and age (Tombaugh & McIntyre,
aphasia. The Wechsler Test of Adult Reading 1992). The Clinical Dementia Rating (CDR)
(Wechsler, 2001)and the reading subtest of the is a survey of the impact of dementia symp-
Wide Range Achievement Test-IV (Wilkinson toms on activities of daily living and has been
& Robertson, 2006)can also yield an estimated shown to have high reliability, validity, and
IQ. In patients with limited levels of educa- association with pathologically verified AD
tion, the highest level of achievement in work (Morris, 1997). Caution should be exercised
492 part iiiAssessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
in examining the aphasic patient with most patient. The Neuropsychiatric Inventory
tests since questions require normal language (NPI) (Cummings et al., 1994) and the
for responding. Thus, the MMSE, for exam- BEHAVE-AD (Reisberg, Auer, & Monteiro,
ple, may overestimate the severity of impair- 1996)provide a review of symptoms such as
ment in a patient with PPA (Osher, Wicklund, paranoia, depression, agitation, and hostility
Rademaker, Johnson, & Weintraub, 2007). and the extent to which they cause distress
Also, cultural and language differences can to the caregiver. The Geriatric Depression
affect performance (Dodge etal., 2009). Scale (Yesavage et al., 1983) may be use-
Next, the neuropsychologist should ful in early stages. The Frontal Behavioral
review test performance in each of the neu- Inventory (Kertesz, Davidson, & Fox, 1997;
rocognitive domains and construct a profile Kertesz, Nadkarni, Davidson, & Thomas,
of strengths and weaknesses. Tests or ques- 2000) reviews symptoms specific to fronto-
tionnaires should be administered to evalu- temporal dementia and is completed in an
ate attention, mood and motivation, episodic interview with the informant.
memory (including learning and retention of In addition to assessing the cognitive and
information), visual perception, language, affective domains described previously,
executive functions, and reasoning. Box 20.1 the neuropsychologist needs to obtain a
contains suggested tests to evaluate symp- measure of the patients ability to perform
toms in each domain. These domains are activities of daily living. The Activities
well defined in terms of their cerebral orga- of Daily Living Questionnaire (ADLQ)
nization and are also relevant for detecting (Johnson, Barion, Rademaker, Rehkemper,
patterns, or profiles, that are associated & Weintraub, 2004) measures the impact of
with different types of dementia (Table20.2). dementia on daily living activities in mildly
Thus, the amnesia of AD is a primary defect demented, noninstitutionalized individu-
and not secondary to impairment in other als. The ADLQ shows distinctive patterns of
processes such as poor attention, decreased functional limitations in patients with non-
motivation, or anomia. A careful examina- Alzheimer dementia (Wicklund, Johnson,
tion can distinguish among these possi- Rademaker, Weitner, & Weintraub, 2007)
bilities. Patients also differ with respect to and may be preferable to the MMSE as a
specific symptoms, and knowledge of their measure of dementia severity in patients
specific deficits can lead to more personal- with PPA (Osher et al., 2007). The ADLQ
ized recommendations for management. To correlates with the CDR and is sensitive to
construct the profile of strengths and weak- change over time. Activities that may jeop-
nesses in these domains, the patients scores ardize the patients or others safety (e.g.,
must be compared to normative values for a driving, financial management, cooking)
group of individuals of the same age, level of should be reviewed carefully. Sometimes
education, gender, and race, where available, there is a request for assistance with a deter-
and also to the patients estimated premorbid mination of competency to manage finances
level of functioning. From this information, or make health care decisions and there are
the neuropsychologist can answer the fol- neuropsychological test performance factors
lowing question:Is the patient performing as that can affect decision making in different
well as others in his or her own peer group? realms (Marson, Cody, Ingram, & Harrell,
Based on this information and information 1995; Marson, Ingram, Cody, & Harrell,
from the history, the neuropsychologist can 1995; Marson et al., 2000, 2009). Assessment
infer whether the patient is functioning at the of safety can be accomplished with the
level of her or his own peak prior ability. Independent Living Scales (Loeb, 1999).
Noncognitive behavioral symptoms, Neuropsychological tests are tools and
including apathy, disengagement from the require professional interpretation. Clinical
environment, depression, agitation, and neuropsychologists are trained in psycho-
hallucinations can constitute the earliest metric theory and measurement, psychology,
symptoms of a dementia, as is often the case brain anatomy, and physiology and on the
in Lewy body dementia or frontotempo- impact of neurological, psychiatric, and med-
ral dementia. These are typically evaluated ical disorders on brain functioning. The neu-
using interviews or questionnaires given ropsychologist interprets test findings just
to the informant and in some cases also the as the physician might interpret laboratory
CHAPTER 20. Neuropsychological Assessment of Dementia 493
Behavioral Symptoms
Neuropsychiatric Inventory (NPI-Q) (Cummings etal., 1994, Kaufer etal., 2000)
Frontal Behavior Inventory (Kertesz etal., 1997)
Clinical Ratings
Clinical Dementia Rating (CDR) (Knopman, Weintraub, & Pankratz, 2011; Morris, 1993)
Functional Assessment Staging (FAST) (Reisberg, 1988)
Estimate of Premorbid IQ
Wechsler Test of Adult Reading (Wechsler, 2001)
Mood
Beck Depression Inventory-II
Geriatric Depression Scale
Perseverance
Serial Recitation Tests (WMS) (Wechsler, 1998)
Word List Generation (Spreen & Strauss, 1998)
(continued)
494 part iiiAssessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Executive Function
Trail Making Tests (Reitan, 1958)
Motor Go- No Go (Weintraub, 2000)
Stroop Test (Golden etal., 2002)
Perceptual/Constructional Tasks
Hooper Visual Organization Test (Hooper, 1958)
Judgment of Line Orientation (Benton, Hamsher, Varney, & Spreen, 1983)
Facial Recognition (Benton et al., 1983)
Visual Target Cancellation Tasks (Weintraub, 2000)
Benson Complex Figure (Possin et al., 2011)
Copying a cube, drawing a clock
Language
Verbal Fluency Measures (Lezak, Howieson, & Loring, 2004; Spreen & Strauss, 1998)
Boston Naming Test (Kaplan, Goodglass, & Weintraub, 1983)
Boston Diagnostic Aphasia Examination (BDAE) (Goodglass etal., 2001)
Western Aphasia Battery (WAB) (Kertesz, 2006)
PALPA (Kay, Lesser, & Coltheart, 1992)
Northwestern Anagram Test (Weintraub et al., 2009)
Northwestern Naming Battery (Thompson, King, Lukic, Mesulam, & Weintraub, 2012)
Calculation Abilities
BDAE, WAB
Episodic Memory
Orientation
Wechsler Memory Scale (stories, word lists, designs) (Wechsler, 1998)
Rey Auditory Verbal Learning Test (word list) (Rey, 1941)
California Verbal Learning Test (word list) (Delis, Kramer, Kaplan, & Ober, 2000)
Rey-Osterreith Complex Figure (Rey, 1941)
Selective Reminding Procedure (Buschke, 1973)
Three Words Three Shapes Test (Weintraub, 2000; Weintraub etal., 2012, 2013)
Drilled Word Span Procedure (Weintraub, 2000)
Note. This list is neither exhaustive nor exclusive. For additional instruments, consult Spreen and
Strauss (1998) and Lezak and colleagues (2004).
TABLE20.2 Neuropsychological Profiles of Mental State in Clinical Dementia Syndromes
Clinical Dementia Syndrome Defined by Primary Neurocognitive Domains Neuroanatomical Network
Prominent Symptoms
Attention Emotions/ Language Visuospatial Explicit Comportment
Mood Memory Executive
values, in the context of a diagnostic hypoth- decline in memory and other cognitive test
esis and comprehensive understanding of the scores after age 65. A decline in cognitive
history. test scores, or the normal aging trajectory,
The examiner should have the flexibility to however, can be identified in cross-sectional
choose tests that are suitable for the individ- normative data even in younger individu-
ual patient. Thus, a patient with a third-grade als (Evans, Grodstein, Loewenstein, Kaye, &
education who worked as a housekeeper Weintraub, 2011). It is not known if a faster
should be given tests that avoid floor effects, decline over early and middle adulthood
while a patient with advanced education and presages later development of dementia.
occupational attainment should be given However, if detected earlier, such cognitive
tests that avoid ceiling effects. In the for- decline could be potentially amenable to
mer example, if the tests are so hard that the interventions aimed at reducing risk. Second,
patient fails everything, there is no resulting the neuropsychological assessment should
profile of strengths and weaknesses. In the identify the overall level of cognitive impair-
latter case, if the patient performs normally ment (i.e., absent, questionable, very mild,
for age on all tests, subtle decline could be mild, moderate, or severe), as well as the
missed. relative level of impairment or preservation
Neuropsychologists also consider demo- among the specific domains. Third, based on
graphic variables that can alter the interpre- the history and functional assessment, the
tation of test scores based on such factors neuropsychologist should be able to deter-
as age, gender, ethnic/racial background, mine the impact of cognitive dysfunction on
years of education, and quality of education activities of daily living. This is critical since
(Brickman, Cabo, & Manly, 2006; Manly, 2005, the diagnosis of dementia requires that the
2008; Manly etal., 2011). In medical practice, cognitive changes have had an impact on
there is a desire for norms, or standards, functional capacity. Fourth, the results of the
against which to measure individual patient neuropsychological examination should help
values on laboratory tests. In neuropsycho- to narrow or expand the differential diag-
logical assessment, as already noted, unlike nosis. Neuropsychological reports should
in medical laboratory tests, there are many contain specific suggestions for further
variables that can affect the interpretation of workup as needed (i.e., neurological and/
a score in the individual patient. In addition, or psychiatric evaluation, medical evalua-
the individuals test performance should tion, and neuroimaging.) The examination
be interpreted not only in comparison with results provide a neurocognitive profile of
age-relevant norms but also with respect to relative strengths and weaknesses that can
his or her own past peak level of cognitive be used to predict the neuroanatomical dis-
ability. For example, if an individual would tribution of pathology and the probability
have performed in the top 2% of the popula- of different neuropathologic (disease) diag-
tion on a memory test at the age of 30, the noses (Weintraub & Mesulam, 1993). Finally,
fact that her current score at age 80 is aver- the neuropsychological examination should
age for age by normative standards alerts contribute to management planning tailored
the neuropsychologist to the fact that there to the patients individual profile of strengths
has likely been cognitive decline for that par- and weaknesses. Potential safety issues can
ticular individual, even though the score is be identified and recommendations made
not abnormal. Some test scores (Vocabulary, regarding further resources (e.g., a driving
estimated IQ) can be used to correct other evaluation or financial supervision). Specific
obtained test scores before comparing them suggestions for practical community-based
with normative data to obtain a measure of resources for assistance are also useful (e.g.,
how much an individual has changed from Alzheimers Association, Association for
her own peak performance level (Rentz etal., Frontotemporal Degeneration, local social
2004, 2006, 2007; Rentz and Weintraub, 2000). service agencies, adult day health programs,
The comprehensive neuropsychological geriatric care managers). Some neuropsy-
examination should accomplish the following chologists may also provide education and
goals. The first goal is to detect the presence of counseling services for patients and caregiv-
cognitive impairment. Most longitudinal cog- ers. While not changing the nature of the dis-
nitive aging studies have shown a significant ease itself, such support and information can
CHAPTER 20. Neuropsychological Assessment of Dementia 497
improve a patients (and caregivers) quality and temporal disorientation (see Weintraub
of life (Weintraub & Morhardt, 2005). et al., 2012). The original description of the
clinical syndrome of probable AD (PrAD)
was marked by impairments on tests of learn-
Neuropsychological Features of Selected ing and delayed recall (McKhann etal., 1984).
Dementia and Prodromal Syndromes Delayed recall shows a floor effect early in
the course of AD and therefore cannot be
Neuropsychological Features of Mild used to track disease progression, but recog-
Cognitive Impairment nition memory performance can be used for
this purpose (Locascio, Growdon, & Corkin,
Some individuals experience an isolated 1995). Although amnesia is a salient feature
impairment of memory or other cognitive of AD, other cognitive deficits also emerge,
functions but may perform relatively nor- including decreased verbal fluency on cate-
mally in daily living activities. This state has gory list generation and reduced object nam-
been referred to as mild cognitive impair- ing. Impairments of attention and working
ment (Petersen, 2000a, 2000b; Petersen etal., memory can be seen in patients with mild
1997) or age-associated memory impair- to moderate dementia severity. In the most
ment (Crook, Bahar, & Sudilovsky, 1987-88). recent revision of the diagnostic criteria for
Petersen (2004) has proposed a classification AD dementia, it is also recognized that other
to include nonamnestic and multidomain cognitive deficits (e.g., language, visuospa-
forms of MCI. Individuals in whom episodic tial dysfunction) can lead the clinical pic-
memory is impaired are at elevated risk for ture in the early stages, although memory
progressing to AD dementia (Dubois & Albert, loss remains the most common presenting
2004; Dubois etal., 2007). The significance of symptom (McKhann et al., 2011, online.).
other profiles of MCI, for example, isolated The Multilingual Aphasia Examination can
attention impairment, is not currently known screen for language deficits in adults up to
(Luis etal., 2004; Luis, Loewenstein, Acevedo, 69 years of age (Benton, Hamsher, & Sivan,
Barker, & Duara, 2003). It is important in this 1994). On average, patients with AD demen-
population to obtain a detailed neuropsycho- tia decline annually by 3.24 points on the
logical assessment and then to use the patients Information-Memory-Concentration sub-
own raw scores for comparison over time. test of the BDS, 2.81 points on the MMSE,
Scores on memory and executive function and 11.38 points on the DRS (Salmon et al.,
tests (e.g., Trail Making Test) are particularly 1990). The Alzheimers Disease Assessment
useful in predicting who is likely to progress Scale (ADAS) (Rosen, Mohs, & Davis,
to AD dementia in the future (Albert, Moss, 1984)has been used extensively to measure
Tanzi, & Jones, 2001). In addition, some inves- medication effects on the symptoms of AD
tigators have suggested that intraindividual dementia in clinical trials. The CERAD test
variability in test performance, rather than a battery focuses on the salient symptoms of
single-point-in-time measurement, may have AD dementia and includes tests of word
greater predictive value for MCI or dementia list learning, category generation, naming,
(Strauss, Bielak, Bunce, Hunter, & Hultsch, and constructions (Morris etal., 1989; Welsh
2007). Much of the work on this topic to date et al., 1994). See Chapter 16 for additional
has focused on groups of participants in lon- information on AD.
gitudinal studies; further work in this area is
required to develop prognostic models appli-
cable to individual patients in clinical practice. Neuropsychological Features ofPrimary
See Chapter17 for more information on MCI. Progressive Aphasia
Figure Test (Possin, Laluz, Alcantar, Miller,& in other domains as the disease spreads to
Kramer, 2011). Patients are often described other cortical areas. The profiles of PPA and
as fluctuating in their mental state with epi- bvFTD differ from these two profiles in the
sodes of confusion interspersed with near early prominence of language and behavioral
normal functioning (Ferman et al., 2002; symptoms, respectively.
Geser, Wenning, Poewe, & McKeith, 2005; Even though the dementia may be quite
Metzler-Baddeley, Baddeley, Lovell, Laffan, & selective in its behavioral and cognitive
Jones, 2010; Salmon etal., 1996). Fluctuation profile, however, it may be difficult to dif-
on neuropsychological test scores from one ferentiate among syndromes solely on the
test session to another over time is common basis of objective neuropsychological tests
in this syndrome. See Chapter 12 for more (Weintraub & Mesulam, 1993). The reason for
details on dementia with Lewy bodies. this is that most neuropsychological tests are
multifactorial and tend to engage more than
a single cognitive process. For example, clock
Determination of the Clinical drawing is intended to serve as a visuospa-
Neuropsychological Profile tial test. However, a primary disturbance in
executive functions can lead to poor perfor-
At the completion of the neuropsychological mance on this task even in the presence of
evaluation, a clinical profile will emerge that preserved visuospatial functions. Similarly,
can assist in differential diagnosis. Especially word-finding difficulty may impair perfor-
in the earliest stages of illness, it is likely mance on verbal memory tests despite pre-
that a patient will show significant impair- served episodic memory. Thus, the clinician
ment in one or a few domains with either needs to determine whether failure on a
normal or relatively preserved performance test is indicative of dysfunction in the tar-
in others. Figure20.2 illustrates this concept geted domain or if it is secondary to failure
using early- and late-stage neurocognitive in another domain not targeted by the test
profiles of the progressive amnestic demen- construct. In early stages of frontotemporal
tia associated with AD neuropathology and dementia, all formal neuropsychological test
contrasts this profile with that seen in the scores may be abnormal, because impair-
clinical syndrome of progressive visuospatial ments of motivation and executive functions
dysfunction, also known as posterior cortical may interfere with performance in a general
atrophy (PCA; see Chapter 10). The visuo- manner. Conversely, all test scores may be
spatial profile of PCA is also associated with normal because the primary deficit lies in
AD neuropathology (Renner etal., 2004), but social cognition and is not reflected in stan-
in an unusual neuroanatomical distribution dard testing. Table 20.2 illustrates primary
that favors the visual association cortex (Hof, and secondary deficits on neuropsycho-
Bouras, Constantinidis, & Morrison, 1990; logical testing of common clinical dementia
Hof, Vogt, Bouras, & Morrison, 1997). Other syndromes.
pathological entities associated with PCA
include cortical Lewy body disease and fatal Neuropsychological Consultation:When
familial insomnia (cf. Renner etal., 2004). andWhy?
See Figure 20.3 for a summary of clinico-
pathologic relationships in AD dementia Neuropsychological consultation is not nec-
and PCA. Early in the course of the amnes- essary in every patient with dementia. The
tic dementia of the Alzheimer type, episodic following section provides some guidelines
memory scores are typically impaired, while for identifying patients for whom a neuro-
scores on tests in other domains are normal psychological evaluation may be helpful.
or relatively preserved. With time, how- In some patients, the detection of cognitive
ever, performance on tests in other domains decline may be difficult in a routine physi-
becomes impaired as well. In progressive cians office visit. This is particularly true in
visuospatial dysfunction, the earliest impair- mild phases of neurodegenerative dementias
ments are seen on tests of visuospatial func- or in patients with high premorbid intelli-
tions, while scores on episodic memory and gence. Thus, the clinician may request neu-
other tests remain normal. With time, how- ropsychological assessment to determine
ever, these patients also develop deficits whether the patient is experiencing cognitive
500 part iiiAssessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Early
Level of Impairment
SEVERE Late
MODERATE
MILD
ive
t
n
ct
vis ge
o it
en
in
io
tio
em lic
fe
ua
Pe l
Re ry
ut
on
nt
rtm
ua
M Exp
ep
Af
ec
te
ng
as
d/
rc
po
At
Ex
La
oo
m
M
Co
Level of Impairment Early
SEVERE Late
MODERATE
MILD
g
ive
t
n
ct
vis ge
or it
en
in
io
tio
em lic
fe
ua
Pe l
ut
on
nt
rtm
ua
M Exp
ep
Af
ec
te
ng
as
d/
rc
po
At
Ex
La
Re
oo
m
M
Co
deficits that are abnormal for his or her age work, other activities, or social relationships,
and level of education. For example, a patient neuropsychological testing may help reveal
may complain of, and family members may evidence of early-onset dementia. With
corroborate, memory difficulties in daily life, regard to atypical dementias, the early symp-
and he or she may obtain a normal score on toms of primary progressive aphasia are
the MMSE; neuropsychological assessment often misdiagnosed as symptoms of stress
may be helpful to determine whether there is or depression; formal cognitive assessment
a memory deficit on more sensitive measures. often reveals subtle but clear language abnor-
Neuropsychological testing may be use- malities in these patients. Early symptoms of
ful for the detection of atypical or early-onset behavioral variant frontotemporal dementia
(young-onset or presenile) dementias. In a are often also misdiagnosed as psychiatric in
patient under 60 who presents with unchar- nature, and often executive dysfunction can
acteristic behavior that is interfering with be observed on neuropsychological testing.
CHAPTER 20. Neuropsychological Assessment of Dementia 501
Progressive
Progressive Visuospatial
Amnestic Dementia
Dementia (aka Posterior
(aka PrAD) Cortical
Atrophy)
AD Prion
FTLDs Lewy
(CBD) Body
NEUROPATHOLOGIC TISSUE
DIAGNOSES
Figure 20.3 Neuropsychological profiles predict neuropathologic diagnoses with different
probabilities. There is no one-to-one correspondence between clinical dementia profiles and the
disease diagnosis at postmortem brain autopsy. This figure shows the association between the
clinical diagnosis of dementia (circles at top, an early amnestic dementia profile and an early
visuospatial dementia profile) and the neuropathologic tissue diagnoses following postmortem
brain autopsy (circles at bottom). The thickness of the arrows represents the relative probability
with which different types of diagnoses are associated with each profile.
Generally speaking, when a patient or family for the future. Since dementia is progressive,
presents with cognitive-behavioral concerns regular checkups are important for alter-
and the initial physician office evaluation ing management strategies and considering
does not offer a clear diagnosis, neuropsy- alternative living/care arrangements and
chological testing can be a reasonable next safety issues. This monitoring may be pos-
step in the evaluation; results can provide not sible to accomplish in the physicians office
only documentation of a cognitive-behavioral or may be augmented through longitudi-
deficit but also assistance in determining the nal neuropsychological testing. In addition,
likely cause of these deficits (e.g., differen- this testing can help measure the effects of
tial diagnosis between depression, stroke, treatment, although it is always impossible
Alzheimers, traumatic brain injury, etc.) to know how the patient would have per-
based on the test profile. formed without treatment. In addition, if a
Neuropsychological testing can also pro- patient with a known dementia experiences
vide valuable information regarding safety, an acute or subacute worsening in behav-
planning, and related issues. In a patient ior, brief focused cognitive or neuropsy-
with an obvious dementia or milder cogni- chological assessment may be valuable in
tive impairment, the test profile can give identifying whether there is another factor
indications of whether he or she is safe to (e.g., toxic-metabolic encephalopathy) that
live alone, drive, make financial decisions, or is temporarily worsening mental state (i.e.,
related activities. causing a beclouded dementia?).
In addition to the value of baseline testing,
longitudinal neuropsychological assessment
can be very important since it enables the A Word on Brain Health Throughout
clinician to identify changes in performance the Life Span
relative to the patients own prior baseline.
In a patient diagnosed with dementia, this The field of neuropsychology has highlighted
can help to document the rate of decline and the importance of brain health throughout
assist the patient and caregiver in planning the life span. Developmental disorders that
502 part iiiAssessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
strategies. International Journal of Neurology, Gavett, B.E., Stern, R.A., Cantu, R.C., Nowinski,
21-22, 7382. C. J., & McKee, A. C. (2010). Mild traumatic
Cummings, J., Benson, D.F.,& LoVerme, S., Jr. brain injury:Arisk factor for neurodegenera-
(1980). Reversible dementia. Illustrative cases, tion. Alzheimers Research and Therapy, 2(3), 18.
definition, and review. Journal of the American Geser, F., Wenning, G. K., Poewe, W., &
Medical Association, 243(23), 24342439. McKeith, I. (2005). How to diagnose dementia
Cummings, J. L., Mega, M., Gray, K., with Lewy bodies:State of the art. Movement
Rosenberg-Thompson, S., Carusi, D. A., & Disorders, 20(Suppl 12), S11S20.
Gornbein, J. (1994). The Neuropsychiatric Golden, C., Freshwater, S.,& Golden, Z. (2002).
Inventory: Comprehensive assessment of Stroop Color and Word Test. Wood Dale,
psychopathology in dementia. Neurology, 44, IL:Stoelting.
23082314. Goodglass, H., Kaplan, E.,& Barresi, B. (2001).
Delis, D.C., Kaplan, E.,& Kramer, J.H. (2001). Boston Diagnostic Aphasia Examination 3rd edi-
Delis-Kaplan executive function system. San tion (BDAE-3). Lutz, FL:Par.
Antonio, TX:The Psychological Corporation. Gorno-Tempini, M. L., Hillis, A., Weintraub,
Delis, D.C., Kramer, J.H., Kaplan, E.,& Ober, S., Kertesz, A., Mendez, M. F., Cappa,
B.A. (2000). The California Verbal Learning Test S.F.,...Grossman, M. (2011). Classification of
(2nd ed.). San Antonio, TX: Psychological primary progressive aphasia and its variants.
Corporation. Neurology, 76, 10061114.
Dodge, H. H., Meguro, K., Ishii, H., Grober, E.,& Sliwinski, M. (1991). Development
Yamaguchi, S., Saxton, J. A., & Ganguli, M. and validation of a model for estimat-
(2009). Cross-cultural comparisons of the ing premorbid verbal intelligence in the
Mini-mental State Examination between elderly. Journal of Clinical and Experimental
Japanese and U.S. cohorts. International Neuropsychology, 13, 933949.
Psychogeriatrics, 21(1), 113122. Heaton, R. K., Chelune, G. J., Talley, J. L.,
Dubois, B., & Albert, M. L. (2004). Amnestic Kay, G. G., & Curtis, C. (1993). Wisconsin
MCI or prodromal Alzheimers disease? Card Sorting Test (WCST), manual revised
Lancet Neurology, 3(4), 246248. and expanded. Odessa, FL: Psychological
Dubois, B., Feldman, H.H., Jacova, C., Dekosky, Assessment Resources.
S. T., Barberger-Gateau, P., Cummings, Hof, P. R., Bouras, C., Constantinidis, J., &
J.,...Scheltens, P. (2007). Research crite- Morrison, J. H. (1990). Selective disconnec-
ria for the diagnosis of Alzheimers dis- tion of specific visual association pathways in
ease:Revising the NINCDS-ADRDA criteria. cases of Alzheimers disease presenting with
Lancet Neurology, 6(8), 734746. Balints syndrome. Journal of Neuropathology
Evans, D. A., Grodstein, F., Loewenstein, D., and Experimental Neurology, 49(2), 168184.
Kaye, J., & Weintraub, S. (2011). Reducing Hof, P.R., Vogt, B.A., Bouras, C.,& Morrison,
case ascertainment costs in U.S. population J. H. (1997). Atypical form of Alzheimers
studies of Alzheimers disease, dementia, disease with prominent posterior cortical
and cognitive impairment-Part 2. Alzheimers atrophy:Areview of lesion distribution and
and Dementia, 7(1), 110123. circuit disconnection in cortical visual path-
Ferman, T. J., Boeve, B. F., Smith, G. E., ways. Vision Research, 37(24), 36093625.
Silber, M. H., Lucas, J. A., Graff-Radford, Hooper, H. (1958). The Hooper visual organiza-
N. R.,...Ivnik, R. J. (2002). Dementia with tion test manual. Los Angeles, CA: Western
Lewy bodies may present as dementia and Psychological Services.
REM sleep behavior disorder without par- Jack, C. R., Jr., Albert, M. S., Knopman, D. S.,
kinsonism or hallucinations. Journal of the McKhann, G. M., Sperling, R. A., Carrillo,
International Neuropsychological Society, 8(7), M. C.,...Phelps, C. H. (2011). Introduction
907914. to the recommendations from the National
Folstein, M., Folstein, S., & McHugh, P. R. Institute on Aging-Alzheimers Association
(1975). Mini-mental state:Apractical method workgroups on diagnostic guidelines for
for grading the cognitive state of patients for Alzheimers disease. Alzheimers and Dementia,
the clinician. Journal of Psychiatric Research, 12, 7(3), 257262.
189198. Jack, C. R., Jr., Knopman, D. S., Jagust,
Galasko, D., Bennett, D., Sano, M., Ernesto, C., W. J., Shaw, L. M., Aisen, P. S., Weiner,
Thomas, R., Grundman, M.,& Ferris, S. (1997). M. W.,...Trojanowski, J. Q. (2010).
An inventory to assess activities of daily liv- Hypothetical model of dynamic biomark-
ing for clinical trials in Alzheimers disease. ers of the Alzheimers pathological cascade.
The Alzheimers Disease Cooperative Study. Lancet Neurology, 9(1), 119128.
Alzheimers Disease and Associated Disorders, Johnson, N., Barion, A., Rademaker,
11(Suppl 2), S33S39. A., Rehkemper, G., & Weintraub, S.
504 part iiiAssessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
(2004). The Activities of Daily Living dementia among two groups with cognitive
Questionnaire:Avalidation study in patients impairment. A preliminary report. Dementia
with dementia. Alzheimers Disease and and Geriatric Cognitive Disorders, 18(3-4),
Associated Disorders, 18(4), 223230. 307313.
Julayanont, P., Brousseau, M., Chertkow, Luis, C. A., Loewenstein, D. A., Acevedo, A.,
H., Phillips, N., Nasreddine, Z. S. (2014). Barker, W.W.,& Duara, R. (2003). Mild cog-
Montreal Cognitive Assessment Memory nitive impairment: Directions for future
Index Score (MoCA-MIS) as a predictor of research. Neurology, 61(4), 438444.
conversion from mild cognitive impairment Manly, J. J. (2005). Advantages and disad-
to Alzheimers disease. Journal of the American vantages of separate norms for African
Geriatrics Society, 62(4), 679684. Americans. Clinical Neuropsychology, 19(2),
Kaplan, E., Goodglass, H., & Weintraub, S. 270275.
(1983). The Boston Naming Test. Philadelphia, Manly, J. J. (2008). Critical issues in cultural
PA: Lea and Febiger. neuropsychology: Profit from diversity.
Kaufer, D.I., Cummings, J.L., Ketchel, P., Smith, Neuropsychology Review, 18(3), 179183.
V., MacMillan, A., Shelley, T.,...DeKosky, S.T. Manly, J.J., Smith, C., Crystal, H.A., Richardson,
(2000). Validation of the NPI-Q, a brief clini- J., Golub, E. T., Greenblatt, R.,...Young, M.
cal form of the neuropsychiatric inventory [In (2011). Relationship of ethnicity, age, educa-
Process Citation]. Journal of Neuropsychiatry tion, and reading level to speed and executive
and Clinical Neuroscience, 12(2), 233239. function among HIV+ and HIV- women:The
Kay, J., Lesser, R., & Coltheart, M. (1992). Womens Interagency HIV Study (WIHS)
Psycholinguistic assessment of language process- Neurocognitive Substudy. Journal of Clinical
ing in aphasia. Hove, UK:Erlbaum. and Experimental Neuropsychology, 33(8),
Kertesz, A. (2006). Western Aphasia Battery- 853863.
Revised (WAB-R). Austin, TX:Pro-Ed. Marson, D. C., Cody, H. A., Ingram, K. K., &
Kertesz, A., Davidson, W., & Fox, H. (1997). Harrell, L. E. (1995). Neuropsychologic pre-
Frontal behavioral inventory: Diagnostic dictors of competency in Alzheimers dis-
criteria for frontal lobe dementia. Canadian ease using a rational reasons legal standard.
Journal of Neurological Science, 24(1), 2936. Archives of Neurology, 52(10), 955959.
Kertesz, A., Nadkarni, N., Davidson, W., & Marson, D. C., Ingram, K. K., Cody, H. A., &
Thomas, A. W. (2000). The frontal behavioral Harrell, L. E. (1995). Assessing the compe-
inventory in the differential diagnosis of fron- tency of patients with Alzheimers disease
totemporal dementia. Journal of the International under different legal standards. Aprototype
Neuropsychological Society, 6(4), 460468. instrument. Archives of Neurology, 52(10),
Knopman, D. S., Weintraub, S., & Pankratz, 949954.
V. S. (2011). Language and behavior domains Marson, D.C., Martin, R.C., Wadley, V., Griffith,
enhance the value of the clinical dementia rat- H.R., Snyder, S., Goode, P.S.,...Harrell, L.E.
ing scale. Alzheimers and Dementia, 7(3), 293299. (2009). Clinical interview assessment of finan-
Lezak, M.D., Howieson, D.B.,& Loring, D.W. cial capacity in older adults with mild cogni-
(2004). Neuropsychological assessment (5th ed.). tive impairment and Alzheimers disease.
NewYork, NY:Oxford University Press. Journal of the American Geriatric Society, 57(5),
Lhermitte, F., Pillon, B., & Serdaru, M. (1986). 806814.
Human autonomy and the frontal lobes. Part Marson, D. C., Sawrie, S. M., Snyder, S.,
I: Imitation and utilization behavior: A neu- McInturff, B., Stalvey, T., Boothe, A.,...Harrell,
ropsychological study of 75 patients. Annals L. E. (2000). Assessing financial capacity
of Neurology, 19, 326334. in patients with Alzheimer disease: A con-
Locascio, J. J., Growdon, J. H., & Corkin, S. ceptual model and prototype instrument.
(1995). Cognitive test performance in detect- Archives of Neurology, 57(6), 877884.
ing, staging, and tracking Alzheimers dis- Mathuranath, P. S., Nestor, P. J., Berrios, G. E.,
ease. Archives of Neurology, 52(11), 10871099. Rakowicz, W., & Hodges, J. R. (2000). A
Loeb, P.A. (1999). Independent living scales. San brief cognitive test battery to differentiate
Antonio, TX:Pearson Assessments. Alzheimers disease and frontotemporal
Lucas, J. A., Ivnik, R. J., Smith, G. E., Bohac, dementia. Neurology, 55(11), 16131620.
D.L., Tangalos, E.G., Kokmen, E.,...Petersen, Mattis, S. (2001). Dementia Rating Scale-2. Odessa,
R. C. (1998). Normative data for the Mattis FL:Psychological Assessment Resources.
Dementia Rating Scale. Journal of Clinical and McKeith, I. G., Burn, D. J., Ballard,
Experimental Neuropsychology, 20(4), 536547. C. G., Collerton, D., Jaros, E., Morris,
Luis, C. A., Barker, W. W., Loewenstein, C. M.,...OBrien, J. T. (2003). Dementia
D. A., Crum, T. A., Rogaeva, E., Kawarai, with Lewy bodies. Seminars in Clinical
T.,...Duara, R. (2004). Conversion to Neuropsychiatry, 8(1), 4657.
CHAPTER 20. Neuropsychological Assessment of Dementia 505
McKhann, G., Drachman, D., Folstein, M., assessment of Alzheimers disease. Neurology,
Katzman, R., Price, D., & Stadlan, E. (1984). 39(9), 11591165.
Clinical diagnosis of Alzheimers dis- Nasreddine, Z. S., Phillips, N. A., Bedirian,
ease: Report of the NINCDS-ADRDA Work V., Charbonneau, S., Whitehead, V., Collin,
Group* under the auspices of Department of I.,
.
..Chertkow, H. (2005). The Montreal
Health and Human Services Task Force on Cognitive Assessment, MoCA: A brief
Alzheimers Disease. Neurology, 34, 939944. screening tool for mild cognitive impairment.
McKhann, G. M., Knopman, D. S., Chertikow, Journal of the American Geriatric Society, 53(4),
H., Hyman, B. T., Jack, C. R. Jr., Kawas, 695699.
C. H.,...Phelps, C. H. (2011). The diagno- Osher, J., Wicklund, A., Rademaker, A., Johnson,
sis of dementia due to Alzheimers dis- N.,& Weintraub, S. (2007). The Mini-Mental
ease: Recommendations from the National State Examination in behavioral variant fron-
Institute on Aging and the Alzheimers totemporal dementia and primary progres-
Association workgroup. Alzheimers and sive aphasia. American Journal of Alzheimers
Dementia, 7(3), 263269. Disease and Other Dementias, 22, 468473.
Medina, J.,& Weintraub, S. (2007). Depression in Pendlebury, S. T., Mariz, J., Bull, L., Mehta,
primary progressive aphasia. Journal of Geriatric Z.,& Rothwell, P.M. (2012). MoCA, ACE-R,
Psychiatry and Neurology, 20(3), 153160. and MMSE versus the National Institute of
Mesulam, M. (2008). Primary progressive apha- Neurological Disorders and Stroke-Canadian
sia pathology. Annals of Neurology, 63(1), Stroke Network Vascular Cognitive
124125. Impairment Harmonization Standards
Mesulam, M., & Weintraub, S. (2008). Primary Neuropsychological Battery after TIA and
progressive aphasia and kindred disorders. stroke. Stroke, 43(2), 464469.
In C. Duyckaerts& I. Litvan (Eds.), Handbook Petersen, R. C. (2000). Aging, mild cognitive
of clinical neurology (pp. 573587). NewYork, impairment, and Alzheimers disease [In
NY:Elsevier. Process Citation]. Neurological Clinics, 18(4),
Mesulam, M., Wieneke, C., Rogalski, E., Cobia, 789806.
D., Thompson, C.K.,& Weintraub, S. (2009). Petersen, R. C. (2000b). Mild cognitive impair-
Quantitative template for subtyping primary ment: Transition between aging and
progressive aphasia. Archives of Neurology, Alzheimers disease. Neurologia, 15(3), 93101.
66(12), 15451551. Petersen, R. C. (2004). Mild cognitive impair-
Mesulam, M. M. (1999). Neuroplasticity fail- ment as a diagnostic entity. Journal of Internal
ure in Alzheimers disease:Bridging the gap Medicine, 256(3), 183194.
between plaques and tangles. Neuron, 24(3), Petersen, R. C., Smith, G. E., Waring, S. C.,
521529. Ivnik, R. J., Kokmen, E., & Tangelos, E. G.
Metzler-Baddeley, C., Baddeley, R. J., Lovell, (1997). Aging, memory, and mild cognitive
P. G., Laffan, A., & Jones, R. W. (2010). impairment. International Psychogeriatrics,
Visual impairments in dementia with 9(Supplement 1), 6569.
Lewy bodies and posterior cortical atrophy. Pfeffer, R. I., Kurosaki, T. T., Harrah, C. H., Jr.,
Neuropsychology, 24(1), 3548. Chance, J.M.,& Filos, S. (1982). Measurement
Morris, J. C. (1993). The Clinical Dementia of functional activities in older adults in the
Rating (CDR), Current version and scoring community. Journal of Gerontology, 37(3),
rules. Neurology, 43, 24122414. 323329.
Morris, J. C. (1997). Clinical dementia rat- Plassman, B. L., Havlik, R. J., Steffens, D. C.,
ing: A reliable and valid diagnostic and Helms, M. J., Newman, T. N., Drosdick,
staging measure for dementia of the D.,...Breitner, J. C. (2000). Documented
Alzheimer type. International Psychogeriatrics, head injury in early adulthood and risk of
9(Supplement 1), 173176; discussion 78. Alzheimers disease and other dementias.
Morris, J.C., Edland, S., Clark, C., Galasko, D., Neurology, 55(8), 11581166.
Koss, W., Mohs, R.,...Heyman, A. (1993). Possin, K. L., Laluz, V. R., Alcantar, O. Z.,
The Consortium to Establish a Registry for Miller, B. L., & Kramer, J. H. (2011). Distinct
Alzheimers Disease (CERAD). Part IV. neuroanatomical substrates and cognitive
Rates of cognitive change in the longitudinal mechanisms of figure copy performance in
assessment of probable Alzheimers disease. Alzheimers disease and behavioral variant
Neurology, 43, 24572465. frontotemporal dementia. Neuropsychologia,
Morris, J.C., Heyman, A., Mohs, R.C., Hughes, 49(1), 4348.
J. P., van Belle, G., Fillenbaum, G.,...Clark, Randolph, C. (1998). Repeatable battery for
C. (1989). The Consortium to Establish a the assessment of neuropsychological status
Registry for Alzheimers Disease (CERAD). (RBANS). San Antonio, TX:The Psychological
Part I. Clinical and neuropsychological Corporation.
506 part iiiAssessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Rankin, K.P., Santos-Modesitt, W., Kramer, J.H., Roman, G. C. (2003). Vascular demen-
Pavlic, D., Beckman, V.,& Miller, B.L. (2008). tia: Distinguishing characteristics, treatment,
Spontaneous social behaviors discriminate and prevention. Journal of the American Geriatric
behavioral dementias from psychiatric disor- Society, 51(5 Suppl Dementia), S296304.
ders and other dementias. Journal of Clinical Rosen, W.G., Mohs, R.C.,& Davis, K.L. (1984).
Psychiatry, 69(1), 6073. A new rating scale for Alzheimers dis-
Rascovsky, K., Hodges, J. R., Kipps, C. M., ease. American Journal of Psychiatry, 141(11),
Johnson, J. K., Seeley, W. W., Mendez, 13561364.
M. F.,...Miller, B. M. (2007). Diagnostic cri- Rossetti, H.C., Lacritz, L.H., Cullum, C.M.,&
teria for the behavioral variant of frontotem- Weiner, M. F. (2011). Normative data for the
poral dementia (bvFTD):Current limitations Montreal Cognitive Assessment (MoCA) in a
and future directions. Alzheimers Disease and population-based sample. Neurology, 77(13),
Associated Disorders, 21(4), S14-S18. 12721275.
Rascovsky, K., Hodges, J. R., Knopman, D., Salmon, D. P., Galasko, D., Hansen, L. A.,
Mendez, M. F., Kramer, J. H., Neuhaus, Masliah, E., Butters, N., Thal, L.J.,& Katzman,
J.,...Miller, B.L. (2011). Sensitivity of revised R. (1996). Neuropsychological deficits associ-
diagnostic criteria for the behavioural variant ated with diffuse Lewy body disease. Brain
of frontotemporal dementia. Brain, 134(Pt 9), and Cognition, 31, 148165.
24562477. Salmon, D.P., Thal, L.J., Butters, N.,& Heindel,
Reisberg, B. (1988). Functional assessment stag- W. C. (1990). Longitudinal evaluation of
ing (FAST). Psychopharmacological Bulletin, dementia of the Alzheimer type:Acompari-
24(4), 653659. son of 3 standardized mental status examina-
Reisberg, B., Auer, S.R.,& Monteiro, I.M. (1996). tions. Neurology, 40, 12251230.
Behavioral pathology in Alzheimers disease Saykin, A. J., Wishart, H. A., Rabin, L. A.,
(BEHAVE-AD) rating scale. International Santulli, R. B., Flashman, L. A., West,
Psychogeriatrics, 8(Suppl 3), 301308; discus- J. D.,...Mamourian, A. C. (2006). Older
sion 5154. adults with cognitive complaints show brain
Reitan, R.M. (1958). Validity of the Trail-Making atrophy similar to that of amnestic MCI.
Test as an indication of organic brain damage. Neurology, 67(5), 834842.
Perceptual Motor Skills, 8, 271276. Schmidt, R., Freidl, W., Fazekas, F., Reinhart, B.,
Renner, J.A., Burns, J.M., Hou, C.E., McKeel, Grieshofer, P., Koch, M.,...Lechner, H. (1994).
D.W., Jr., Storandt, M.,& Morris, J.C. (2004). The Mattis Dementia Rating Scale:Normative
Progressive posterior cortical dysfunc- data from 1,001 healthy volunteers. Neurology,
tion: A clinicopathologic series. Neurology, 44(5), 964966.
63(7), 117511880. Seeley, W. W., Crawford, R. K., Zhou, J.,
Rentz, D. M., Huh, T. J., Faust, R. R., Budson, Miller, B. L., & Greicius, M. D. (2009).
A.E., Scinto, L.F., Sperling, R.A.,& Daffner, Neurodegenerative diseases target large-scale
K.R. (2004). Use of IQ-adjusted norms to pre- human brain networks. Neuron. 2009 Apr
dict progressive cognitive decline in highly 16;62(1), 4252.
intelligent older individuals. Neuropsychology, Shao, H., Breitner, J.C., Whitmer, R.A., Wang,
18(1), 3849. J., Hayden, K., Wengreen, H.,...Zandi, P.P.
Rentz, D.M., Huh, T.J., Sardinha, L.M., Moran, (2012). Hormone therapy and Alzheimer
E.K., Becker, J.A., Daffner, K.R.,...Johnson, disease dementia: New findings from the
K. A. (2007). Intelligence quotient-adjusted Cache County Study. Neurology, 79(18),
memory impairment is associated with abnor- 18461852.
mal single photon emission computed tomog- Smith, T., Gildeh, N.,& Holmes, C. (2007). The
raphy perfusion. Journal of the International Montreal Cognitive Assessment:Validity and
Neuropsychological Society, 13(5), 821831. utility in a memory clinic setting. Canadian
Rentz, D. M., & Weintraub, S. (2000). Journal of Psychiatry, 52(5), 329332.
Neuropsychological detection of early Sperling, R. A., Aisen, P. S., Beckett,
probable Alzheimers disease. In L. F. M. L. A., Bennett, D. A., Craft, S., Fagan,
Scinto& K. R.Daffner (Eds.), Early diagnosis A. M.,...Phelps, C. H. (2011). Toward defin-
of Alzheimers disease (pp. 169189). Totowa, ing the preclinical stages of Alzheimers dis-
NJ:Humana Press. ease: Recommendations from the National
Rentz, D.M., Sardinha, L.M., Huh, T.J., Searl, Institute on Aging-Alzheimers Association
M.M., Daffner, K.R.,& Sperling, R.A. (2006). workgroups on diagnostic guidelines for
IQ-based norms for highly intelligent adults. Alzheimers disease. Alzheimers and Dementia,
Clinical Neuropsychology, 20(4), 637648. 7(3), 280292.
Rey, A. (1941). Lexamen psychologique dan les Spreen, O., & Strauss, E. (1998). A compen-
cas dencephalopathie traumatique. Archives dium of neuropsychological tests. New York,
of Psychology (Frankfurt), 28(112). NY:Oxford University Press.
CHAPTER 20. Neuropsychological Assessment of Dementia 507
Strauss, E., Bielak, A. A., Bunce, D., Hunter, primary progressive aphasia. American
M.A.,& Hultsch, D.F. (2007). Within-person Journal of Alzheimers Disease and Other
variability in response speed as an indica- Dementias, 24(5), 408416.
tor of cognitive impairment in older adults. Weintraub, S., & Morhardt, D. J. (2005).
Neuropsychology, Development and Cognition Treatment, education and resources for non
B:Aging, Neuropsychology and Cognition, 14(6), Alzheimer dementia: One size does not fit
608630. all. Alzheimers Care Quarterly, July/September,
Thompson, C. K., King, M. C., Lukic, S., 201214.
Mesulam, M-M., & Weintraub, S. (2012). Weintraub, S., Rogalski, E., Shaw, E., Salwani,
Noun and verb production and comprehen- S., Rademaker, A., Wieneke, C.,& Mesulam,
sion in stroke-induced and primary pro- M. (2013). Verbal and nonverbal memory
gressive aphasia: An introduction to the in primary progressive aphasia: The three
Northwestern Naming Battery Performance. words three shapes test. Behavioral Neurology,
Aphasiology, 26(5), 632655. 26(1-2), 6776.
Tiraboschi, P., Salmon, D. P., Hansen, L. A., Weintraub, S., Wicklund, A. H., & Salmon,
Hofstetter, R.C., Thal, L.J.,& Corey-Bloom, D. P. (2012). The neuropsychological profile of
J. (2006). What best differentiates Lewy body Alzheimer disease. Biology of Alzheimer dis-
from Alzheimers disease in early-stage ease. Woodbury, NY: Cold Springs Harbor
dementia? Brain, 129(Pt 3), 729735. Laboratory Press
Tombaugh, T.N. (2004). Trail Making Test Aand Welsh, K. A., Butters, N., Mohs, R. C., Beekly,
B:Normative data stratified by age and edu- D., Edland, S., Fillenbaum, G., & Heyman,
cation. Archives of Clinical Neuropsychology, A. (1994). The Consortium to Establish a
19(2), 203224. Registry for Alzheimers Disease (CERAD).
Tombaugh, T.N.,& McIntyre, N.J. (1992). The Part V. A normative study of the neuropsy-
mini-mental state examination: A compre- chological battery. Neurology, 44, 609614.
hensive review.[see comment]. Journal of the Wicklund, A. H., Johnson, N., Rademaker, A.,
American Geriatric Society, 40(9), 922935. Weitner, B.B.,& Weintraub, S. (2007). Profiles
Wechsler, D. (1997). Wechsler Adult Intelligence of decline in activities of daily living in
Scale (3rd ed.). San Antonio, TX: The non-Alzheimer dementia. Alzheimers Disease
Psychological Corporation. and Associated Disorders, 21(1), 813.
Wechsler, D. (1998). Wechsler Memory Scale-III. San Wicklund, A. H., Johnson, N., & Weintraub,
Antonio, TX:The Psychological Corporation. S. (2004). Preservation of reasoning in pri-
Wechsler, D. (2001). Wechsler Test of Adult Reading. mary progressive aphasia: Further differ-
San Antonio, TX:Psychological Corporation. entiation from Alzheimers disease and the
Weintraub, S. (2000). Neuropsychological behavioral presentation of frontotemporal
assessment of mental state. In M-M. Mesulam dementia. Journal of Clinical and Experimental
(Ed.), Principles of cognitive and behavioral neu- Neuropsychology, 26(3), 347355.
rology (pp. 121173). New York, NY: Oxford Wicklund, A. K., & Weintraub, S. (2005).
University Press. Neuropsychological features of common
Weintraub, S.,& Mesulam, M. (1993). Four neu- dementia syndromes. Turkish Journal of
ropsychological profiles of dementia. In F. Neurology, 11, 566588.
Boller & J. Grafman (Eds.), Handbook of neu- Wilkinson, G. S., & Robertson, G. J. (2006).
ropsychology (pp. 258282). Amsterdam, The Wide range achievement test 4 (WRAT4). Lutz,
Netherlands:Elsevier. FL:Psychological Assessment Resources.
Weintraub, S., & Mesulam M-M. (1996). From Wilson, B.A. (2008). Neuropsychological reha-
neuronal networks to dementia: Four clini- bilitation. Annual Review of Clinical Psychology,
cal profiles. In F. Fret, Y. Christen& F. Boller 4, 141162.
(Eds.), La demence: Pourquoi? (pp. 7597). Yesavage, J.A., Brink, T.L., Rose, T.L., Lum, O.,
Paris, France: Foundation Nationale de Huang, V., Adey, M.,...Leirer, V. O. (1983).
Gerontologie. Development and validation of a geriatric
Weintraub, S., & Mesulam, M. (2009). With or depression screening scale: A preliminary
without FUS, it is the anatomy that dictates report. Journal of Psychiatric Research, 17,
the dementia phenotype. Brain, 132(Pt 11), 3749.
29062908. Yesavage, J. A., Brooks, J. O., III, Taylor, J., &
Weintraub, S., Mesulam, M. M, Wieneke, C., Tinklenberg, J. (1993). Development of
Rademaker, A., Rogalski, E.J.,& Thompson, aphasia, apraxia, and agnosia and decline
C. K. (2009). The Northwestern Anagram in Alzheimers disease. American Journal of
Test: Measuring sentence production in Psychiatry, 150(5), 742747.
21
In 1907, Alois Alzheimer described the husband or daughter and seems to have
first case study of Alzheimers dementia auditory hallucinations. Often, she screams
(AD) (Alzheimer, Stelzmann, Schnitzlein, & for many hours in a horrible voice.
Murtagh, 1995). His patient had significant
and disruptive behavioral and psychiatric In this case, neuropsychiatric symptoms
symptoms in addition to memory and cogni- preceded and developed coincident with the
tive difficulties. He reported: onset of cognitive difficulties. Delusions of
jealousy and paranoia were early manifes-
The first noticeable symptom of illness tations. Later, her social graces deteriorated
shown by this 51-year old woman was sus- and auditory hallucinations developed along
piciousness of her husband. Soon, a rapidly with agitation and a delirious appearance.
increasing memory impairment became evi- Although AD has been viewed as predomi-
dent; she could no longer orient herself in nantly a disorder of memory and cognition,
her own dwelling, dragged objects here and the vast majority of AD patients develop neu-
there and hid them, and at times, believing ropsychiatric symptoms during the course of
that people were out to murder her, started the illness (Lyketsos, 2002). It has been estab-
to scream loudly. On observation at the insti- lished that AD pathology prominently dis-
tution, her entire demeanor bears the stamp turbs cerebral networks crucial for episodic
of utter bewilderment. She is completely memory functioning, namely the entorhinal,
disoriented to time and place. Occasionally, hippocampal, and mesial temporal struc-
she remarks that she does not understand tures. Similarly, neuropsychiatric symptoms
anything and is at her wits end. Sometimes occur when AD pathology affects regions of
she greets the doctor as if he were a visitor cerebral circuitry responsible for regulating
and excuses herself that she has not fin- mood and affect, motivation, decision mak-
ished with her work; on other occasions, ing, and higher level perceptual processing.
she screams that he wants to cut her open, Specific circuitry involved includes the orbi-
and on yet others, she dismisses him, full of tofrontal regions, the anterior cingulate, the
indignation and with expressions indicating dorsolateral prefrontal cortex, heteromodal
that she fears him as a threat to her honor regions of the neocortex, as well as the amyg-
as a woman. At times, she is totally deliri- dala, periventricular and septal nuclei, and
ous, drags her bedding around, calls for her striatum.
508
CHAPTER 21. Neuropsychiatric Symptoms of Dementia 509
Neuropsychiatric symptoms are not lim- be associated with worse cognitive perfor-
ited to AD among the dementing illnesses. mance, reduced functional ability and quality
Frontotemporal dementia (FTD), Lewy of life, and increased caregiver and patient
body dementia (DLB), vascular demen- distress (DOnofrio, 2012; Hargrave, Reed,&
tia (VaD), and other dementia subtypes all Mungas, 2000; Lechowski, 2009; Schneider,
have prominent neuropsychiatric manifes- Murray, Banerjee, & Mann, 1999). They are
tations. Recognition and treatment of these a major reason for institutionalization and
features can substantially impact the clinical nursing home placement (Callahan, 2006;
course of the disease and the well-being of Rabins, 1991).
caregivers. The following sections review the major
In this chapter, the neuropsychiatric aspects neuropsychiatric manifestations of dementia,
of dementia will be reviewed focusing on their neuroanatomical substrates, and the rel-
the phenomenology and a clinical approach ative prevalence of these features in the major
toward evaluation. Subsequent chapters will dementing illnesses.
focus on management of symptoms.
Depression
Overview of the Major Neuropsychiatric
Symptoms in Dementia Both depression and cognitive impairment
occur commonly in the elderly. The relation-
A variety of neuropsychiatric features ship between the two is complex (Box 21.1).
are well recognized as integral aspects of Elderly patients with depression can have
dementing illnesses. These features may associated cognitive impairments, previously
precede or develop concurrently with the referred to as pseudodementia, but now more
cognitive and functional decline. Whereas accurately designated as depression-related
cognitive and functional deficits in demen- cognitive impairment (DRCI). There is evi-
tia tend to be relentlessly progressive and dence that such depression-associated cogni-
show relatively linear decline within differ- tive impairments may persist in a subset of
ent stages of the illness, neuropsychiatric elderly individuals despite resolution of their
symptoms may emerge more variably. They depression. Indeed, epidemiologic studies
may remit, relapse, or transition from one have correlated depression with an increased
symptom to another. The neuropathologi- later risk of developing dementia (Devanand
cal correlates of these symptoms are only & Sano, 1996). A potential mechanism for
partially understood. A growing body of this may be found in the excessive glucocor-
evidence links individual symptoms to ticoid induction associated with depression,
dysfunction in discrete cerebral networks which in turn may result in a cascade of neu-
affected by neurodegenerative processes rotransmitter-induced excitotoxicity, leading
(see Table 21.1 and Table 21.2 for a synopsis to subsequent neuronal injury. Alternatively,
of the cerebral substrates of neuropsychiat- late-life depression could be viewed as a
ric symptoms). prodromal symptom for a dementing ill-
Neuropsychiatric symptoms adversely ness, related to early involvement of cere-
impact not only patients but also their care- bral circuits crucial for mood regulation that
givers. Many symptoms have been shown to are damaged by the neurodegenerative or
Apathy
Ott, Noto,& Fogel, 1996 SPECT DBDS Right temporoparietal
Craig etal., 1996 SPECT NPI Prefrontal and anterior temporal
Benoit etal., 1999 SPECT NPI Right cingulate
Migneco etal., 2001 SPECT NPI Anterior cingulate bilaterally
Benoit etal., 2002 SPECT NPI Left ACC, right inferior and medial gyrus frontalis,
the left OFC, right gyrus lingualis
Benoit etal., 2004 SPECT AI Bilateral superior OFC, left middle frontal gyrus,
right ACC, left superior DLPFC
Robert etal., 2006 SPECT AI Right ACC
Lanctot etal., 2007 SPECT NPI Right OFC, left ACC
Holthoff etal., 2005 FDG-PET NPI Left OFC
Marshall etal., 2007 FDG-PET SANS Bilateral ACC, medial OFC, bilateral medial
thalamus
Apostolova etal., 2007 MRI VBM NPI Right superior, bilateral middle frontal, left superior
frontal, anterior cingulate correction
Bruen etal., 2008 MRI VBM NPI Bilateral ACC and frontal cortex, left head of
caudate, bilateral putamen
Depression
Levy-Cooperman etal., SPECT CSDD Right superior and bilateral middle frontal gyri, left
2008 superior frontal gyrus, AC gyrus
Akiyama H, 2008 SPECT NPI Left prefrontal cortex
Galynker etal., 2000 SPECT SANS, HDS DLPFC, AC gyrus
Liao etal., 2003 SPECT HDS Anterior and posterior cingulate, precuneus
Psychosis
Kotrla etal., 1995 SPECT HDS, BPAD Left frontal (delusions)
Parietal (hallucinations)
Staff etal., 1999 SPECT Right hemisphere (frontal and limbic)
Mega etal., 2000 SPECT NPI DLPFC, left AC, dorsolateral parietal
Staff et al., 2000 SPECT Presence of Right frontal lobe
CSAD
Fukuhara etal., 2001 SPECT Presence Right medial posterior parietal
of theft
delusions
Nakano etal., 2006 SPECT NPI Posterior cingulate, precunei, parietal association
cortex with right-sided dominance
Starkstein etal., 1994 SPECT PSE Bitemporal
Metnis etal., 1995 PET Presence of OF and cingulate and left medial temporal
DMS
Hirono etal., 2998 FDG-PET BPAD Left inferior temporal (hypermetabolic), left medial
occipital
Lopez etal., 2001 FDG-PET Left DLPFC, left medial temporal (delusions)
Right parietal, left medial temporal, left DLPFC
(hallucinations)
Sultzer etal., 2003 FDG-PET NRS Right superior DLPFC, right inferior frontal pole,
and right lateral OF region
Geroldi etal., 2002 CT NPI Right temporal and left frontal
ACC, anterior cingulate cortex; CT, computerized tomography; DLPFC, dorsolateral prefrontal cortex; FDG-PET, flu-
deoxyglucose positron emission tomography; MRI, magnetic resonance imaging; NPI, Neuropsychiatric Inventory; OFC,
orbitofrontal cortex; SPECT, single-photon emission computed tomography.
CHAPTER 21. Neuropsychiatric Symptoms of Dementia 511
AD
AD
TD
TD
CI
LB
Va
-F
ild
re
fv
tv
at
ve
M
er
BOX 21.2 Clinical Clues That May Improve the Detection of Depression in Patients With
Dementia
Rapid uncharacteristic and unexplained deterioration of cognition
Blunted affect, decline in psychomotor reactivity
Dysthymic agitation
Disturbance in sleep/wake cycle
Food refusal, appetite decrease, and rapid weight loss
Prior history of depression
Family history of depression
Change in environment or caregiver
TABLE21.3 Proposed Diagnostic Criteria for Depression in Alzheimers Disease
Major Depressive Episode Depression of AD
Number of Five (or more) of the following Three (or more) of the following symptoms
symptoms symptoms have been present during have been present during the same 2-week
required the same 2-week period and represent period and represent a change from
a change from previous functioning previous functioning
Caveat Do not include symptoms that are Do not include symptoms that, in your
clearly due to a general medical judgment, are clearly due to a medical
condition, or mood-incongruent condition other than AD or are a direct
delusions or hallucinations result of non-mood-related dementia
symptoms (e.g., loss of weight due to
difficulties with food intake)
Symptoms 1. Depressed mood most of the day, 1. Clinically significant depressed
nearly every day. as either indicated mood (e.g., depressed, sad, hopeless,
by subjective report or observation discouraged, tearful)
of others
2. Markedly diminished interest 2. Decreased positive affect or pleasure in
or pleasure in all, or almost all, response to social contacts and usual
activities most the day, nearly every activities (either 1 or 2 is required)
day (either 1 or 2 is required)
3. Significant weight loss when not 3. Disruption in appetite
dieting or weight gain or decrease or
increase in appetite nearly every day
4. Insomnia or hypersomnia nearly 4. Disruption in sleep
every day
5. Psychomotor agitation or retardation 5. Psychomotor changes (e.g., agitation or
nearly every day retardation)
6. Fatigue or loss of energy nearly 6. Fatigue or loss of energy
every day
7. Feelings of worthlessness or 7. Feelings of worthlessness, hopelessness,
excessive or inappropriate guilt or excessive or inappropriate guilt
nearly every day
8. Diminished ability to think or 8. Recurrent thoughts of death, suicidal
concentrate ideation, plan, attempt
9. Recurrent thoughts of death, 9. Social isolation or withdrawal
recurrent suicidal ideation without a
specific plan, or a suicide attempt or a
specific plan for committing suicide
10. irritability
Other Does not meet criteria for a mixed All criteria are met for dementia of the
considerations episode Alzheimers type (DSM-IV-TR). The
symptoms are not better accounted for by
other conditions such as major depressive
disorder, bipolar disorder, bereavement,
schizophrenia, schizoaffective disorder,
psychosis of AD, anxiety disorders or
substance-related disorder
The symptoms are not better accounted
for by bereavement
Physiological rule The symptoms are not due to the direct The symptoms are not due to the direct
out physiological effects or a substance physiological effects of substance (e.g., a
(e.g., a drug of abuse or a medication) drug of abuse or medication)
or a general medical condition (e.g.,
hypothyroidism)
Functional The symptoms cause clinically The symptoms cause clinically significant
impairment significant distress or impairment distress or disruption in functioning
in social, occupational, or other
important areas of functioning
AD, Alzheimer's disease; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision.
Source:Olin etal. (2002).
CHAPTER 21. Neuropsychiatric Symptoms of Dementia 513
Se AD
AD
CI
A
LB
FT
FT
Va
M
Cummings, 2010). Bizarre delusions, such
ild
re
-
fv
tv
at
ve
M
For a diagnosis of apathy the patient should fulfil the criteria A, B, C, and D:
ALoss of or diminished motivation in comparison to the patient's previous level of functioning and
which is not consistent with his age or culture. These changes in motivation may be reported by the
patient himself or by the observations of others.
BPresence of at least one symptom in at least two of the three following domains for a period of at least
4 weeks and present most of the time.
Domain B1Behavior
Loss of, or diminished, goal-directed behavior as evidenced by at least one of the following:
Initiation symptom:loss of self-initiated behavior (e.g., starting conversation, doing basic tasks of day-to-
day living, seeking social activities, communicating choices)
Responsiveness symptom:loss of environment-stimulated behavior (e.g., responding to conversation,
participating in social activities)
Domain B2Cognition
Loss of, or diminished, goal-directed cognitive activity as evidenced by at least one of the following:
Initiation symptom:loss of spontaneous ideas and curiosity for routine and new events (i.e., challenging
tasks, recent news, social opportunities, personal, family, and social affairs).
Responsiveness symptom:loss of environment-stimulated ideas and curiosity for routine and new events
(i.e., in the person's residence, neighborhood, or community),
Domain B3Emotion
Loss of, or diminished, emotion as evidenced by at least one of the following:
Initiation symptom:loss of spontaneous emotion, observed or self-reported (e.g., subjective feeling of
weak or absent emotions, or observation by others of a blunted affect)
Responsiveness symptom:loss of emotional responsiveness to positive or negative stimuli or events (e.g.,
observer-reports of unchanging affect or of little emotional reaction to exciting events, personal loss,
serious illness, emotional-laden news)
GThese symptoms (A and B) cause clinically significant impairment in personal, social, occupational, or
other important areas of functioning.
0The symptoms (A and B) are not exclusively explained or due to physical disabilities (e.g., blindness
and loss of hearing), to motor disabilities, to diminished level of consciousness, or to the direct
physiological effects of a substance (e.g., drug of abuse, a medication).
100
90
80
70
60
50 Delusions
40 Hallucinations
30
20
10
0
AD
AD
AD
TD
TD
CI
Va
LB
M
-F
-F
ild
re
fv
tv
at
ve
M
er
Se
od
M
AD
AD
TD
TD
CI
LB
Va
M
-F
-F
fv
tv
at
er
M
er
v
Se
Figure21.4 Prevalence of anxiety in major major dementias, including AD, VaD, mixed
dementias and MCI. AD=alzheimer dementia, DLB, and FTD (Fig. 21.5), with
disease, LBD=Lewy body dementia, some differences in the typical neuropsy-
fv-FTD=frontal-variant frontotemporal chiatric profile of each of these illnesses as
dementia, tv-FTD=temporal variant FTD, discussed later. As many as 70% of persons
VaD=vascular dementia, MCI=mild with dementia manifest agitation during
cognitive impairment. the course of their illness (Cohen-Mansfield,
1986). Physical injury to the patient or oth-
ers may result. Agitation adversely impacts
comorbidity of anxiety with depression is prognosis, is associated with an increase in
high. Seventy-five percent of those who have the rate of cognitive decline, and reduces
dementia with anxiety also have depression functional status. Agitated behaviors are a
(Starkstein, Jorge, Petracca, & Robinson, major precipitant of institutionalization and
2007). As dementia severity increases and nursing home placement (Chen et al., 2000;
insight deteriorates, overt anxiety becomes DOnofrio, 2012; Rabins, 1991).
less prevalent (Chen, Borson, & Scanlan, The root causes of agitated behaviors may
2000). Anxiety may then manifest as agitated sometimes lie in other symptoms present in
behavior (Twelftree & Qazi, 2006). Anxiety the dementia. Those who have agitation are
can be a feature of all major dementia syn- more likely to have other neuropsychiat-
dromes (Fig. 21.4), with some reports sug- ric symptoms (excluding apathy) (Deutsch,
gesting it is particularly common in early to Bylsma, Rovner, Steele, & Folstein, 1991).
moderate AD, Parkinsons disease dementia The increased comorbidity of anxiety with
(PDD), and FTD (Aarsland et al., 2007). agitation may suggest that anxiety is a con-
tributing factor to agitation (Twelftree &
Qazi, 2006). Depression may also be impli-
Agitation, Impulsivity, and cated, since 75% of those who meet criteria
Obsessive-Compulsive Behaviors for dementia plus generalized anxiety disor-
der also fulfill diagnostic criteria for depres-
Patients with dementia may manifest a wide sion (Starkstein et al., 2007). Evidence points
range of disruptive behaviors. Agitation is toward psychosis occurring more commonly
an umbrella term that is usually defined to in persons who have agitation. Furthermore,
include motor or vocal behaviors that are the root cause of agitated behaviors may lie
disruptive or unsafe in a given environment in medical issues that are overlooked due
(Rosen etal., 1994). This includes various com- to the inability of patients to fully appreci-
binations of irritability, restlessness, scream- ate and effectively communicate their prob-
ing, threatening behavior, aggressiveness, and lems. Physical discomfort and malaise due
even violence and crime. Patients with demen- to illness may produce agitation. Infections,
tia may also manifest other forms of related upper or lower gastrointestinal distress, mus-
impulsive and obsessive behaviors such as culoskeletal pain, headaches, neuropathic
CHAPTER 21. Neuropsychiatric Symptoms of Dementia 517
AD
AD
TD
TD
CI
Va
LB
M
-F
-F
e
re
at
fv
tv
ve
M
er
Figure21.5 Estimated prevalence of agitation families and health care providers. This may
in the major neurodegenerative dementias and lead to the erroneous conclusion that com-
MCI. AD=alzheimer disease, LBD=Lewy plex decision-making abilities are entirely
body dementia, fv-FTD=frontal-variant preserved (Carr, Ott, Noto, & Fogel, 2010;
frontotemporal dementia, tv-FTD=temporal Tarawneh & Holtzman, 2012). This can have
variant FTD, VaD=vascular dementia, significant medical, financial, and legal con-
MCI=mild cognitive impairment. sequences related to the patients and their
families. Examples of complex competencies
pain, dystonia, medication side effects, and and social skills that can be impaired early
environmental factors may each produce in dementia are listed in Box 21.4. Clinicians
agitation. Physical abuse may also result in must be prepared to assist patients and fami-
agitated behavior. lies in determining whether a patient with
Agitation represents a distinct and inde- dementia has the capacity to make medical,
pendent clinical syndrome in dementia legal, and financial decisions. Involving fam-
(Senanarong etal., 2004). It is consistently found ily members early during this process can
in association with increased dementia severity be beneficial by allowing more time to make
(Aries etal., 2010; Ballard etal., 1999). Avariety decisions. Advanced directives and a living
of evidence supports that it is a manifestation
of dysfunction in frontal cortical-subcortical cir-
cuits. Neuropsychological studies have shown
an association between agitation and executive BOX 21.4 Complex Competencies That
dysfunction, indicating that it might be viewed May Be Impaired Early On in the Early
as another feature of frontal lobe dysfunction Course of a Dementing Illness
(Chen, Sultzer, Hinkin, Mahler,& Cummings,
1998). Functional imaging abnormalities in The abilityto:
frontal lobe regions have been associated with
symptoms of agitation (Hirono, Mega, Dinov, Respond to emergencies
Mishkin, & Cummings, 2000; Sultzer et al., Pilot or drive transportation vehicles
1995). Pathological corroboration is found in Make medical decisions
the increased prevalence of neurofibrillary tan- Manage complex medical treatments
gles occurring in these same areas in persons Stand trial
with AD who manifest agitation compared to Testify as a witness
their age-matched peers (Tekin etal., 2001). Qualify as a juror
Handle firearms
Fulfil social and occupational roles
Impairments in Insight, Judgment,
Engage in intimate, sexual relations
andComplex Competencies Resist undue influence over personal
decisions
As a product of the neuropsychiatric and
Execute a will and last testament
cognitive changes of dementia, insight,
518part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
will promote the recognition and incorpora- physical enactment of dream activity. This
tion of the patients wishes and values into can result in self-injury or injury to a sleep-
their health care when they are no longer able ing partner. This condition is associated
to make these decisions for themselves. These with neurodegenerative synucleinopathies,
documents may spare the family conflicts including Parkinsons disease (PD), DLB,
that can sometimes arise in such situations. and multiple system atrophy (MSA) (Boeve,
As a general principle of care for the elderly, Silber, & Ferman, 2003, 2004). In fact, evi-
it is to the patients and familys advantage dence suggests that the presence of RBD may
for the health care provider to encourage the be an early manifestation of synucleinopa-
completion of estate planning before cogni- thies, which appear to have selectivity for
tive impairment occurs or progresses. brain stem structures important in REM sleep
regulation (Boeve etal., 2004). RBD may pre-
cede parkinsonism as may visual hallucina-
Sleep Disturbances tions in persons who later go on to develop
DLB. Persons with dementia and RBD have
The prevalence of persistent sleep distur- cognitive profiles similar to those with DLB,
bances has been estimated to be 44% of demonstrating visuospatial and executive
patients with AD (Vitiello & Borson, 2001). functional impairments in contrast to per-
Poor sleep hygiene is present in a relatively sons with AD who manifest more significant
large proportion of the demented popula- deficits in memory and language function
tion, particularly in nursing homes (Bliwise, (Boeve etal., 2004; Ferman etal., 2002).
2004). Circadian rhythm disturbances are Medications commonly used for treating
a feature of dementias that can be particu- dementia may also be associated with sleep
larly problematic during the period when disturbance. For example, the cholinester-
daylight is lengthening (Hofman & Swaab, ase inhibitors, particularly donepezil, may
2006). Damage to thesuprachiasmatic hypo- cause insomnia in 10% of persons (Grossberg,
thalamic nucleus, disturbance of melatonin Irwin, Satlin, Mesenbrink, & Spiegel, 2004).
secretion, optic nerve axonal degeneration, Galantamine and rivastigmine are less asso-
loss of retinal ganglion cells, and decreased ciated with this potentially troublesome side
exposure to environmental light may all be effect (Schnelle et al., 1998). Daytime dosing of
contributing factors (Ancoli-Israel etal., 2003; the medication or switching to different mem-
Blanks etal., 1996; Shochat, Martin, Marler,& bers of the same class may be helpful in some
Ancoli-Israel, 2000; Wu& Swaab, 2005). cases. Antipsychotics may produce painful
Obstructive sleep apnea (OSA) is a dystonia, akathisia and sleep disturbances.
well-known comorbidity of dementia that Periodic limb movements of sleep tend
can potentially worsen cognition (Bedard, to be elevated in patients with LBD and PD
Montplaisir, Richer, Rouleau, & Malo, 1991; and may disrupt sleep architecture leading to
Redline et al., 2010; Young, Peppard, & daytime hypersomnolence (Hibi et al., 2012).
Gottlieb, 2002). It also adversely impacts Painful conditions, frequent urination due to
cardiovascular health and may increase the prostatic hypertrophy or diuretic treatment of
chance of stroke (Redline et al., 2010) and hypertension, urinary tract infections causing
diabetes (Botros et al., 2009). Its effects on discomfort and polyuria, poorly regulated dia-
cognition may be mediated via chronic inter- betes, consumption of caffeine or stimulants
mittent cerebral hypoxia and/or sleep depri- during the day or night, nighttime pill admin-
vation with subsequent daytime sleepiness. istration, and acquisition of vital signs at night
Treatment, such as with continuous positive may each contribute to sleep disruption.
airway pressure (CPAP), may improve cogni-
tive performance (Ferman etal., 2002). There
is also a potential risk for irreversible execu- Neuropsychiatric Symptom Profile
tive dysfunction, most likely due to anoxic ofMain Dementia Subtypes
brain damage to frontal systems, highlight-
ing the importance of early detection and Alzheimers Disease
treatment of OSA (Bedard etal., 1991).
REM sleep behavior disorder (RBD) occurs The neuropsychiatric profile of AD encom-
as a result of the loss of the normal skeletal passes the breadth of neuropsychiatric symp-
muscle atonia during REM sleep, allowing toms described in previous sections. These
CHAPTER 21. Neuropsychiatric Symptoms of Dementia 519
100
Agitation
80
Prevalence (% of patients)
Diurnal
60 rhythm
Depression
Irritability
Wandering
Social Aggression
40
withdrawal Anxiety Mood
Paranoia change Hallucinations
20 Socially unacceptable behaviors
Suicidal Accusatory behavior Delusions
ideation Sexually inappropriate behaviors
0
40 30 20 10 0 10 20 30
Months Before/After Diagnosis
Figure21.6 Neuropsychiatric profile depending on disease stage in Alzheimers disease (Jost&
Grossberg, 1996).
symptoms may occur at any point during increased caregiver dissatisfaction (Steele,
the course of the illness, but certain features Rovner, Chase, & Folstein, 1990).
are more likely to appear in different disease Delusions are rarely bizarre as in primary
stages (Fig. 21.6). Using the Neuropsychiatric psychotic disorders. Common delusional
Inventory (NPI), it has been found that up themes include theft, infidelity, and delu-
to 60% of patients with AD had at least one sional misidentification syndromes (Table
neuropsychiatric symptom at the time of 21.5). Hallucinations are less common, are
presentation (Fig. 21.7). Apathy and depres- typically visual, and tend to resolve over
sion are common early features. Apathy is time (Marin et al., 1997). The occurrence of
present in 42% of mild AD, 80% of moder- psychotic symptoms early in the disease
ate AD, and 92% of advanced AD patients course is not typical of AD and may be a clue
(Boyle et al., 2003; Mega et al., 1996). It is to the diagnosis of DLB or FTD. Psychosis
associated with a reduced quality of life. also occurs in the context of delirium, often
Depressive symptoms are present in about driven by infections, medications, or toxic or
half of AD patients and are associated with metabolic factors. Hence, acute or subacute
diminished quality of life, functional impair- onset psychosis in a patient with dementia
ment, aggression, and institutionalization should prompt a thorough evaluation to rule
as well as increased caregiver burden and out medical illness. Persons with dementia
depression (DOnofrio, 2012; Hargrave, are more vulnerable to mental status changes
2000; Rabins, 1991). Psychotic symptoms due to illnesses, electrolyte derangements,
occur in 30% to 40% of AD patients during baseline respiratory hypoxia, and medica-
the course of the illness, typically in the mid- tion side effects. They also recover more
dle to late stages (Mega et al., 1996; Wragg & slowly than the cognitively normal popu-
Jeste, 1989). They are a common reason for lation. Persons with AD usually have rela-
early residential placement, institutionaliza- tively intact social graces early during the
tion, increased levels of patient distress, and disease. However, as many as 15% of AD
80.00%
70.00% Eating
Sleep
60.00% Irritability
50.00% Disinhibition
Apathy
40.00%
Elation
30.00% Anxiety
20.00% Depression
Agitation
10.00% Hallucinations
0.00% Delusions
Neuropsychiatric Symptoms
Figure 21.7 Relative prevalence of various neuropsychiatric symptoms in AD (Aarsland et al., 2007;
Ballard et al., 1999; Geda & Roberts, 2008; Liu et al., 2004; Lyketsos et al., 2000; Mega et al., 1996).
patients have a frontal variant wherein they delusions, and hallucinations can be seen in
present with difficulties attributable to the both early and late phases during the course
frontal circuits rather than an amnesic syn- of FTD (Liu etal., 2004).
drome (Balasa etal., 2011). Nonetheless, early
impairment in social comportment and dis-
inhibition should prompt consideration of Lewy Body Dementia
other possible causes such as conditions that
primarily affect the frontallobe. The neuropsychiatric profile can often be
helpful for distinguishing DLB from other
dementias (see Chapter12). Visual hallucina-
Frontotemporal Dementias tions are common in DLB, occurring in up to
80% of those affected at some point during
Our focus here will be on bvFTD, as opposed the course of the illness. These may be early
to the aphasic forms of FTD, in which neu- features. More than 90% of patients who have
ropsychiatric symptoms are the sine qua non visual hallucinations coupled with a mild
(see Chapter2). These same features may also dementia will be found to have DLB rather
occur in the other FTD subtypes (Modirrousta, than other types of dementia. In one series,
Price, & Dickerson, 2013). The presenting visual hallucinations were seen at onset in
manifestation is often a personality change 65% of pathologically proven DLB, compared
marked by disinhibition, impulsivity, loss to only 25% in AD patients. Visual hallucina-
of social comportment, apathy, and impair- tions in DLB are typically well formed and
ment in judgment and insight. The behav- complex, and more commonly involve ani-
ioral symptoms can be attributed to regions mate rather than inanimate objects (Ballard
where the degenerative process has taken its etal., 1996). Multimodal hallucinations occur
earliest toll, in the frontal and temporal lobes. and can be a distinguishing feature compared
Orbitofrontal cortical dysfunction is more to AD, where they occur rarely. Auditory
associated with disinhibition and impulsiv- hallucinations occur in up to 25%, olfactory
ity, while mesial frontal dysfunction is more hallucinations in 5% to 10% of patients, and
associated with apathy and abulia. Patients tactile hallucinations in up to 3% (Ballard
with FTD may show obsessive-compulsive et al., 1999; Simard et al., 2000). Delusions
behaviors, hoarding behaviors, hyperorality, occur in 50% of cases and revolve around
and complex ritualistic behaviors (Bathgate, themes similar to those seen in AD (Ballard
Snowden, Varma, Blackshaw,& Neary, 2001; etal., 1999).
Mendez etal., 2008). Depressive symptoms in REM sleep behavior disorder is a neu-
FTD have received relatively little systematic ropsychiatric feature that may precede the
investigation and may be confused on the onset of extrapyramidal, cognitive, and even
part of caregivers with apathy, but they may psychotic symptoms in up to 80% of patients
occur in as many as 30% to 40% of patients. with DLB (Bedard et al., 1991). Hence, its
Inappropriate sexual behaviors, agitation, presence may herald the condition, with
CHAPTER 21. Neuropsychiatric Symptoms of Dementia 521
a positive predictive value of 92% (Wu & depression in stroke and the lesions closer
Swaab, 2005). Depression and anxiety are proximity to the frontal pole or its involve-
also common in DLB. The prevalence of ment of the caudate nucleus (Schmahmann,
depression in DLB is about 30% (Ballard 2003), whereas mania tends to have more
et al., 1999). The depressed cognitively of an association with strokes involving
impaired patient is much more likely to have right-sided basal frontotemporal regions
DLB than AD (Papka, Rubio, Schiffer,& Cox, (Starkstein etal., 1990).
1998). Anxiety is reported in 84% of patients
(Ballard et al., 1999). Although treatment
issues will be discussed in further chapters, Awareness, Assessment, and
it is worth mentioning that the diagnosis of Intervention:General Principles
DLB has special implications for treatment
of psychiatric symptoms since these patients Clinicians evaluating dementia patients
are exquisitely sensitive to typical and atypi- should routinely and regularly screen for
cal neuroleptics. Clozapine is the only neuro- neuropsychiatric symptoms. Initial evalua-
leptic that can be safely recommended for use tions should establish a baseline to facilitate
when one is needed. early detection of subtle behavioral altera-
tions and accurate monitoring of changes
in preexisting ones. This is important since
Vascular Dementias neuropsychiatric manifestations can change
throughout the course of the illness, and
Psychomotor slowing is often a prominent they may fluctuate with medication changes,
feature of vascular dementia, particularly stress, or changes in the patients living
multi-infarct dementia, with a heavy vascu- arrangements. The practitioner should edu-
lar disease burden in the subcortical white cate the patient, family, and significant oth-
matter (see Chapter 13). Cognitive deficits ers about neuropsychiatric symptoms so as
frequently include memory retrieval, and to improve recognition. Their observations
attentional and processing speed difficulties can be vital to understanding the cause of the
(Schmidtke & Hull, 2002). Depression and symptoms and to selecting the best manage-
aggression, followed by apathy, irritability, ment options (Rabins etal., 2007).
and anxiety, are commonly seen. Delusions, Measurement scales are important for
hallucinations, disinhibition, aberrant motor research purposes but can also be useful in
behavior, and euphoria may occur, but they the clinic to monitor behavioral changes.
are less frequent than in other dementias Some scales focus on the assessment of a
(Lyketsos etal., 2000). single neuropsychiatric feature, whereas
Strategic-infarct dementia occurs when the others rate a number of them together. The
vascular insult affects a crucial hub in cogni- BEHAVE-AD (Reisberg, Auer, & Monteiro,
tive and neuropsychiatric circuitry. Examples 1996)is an example of a multisymptom rating
include various thalamic vascular syndromes scale and is considered by some to be the gold
that each have different neuropsychiatric standard. The NPI (Cummings et al., 1994),
profiles. Personality changes, apathy, and validated against BEHAVE-AD, may be easier
abulia are seen in the tuberothalamic artery to use within the time constraints of a clinic
syndrome, which involves the reticular, intra- evaluation. Other assessment scales focus on
laminar, ventral anterior, rostral ventrolateral, quantifying single symptoms (see Table 21.6
mediodorsal, and anterior thalamic nuclei. for examples) and may be useful alone or in
Altered social skills, apathy, aggression, and combination with a multisymptom tool.
agitation are seen in the paramedian artery Regular clinical assessment allows for
thalamic syndrome, which involves the ven- timely implementation of intervention strate-
tral internal medullary lamina, ventral amyg- gies to improve the quality of life for patients
dalofugal pathway, and mamillothalamic tract. and their caregivers (see Chapters 2426).
Poststroke dementia is another presenta- Management strategies include pharmaco-
tion of vascular dementia that is associated logical and therapeutic interventions as well
with neuropsychiatric symptoms related as alterations in the patients living environ-
to the location of the stroke. There is a high ment. Cholinesterase inhibitors, memantine,
positive association between the incidence of antidepressants, anxiolytics, neuroleptics,
522part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
and stimulants are among the medication demonstrated by eZIS in patients with DAT.
classes that may be helpful in managing Neuroscience Letters, 441, 328331.
neuropsychiatric symptoms in dementia. Alexopoulos, G., Abrams, R., Young, R., &
Electroconvulsive therapy may have a role in Shamoian, C. (1988). Cornell Scale for
Depression in Dementia. Biological Psychiatry,
carefully selected cases.
23(3), 271284.
Alzheimer, A., Stelzmann, R., Schnitzlein, H.,&
Murtagh, F. (1995). An English translation of
Conclusion Alzheimers 1907 paper, Uber eine eigen-
artige Erkankung der Hirnrinde. Clincial
Neuropsychiatric symptoms frequently occur Anatomy, 8(6), 429431.
during the course of dementing illnesses as Ancoli-Israel, S., Gehrman, P., Martin, J.,
a result of dysfunction in neural networks Shochat, T., Marler, M., Corey-Bloom, J., &
subserving mood, affect, perception, and Levi, L. (2003). Increased light exposure
thought processes. These features may herald consolidates sleep and strengthens circa-
the onset of the dementia and also are seen dian rhythms in severe Alzheimers disease
patients. Behavioral Sleep Medicine, 1(1), 2236.
in all stages of dementia. Different dement-
Apostolova, L., & Cummings, J. (2008).
ing processes have different neuropsychiat- Neuropsychiatric manifestations in mild cog-
ric symptom profiles, which can aid in the nitive impairment: A systematic review of
differential diagnosis and have therapeutic the literature. Dementia and Geriatric Cognitive
implications. Neuropsychiatric symptoms Disorders, 25(2), 115126.
may have an adverse impact on the quality Apostolova, L., & Cummings, J. (2010).
of life and well-being of patients as well as Neuropsychiatric aspects of Alzheimers
their caregivers. Impairment of insight and disease and other dementing illnesses. In S.
judgment can lead to financial, medical, C. Yudofsky (Ed.), Essentials of neuropsy-
and testamentary decision-making impair- chiatry and behavioral neurosciences (2nd
ed., pp 409). Washington, DC: American
ments. Early recognition of neuropsychiatric
Psychiatric Publishing.
changes is a crucial step towards instituting Apostolova, L. A., Akopyan, G. G., Partiali,
timely social and medical interventions. N., Steiner, C. A., Dutton, R. A., Hayashi,
K. M.,...Thompson, P. M. (2007). Structural
References correlates of apathy in Alzheimers disease.
Dementia and Geriatric Cognitive Disorders,
Aarsland, D., Brnnick, K., Ehrt, U., De Deyn, P., 24(2), 9197.
Tekin, S., Emre, M.,& Cummings, J.L. (2007). Aries, M., Le Bastard, N., Debruyne, H., Van
Neuropsychiatric symptoms in patients Buggenhout, M., Nagels, G., De Deyn, P., &
with Parkinsons disease and demen- Engelborghs, S. (2010). Relation between
tia: Frequency, profile and associated care frontal lobe symptoms and dementia sever-
giver stress. Journal of Neurology, Neurosurgery ity within and across diagnostic dementia
and Psychiatry, 78(1), 3642. categories. International Journal of Geriatric
Akiyama, H., Hashimoto, H., Kawabe, J., Psychiatry, 25(11), 11861195.
Higashiyama, S., Kai, T., Kataoka, K.,...Kiriike, Baddeley, A., Baddeley, H., Bucks, R.,& Wilcock,
N. (2008). The relationship between depres- G. (2001). Attentional control in Alzheimers
sive symptoms and prefrontal hypoperfusion disease. Brain, 124(Pt 8), 14921508.
CHAPTER 21. Neuropsychiatric Symptoms of Dementia 523
Balasa, M., Gelpi, E., Antonell, A., Rey, M. J., Bjelland, I., Dahl, A., Haug, T.,& Neckelmann,
Snchez-Valle, R., Molinuevo, J.L.,& Llad, D. (2002). The validity of the Hospital Anxiety
A. (2011). Clinical features and APOE geno- and Depression Scale - An updated litera-
type of pathologically proven early-onset ture review. Journal of Psychosomatic Research,
Alzheimer disease. Neurology, 76(20), 52(2), 6977.
17201725. Blanks, J., Schmidt, S., Torigoe, Y., Porrello,
Ballard, C., Boyle, A., Bowler, C.,& Lindesay, J. K., Hinton, D., & Blanks, R. (1996). Retinal
(1996). Anxiety disorders in dementia suffer- pathology in Alzheimers disease. II.
ers. International Journal of Geriatric Psychiatry, Regional neuron loss and glial changes in
11(11), 987990. GCL. Neurobiology of Aging, 17(3), 385395.
Ballard, C., Holmes, C., McKeith, I., Neill, D., Bliwise, D. (2004). Sleep disorders in
OBrien, J., Cairns, N., .
.
.
Perry, R. (1999). Alzheimers disease and other dementias.
Psychiatric morbidity in dementia with Clinical Cornerstone, 6(28), S16S28.
Lewy bodies: A prospective clinical and Boeve, B., Silber, M., & Ferman, T. (2003).
neuropathological comparative study with Melatonin for treatment of REM sleep behav-
Alzheimers disease. American Journal of ior disorder in neurologic disorders: Results
Psychiatry, 156(7), 10391045. in 14 patients. Sleep Medicine, 4(4), 281284.
Ballard, C., Margallo-Lana, M., Fossey, J., Boeve, B., Silber, M.,& Ferman, T. (2004). REM
Reichelt, K., Myint, P., Potkins, D.,& OBrien, sleep behavior disorder in Parkinsons dis-
J. (2001). A 1-year follow-up study of behav- ease and dementia with Lewy bodies. Journal
ioral and psychological symptoms in demen- of Geriatric Psychiatry and Neurology, 17(3),
tia among people in care environments. 146157.
Journal of Clinical Psychiatry, 62(8), 631636. Botros, N., Concato, J., Mohsenin, V., Selim, B.,
Ballard, C., Neill, D., OBrien, J., McKeith, I., Doctor, K., & Yaggi, H. (2009). Obstructive
Ince, P., & Perry, R. (2000). Anxiety, depres- sleep apnea as a risk factor for type 2 dia-
sion and psychosis in vascular demen- betes. American Journal of Medicine, 122(12),
tia: Prevalence and associations. Journal of 11221127.
Affective Disorders, 59(2), 97106. Boyle, P., Malloy, P., Salloway, S., Cahn-Weiner,
Bathgate, D., Snowden, J., Varma, A., Blackshaw, D., Cohen, R., & Cummings, J. (2003).
A., & Neary, D. (2001). Behaviour in fron- Executive dysfunction and apathy predict
totemporal dementia, Alzheimers disease functional impairment in Alzheimer disease.
and vascular dementia. Acta Neurologica American Journal of Geriatric Psychiatry, 11(2),
Scandinavica, 103(6), 367378. 214221.
Baudic, S., Barba, G., Thibaudet, M., Smagghe, A., Bruen, P., McGeown, W., Shanks, M.,& Venneri,
Remy, P.,& Traykov, L. (2006). Executive func- A. (2008). Neuroanatomical correlates of neu-
tion deficits in early Alzheimers disease and ropsychiatric symptoms in Alzheimers dis-
their relations with episodic memory. Archives ease. Brain, 131(Pt 9), 24552463.
of Clinical Neuropsychology, 21(1), 1521. Butters, M., Klunk,W. E., Mathis, C. A., Price,
Bedard, M., Montplaisir, J., Richer, F., Rouleau, J. C., Ziolko, S. K., Hoge, J. A.,...Meltzer,
I., & Malo, J (1991). Obstructive sleep apnea C. C. (2008). Imaging Alzheimer pathol-
syndrome:Pathogenesis of neuropsychologi- ogy in late-life depression with PET and
cal deficits. Journal of Clinical and Experimental Pittsburgh Compound-B. Alzheimers Disease
Neuropsychology, 13(6), 950964. and Associated Disorders, 22(3), 261268.
Benoit, M., Dygai, I., Migneco, O., Robert, Callahan, C. M., Boustani, M. A., Unverzagt,
P.H., Bertogliati, C., Darcourt, J.,...Prinquey, F.W., Austrom, M.G., Damush, T.M., Perkins,
D. (1999). Behavioral and psychological A. J.,...Hendrie, H. C. (2006). Effectiveness
symptoms in Alzheimers disease. Relation of collaborative care for older adults with
between apathy and regional cerebral per- Alzheimer disease in primary care:Arandom-
fusion. Dementia and Geriatric Cognitive ized controlled trial. Journal of the American
Disorders, 10(6), 511517. Medical Association, 295(18), 21482157.
Benoit, M., Koulibaly, P. M., Migneco, O., Carr, D., Ott, B., Noto, R., & Fogel, B. (2010).
Darcourt, J., Pringuey, D. J., & Robert, P. H. The older adult driver with cognitive impair-
(2002). Brain perfusion in Alzheimers dis- ment: Its a very frustrating life. Journal
ease with and without apathy: A SPECT of the American Medical Association, 303(16),
study with statistical parametric mapping 16321641.
analysis. Psychiatric Research, 114(2), 103111. Chemerinski, E., Petracca, G., Sabe, L., Kremer,
Berrios, G. (1982). Tactile hallucina- J., & Starkstein, S. E. (2001). The specific-
tions: Conceptual and historical aspects. ity of depressive symptoms in patients with
Journal of Neurology, Neurosurgery and Alzheimers disease. American Journal of
Psychiatry, 45(4), 285293. Psychiatry, 158(1), 6872.
524part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Chen, J., Borson, S., & Scanlan, J. (2000). Flynn, F., Cummings, J., & Gornbein, J.
Stage-specific prevalence of behavioral symp- (1991). Delusions in dementia syn-
toms in Alzheimers disease in a multi-ethnic dromes: Investigation of behavioral and
community sample. American Journal of neuropsychological correlates. Journal of
Geriatric Psychiatry, 8(2), 123133. Neuropsychiatry and Clinical Neuroscience, 3(4),
Chen, S., Sultzer, D., Hinkin, C., Mahler, M.,& 364370.
Cummings, J. (1998). Executive dysfunction Galynker, I., Dutta, E., Vilkas, N., Ongseng, F.,
in Alzheimers disease: Association with Finestone, H., Gallagher, R.,...Rosenthal, R.N.
neuropsychiatric symptoms and functional (2000) Hypofrontality and negative symptoms
impairment. Journal of Neuropsychiatry and in patients with dementia of Alzheimer type.
Clinical Neuroscience, 10(4), 426432. Neuropsychiatry Neuropsychology and Behavioral
Cohen-Mansfield, J. (1986). Agitated behav- Neurology, 13(1), 5359.
iors in the elderly. II. Preliminary results in Geda, Y., & Roberts, R. (2008). Prevalence of
the cognitively deteriorated. Journal of the neuropsychiatric symptoms in mild cog-
American Geriatric Society, 34(10), 722727. nitive impairment and normal cognitive
Craig, A. H., Cummings, J. L., Fairbanks, L., aging: Population-based study. Archives of
Itti, L., Miller, B.L., Li, J.,& Mena, I. (1996). General Psychiatry, 65(10), 11931198.
Cerebral blood flow correlates of apathy in Geda, Y. E. (2010). Blowing hot and cold over
Alzheimer disease. Archives of Neurology, depression and cognitive impairment.
53(11), 11161120. Neurology, 75, 1214.
Cummings, J., Mega, M., Gray, K., Grossberg, G., Irwin, P., Satlin, A., Mesenbrink,
Rosenberg-Thompson, S., Carusi, D., & P., & Spiegel, R. (2004). Rivastigmine in
Gornbein, J. (1994). The Neuropsychiatric Alzheimer disease: Efficacy over two years.
Inventory. Neurology, 44(12), 2308. American Journal of Geriatric Psychiatry, 12(4),
DOnofrio, G., Sancarlo, D., Panza, F., Copetti, 420431.
M., Cascavilla, L., Paris, F.,...Pilotto, A. Hargrave, R., Reed, B., & Mungas, D. (2000).
(2012). Neuropsychiatric symptoms and Depressive syndromes and functional disabil-
functional status in Alzheimers disease and ity in dementia. Journal of Geriatric Psychiatry
vascular dementia patients. Current Alzheimer and Neurology, 13(2), 7277.
Research, 9(6), 759771. Hibi, S., Yamaguchi, Y., Umeda-Kameyama,
de Beurs, E., Beekman, A., van Balkom, A., Y., Yamamoto, H., Iijima, K., Momose, T.,
Deeg, D., van Dyck, R., & van Tilburg, W. Akishita, M., & Ouchi Y. (2012). The high
(1999). Consequences of anxiety in older per- frequency of periodic limb movements in
sons: Its effect on disability, well-being and patients with Lewy body dementia. Journal of
use of health services. Psychological Medicine, Psychiatric Research, 46(12), 15901594.
29(3), 583593. Hirono, N., Mega, M., Dinov, I., Mishkin, F., &
Deutsch, L., Bylsma, F., Rovner, B., Steele, C.,& Cummings, J. (2000). Left frontotemporal
Folstein, M. (1991). Psychosis and physi- hypoperfusion is associated with aggres-
cal aggression in probable Alzheimers dis- sion in patients with dementia. Archives of
ease. American Journal of Psychiatry, 148(9), Neurology, 57(6), 861866.
11591163. Hofman, M.,& Swaab, D. (2006). Living by the
Devanand, D., Jacobs, D. M., Tang, M. X., Del clock:The circadian pacemaker in older peo-
Castillo-Castaneda, C., Sano, M., Marder, ple. Ageing Research Reviews, 5(1), 3351.
K.,..
.
Stern, Y. (1997). The course of psy- Janzing, J., Teunisse, R., Bouwens, P., van t.
chopathologic features in mild to moder- Hof, M., & Zitman, F. (2000). The course of
ate Alzheimer disease. Archives of General depression in elderly subjects with and with-
Psychiatry, 54(3), 257263 out dementia. Journal of Affective Disorders,
Devanand, D.P., Sano, M., Tang, M.X., Taylor, 57(1-3), 4954.
S., Gurland, B., Wilder, D., .
.
.
Mayeux, R. Jeste, D., & Finkel, S. (2000). Psychosis of
(1996). Depressed mood and the incidence of Alzheimers disease and related dementias.
Alzheimers disease in the elderly living in Diagnostic criteria for a distinct syndrome.
the community. Archives of General Psychiatry, American Journal of Geriatric Psychiatry, 8(1),
53, 175182. 2934.
Ferman, T., Boeve, B., Smith, G., Silber, M., Lucas, Johns, E., Phillips, N., Belleville, S., Goupil,
J., Graff-Radford, N.,...Ivnik, R. J. (2002). D., Babins, L., Kelner, N.,...Chertkow, H.
Dementia with Lewy bodies may present (2012). The profile of executive function-
as dementia and REM sleep behavior disor- ing in amnestic mild cognitive impair-
der without Parkinsonism or hallucinations. ment: Disproportionate deficits in
Journal of the International Neuropsychological inhibitory control. Journal of the International
Society, 8(7), 907914. Neuropsychological Society, 18(3), 541555.
CHAPTER 21. Neuropsychiatric Symptoms of Dementia 525
Jost, B., & Grossberg, G. (1996). The evolution in depressed AD patients: A brain SPECT
of psychiatric symptoms in Alzheimers dis- finding by statistical parametric mapping.
ease: A natural history study. Journal of the Dementia and Geriatric Cognitive Disorders,
American Geriatric Society, 44(9), 10781081. 16(4), 238244.
LaBarge, E. (1993). A preliminary scale to mea- Liu, W., Miller, B., Kramer, J., Rankin, K.,
sure the degree of worry among mildly Wyss-Coray, C., Gearhart, R.,...Rosen, H. J.
demented Alzheimer disease patients. (2004). Behavioral disorders in the frontal and
Physical and Occupationa Therapy in Geriatrics, temporal variants of frontotemporal demen-
11(3), 4357. tia. Neurology, 62(5), 742748.
Lanctot, K., Moosa, S., Herrmann, N., Lopez, O., Becker, J., Brenner, R., Rosen,
Leibovitch, F., Rothenburg, L., Cotter, J., Bajulaiye, O., & Reynolds, C. (1991).
A.,...Black, S. E. (2007). A SPECT study of Alzheimers disease with delusions and hal-
apathy in Alzheimers disease. Dementia and lucinations:Neuropsychological and electro-
Geriatric Cognitive Disorders, 24(1), 6572. encephalographic correlates. Neurology, 41(6),
Landes, A., Sperry, S., & Strauss, M. (2005). 906912.
Prevalence of apathy, dysphoria, and depres- Lyketsos, C., Steinberg, M., Tschanz, J., Norton,
sion in relation to dementia severity in M., Steffens, D., & Breitner, J. (2000). Mental
Alzheimers disease. Journal of Neuropsychiatry and behavioral disturbances in demen-
and Clinical Neuroscience, 17(3), 342349. tia: Findings from the Cache County Study
Landes, A. S., Sperry, S. D., Strauss, M. E., & on Memory in Aging. American Journal of
Geldmacher, D. S. (2001). Apathy in Psychiatry, 157(5), 708714.
Alzheimers disease. Journal of the American Lyketsos, C.G., Lopez, O., Jones, B., Fitzpatrick,
Geriatrics Society, 49(12), 17001707. A. L., Breitner, J., & DeKosky, S. (2002).
Lechowski, L., Benoit, M., Chassagne, P., Vedel, Prevalence of neuropsychiatric symptoms
I., Tortrat, D., Teillet, L., & Vellas, B. (2009). in dementia and mild cognitive impair-
Persistent apathy in Alzheimers disease as ment: Results from the cardiovascular
an independent factor of rapid functional health study. Journal of the American Medical
decline:The REAL longitudinal cohort study. Association, 288, 14751483.
International Journal of Geriatric Psychiatry, 24, Marin, D., Green, C., Schmeidler, J., Harvey, P.,
341346. Lawlor, B., Ryan, T.,...Mohs, R. C. (1997).
Lesher, E.,& Berryhill, J. (1994). Validation of the Noncognitive disturbances in Alzheimers
geriatric depression scale--short form among disease: Frequency, longitudinal course,
inpatients. Journal of Clinical Psychology, 50(2), and relationship to cognitive symptoms.
256260. Journal of the American Geriatric Society, 45(11),
Levy, M., Cummings, J., Fairbanks, L., Bravi, D., 13311338.
Calvani, M.,& Carta, A. (1996). Longitudinal Marin, R. (1990). Differential diagnosis and
assessment of symptoms of depression, agi- classification of apathy. American Journal of
tation, and psychosis in 181 patients with Psychiatry, 147(1), 2230.
Alzheimers disease. American Journal of Marshall, G., Fairbanks, L., Tekin, S., Vinters,
Psychiatry, 153(11), 14381443. H.,& Cummings, J. (2006). Neuropathologic
Levy, M., Cummings, J., Fairbanks, L., correlates of apathy in Alzheimers disease.
Masterman, D., Miller, B., Craig, A.,...Litvan, Dementia and Geriatric Cognitive Disorders,
I. (1998). Apathy is not depression. Journal 21(3), 144147.
of Neuropsychiatry and Clinical Neuroscience, Marshall, G., Monserratt, L., Harwood, D.,
10(3), 314319. Mandelkern, M., Cummings, J.,& Sultzer, D.
Levy-Cooperman, N., Burhan, A., Rafi-Tari, (2007). Positron emission tomography meta-
S., Kusano, M., Ramirez, J., Caldwell, C., & bolic correlates of apathy in Alzheimer dis-
Black, S. E. (2008). Frontal lobe hypoperfu- ease. Archives of Neurology, 64(7), 10151020.
sion and depressive symptoms in Alzheimer Mega, M., Cummings, J., Fiorello, T.,& Gornbein,
disease. Journal of Psychiatry and Neuroscience, J. (1996). The spectrum of behavioral changes in
33(3), 218226. Alzheimers disease. Neurology, 46(1), 130135.
Leyhe, T., Saur, R., Eschweiler, G.,& Milian, M. Mendez, M., Lauterbach, E., & Sampson, S.
(2011). Impairment in proverb interpretation (2008). An evidence-based review of the
as an executive function deficit in patients psychopathology of frontotemporal demen-
with amnestic mild cognitive impairment tia: A report of the ANPA Committee on
and early Alzheimers disease. Dementia and Research. Journal of Neuropsychiatry and
Geriatric Cognitive Disorders Extra, 1(1), 5161. Clinical Neuroscience, 20(2), 130149.
Liao, Y.C., Liu, R.S., Lee, Y.C., Sun, C.M., Liu, Migneco, O., Benoit, M., Koulibaly, P.M., Dygai,
C.Y., Wang, P.S.,& Liu, H.C. (2003). Selective I., BertogliatI, C., Desvignes, P.,...Darcourt, J.
hypoperfusion of anterior cingulate gyrus (2001). Perfusion brain SPECT and statistical
526part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
parametric mapping analysis indicate that Robert, P., Onyike, C., Leentjens, A., Dujardin,
apathy is a cingulate syndrome: A study K., Aalten, P., Starkstein, S.,...Byrne, J. (2009).
in Alzheimers disease and nondemented Proposed diagnostic criteria for apathy in
patients. Neuroimage, 13(5), 896902. Alzheimers disease and other neuropsychi-
Modirrousta, M., Price, B.H.,& Dickerson, B.C. atric disorders. European Psychiatry, 24(2),
(2013) Neuropsychiatric symptoms in pri- 98104.
mary progressive aphasia: Phenomenology, Robert, P. H., Darcourt, G., Koulibaly, M. P.,
pathophysiology, and approach to assess- Clairet, S., Benoit, M., Garcia, R.,...Darcourt,
ment and treatment. Neurodegenerative Disease J. (2006). Lack of initiative and interest in
Management, 3(2), 133146. Alzheimers disease: A single photon emis-
Olin, J., Schneider, L.S., Katz, I.R., Meyers, B.S., sion computed tomography study. European
Alexopoulos, G.S., Breitner, J.C.,...Lebowitz, Journal of Neurology, 13(7), 729735.
B. D. (2002). Provisional diagnostic crite- Rockwell, E., Krull, A., Dimsdale, J., & Jeste,
ria for depression of Alzheimer disease. D. (1994). Late-onset psychosis with somatic
American Journal of Geriatric Psychiatry, 10(2), delusions. Psychosomatics, 35(1), 6672.
125128. Rosen, J., Burgio, L., Kollar, M., Cain, M.,
Ott, B. R., Noto, R. B., & Fogel, B. S. (1996). Allison, M., Fogleman, M.,...Zubenko,
Apathy and loss of insight in Alzheimers G. S. (1994). The Pittsburgh Agitation
disease: A SPECT imaging study. Journal of Scale: A user-friendly instrument for rat-
Neuropsychiatry and Clinical Neuroscience, 8(1), ing agitation in dementia patients. American
4146. Journal of Geriatric Psychiatry, 2, 5259.
Papka, M., Rubio, A., Schiffer, R., & Cox, C. Schmahmann, J. (2003). Vascular syndromes of
(1998). Lewy body disease:Can we diagnose the thalamus. Stroke, 34(9), 22642278.
it?. Journal of Neuropsychiatry and Clinical Schmidtke, K., & Hull, M. (2002).
Neuroscience, 10(4), 405412. Neuropsychological differentiation of small
Rabins, P., Blacker, D., Rovner, B., Rummans, vessel disease, Alzheimers disease and mixed
T., Schneider, L., Tariot, P.,...Fochtmann, dementia. Journal of Neurological Sciences, 204,
L.J. (2007). American Psychiatric Association 1722.
practice guideline for the treatment of Schneider, J., Murray, J., Banerjee, S., & Mann,
patients with Alzheimers disease and other A. (1999). EUROCARE: A cross-national
dementias, second edition. American Journal of study of co-resident spouse carers for people
Psychiatry, 164(12 Suppl), 556. with Alzheimers disease: I--Factors associ-
Rabins, P. V., & Nicholson, M. (1991). Acute ated with carer burden. International Journal of
psychiatric hospitalization for patients with Geriatric Psychiatry, 14, 651661.
irreversible dementia. International Journal of Schnelle, J., Cruise, P.A., Alessi, C.A., Ludlow,
Geriatric Psychiatry, 6(4), 209211. K., al-Samarrai, N. R., & Ouslander, J. G.
Redline, S., Yenokyan, G., Gottlieb, D., Shahar, E., (1998). Sleep hygiene in physically dependent
OConnor, G., Resnick, H.,...Punjabi, N. M. nursing home residents:Behavioral and envi-
(2010). Obstructive sleep apnea-hypopnea ronmental intervention implications. Sleep,
and incident stroke: The sleep heart health 21(5), 515523.
study. American Journal of Respiratory Critical Senanarong, V., Cummings, J., Fairbanks,
Care Medicine, 182(2), 269277. L., Mega, M., Masterman, D., OConnor,
Reisberg, B., Auer, S., & Monteiro, I. (1996). S., & Strickland, T. L. (2004). Agitation in
Behavioral pathology in Alzheimers dis- Alzheimers disease is a manifestation
ease (BEHAVE-AD) rating scale. International of frontal lobe dysfunction. Dementia and
Psychogeriatrics, 3, 301308. Geriatric Cognitive Disorders, 17(1-2), 1420.
Robert, P., Berr, C., Volteau, M., Bertogliati, Shanka, K., Walker, M., Frost, D., & Orrell, M.
C., Benoit, M., Sarazin, M., ..
.
Dubois, B. (1999). The development of a valid and reli-
(2006). Apathy in patients with mild cogni- able scale for rating anxiety in dementia
tive impairment and the risk of developing (RAID). Aging and Mental Health, 3(1), 3949.
dementia of Alzheimers disease:Aone-year Shochat, T., Martin, J., Marler, M., &
follow-up study. Clinical Neurology and Ancoli-Israel, S. (2000). Illumination levels in
Neurosurgery, 108(8), 733736. nursing home patients: Effects on sleep and
Robert, P., Clairet, S., Benoit, M., Koutaich, activity rhythms. Journal of Sleep Research,
J., Bertogliati, C., Tible, O.,...Bedoucha, P. 9(4), 373379.
(2002). The apathy inventory:Assessment of Simard, M., van Reekum, R.,& Cohen, T. (2000).
apathy and awareness in Alzheimers dis- A review of the cognitive and behavioral
ease, Parkinsons disease and mild cognitive symptoms in dementia with Lewy bod-
impairment. International Journal of Geriatric ies. Journal of Neuropsychiatry and Clinical
Psychiatry, 17(12), 10991105. Neuroscience, 12(4), 425450.
CHAPTER 21. Neuropsychiatric Symptoms of Dementia 527
Skogseth, R., Mulugeta, E., Jones, E., Ballard, C., Sultzer, D., Mahler, M., Mandelkern, M.,
Rongve, A., Nore, S.,...Aarsland, D. (2008). Cummings, J., Van Gorp, W., Hinkin, C., &
Neuropsychiatric correlates of cerebrospi- Berisford, M. A. (1995). The relationship
nal fluid biomarkers in Alzheimers disease. between psychiatric symptoms and regional
Dementia and Geriatric Cognitive Disorders, cortical metabolism in Alzheimers dis-
25(6), 559563. ease. Journal of Neuropsychiatry and Clinical
Sperling, R., Aisen, P., Beckett, L., Bennett, D., Neuroscience, 7(4), 476484.
Craft, S., Fagan, A.,...Phelps, C. H. (2011). Sunderland, T., & Minichiello, M. (1997).
Toward defining the preclinical stages of Dementia mood assessment scale. International
Alzheimers disease:Recommendations from Psychogeriatrics, 8(Suppl S3), 329331.
the National Institute on Aging-Alzheimers Tarawneh, R.,& Holtzman, D. (2012). The clini-
Association workgroups on diagnostic guide- cal problem of symptomatic Alzheimer dis-
lines for Alzheimers disease. Alzheimers and ease and mild cognitive impairment. Cold
Dementia, 7(3), 280292. Spring Harbor Perspectives in Medicine, 2(5),
Starkstein, S., Chemerinski, E., Sabe, L., Kuzis, a006148.
G., Petracca, G., Teson, A.,...Leiguarda, R. Tekin, S., Mega, M., Masterman, D., Chow, T.,
(1997). Prospective longitudinal study of Garakian, J., Vinters, H., & Cummings, J. L.
depression and anosognosia in Alzheimers (2001). Orbitofrontal and anterior cingulate
disease. British Journal of Psychiatry, 171, 4752. cortex neurofibrillary tangle burden is asso-
Starkstein, S., Jorge, R., Petracca, G.,& Robinson, ciated with agitation in Alzheimer disease.
R. (2007). The construct of generalized anxi- Annals of Neurology, 49(3), 355361.
ety disorder in Alzheimer disease. American Twelftree, H., & Qazi, A. (2006). Relationship
Journal of Geriatric Psychiatry, 15(1), 4249. between anxiety and agitation in dementia.
Starkstein, S., Jorge, R., Mizrahi, R.,& Robinson, R. Aging and Mental Health, 10(4), 362367.
(2006). A diagnostic formulation for anosogno- Vitiello, M., & Borson, S. (2001). Sleep distur-
sia in Alzheimers disease. Journal of Neurology, bances in patients with Alzheimers dis-
Neurosurgery and Psychiatry, 77(6), 719725. ease: Epidemiology, pathophysiology and
Starkstein, S.,& Leentjens, A. (2008). The noso- treatment. CNS Drugs, 15(10), 777796.
logical position of apathy in clinical prac- Wragg, R., & Jeste, D. (1989). Overview of
tice. Journal of Neurology, Neurosurgery and depression and psychosis in Alzheimers
Psychiatry, 79(10), 10881092. disease. American Journal of Psychiatry, 146(5),
Starkstein, S., Mayberg, H., Berthier, 577587.
M., Fedoroff, P., Price, T., Dannals, Wu, Y., & Swaab, D. (2005). The human
R.,...Robinson, R.G. (1990). Mania after brain pineal gland and melatonin in aging and
injury:Neuroradiological and metabolic find- Alzheimers disease. Journal of Pineal Research,
ings. Annals of Neurology, 27(6), 652659. 38(3), 145152.
Steele, C., Rovner, B., Chase, G.,& Folstein, M. Young, T., Peppard, P., & Gottlieb, D.
(1990). Psychiatric symptoms and nursing (2002). Epidemiology of obstructive sleep
home placement of patients with Alzheimers apnea: A population health perspective.
disease. American Journal of Psychiatry, 147(8), American Journal of Respiratory Critical Care
10491051. Medicine, 165(9), 12171239.
22
Candidate disease-modifying therapies for (DeKosky& Marek, 2003). Partly because sub-
Alzheimers disease (AD) have been in clini- stantial synaptic and neuronal loss is typically
cal trials for a number of years (Cummings, present by the time patients exhibit mild AD
Doody,& Clark, 2007), with a growing list of dementia (Gomez-Isla etal., 1996; Price etal.,
failures. These compounds are being tested 2001; Scheff, Price, Schmitt,& Mufson, 2005),
in patients with a clinical diagnosis of prob- it is possible that some disease-modifying
able AD dementia to determine whether they therapies may be less efficacious if initiated
will slow the inexorable course of progressive at this stage than they would be if begun
decline. Yet a clinical diagnosis of probable earlier. There has been growing consensus
AD has traditionally required the determina- for over 5 years that adequate knowledge
tion that the patient has dementia, defined exists about the clinical and neurobiologic
as the loss of social or occupational function phenotype of typical AD that we should be
due to multidomain cognitive impairment. attempting to make an earlier diagnosis
In practice, this is often operationalized for prior to mild dementiaparticularly for the
clinical trial criteria as a Clinical Dementia purposes of earlier clinical trial enrollment
Rating (CDR) of 1 (mild dementia) or in some (Dubois et al., 2007, 2010). Although a care-
cases CDR 0.5 (very mild dementia) and a ful history and examination is at the core of
Mini-Mental State Exam (MMSE) score less clinical practice and research (Chapter9), the
than 24 or in some cases 26 (as discussed in new diagnostic criteria that were published
detail in Chapter19). By the time this level of in April 2011 formally incorporate the use of
impairment is reached, many patients have various types of biomarkers in the diagnosis
substantial difficulties in complex activities of of AD at dementia and prodromal dementia
daily living, such as community affairs, driv- stages (Albert et al., 2011; Jack et al., 2011;
ing, financial or household management, and McKhann etal., 2011; Sperling etal., 2011). As
planning and decision making. If efficacious discussed in other chapters in this book, we
disease-modifying treatments for AD are can now diagnose an individual with mild
developed, it would be ideal to administer cognitive impairment that is highly likely
them to patients with the disease prior to the to be due to AD based on a combination of
point at which impairment is this prominent clinical and biomarker data. Furthermore, we
528
CHAPTER 22. Neuroimaging, Cerebrospinal Fluid Markers, and Genetic Testing in Dementia 529
can identify individuals with preclinical AD situations, and other kinds of biomarkers may
for recruitment for research, including clini- be valuable in this regard as well. Traits mea-
cal trials of interventions aimed at delaying sured by biomarkers are typically thought of
symptoms. as risk factors for disease, which may involve
A major source of such information is genetic, anatomic, or physiologic elements.
neuroimaging technology. Various types of For example, a number of imaging studies
neuroimaging techniques enable elements of cognitively intact individuals at a younger
of brain structure and function to be visual- age than the typical onset of AD have begun
ized in living people and allow quantitative to investigate anatomic or physiologic dif-
measurements to be made of the anatomy, ferences between those at elevated genetic
connectivity, perfusion, metabolism, and risk for AD and controls, and to follow these
activity of various brain regions and net- changes over time (e.g., temporoparietal
works. Furthermore, new molecular imag- hypometabolism in young APOE-4 carriers;
ing techniques allow amyloid pathology to Reiman et al., 2004). Ultimately, since most
be identified in living individuals, and in AD-related traits indicate risk but are not
vivo molecular imaging markers are emerg- deterministic (i.e., not all APOE-4 carriers
ing for tau. Specific abnormalities in brain will manifest clinical dementia symptoms),
structure and function, and the presence of long-term clinical follow-up coupled with
pathologic molecular markers, have taken on the longitudinal assessment of biomarkers
prime importance in the early diagnosis and will be needed to determine which individu-
monitoring of progression of AD and related als in these risk groups develop cognitive
disorders. While to date many of these decline and clinical AD. Thus, biomarkers
advanced imaging approaches have primar- of disease traits would indicate susceptibil-
ily been used in research and clinical trials, ity and could potentially be combined with
they are rapidly moving toward use in clini- other risk factors to improve the accuracy of
cal practice. In parallel, cerebrospinal fluid risk estimation and prediction of clinical dis-
(CSF) biomarkers of amyloid and tau have ease, or to increase the yield of screening for
rapidly matured as very valuable biomarkers preclinical AD.
of AD molecular pathology and are used in A biomarker of disease state enables the
both research and practice in many countries detection of an abnormality associated with
(Herskovits& Growdon, 2010). disease pathobiology in an individual, and
While knowledge about imaging and CSF it is typically thought of as a diagnostic
markers of AD is robust, such knowledge is marker. In AD, disease markers are usually
less mature in other neurodegenerative dis- considered to reflect the presence of neuropa-
eases that cause dementia. Further funda- thology, and they include measures derived
mental research is needed to improve our from neuroimaging, serum, and cerebrospi-
knowledge of the anatomic, physiologic, nal fluid, and other biologic materials. The
and molecular phenotypes that can be mea- individual in whom a marker is positive
sured using in vivo methods in patients with is presumed to have a biological abnormal-
non-AD dementias. This chapter will provide ity consistent with AD neuropathology, but
a detailed review of imaging and fluid bio- he or she may or may not have symptoms.
markers with an emphasis on AD but with Studies of markers of disease state have been
discussion of other dementias as well. confounded by the notorious difficulty in cor-
relating neuropathologic states themselves
with clinical state. That is, patients with
Biomarker Constructs clinically probable AD who are equated on
clinical metrics may exhibit marked variabil-
Before considering specific biomarkers, it is ity in the density and distribution of senile
important to review a general framework plaques, neurofibrillary tangles, neuronal
for how they can be used. Fox et al. (2004) loss, and other measures of abnormal brain
enumerated three aspects of disease patho- structure. Furthermore, postmortem studies
physiology in which biomarkers may play indicate that some cognitively intact individ-
important roles:as markers of trait, state, and uals and many mild cognitive impairment
rate. Neuroimaging- and fluid-based mea- (MCI) patients already carry a heavy burden
sures may provide useful data in all of these of AD neuropathology (Gomez-Isla et al.,
530part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
1996; Kordower etal., 2001; Price etal., 2001). (e.g., hippocampal volume, fludeoxyglucose
Thus, it is not surprising that findings from positron emission tomography [FDG-PET]).
cross-sectional studies show imaging-based Finally, individual variability in rates of
markers of brain structure and function in decline in MCI and AD and related disor-
MCI overlap substantially with both cogni- ders is substantial. Imaging-based biomark-
tively intact older control groups and with ers may offer an opportunity for additional
AD patient groups. These significant individ- power in this regard, which could be gained
ual differences that confound cross-sectional using a run-in phase to quantify subjects
studies of clinicopathologic state again rein- individual rates of change in the imaging
force the notion that detailed longitudinal marker (e.g., hippocampal volume) prior to
investigations are needed to clarify the rela- the randomization phase of the clinical trial.
tionships between clinical state and measures However, the widely ranging initial esti-
of neuroanatomy, physiology, and pathology. mates of sample sizes for clinical trials from
These ideas have been further reinforced by preliminary studies have highlighted the
recent papers proposing biomarker trajectory need for further fundamental knowledge
models of AD (Jack etal., 2010, 2013). Some regarding the natural history of in vivo ana-
of these types of measures might be useful tomic and physiologic and biofluid changes
not only to increase or reduce confidence in in MCI and AD, which will likely be similarly
a particular presumed pathologic diagnosis true in frontotemporal dementia (FTD), pro-
in a symptomatic patient but also to iden- gressive supranuclear palsy with corticobasal
tify asymptomatic/preclinical disease states syndrome (PSP/CBS), Lewy body dementia
(e.g., a cognitively normal individual with (DLB), and other diseases. Sample size esti-
brain amyloid, similar to a neurologically mates derived from power calculations are
intact patient with imaging evidence of prior influenced primarily by the proposed size of
stroke). the effect of interest (e.g., difference in rate
Finally, imaging markers of the rate of of atrophy in treated vs. control patients)
disease progressionwhich allow the and the variance of the data derived from
tracking of changes over time in pathoana- the particular measure used. The effect size
tomic or pathophysiologic alterations in the may range from 0% (no difference) to 100%
brain associated with ADwould be par- (maximum difference, which is the differ-
ticularly useful in evaluating the efficacy of ence between atrophy rates in AD patients
disease-modifying therapeutics. Importantly, and controls). Imaging data on which to
although changes in any of these markers base estimates of effect sizes for putative
may represent changes in the underlying dis- disease-modifying therapies for AD have
ease process, the rates of change of a marker increasingly begun appearing in the litera-
may or may not correlate with that of other ture. Variance of the data may be influenced
biomarkers or of clinical metrics during the by biologic variability, such as heterogeneity
time period of interest. Using imaging-based of atrophy rates in the sample, which may
measures, it may be possible to detect the relate to age, disease severity, or individual
ability of a putative disease-modifying agent differences in rate of disease progression.
to impede the degenerative process of AD in Variance is also influenced by measurement
a shorter period of time than would be nec- variability, which may result from differences
essary to judge slowing of cognitive decline. in the data acquired between multiple time
While validation of biomarkers against clini- points (e.g., due to changes in instrumenta-
cal outcomes is ultimately essential, as the tion or signal acquisition) or in differences in
focus of therapeutics shifts toward preven- postscan processing of the data (e.g., selection
tion or modulation of the neurodegenerative of regions of interest). Both sources of mea-
process prior to the presence of substantial surement variability may be compounded by
symptoms, such validation takes longer differences between sites in multicenter stud-
and becomes more difficult. Therefore, the ies. Such data may be seriously confounded
validation of new potential imaging bio- if systematic bias is introduced in any of
markers (e.g., amyloid imaging, functional these sources of variability. Further serial
magnetic resonance imaging [fMRI]) may imaging studies examining the natural his-
be performed more efficiently in conjunc- tory of changes in brain structure, function,
tion with more established imaging markers and molecular composition in the context of
CHAPTER 22. Neuroimaging, Cerebrospinal Fluid Markers, and Genetic Testing in Dementia 531
detailed clinical assessments in MCI and AD common in the elderly with or without other
has been under way as part of the American neurodegenerative diseases, but they can be
Alzheimers Disease Neuroimaging Initiative easily visualized using CT or MRI. Although
(ADNI) (Weiner etal., 2013), as well as simi- now thought to be relatively uncommon,
lar initiatives around the world. There are normal pressure hydocephalus is a condi-
also similarly designed studies under way in tion in which imaging has been viewed as
FTD and PSP/CBS. essential:if at least part of the clinical triad of
ataxia, incontinence, and dementia is associ-
ated with MR or CT evidence of ventriculo-
Traditional Role of Structural Neuroimaging megaly, the diagnosis is strongly suggested.
in the Diagnosis of Alzheimers Disease and As described further in Chapter 15, a large
Other Dementias volume lumbar puncture may or may not
produce substantial clinical improvement,
In the past, the major role of neuroimaging potentially predicting shunt responsiveness.
in dementia assessment has been to assist in Creutzfeldt-Jakob disease often has charac-
the exclusion of nondegenerative etiologies teristic diffusion-weighted imaging (DWI)
of cognitive impairment or dementia (such MRI abnormalities (hyperintensity of cortical
as tumors, inflammatory conditions, infec- ribbon and deep gray structures) (Fig. 22.1),
tious processes, etc.) or the identification of as described in more detail in Chapter 15.
features of unusual forms of dementia (such Anumber of other rare and/or rapidly pro-
as prion diseases) (Knopman et al., 2001). gressive dementias are associated with rela-
Neuroimaging can also be particularly useful tively sensitive and specific neuroimaging or
for the detection of cerebrovascular contribu- CSF or other biomarker findings, as described
tions to cognitive impairment. in detail in Chapter15.
Some examples of differential diagnoses
of cognitive disorders that can be informed
by structural imaging include the following The Neurobiologic Phenotype of Typical
(see Chapter 15 for more detail on many of Amnesic Alzheimers Disease Dementia
these conditions). In suspected cerebrovascu-
lar disease or patients with a history of stroke Research over the past two decades has led
or significant cardiovascular risk factors, revolutionary changes in dementia research
computerized tomography (CT) or magnetic and practice, with a growing array of imag-
resonance imaging (MRI) can be very helpful. ing and fluid biomarkers taking center stage
However, it is difficult to determine to what in diagnostic evaluation and monitoring of
degree cerebrovascular disease is the primary progression. AD has led the way as an exem-
cause of a patients dementia, as opposed to plar showing how imaging and fluid assay
being a contributing factor along with neu- technology can be used to measure biomark-
rodegenerative disease (see Chapter 13). ers of the disease and incorporate these into
Mixed dementia is a clinical diagnosis clinical diagnostic criteria, as described in
that is associated with structural evidence of more detail in Chapters 1618, but nearly
infarction (often with cavitary or encephalo- all other major forms of dementia have also
malacic change) or signal changes consistent now incorporated biomarkers into diagnostic
with small vessel cerebrovascular disease, evaluation formally or informally (see Part II
along with evidence of neurodegenerative of this volume).
atrophy consistent with AD or a related Although a great deal of our knowledge of
disorder. Neoplastic processes may include the neurobiologic phenotype of AD has come
primary or metastatic brain tumors that can from postmortem studies of brain tissue, a
sometimes present with cognitive decline rapidly growing body of literature includes
rather than focal sensorimotor dysfunction or in vivo measurements that attempt to cap-
other neurologic signs. Meningiomas may be ture elements of the biology of AD (Jack etal.,
possible to treat surgically. These lesions usu- 2010, 2013). While many of these studies have
ally, but not always, present with symptoms not followed patients to autopsy, and so we
that are atypical for a neurodegenerative dis- do not yet have the gold standard diagnosis
ease and raise the question of a focal brain of definite AD to corroborate the clinical diag-
lesion. Subdural hygroma/hematomas are noses, there is enough consistency in some of
532part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Figure 22.1 Diffusion-weighted magnetic resonance imaging (MRI, image left is patient left)
from a patient who presented with progressive aphasia, which evolved over rapidly 2 years to
severe dementia and death. The cortical ribbon hyperintensity shown here was localized in part to
frontoparietal language regions, consistent with initial symptoms.
these measures to provide confidence that Initiative (Mueller et al., 2005; Weiner et al.,
they are valid biomarkers of neurobiologic 2011)and other large natural history studies
abnormalities of AD. These markers include around the world.
neuroimaging measures of brain structure,
function, and connectivity, all of which are
able to show patterns of abnormalities char- Imaging the Anatomic Changes of Alzheimers
acteristic of AD rather than simply exclud- Disease
ing other possible contributors to cognitive
impairment. Thus, they can provide data in Quantitative Magnetic Resonance Imaging
support of a diagnosis of probable AD. Even Measurements of the Medial Temporal Lobe
more importantly, measures from molecular
neuroimaging and CSF have been developed In the late 1980s, the first magnetic resonance
in the past decade that are sensitive and spe- imaging (MRI) data began appearing that
cific indicators of amyloid or tau pathology. enabled the clear visualization of the human
The important advantage of such in vivo hippocampal formation in vivo (Jack et al.,
biomarkers is that they can be measured 1989; Naidich etal., 1987a, 1987b; Seab etal.,
in individuals at a time when their clinical 1988). Initial efforts at quantification pro-
phenotype is specifically characterized, in vided data indicating that manual tracings
contrast to postmortem studies in which the by trained operators were valid and reliable
clinical phenotype may have less specificity (Jack et al., 1988, 1989). These new meth-
due to progression to advanced disease. All ods were immediately applied to visualize
of these putative biomarkers have under- and quantify atrophy in patients with AD
gone intensive longitudinal study as part (Jack et al., 1987; Jack, Petersen, OBrien, &
of the Alzheimers Disease Neuroimaging Tangalos, 1992; Seab et al., 1988). As stated
CHAPTER 22. Neuroimaging, Cerebrospinal Fluid Markers, and Genetic Testing in Dementia 533
Figure22.2 Manual tracing of the hippocampal formation and parahippocampal gyrus performed
by the author in 1996. Image on left is from a cognitively intact older adult, and the image on the
right is from a patient with mild Alzheimers disease dementia.
by Jack (Jack etal., 1992), these new methods was determined possible to detect atrophy of
were quickly seen as having utility in the these regions up to 5years before the expres-
diagnostic evaluation ofAD: sion of clinical symptoms in individuals with
APP mutations (Schott etal., 2003).
The rationale for quantitative MRI of MTL As MRI and computational technologies
atrophy in the diagnosis of AD is: (1) a have matured, it has become possible to
memory impairment is usually the earliest perform increasingly sophisticated inves-
and most severe clinical manifestation of tigations of brain morphometry, includ-
AD, (2)MTL limbic structures are central to ing automated measurement of a variety of
the integrity of declarative memory func- brain regions, voxel-based morphometry and
tion, (3)MTL limbic structures are involved related unbiased exploratory analyses of
earliest and most extensively in the pathol- the whole brain or cerebral cortex, and analy-
ogy of AD, and (4)several principal MTL sis of the shape and other sophisticated mea-
limbic structures are amenable to accurate sures of aspects of brain structure (Ashburner
volumetric quantitation by MRI--the hip- etal., 2003). In addition, new techniques for
pocampal formation, amygdala, and para- the coregistration of one scan to another
hippocampal gyrus (PHG) [page183]. improved the quantification of structural
change over time within individuals (Fox&
During the 1990s, the scope of quanti- Schott, 2004). This enables individuals to be
tative structural MRI efforts expanded to used as their own controls, which reduces
include more sophisticated studies of larger the noise of individual differences in neu-
samples of patients with AD, in addition to roanatomy that are inherently present in
investigations of normal development and group-comparison studies. MRI measures of
aging. During those early years, quantita- brain structure may also be confounded by
tive MRI-based measures of brain anatomy within-subject variability in hydration status
were almost entirely obtained from manual and probably other as yet unknown factors
tracings by anatomists or trained technicians. (Walters, Fox, Crum, Taube,& Thomas, 2001).
Hippocampal volume derived from MRI was Despite these caveats, longitudinal MRI mea-
shown to correlate strongly with histologi- sures of changes in brain structure have been
cal HF volume and neuronal loss (Bobinski successfully used as outcome measures in
et al., 2000) and severity of AD pathology clinical trials of disease-modifying thera-
(Gosche, Mortimer, Smith, Markesbery, & pies for multiple sclerosis (Filippi, Dousset,
Snowdon, 2002; Jack et al., 2002), as well as McFarland, Miller, & Grossman, 2002), and
memory impairment (De Leon et al., 1997; they have been increasingly investigated in
de Toledo-Morrell etal., 2000). Hippocampal AD clinical trials (Fox etal., 2005).
and entorhinal volumetric measures were The most intensively investigated
also demonstrated useful for the identifica- MRI-based biomarkers include atrophy
tion of subgroups of individuals with MCI of the whole brain, hippocampal forma-
who would progress to a clinical diagno- tion, and entorhinal cortex or enlargement
sis of AD within a few years (Convit et al., of the temporal horn of the lateral ventricle
2000; Dickerson etal., 2001; Jack etal., 1999; (Dickerson & Sperling, 2005). Since it is
Killiany et al., 2000; Mungas et al., 2002; highly reliable, whole brain atrophy (as mea-
Visser etal., 1999)(Fig. 22.2). Furthermore, it sured using typical volumetric approaches
534part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Right Left
Lateral
Medial
Figure 22.3 Computational neuroscience now offers methods to quantify aspects of brain
structure from magnetic resonance imaging (MRI) scans. The left image depicts cortical thickness
measurement from a T1-weighted MRI scan. The right image shows a map of the areas in yellow
and red where the cerebral cortex is thinner in a group of mild Alzheimers disease dementia
patients compared to controls. (See color plate section)
etal.; Van Leemput etal., 2009; Wang etal., disease is being scanned. Previously, the MRI
2010; Yushkevich et al., 2008, 2009, 2010). data acquisition methodology for obtaining
The development of new methods for higher reasonably high-resolution images suitable
resolution MRI data acquisition is fueling for the assessment of regional atrophy existed
many of these efforts, along with new com- primarily in specialized research centers. It
putational analytic methods. Some of these is now commonplace on clinical scanners
methods can be used to visualize and mea- in routine use to obtain three-dimensional
sure detailed aspects of medial temporal lobe (which can be reformatted in multiple planes,
(MTL) atrophy in AD and other neurodegen- as opposed to the early scans that were essen-
erative diseases (Fig. 22.4). tially only viewable in one orientation) MRI
data with high signal-to-noise properties at
resolutions of 1mm3 or better. Using widely
Clinical Use of Structural Magnetic available MRI technology, radiologists can
Resonance Imaging in Dementia Evaluation set up protocols (e.g., Dementia protocol
or Memory Loss protocol) in which rela-
The atrophy patterns typical of neurodegen- tively high-resolution three-dimensional
erative diseases are often very difficult to visu- coronal sequences are obtained in addition
alize from relatively thick, two-dimensional to routine diagnostic images. Particularly
axial slices that are still often the routine with the use of new parallel acquisition tech-
protocol in many imaging centers when a niques that enable faster data collection, such
patient with suspected neurodegenerative high-resolution sequences can be acquired
Figure22.4 Higher resolution magnetic resonance imaging (MRI) scans offer better visualization
of neuroanatomy. The left image shows a 500 micrometer resolution T1-weighted MRI scan of a
cognitively intact 72-year-old adult, and the right image shows a similar image of a patient with
mild Alzheimers disease dementia, illustrating mild hippocampal atrophy.
536part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Figure22.5 Visual inspection of magnetic resonance imaging (MRI) scans can reveal patterns of
atrophy consistent with a particular type of neurodegenerative dementia. Top/bottom left images
show a patient with typical amnesic Alzheimers disease (AD) dementia, illustrating medial
temporal and parietal atrophy. Middle top/bottom images show a patient with posterior cortical
atrophy with cerebrospinal fluid biomarkers consistent with AD pathobiology, illustrating relative
preservation of medial temporal lobe with prominent parietal atrophy. Top right image shows a
patient with agrammatic primary progressive aphasia. Bottom right image shows a patient with
semantic primary progressive aphasia.
CHAPTER 22. Neuroimaging, Cerebrospinal Fluid Markers, and Genetic Testing in Dementia 537
are employed (and partly because of unclear (Drummond etal., 2000), and aging (Cabeza,
reimbursement practices). Efforts are under Anderson, Locantore, & McIntosh, 2002).
way to try to harmonize these measurements The evidence aforementioned also indicates
for the purposes of clinical research and trials that increased MTL activation can be seen
(Frisoni& Jack, 2011), and hopefully this will in the absence of significant MTL atrophy,
facilitate the use of quantitative MRI-based which provides in vivo support for labora-
morphometry in clinical practice. tory and animal data suggesting that physi-
ologic alterations may precede significant
structural abnormalities in very early AD
Imaging the Physiologic Changes of (Selkoe, 2002; Walsh& Selkoe, 2004)and may
Alzheimers Disease With Magnetic represent inefficient neural circuit function
Resonance Imaging (Stern etal., 2004). Thus, fMRI may provide
a means to detect changes in human mem-
Task-Related Functional Magnetic Resonance ory circuit function that underlie the earli-
Imaging est symptoms of AD (Sperling et al., 2009),
and it may be useful in identifying groups
A number of fMRI studies in patients with of subjects at high risk for future cognitive
clinically diagnosed AD, using a variety of decline prior to a diagnosis of AD (Miller
visually presented stimuli, have identified etal., 2006).
decreased activation in hippocampal and Recent studies are extending these initial
parahippocampal regions compared to con- insights using longitudinal and multimodal
trol subjects during episodic encoding tasks approaches. We recently showed that MCI
(Kato, Knopman, & Liu, 2001; Machulda subjects who declined over 2years of clinical
et al., 2003; Rombouts et al., 2000; Small, follow-up demonstrated an initial hippocam-
Perera, DeLaPaz, Mayeux, & Stern, 1999; pal hyperactivation during encoding but after
Sperling et al., 2003). As for MCI, the pro- 2years a reduced level of activity, consistent
dromal stage of AD, studies have demon- with the inverse U-shaped curve model
strated conflicting results with some findings (OBrien etal., 2010). Evidence of the earliest
of hippocampal hypoactivation (Johnson stages of this process can be seen in cogni-
etal., 2006; Machulda etal., 2003)similar to tively intact older adults with brain amyloid,
that seen in AD dementia and some findings who hyperactivate the hippocampus during
of hyperactivation (Dickerson et al., 2005; memory encoding relative to the activation
Hamalainen etal., 2006; Kircher etal., 2007). of similarly aged adults without brain amy-
Despite the inconsistencies, which we believe loid (Sperling et al., 2009). Extending these
can be explained by a number of factors approaches to genetic risk, in cognitively
(Dickerson & Sperling, 2008), there is repli- intact older adults (Bondi, Houston, Eyler,&
cated evidence to support the hypothesis that Brown, 2005; Bookheimer etal., 2000; Fleisher
there is a phase of increased MTL activation etal., 2005; Xu etal., 2009)at elevated genetic
early in the course of prodromal AD, prior to risk for AD, hippocampal activation during
clinical dementia. memory tasks is greater than in those with-
Accumulating evidence indicates that out such elevated risk.
task-related regional brain hyperactiva-
tion may be a universal neural response to
insult, as it occurs in a variety of neuropsy- Resting-State Functional Magnetic
chiatric disorders and conditions, includ- Resonance Imaging
ing AD/MCI, Huntingtons disease (Rosas,
Feigin,& Hersch, 2004), Parkinsons disease Recent functional magnetic resonance imag-
(Monchi et al., 2004), cerebrovascular dis- ing (fMRI) studies are beginning to reveal a
ease (Carey etal., 2002; Johansen-Berg etal., link between disease-related hemodynamic
2002), multiple sclerosis (Morgen etal., 2004; alterations and the well-described resting
Reddy et al., 2000), traumatic brain injury perfusion/metabolic abnormalities in AD.
(McAllister etal., 1999), HIV (Ernst, Chang, Hypoperfusion/metabolism is typically seen
Jovicich, Ames, & Arnold, 2002), alcohol- with nuclear medical imaging techniques
ism (Desmond et al., 2003), schizophrenia (such as FDG-PET or single-photon emission
(Callicott et al., 2003), sleep deprivation computed tomography [SPECT], as reviewed
538part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
part of natural history studies such as ADNI, scans, but they are generally less widely
which will likely provide clearer data regard- available. The measures commonly obtained
ing their potential for use in clinical trials or using these tools include blood flow, glu-
practice settings. cose metabolism, and oxygen consumption.
Measures of neurotransmitter function have
also been developed.
Molecular Imaging in Alzheimers Disease It has been known for nearly 20years that
PET and SPECT imaging reveals a fairly
Molecular neuroimaging techniques enable specific pattern of lateral temporoparietal
in vivo images to be obtained of radiolabeled and posterior cingulate hypometabolism or
compounds (radioligands) that are typi- hypoperfusion in AD (Herholz et al., 2002;
cally injected intravenously into the person Jagust, Friedland, Budinger, Koss, & Ober,
undergoing imaging. A wide range of com- 1988)(Fig. 22.6). The presence of such a defi-
pounds can be labeled, and radiochemists cit in regional brain function is useful for the
regularly develop new compounds of use prediction of AD dementia in mildly symp-
for neuroimaging. The two primary methods tomatic groups of subjects (such as MCI)
for obtaining images are PET and SPECT. In (Chetelat et al., 2005; Johnson et al., 1998;
PET scanning, positrons are emitted by the Mosconi etal., 2005; Minoshima etal., 1997).
radioligand, collide with electrons, and gen- Furthermore, in the proper clinical context,
erate gamma radiation, which is ultimately the spatial locations of functional impairment
detected by the sensor arrays and used to relate to the presence of AD pathology in the
derive an image. Commonly used radioli- same regions (Buckner et al., 2005; Mega
gands include carbon-11, oxygen-15, and etal., 1999).
fluorine-18 (18F). 18F is desirable because it
has the longest half-life. SPECT scans work
in a somewhat similar manner but employ Molecular Imaging in the Differential
compounds such as technetium-99 and Diagnosis of Neurodegenerative Diseases
xenon-133, which have longer half-lives than
compounds used in PET scanning. For a vari- The early detection and differential diagnosis
ety of technical reasons, PET scans are able to of neurodegenerative disorders is a promis-
obtain higher resolution images than SPECT ing aim for further work using molecular
Figure22.6 In mild Alzheimers disease, cortical glucose metabolism is typically reduced in the
temporoparietal region, as well as posterior midline and orbitofrontal regions. This now classic
finding is useful clinically in differential diagnosis and may be valuable as an imaging biomarker
for early detection of the metabolic signature of the disease in patients with minimal or no
symptoms. This figure shows the largest reduction in metabolism in yellow, with lesser reductions
in red hues from a single patient with mild AD, displayed on that patients cortical surface as
reconstructed from the anatomic magnetic resonance image. Areas without color exhibited normal
metabolism compared to age-matched cognitively intact individuals. (See color plate section)
540part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Figure22.7 Fludeoxyglucose positron emission tomography (FDG-PET) can be very useful in the
clinical evaluation of patients with dementia, particularly for the differentiation of Alzheimers
disease (AD) versus frontotemporal dementia (FTD). (A) Cognitively normal older adult; (B) mild
AD dementia patient; (C) mild FTD dementia patient. (Images courtesy of Dr.Keith Johnson,
Massachusetts General Hospital) (See color plate section)
CHAPTER 22. Neuroimaging, Cerebrospinal Fluid Markers, and Genetic Testing in Dementia 541
principal component analysis was applied with a number of studies having been done
to 153 subjects and was able to differentiate in populations at elevated genetic risk for AD
the groups with 100% accuracy (Kerrouche, and other neurodegenerative disorders.
Herholz, Mielke, Holthoff, & Baron, 2006). The APOE 4 allele is a major genetic sus-
The AD group showed the typical findings ceptibility factor associated with increased
as described previously, but the VaD group risk for AD (Saunders, 2000). A number of
showed hypometabolism in deep gray nuclei, studies have demonstrated that cognitively
cerebellum, primary cortices, middle tempo- intact subjects who are carriers of the APOE
ral gyrus, and anterior cingulate gyrus. 4 allele show evidence of temporo-parietal
Further insights into the utility of molec- hypometabolism with a pattern similar
ular imaging in assisting with differential to, but of milder severity, that of AD. In
diagnosis may potentially be gained through individuals in their 50s without cognitive
prospective studies of patients presenting decline, progressive metabolic decline has
for clinical evaluation with subtle symptoms been observed in 4 carriers after 2 years
consistent with a degenerative condition (Reiman etal., 2001). Intriguingly, this find-
who do not yet have a clear clinical diagno- ing has been observed in carriers of the 4
sis. If such individuals are scanned and then allele who are young, in their 20s and 30s
followed clinically (and ultimately patho- (Reiman, 2007). Thus, it may be a lifelong
logically), it may be possible to learn more vulnerability pattern (endophenotype) that
about the predictive power of molecular mediates the risk effects of the gene, since it
imaging in differential diagnosis (Herholz, would be very unusual for young individu-
2003). als to already have begun to accumulate AD
pathology.
Tantalizing results are emerging from lon-
Molecular Imaging as a Biomarker for gitudinal studies with serial FDG-PET mea-
Monitoring or Prediction of Clinical Status sures in subjects at elevated risk for clinical
AD, but in whom symptoms are very mild
Longitudinal studies have shown that base- or absent. Progressive metabolic abnormali-
line PET and SPECT measures are useful for ties parallel cognitive decline in both older
the prediction of future cognitive decline in cognitively intact individuals (de Leon etal.,
AD patients (Jagust, Haan, Eberling, Wolfe,& 2001)and subjects with mild memory impair-
Reed, 1996; Wolfe, Reed, Eberling,& Jagust, ment who carry the APOE- 4 allele (Small
1995)and the early detection of disease state etal., 2000).
in individuals with MCI (Arnaiz etal., 2001;
Chetelat et al., 2003; Herholz et al., 1999;
Johnson etal., 1998). Serial functional imag- Uses of Molecular Imaging in Understanding
ing studies have demonstrated that pro- and Monitoring Neurotherapeutics
gressive metabolic decline correlates with
cognitive decline in AD patients (Haxby Molecular imaging may be particularly valu-
etal., 1990; Jagust etal., 1988). Power calcu- able in evaluating acute and subacute effects
lations suggest that PET measures may be of medications on neural activity. PET and
more sensitive than cognitive measures in a SPECT measures of resting brain function
1-year clinical drug trial (Alexander, Chen, appear to be sensitive to medication effects
Pietrini, Rapoport,& Reiman, 2002). in clinical drug trials and relate to clinical
measures in a manner that suggests their
potential utility as surrogate markers. In four
The Modulatory Effects of Genetic Risk studies of cerebral metabolism or perfusion
Factors for Neurologic Disease on Brain in AD patients given cholinesterase inhibi-
Activity tors, these functional brain measures parallel
clinical measures in demonstrating stability
In the last 15 years, there has been an or improvement in treated versus placebo
explosion in literature on the basic science groups or in predicting response in treated
of genetic modulators of brain function patients (Mega et al., 2001; Nakano, Asada,
(Hariri & Weinberger, 2003). This is an area Matsuda, Uno,& Takasaki, 2001; Nobili etal.,
that is ripe for study in neurologic disease, 2002; Tune etal., 2003).
542part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Although the 2001 American Academy Radiochemistry research has led to the devel-
of Neurology practice parameter for the opment of a class of tracers that specifically
diagnostic evaluation of dementia did not bind to amyloid plaques in mouse models
recommend the use of FDG-PET or related of AD (Mathis etal., 2002), cross the blood
techniques, citing the need for further brain barrier, and label plaques in vivo in
prospective studies...to establish the value humans. The first such compound, known as
that it brings to diagnosis over and above Pittsburgh Compound B (PiB), was initially
a competent clinical diagnosis (Knopman developed through rigorous studies in ani-
et al., 2001, page 1147), a number of stud- mal models of AD, human AD postmortem
ies in the decade since then have provided brain tissue, and in living healthy elderly
clear evidence of added value in certain subjects and patients with a clinical diagnosis
situations, as summarized previously and of AD (Klunk etal., 2004).
reviewed elsewhere in more detail (Bohnen, PiB and other [18F] amyloid imaging
Djang, Herholz, Anzai, & Minoshima, tracers have now been tested extensively
2012). in living human subjects, including nor-
Nevertheless, FDG-PET faces several chal- mal elderly and patients with the clinical
lenges in becoming more routinely used in diagnosis of mild probable AD. The abso-
the diagnosis of AD and related disorders. lute level of PiB retention is approximately
First, the clinician needs to be familiar with the same in the cerebellum and white mat-
its utility and have access to a facility in ter of AD patients and normal control sub-
which it is performed. Second, reimburse- jects, brain areas known to lack substantial
ment for FDG-PET in the diagnostic evalu- deposits of fibrillar amyloid. In contrast,
ation of dementia or cognitive impairment PiB retention is very high in AD patients in
needs to improve in the private sector; it is frontal, temporal, and parietal neocortical
often particularly difficult (and sometimes regions (Klunk etal., 2004; Nordberg, 2007).
impossible) to obtain authorization from As expected, PiB binding similar to AD is
private insurers for FDG-PET in patients seen in some subjects with MCI (Forsberg
younger than Medicare-eligible age, ironi- et al., 2007), reflecting the presence of sig-
cally the patients in whom it may be most nificant pathology even at this mild level of
useful. Finally, improved standardiza- clinical impairment, as has also been seen
tion of interpretation and quantification of in pathologic studies. However, many MCI
FDG-PET scans is an important goal; a num- subjects have intermediate or low levels of
ber of research groups are working on com- tracer uptake on amyloid imaging, reflecting
parisons of different quantitative techniques clinical heterogeneity. PiB imaging has also
and on comparisons of visual interpretation confirmed what has long been known from
versus quantitative analysis, partly with the postmortem studies (Tomlinson, Blessed, &
goal of incorporating FDG-PET into clinical Roth, 1968):Many elderly cognitively intact
trials. individuals carry a substantial burden of
Further research in clinical practice settings AD neuropathology (Mintun et al., 2006).
will be necessary to determine the best place Yet brain amyloid levels may plateau and
for FDG-PET in relation to structural MRI, remain fairly stable longitudinally in AD
other forms of MRI, and spinal fluid mark- dementia (Engler et al., 2006). Thus, PET
ers of diseases causing cognitive impairment pathology markers may assist in diagnosis,
and dementia. Investigations of the com- but PET metabolic markers or MRI atrophy
parative utility of FDG-PET versus amyloid markers will likely be important for measur-
PET imaging are badly needed. As these ing changes in the rate of disease progres-
new tests become more widely available, sion. Whether these findings will be useful in
practically oriented studies will contribute the prediction of the eventual development
importantly to dialogue among neurologists of AD dementia in nondemented individu-
aiming to balance diagnostic rigor with cost als remains a topic of intense investiga-
effectiveness. tion. Nevertheless, amyloid imaging factors
CHAPTER 22. Neuroimaging, Cerebrospinal Fluid Markers, and Genetic Testing in Dementia 543
(A) (B)
prominently in the revised diagnostic crite- measures of tracer uptake and cut point
ria for MCI and particularly for preclinical thresholds of abnormality. Quantitatively,
AD, as discussed in Chapter2 (Fig. 22.8). FDG-PET was AD-like if tracer uptake was
The successful visualization of direct mark- more abnormal in temporoparietal than in
ers of AD neuropathology in living humans either frontal or temporal FTLD-vulnerable
is a major step forward in the field, and it regions and was FTLD-like if metabolism
suggests that more specific in vivo diagnos- was worse in the FTLD-vulnerable areas. PiB
tic and monitoring capabilities may be on the PET was AD-like if it exceeded a threshold
horizon. Furthermore, initial studies compar- that was based on the mean of a PiB-negative
ing AD and FTD patients suggest that it may normal control group. The authors report
be possible to differentiate neurodegenerative that PiB qualitative and quantitative readouts
diseases using specific tracers that bind to were virtually identical, which is consistent
pathologic proteins (Rabinovici et al., 2007), with the very large difference in the amount
rather than indirectly through the effects of of tracer retained after 90 minutes in most
the diseases on brain function and structure. amyloid-positive patients compared to most
In a recent study (Rabinovici et al., 2012), amyloid-negative patients. In contrast, FDG
107 patients with early-onset AD or FTLD, specificity was substantially improved by the
12 with known histopathology, underwent quantitative readout compared to the visual
both FDG-PET and amyloid PET with PiB. readout, similar to a previous report (Foster,
Images were classified as either AD-like or 2007).
FTLD-like with a pair of blinded qualita- These data are convincing that the pres-
tive, visual reads and also with quantitative ence or absence of AD neuropathology in
544part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
these two dementias can be determined by with brain amyloid may remain relatively
the use of PiB, and that PiBwhether read stable over time, which would challenge the
visually or analyzed quantitativelyis also value of these markers for prognostication at
highly sensitive to the clinical diagnosis of the individual level.
AD. FDG, on the other hand, may still play a Further research will be necessary to deter-
very important role with its ability to improve mine the best place for amyloid PET in rela-
specificity of the diagnosis of AD (i.e., in this tion to FDG-PET, MRI, spinal fluid analysis,
case to identify FTLD). The authors point out and other tests in the sequence of steps rec-
that the use of FDG in clinical settings is less ommended for the diagnostic evaluation of
consistent than PiB with regard to interrater patients with dementia, which will likely vary
reliability, especially when a quantitative depending on the setting and the goals. An
comparison with a group of normal subjects international committee of experts recently
is not available. One unstated conclusion is published appropriate use guidelines for
that such quantitative FDG comparisons the clinical use of amyloid PET imaging in
could improve clinical practice and should be the evaluation of patients with cognitive
more widely adopted. For example, a recent impairment (Johnson etal., 2013a, 2013b) (see
report focused on a different regional strat- Table 22.1). This consensus greatly restricts
egy for identifying FTLD-like FDG patterns, the recommended usage of amyloid PET
in which greater emphasis placed on ante- imaging to specific scenarios with an empha-
rior cingulate and anterior temporal regions sis on clinically uncertain dementia cases in
resulted in greater accuracy (Womack, 2011). whom AD is a possible diagnosis.
Thus, it is possible that the method used here Exciting new tracers have very recently
underestimated the value of FDG in differ- been developed for putatively measur-
ential diagnosis of AD versus FTLD since a ing brain tau aggregates (Chien et al., 2013;
substantial proportion of patients with FTLD Fodero-Tavoletti etal., 2011; Maruyama etal.,
exhibit temporoparietal hypometabolism. 2013; Small et al., 2006). Work is currently
The authors are appropriately cautious ongoing to validate these ligands against
about generalizing these conclusions to postmortem tissue autoradiography as well
situations in which other confounding fea- as in patient populations highly likely to har-
tures, such as older age and vascular disease bor brain tau pathology, such as MAPT muta-
comorbidity, could play an important role. tion carriers or patients with a classical PSP
They also point out that amyloid imaging clinical syndrome.
will likely have less value in differentiating
AD from DLB since many DLB patients have
relatively high uptake consistent with amy- Clinical Use of Molecular Neuropathology
loid pathology (Gomperts et al., 2008) and Imaging in the Evaluation of Dementia
in differentiating among amyloid-negative Patients
dementias.
In addition to use in differential diagnosis, The US Food and Drug Administration
imaging molecular tracers that bind to neuro- has approved amyloid PET imaging in the
pathological constituents of AD and related evaluation of dementia, starting with [18F]
disorders may be very useful in the burgeon- florbetapir in April 2012. The European
ing efforts to improve translational research Medicines Agencys Committee for Medicinal
between animal models and humans. Products for Human Use similarly recom-
However, a number of issues will need to be mended approval for this ligand in October
addressed as part of the validation of these 2012. Although it remains unclear whether
methods as surrogate markers in clinical tri- major reimbursement agencies will decide
als or practice. While visualization of a sig- to pay for clinical use of amyloid imag-
nal of pathology has been demonstrated, ing, it is now available and beginning to be
work is still in progress to refine quantitative used. As mentioned previously, the Amyloid
metrics, harmonize the reporting standards, Imaging Task (AIT) Force, a joint effort of the
and determine the specificity of these mea- Society for Nuclear Medicine and Molecular
sures. Finally, it is not yet clear whether some Imaging and the Alzheimers Association,
prodromal or presymptomatic individuals has published two papers addressing the
CHAPTER 22. Neuroimaging, Cerebrospinal Fluid Markers, and Genetic Testing in Dementia 545
most important issues related to the use of important goals, including greater physician
this class of biomarkers in clinical practice. confidence in the diagnosis of or exclusion of
Interested readers are encouraged to refer to AD. Hopefully, this will result in improved
those primary articles (Johnson etal., 2013a, comprehensive management, including phar-
2013b). macotherapy and education of the patient
In summary, the group pointed out some and family about prognosis. Furthermore,
of the limitations of amyloid imaging, amyloid imaging may help to reduce the use
including the possibility that a positive of additional and repeated tests. Most impor-
scan may be purely incidental given the tant, the continued investigation of amyloid
age-related increase in cerebral amyloid in imaging in practice is warranted.
cognitively normal older adults. In addition,
they pointed out that a positive scan can be
seen in conditions other than AD, including Cerebrospinal Fluid Biomarkers
DLB and CAA. Probably most important, the
group highlighted the need to consider the Although major efforts are under way to
results of amyloid imaging in the context of explore cerebrospinal fluid (CSF) samples
the comprehensive evaluation of a patient from patients with a variety of dementias
with cognitive impairment and/or demen- to try to identify new biomarkers (Hu etal.,
tia, including other biomarkers and ele- 2010), one set of biomarkers is now mature
ments of the clinical profile. Questions were enough to be relatively widely used clini-
also raised about the potential psychological cally in the evaluation of dementia patients
and social implications of a positive amyloid to determine whether they exhibit underly-
scan, which have received very little formal ing CSF indicators of AD pathology. These
investigation. measures are amyloid- 1-42 peptide (A
Ultimately, the hope of the AIT is that amy- 1-42), total tau (t-tau), and tau phosphory-
loid imaging will be used in this context by lated at threonine 181 (p-tau). A number of
dementia experts to achieve a number of studies have demonstrated the utility of
546part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
(A) (B)
Figure22.10 Case 1.Magnetic resonance imaging (MRI) and positron emission tomography
(PET) often provide a reasonably convincing set of biomarkers in early-onset or atypical dementia
patient evaluations. In this 39-year-old woman with familial dementia initially thought to be
frontotemporal dementia, (A) an MRI scan showed relatively mild medial temporal lobe atrophy
but prominent bilateral parietal atrophy, and (B) a fludeoxyglucose positron emission tomography
(FDG-PET) scan showed prominent bilateral temporoparietal hypometabolism, supporting the
diagnosis of Alzheimers disease (AD). She was later found to carry a PSEN1 mutation and
ultimately was determined to have AD pathology at autopsy. (See color plate section)
The other genetic tests relevant at pres- was determined to have a MAPT mutation
ent for early-onset dementia are those for (Fig. 22.11). Our approach, similar to that
frontotemporal lobar degeneration: the described in the algorithm cited, is to per-
microtubule associated protein tau (MAPT), form genetic testing on any young patient
progranulin (GRN), and the hexanucleo- with dementia regardless of family history.
tide repeat expansion on chromosome 9 In the case presented here, it is thought
(C9ORF72) (see Chapter 8 for more infor- that this mutation was possibly inherited
mation). In some cases in which there is a but nonpenetrant in a parent or possibly de
clinical diagnosis of FTD and a strong fam- novo in the patient. Similar cases have been
ily history of a similar condition, the test can reported previously.
be used for diagnostic purposes to confirm While the search continues for novel genes
the molecular etiology. In other cases, there associated with AD, FTD, and other demen-
may be an unclear family history, or even tias, it is currently possible to test for several
the lack of a family history, and genetic test- known genes. Itypically test for these genetic
ing may still reveal a pathogenic mutation. mutations in patients in whom there is a fam-
A recently published study from a large ily history of dementia (often unclear due to
cohort at the University of Pennsylvania lack of precise diagnosis in prior generations)
proposed a valuable algorithm for assigning or in whom the onset is young, which is a
probabilities of genetic abnormalities based similar approach to what others have recom-
on family history information (Wood et al., mended. Several articles serve as excellent
2013). For example, Ifollowed a very young references for the approach to clinical genetic
man with behavioral-variant FTDsymp- testing in dementia (Goldman et al., 2004,
tom onset age 28, death age 33who lacked 2011; Williamson, Goldman,& Marder, 2009).
a family history of any form of dementia but In our group, such testing is usually done
548part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
(A)
(B)
(C)
Figure22.11 Case 2.Serial magnetic resonance imaging (MRI) scans 3years apart show rapid
progression of frontotemporal atrophy in this 31-year-old man who died of frontotemporal
dementia at age 33. (A) Aseries of coronal FLAIR MRI images demonstrates left greater than
right temporal lobe atrophy at a time when symptoms were clearly present but overall function
was mildly impaired. (B) Asimilar series of coronal T1-weighted MRI images demonstrates
marked progression of frontal, insular, and temporal atrophy with parietal involvement at a
time when the patient was minimally communicative and dependent for most activities of daily
living. (C) Postmortem histology demonstrated neuronal and glial cell loss with prominent tau
immunohistochemical abnormalities (left), including Pick bodies (middle). The hematoxylin and
eosin stained sections (right) also clearly demonstrated cellular inclusions typical of Pick-type
tauopathy. (See color plate section)
after a discussion with our genetic counselor, APOE genotype in asymptomatic individu-
who provides extensive education about the als for risk assessment purposes (American
purpose of such testing as well as risks and College of Medical Genetics/American
benefits. Genetic testing for diagnostic pur- Society of Human Genetics, 1995; Post etal.,
poses in symptomatic patients should be 1997), some clinicians believe that testing of
considered distinct from testing of asymp- this gene has value in symptomatic patients
tomatic individuals for the purposes of risk for diagnostic purposes, since its presence
assessment. or absence appears to modulate the clinical
Finally, apolipoprotein E (APOE) will be expression of AD as well as other demen-
briefly discussed. The APOE 4 allele has tias (Agosta et al., 2009; Wolk et al., 2010).
been known to be a major genetic risk fac- Furthermore, APOE genotype may modu-
tor for late-onset AD since 1993 (Saunders late response to or side effects from putative
etal., 1993). Although expert consensus pan- disease-modifying therapies, and in some
els have recommended against testing for clinical trials the dose is adjusted based on
CHAPTER 22. Neuroimaging, Cerebrospinal Fluid Markers, and Genetic Testing in Dementia 549
APOE genotype (Salloway et al., 2009). The 2012). Increase CSF tau and brain atrophy
jury is still out on whether this information could also be detected about 15 years prior
provides value in routine clinical settings, to symptoms, while cerebral hypometabo-
and additional study is needed. lism on PET could be detected about 10years
prior to symptoms. Although the precise
number of years and the specific ordering of
The Combined Use of Multiple Biomarkers these markers will almost certainly change
with continued research, our understanding
The use of multiple biomarkers in combina- of the pathophysiologic process of AD (and
tion will likely be of great value for identifying likely similarly for other neurodegenerative
candidates for clinical trials. Nondemented diseases) will be greatly increased through
mildly amnesic patients with clear abnor- natural history studies of multimodal bio-
malities in two or more of the aforemen- markers. Ultimately, treatment at the pre-
tioned biomarkers will probably be a strong clinical stage will hinge in multiple ways on
candidate target population for clinical trials these measures (Langbaum etal., 2013).
of disease-modifying therapies, as they will
likely be at relatively high risk of progression
to mild dementia within a few years. The Beyond Exclusion:The Use of Imaging
analysis of multiple types of putative bio- and Biofluid Disease Biomarkers
markers has only recently begun, and to date
it has been performed largely in patients with At present, the potential efficacy of
mild to moderate AD dementia. Several stud- disease-modifying therapies for AD and other
ies have been performed of brain structure neurodegenerative diseases is evaluated pri-
and function, highlighting the brain regions marily using clinical measures of cognition,
in which atrophy and hypometabolism occur movement, and other behaviors, but this is
together as well as those in which there is a shifting in recent years to include increasing
dissociation (Chetelat et al., 2008; De Santi information from biomarkers. Although the
et al., 2001; Mosconi et al., 2006). There are efficacy of disease-modifying treatments for
also data to suggest that the diagnostic util- AD and other neurodegenerative diseases
ity of hippocampal volume in differentiating must ultimately be demonstrated using clini-
patients with MCI from controls is improved cally meaningful outcome measures such
with the addition of CSF biomarker measures as the slowing of decline in progression of
(de Leon etal., 2006), and that reduced pari- symptoms or functional impairment, such
etal blood flow and abnormal CSF measures trials will likely require hundreds of patients
are useful together in predicting conversion studied for a minimum of 12 years. Thus,
to dementia in MCI patients (Hansson etal., surrogate markers of efficacy with less vari-
2007). Such initial forays into the territory of ability than clinical assessments are des-
multibiomarker studies provides an optimis- perately needed to reduce the number of
tic perspective on the value of ongoing larger subjects. These markers may also prove par-
scale studies in which multiple data types are ticularly valuable in the early phases of drug
being collected for use in biomarker analyses, development to detect a preliminary signal
such as ADNI. of efficacy over a shorter time period.
Based on results from several groups Since the pathophysiologic process under-
studying early-onset autosomal dominant lying cognitive decline in AD and other
forms of AD, it appears that combinations of neurodegenerative diseases involves the
biomarkers are likely going to be particularly progressive degeneration of particular brain
useful for identifying and monitoring pre- regions, repeatable in vivo neuroimag-
clinical and prodromal phases of the disease. ing measures of brain anatomy, chemistry,
For example, results from the Dominantly physiology, and pathology hold promise as
Inherited Alzheimers Initiative, while based an important class of potential biomarkers
on cross-sectional data, suggest that CSF (DeKosky & Marek, 2003). A growing body
amyloid-beta levels may begin to decrease as of data indicates that the natural history of
much as 25years before expected onset, while gradually progressive cognitive decline in
cerebral amyloid can be detected by PET AD can be reliably related to changes in such
about 15years prior to onset (Bateman etal., imaging measures. Furthermore, regionally
550part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
CSF
amyloid-
level
the patient: molecular neuroimaging with diagnosis for her prognosis as well as treat-
FDG-PET and/or a spinal fluid examination ment considerations. Temporoparietal hypo-
for amyloid- and tau proteins. For example, metabolism was demonstrated, suggesting
a patient presenting in her 50s or 60s with a an atypical form of AD. To confirm this sus-
syndrome of executive or language impair- picion, I obtained CSF, which demonstrated
ment and a relatively unrevealing MRI scan an amyloid/tau profile consistent with AD.
can be challenging to confidently diagnose. Ibegan treatment with donepezil and added
In such patients, I find FDG-PET to be an memantine as her impairments progressed,
extremely valuable next step in the diagnostic and began discussions of AD clinical trials.
evaluation, since it is minimally invasive and She and her family were also referred to the
may provide a clear indication of whether the Alzheimers Association for assistance with
patient has a hypometabolic pattern consis- planning and support. Ibelieve that the con-
tent with atypical AD as opposed to a pattern fident diagnosis was particularly helpful for
supportive of FTD or another neurodegener- her family to proactively adapt to her grad-
ative disease. Ioften perform CSF analysis at ual loss of independent function in a fashion
this stage depending on the patients willing- that has continued to afford her a reasonably
ness to undergo or ability to tolerate a lum- high quality of life, now 4years later into the
bar puncture. Amyloid imaging may become phase of mild-to-moderate AD dementia.
a key element of this stage of the diagnostic
evaluation but has largely not entered center
stage due to reimbursement issues. Acknowledgments
As a final case example (Case 3), a
54-year-old woman presented after having This chapter was written with support from the
difficulty in her job as a psychologist and was National Institute on Aging (R01-AG029411),
found to have a flat affect, mild executive National Institute for Neurological Disorders
dysfunction, and limited insight with pre- and Stroke (R21-NS077059, R21-NS079905,
served language, memory, and visuospatial R21-NS084156), and National Institute of
skills. At initial assessment her clinical status Mental Health (R21-MH097094).
was consistent with MCI given relative pres-
ervation of social and occupational function, References
although some aspects of her job performance
had begun to suffer. She was referred to me Agosta, F., Vossel, K. A., Miller, B. L.,
with a presumptive diagnosis of bvFTD. Migliaccio, R., Bonasera, S. J., Filippi,
M.,...Gorno-Tempini, M. L. (2009).
However, MRI was relatively unrevealing
Apolipoprotein E epsilon4 is associated with
with possible subtle atrophy of the MTL disease-specific effects on brain atrophy in
and parietal cortex (Fig. 22.12). I obtained Alzheimers disease and frontotemporal
an FDG-PET to attempt to maximize my dementia. Proceedings of the National Academy
confidence given the value of a confident of Science USA, 106, 2018-2022.
552part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Albert, M.S., DeKosky, S.T., Dickson, D., Dubois, Bobinski, M., de Leon, M. J., Wegiel, J.,
B., Feldman, H. H., Fox, N. C.,...Phelps Desanti, S., Convit, A., Saint Louis,
C. H. (2011). The diagnosis of mild cogni- L.A.,...Wisniewski, H.M. (2000). The histo-
tive impairment due to Alzheimers dis- logical validation of post mortem magnetic
ease: Recommendations from the National resonance imaging-determined hippocampal
Institute on Aging-Alzheimers Association volume in Alzheimers disease. Neuroscience,
workgroups on diagnostic guidelines for 95, 721725.
Alzheimers disease. Alzheimers and Dementia, Boccardi, M., Ganzola, R., Rossi, R., Sabattoli, F.,
7, 270279. Laakso, M.P., Repo-Tiihonen, E.,...Tiihonen,
Alexander, G.E., Chen, K., Pietrini, P., Rapoport, J. (2010). Abnormal hippocampal shape in
S. I., & Reiman, E. M. (2002). Longitudinal offenders with psychopathy. Human Brain
PET evaluation of cerebral metabolic decline Mapping, 31, 438447.
in dementia: A potential outcome measure Bohnen, N.I., Djang, D.S., Herholz, K., Anzai,
in Alzheimers disease treatment studies. Y., & Minoshima, S. (2012). Effectiveness
American Journal of Psychiatry, 159, 738745. and safety of 18F-FDG PET in the evalua-
Alsop, D. C., Casement, M., de Bazelaire, C., tion of dementia: A review of the recent
Fong, T.,& Press, D.Z. (2008). Hippocampal literature. Journal of Nuclear Medicine, 53,
hyperperfusion in Alzheimers disease. 5971.
Neuroimage, 42, 12671274. Bondi, M. W., Houston, W. S., Eyler, L. T., &
American College of Medical Genetics/ Brown, G. G. (2005). fMRI evidence of com-
American Society of Human Genetics. (1995). pensatory mechanisms in older adults at
Statement on use of apolipoprotein E test- genetic risk for Alzheimer disease. Neurology,
ing for Alzheimer disease. American College 64, 501508.
of Medical Genetics/American Society of Bookheimer, S. Y., Strojwas, M. H., Cohen,
Human Genetics Working Group on ApoE M.S., Saunders, A.M., Pericak-Vance, M.A.,
and Alzheimer disease. Journal of the American Mazziotta, J. C., & Small, G. W. (2000).
Medical Association, 274, 16271629. Patterns of brain activation in people at risk
Arnaiz, E., Jelic, V., Almkvist, O., Wahlund, for Alzheimers disease. New England Journal
L. O., Winblad, B., Valind, S., & Nordberg, of Medicine, 343, 450456.
A. (2001). Impaired cerebral glucose metab- Buckner, R. L., Snyder, A. Z., Shannon,
olism and cognitive functioning predict B. J., LaRossa, G., Sachs, R., Fotenos,
deterioration in mild cognitive impairment. A. F.,...Mintun, M. A. (2005). Molecular,
Neuroreport, 12, 851855. structural, and functional characterization
Ashburner, J., Csernansky, J. G., Davatzikos, of Alzheimers disease: Evidence for a rela-
C., Fox, N. C., Frisoni, G. B., & Thompson, tionship between default activity, amyloid,
P. M. (2003). Computer-assisted imaging to and memory. Journal of Neuroscience, 25,
assess brain structure in healthy and diseased 77097717.
brains. Lancet Neurology, 2, 7988. Cabeza, R., Anderson, N. D., Locantore,
Bakkour, A., Morris, J. C., & Dickerson, B. C. J.K.,& McIntosh, A.R. (2002). Aging grace-
(2009). The cortical signature of prodromal fully: Compensatory brain activity in
AD: Regional thinning predicts mild AD high-performing older adults. Neuroimage,
dementia. Neurology, 72, 10481055. 17, 13941402.
Bakkour, A., Morris, J. C., Wolk, D. A., & Callicott, J. H., Mattay, V. S., Verchinski, B. A.,
Dickerson, B. C. (2013). The effects of aging Marenco, S., Egan, M.F.,& Weinberger, D.R.
and Alzheimers disease on cerebral cortical (2003). Complexity of prefrontal cortical
anatomy:Specificity and differential relation- dysfunction in schizophrenia: More than up
ships with cognition. Neuroimage, 76, 332344. or down. American Journal of Psychiatry, 160,
Bateman, R. J., Xiong, C., Benzinger, T. L., 22092215.
Fagan, A.M., Goate, A., Fox, N.C.,...Morris, Carey, J. R., Kimberley, T. J., Lewis, S. M.,
J. C. (2012). Clinical and biomarker changes Auerbach, E. J., Dorsey, L., Rundquist, P., &
in dominantly inherited Alzheimers disease. Ugurbil, K. (2002). Analysis of fMRI and fin-
New England Journal of Medicine, 367, 795804. ger tracking training in subjects with chronic
Beason-Held, L. L., Kraut, M. A., & Resnick, stroke. Brain, 125, 773788.
S.M. (2008). I. Longitudinal changes in aging Celone, K.A., Calhoun, V.D., Dickerson, B.C.,
brain function. Neurobiology of Aging, 29, Atri, A., Chua, E.F., Miller, S.L.,...Sperling,
483496. R. A. (2006). Alterations in memory net-
Blennow, K., Hampel, H., Weiner, M., & works in mild cognitive impairment and
Zetterberg, H. (2010). Cerebrospinal fluid Alzheimers disease: An independent com-
and plasma biomarkers in Alzheimer disease. ponent analysis. Journal of Neuroscience, 26,
Nature Reviews Neurology, 6, 131144. 1022210231.
CHAPTER 22. Neuroimaging, Cerebrospinal Fluid Markers, and Genetic Testing in Dementia 553
Chetelat, G., Desgranges, B., de la Sayette, Das, S. R., Pluta, J., Mancuso, L., Kliot, D.,
V., Viader, F., Eustache, F., & Baron, J. C. Orozco, S., Dickerson, B. C.,...Wolk, D. A.
(2003). Mild cognitive impairment: Can (2013). Increased functional connectivity
FDG-PET predict who is to rapidly con- within medial temporal lobe in mild cogni-
vert to Alzheimers disease? Neurology, 60, tive impairment. Hippocampus, 23, 16.
13741377. Davatzikos, C., Resnick, S. M., Wu, X.,
Chetelat, G., Desgranges, B., Landeau, B., Parmpi, P.,& Clark, C.M. (2008). Individual
Mezenge, F., Poline, J. B., de la Sayette, patient diagnosis of AD and FTD via
V.,...Baron, J. C. (2008). Direct voxel-based high-dimensional pattern classification of
comparison between grey matter hypome- MRI. Neuroimage, 41, 12201227.
tabolism and atrophy in Alzheimers disease. de Leon, M.J., Convit, A., Wolf, O.T., Tarshish,
Brain, 131, 6071. C. Y., DeSanti, S., Rusinek, H.,...Fowler,
Chetelat, G., Eustache, F., Viader, F., De J. (2001). Prediction of cognitive decline
La Sayette, V., Pelerin, A., Mezenge, in normal elderly subjects with 2-[(18)F]
F.,...Desgranges, B. (2005). FDG-PET mea- fluoro-2-deoxy-D-glucose/poitron-emission
surement is more accurate than neuropsy- tomography (FDG/PET). Proceedings of
chological assessments to predict global the National Academy of Science USA, 98,
cognitive deterioration in patients with mild 1096610971.
cognitive impairment. Neurocase, 11, 1425. de Leon, M. J., DeSanti, S., Zinkowski, R.,
Chien, D. T., Bahri, S., Szardenings, A. K., Mehta, P. D., Pratico, D., Segal, S.,...Davies,
Walsh, J. C., Mu, F., Su, M. Y., .
.
.
Kolb, P. (2006). Longitudinal CSF and MRI bio-
H. C. (2013). Early clinical PET imaging markers improve the diagnosis of mild cog-
results with the novel PHF-tau radioligand nitive impairment. Neurobiology of Aging, 27,
[F-18]-T807. Journal of Alzheimers Disease, 34, 394401.
457468. de Leon, M.J., George, A.E., Golomb, J., Tarshish,
Cole, J., Toga, A. W., Hojatkashani, C., C., Convit, A., Kluger, A.,...Wisniewski,
Thompson, P., Costafreda, S. G., Cleare, H. M. (1997). Frequency of hippocampal
A. J.,...Fu, C. H. (2010). Subregional hip- formation atrophy in normal aging and
pocampal deformations in major depressive Alzheimers disease. Neurobiology of Aging,
disorder. Journal of Affective Disorders, 126, 18, 111.
272277. De Santi, S., de Leon, M.J., Rusinek, H., Convit,
Convit, A., de Asis, J., de Leon, M.J., Tarshish, A., Tarshish, C. Y., Roche, A.,...Fowler, J.
C. Y., De Santi, S., & Rusinek, H. (2000). (2001). Hippocampal formation glucose
Atrophy of the medial occipitotempo- metabolism and volume losses in MCI and
ral, inferior, and middle temporal gyri in AD. Neurobiology of Aging, 22, 529539.
non-demented elderly predict decline to de Toledo-Morrell, L., Dickerson, B., Sullivan,
Alzheimers disease. Neurobiology of Aging, M. P., Spanovic, C., Wilson, R., & Bennett,
21, 1926. D. A. (2000). Hemispheric differences in
Csernansky, J. G., Wang, L., Jones, D., hippocampal volume predict verbal and
Rastogi-Cruz, D., Posener, J.A., Heydebrand, spatial memory performance in patients
G.,...Miller, M.I. (2002). Hippocampal defor- with Alzheimers disease. Hippocampus, 10,
mities in schizophrenia characterized by high 136142.
dimensional brain mapping. American Journal DeKosky, S. T., & Marek, K. (2003). Looking
of Psychiatry, 159, 20002006. backward to move forward: Early detection
Csernansky, J.G., Wang, L., Joshi, S., Miller, J.P., of neurodegenerative disorders. Science, 302,
Gado, M., Kido, D.,...Miller, M. I. (2000). 830834.
Early DAT is distinguished from aging by Desmond, J.E., Chen, S.H., DeRosa, E., Pryor,
high-dimensional mapping of the hippo- M. R., Pfefferbaum, A., & Sullivan, E. V.
campus. Dementia of the Alzheimer type. (2003). Increased frontocerebellar activa-
Neurology, 55, 16361643. tion in alcoholics during verbal working
Cummings, J.L., Doody, R.,& Clark, C. (2007). memory: An fMRI study. Neuroimage, 19,
Disease-modifying therapies for Alzheimer 15101520.
disease: Challenges to early intervention. Dickerson, B.C., Bakkour, A., Salat, D.H., Feczko,
Neurology, 69, 16221634. E., Pacheco, J., Greve, D.N.,...Buckner, R.L.
Dager, S. R., Wang, L., Friedman, S. D., (2009). The cortical signature of Alzheimers
Shaw, D. W., Constantino, J. N., Artru, disease: Regionally specific cortical thinning
A.A.,...Csernansky, J.G. (2007). Shape map- relates to symptom severity in very mild
ping of the hippocampus in young children to mild AD dementia and is detectable in
with autism spectrum disorder. American asymptomatic amyloid-positive individuals.
Journal of Neuroradiology, 28, 672677. Cerebral Cortex, 19, 497510.
554part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Dickerson, B.C., Feczko, E., Augustinack, J.C., Dubois, B., Feldman, H.H., Jacova, C., Dekosky,
Pacheco, J., Morris, J.C., Fischl, B.,& Buckner, S. T., Barberger-Gateau, P., Cummings,
R. L. (2007). Differential effects of aging J.,...Scheltens, P. (2007). Research crite-
and Alzheimers disease on medial tempo- ria for the diagnosis of Alzheimers dis-
ral lobe cortical thickness and surface area. ease:Revising the NINCDS-ADRDA criteria.
Neurobiology of Aging, 30(3), 432440. Lancet Neurology, 6, 734746.
Dickerson, B. C., Goncharova, I., Sullivan, Engler, H., Forsberg, A., Almkvist, O., Blomquist,
M. P., Forchetti, C., Wilson, R. S., Bennett, G., Larsson, E., Savitcheva, I.,...Nordberg, A.
D. A.,...deToledo-Morrell, L. (2001). (2006). Two-year follow-up of amyloid depo-
MRI-derived entorhinal and hippocam- sition in patients with Alzheimers disease.
pal atrophy in incipient and very mild Brain, 129, 28562866.
Alzheimers disease. Neurobiology of Aging, Ernst, T., Chang, L., Jovicich, J., Ames, N., &
22, 747754. Arnold, S. (2002). Abnormal brain activation
Dickerson, B. C., Salat, D. H., Greve, D. N., on functional MRI in cognitively asymptom-
Chua, E. F., Rand-Giovannetti, E., Rentz, atic HIV patients. Neurology, 59, 13431349.
D. M.,...Sperling, R. A. (2005). Increased Filippi, M., Dousset, V., McFarland, H.F., Miller,
hippocampal activation in mild cognitive D.H.,& Grossman, R.I. (2002). Role of mag-
impairment compared to normal aging and netic resonance imaging in the diagnosis and
AD. Neurology, 65, 404411. monitoring of multiple sclerosis: Consensus
Dickerson, B. C., & Sperling, R. A. (2005). report of the White Matter Study Group.
Neuroimaging biomarkers for clinical trials of Journal of Magnetic Resonance Imaging, 15,
disease-modifying therapies in Alzheimers 499504.
disease. Neurorx, 2, 348360. Fleisher, A.S., Houston, W.S., Eyler, L.T., Frye,
Dickerson, B. C., & Sperling, R. A. (2008). S., Jenkins, C., Thal, L. J., & Bondi, M. W.
Functional abnormalities of the medial (2005). Identification of Alzheimer disease
temporal lobe memory system in mild cog- risk by functional magnetic resonance imag-
nitive impairment and Alzheimers dis- ing. Archives of Neurology, 62, 18811888.
ease: Insights from functional MRI studies. Fodero-Tavoletti, M. T., Okamura, N.,
Neuropsychologia, 46, 16241635. Furumoto, S., Mulligan, R.S., Connor, A.R.,
Dickerson, B. C., Stoub, T. R., Shah, R. C., McLean, C. A.,...Villemagne, V. L. (2011).
Sperling, R. A., Killiany, R. J., Albert, 18F-THK523: A novel in vivo tau imaging
M. S.,...Detoledo-Morrell, L. (2011). ligand for Alzheimers disease. Brain, 134,
Alzheimer-signature MRI biomarker predicts 10891100.
AD dementia in cognitively normal adults. Forsberg, A., Engler, H., Almkvist, O., Blomquist,
Neurology, 76, 13951402. G., Hagman, G., Wall, A.,...Nordberg, A.
Drummond, S. P., Brown, G. G., Gillin, J. C., (2007). PET imaging of amyloid deposition
Stricker, J. L., Wong, E. C., & Buxton, R. B. in patients with mild cognitive impairment.
(2000). Altered brain response to verbal learn- Neurobiology of Aging, 29(10), 14561465.
ing following sleep deprivation. Nature, 403, Foster, N. L., Heidebrink, J. L., Clark,
655657. C. M., Jagust, W. J., Arnold, S. E., Barbas,
Duara, R., Barker, W., Loewenstein, D., Pascal, N. R.,...Minoshima, S. (2007). FDG-PET
S.,& Bowen, B. (1989). Sensitivity and speci- improves accuracy in distinguishing fronto-
ficity of positron emission tomography temporal dementia and Alzheimers disease.
and magnetic resonance imaging studies Brain, 130, 26162635.
in Alzheimers disease and multi-infarct Fox, N.C., Black, R.S., Gilman, S., Rossor, M.N.,
dementia. European Neurology, 29(Suppl 3), Griffith, S.G., Jenkins, L.,& Koller, M. (2005).
915. Effects of abeta immunization (AN1792)
Dubois, B., Burn, D., Goetz, C., Aarsland, D., on MRI measures of cerebral volume in
Brown, R.G., Broe, G.A.,...Emre, M. (2007) Alzheimer disease. Neurology, 64, 15631572.
Diagnostic procedures for Parkinsons dis- Fox, N. C., Cousens, S., Scahill, R., Harvey,
ease dementia: Recommendations from R.J.,& Rossor, M.N. (2000). Using serial reg-
the movement disorder society task force. istered brain magnetic resonance imaging to
Movement Disorders, 22, 23142324. measure disease progression in Alzheimer
Dubois, B., Feldman, H. H., Jacova, disease: Power calculations and estimates
C., Cummings, J. L., Dekosky, S. T., of sample size to detect treatment effects.
Barberger-Gateau, P.,...Scheltens, P. (2010). Archives of Neurology, 57, 339344.
Revising the definition of Alzheimers dis- Fox, N.C.,& Schott, J.M. (2004). Imaging cere-
ease: A new lexicon. Lancet Neurology, 9, bral atrophy: Normal ageing to Alzheimers
11181127. disease. Lancet, 363, 392394.
CHAPTER 22. Neuroimaging, Cerebrospinal Fluid Markers, and Genetic Testing in Dementia 555
Frisoni, G.B.,& Jack, C.R. (2011). Harmonization with depression: A preliminary report.
of magnetic resonance-based manual hippo- Psychiatry Research, 40, 195202.
campal segmentation: A mandatory step for Hamalainen, A., Pihlajamaki, M., Tanila,
wide clinical use. Alzheimers and Dementia, 7, H., Hanninen, T., Niskanen, E., Tervo,
171174. S.,...Soininen, H. (2006). Increased fMRI
Galton, C. J., Gomez-Anson, B., Antoun, responses during encoding in mild cognitive
N., Scheltens, P., Patterson, K., Graves, impairment. Neurobiology of Aging, 28(12),
M.,...Hodges, J. R. (2001). Temporal lobe 18891903.
rating scale: Application to Alzheimers dis- Hansson, O., Buchhave, P., Zetterberg, H.,
ease and frontotemporal dementia. Journal Blennow, K., Minthon, L., & Warkentin, S.
of Neurology, Neurosurgery and Psychiatry, 70, (2007). Combined rCBF and CSF biomark-
165173. ers predict progression from mild cogni-
Goldman, J. S., Farmer, J. M., Van Deerlin, tive impairment to Alzheimers disease.
V. M., Wilhelmsen, K. C., Miller, B. L., & Neurobiology of Aging. Epub ahead of print.
Grossman, M. (2004). Frontotemporal demen- Hariri, A. R., & Weinberger, D. R. (2003),
tia: Genetics and genetic counseling dilem- Functional neuroimaging of genetic varia-
mas. Neurologist, 10, 227234. tion in serotonergic neurotransmission. Genes
Goldman, J. S., Rademakers, R., Huey, E. D., Brain and Behavior, 2, 341349.
Boxer, A. L., Mayeux, R., Miller, B. L., & Haxby, J. V., Grady, C. L., Koss, E., Horwitz, B.,
Boeve, B. F. (2011). An algorithm for genetic Heston, L., Schapiro, M.,...Rapoport, S. I.
testing of frontotemporal lobar degeneration. (1990). Longitudinal study of cerebral metabolic
Neurology, 76, 475483. asymmetries and associated neuropsychologi-
Gomez-Isla, T., Price, J. L., McKeel, D. W., Jr., cal patterns in early dementia of the Alzheimer
Morris, J.C., Growdon, J.H.,& Hyman, B.T. type. Archives of Neurology, 47, 753760.
(1996). Profound loss of layer II entorhinal cor- Heo, S., Prakash, R. S., Voss, M. W., Erickson,
tex neurons occurs in very mild Alzheimers K.I., Ouyang, C., Sutton, B.P.,& Kramer, A.F.
disease. Journal of Neuroscience, 16, 44914500. (2010). Resting hippocampal blood flow, spa-
Gomperts, S. N., Rentz, D. M., Moran, tial memory and aging. Brain Research, 1315,
E., Becker, J. A., Locascio, J. J., Klunk, 119127.
W. E.,...Johnson, K. A. (2008). Imaging Herholz, K. (2003). PET studies in dementia.
amyloid deposition in Lewy body diseases. Annals of Nuclear Medicine, 17, 7989.
Neurology, 71, 903910. Herholz, K., Nordberg, A., Salmon, E., Perani,
Gorelick, P.B., Scuteri, A., Black, S.E., Decarli, D., Kessler, J., Mielke, R., .
.
.
Heiss, W. D.
C., Greenberg, S.M., Iadecola, C.,...Seshadri, (1999). Impairment of neocortical metabolism
S. (2011). Vascular contributions to cognitive predicts progression in Alzheimers disease.
impairment and dementia: A statement for Dementia and Geriatric Cognitive Disorders, 10,
healthcare professionals from the American 494504.
Heart Association/American Stroke Herholz, K., Salmon, E., Perani, D., Baron, J.C.,
Association. Stroke, 42, 26722713. Holthoff, V., Frlich, L.,...Heiss, W.D. (2002).
Gorno-Tempini, M.L., Hillis, A.E., Weintraub, Discrimination between Alzheimer dementia
S., Kertesz, A., Mendez, M., Cappa, and controls by automated analysis of multi-
S.F.,...Grossman, M. (2011). Classification of center FDG PET. Neuroimage, 17, 302316.
primary progressive aphasia and its variants. Herskovits, A. Z., & Growdon, J. H. (2010).
Neurology, 76, 10061014. Sharpen that needle. Archives of Neurology, 67,
Gosche, K. M., Mortimer, J. A., Smith, C. D., 918920.
Markesbery, W. R., & Snowdon, D. A. Hoffman, J. M., Welsh-Bohmer, K. A., Hanson,
(2002). Hippocampal volume as an index of M., Crain, B., Hulette, C., Earl, N.,& Coleman,
Alzheimer neuropathology: Findings from R. E. (2000). FDG PET imaging in patients
the Nun Study. Neurology, 58, 14761482. with pathologically verified dementia. Journal
Greicius, M. D., Srivastava, G., Reiss, A. L., & of Nuclear Medicine, 41, 19201928.
Menon, V. (2004). Default-mode network Hogan, R. E., Wang, L., Bertrand, M. E.,
activity distinguishes Alzheimers disease Willmore, L. J., Bucholz, R. D., Nassif,
from healthy aging:Evidence from functional A. S., & Csernansky, J. G. (2004). MRI-based
MRI. Proceedings of the National Academy of high-dimensional hippocampal mapping
Science USA, 101, 46374642. in mesial temporal lobe epilepsy. Brain, 127,
Guze, B. H., Baxter, L. R., Jr., Schwartz, J. M., 17311740.
Szuba, M.P., Mazziotta, J.C.,& Phelps, M.E. Holthoff, V. A., Beuthien-Baumann, B.,
(1991). Changes in glucose metabolism in Kalbe, E., Ludecke, S., Lenz, O., Zundorf,
dementia of the Alzheimer type compared G.,...Herholz, K. (2005). Regional cerebral
556part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
(2009). Voxel-based mapping of brain gray Lehmann, M., Koedam, E.L., Barnes, J., Bartlett,
matter volume and glucose metabolism pro- J. W., Barkhof, F., Wattjes, M. P.,...Fox,
files in normal aging. Neurobiology of Aging, N. C. (2012). Visual ratings of atrophy in
30, 112124. MCI: Prediction of conversion and relation-
Kato, T., Knopman, D., & Liu, H. (2001). ship with CSF biomarkers. Neurobiology of
Dissociation of regional activation in mild AD Aging, 34, 7382.
during visual encoding: A functional MRI Likeman, M., Anderson, V. M., Stevens, J. M.,
study. Neurology, 57, 812816. Waldman, A. D., Godbolt, A. K., Frost,
Kerchner, G. A., Hess, C. P., Hammond- C.,...Fox, N. C. (2005). Visual assessment of
Rosenbluth, K. E., Xu, D., Rabinovici, atrophy on magnetic resonance imaging in
G. D., Kelley, D. A.,...Miller, B. L. (2010). the diagnosis of pathologically confirmed
Hippocampal CA1 apical neuropil atrophy in young-onset dementias. Archives of Neurology,
mild Alzheimer disease visualized with 7T 62, 14101415.
MRI. Neurology, 75, 13811387. Luckhaus, C., Cohnen, M., Fluss, M. O.,
Kerrouche, N., Herholz, K., Mielke, R., Holthoff, Janner, M., Grass-Kapanke, B., Teipel,
V., & Baron, J. C. (2006). 18FDG PET in S. J.,...Wittsack, H. J. (2010). The relation of
vascular dementia: Differentiation from regional cerebral perfusion and atrophy in
Alzheimers disease using voxel-based multi- mild cognitive impairment (MCI) and early
variate analysis. Journal of Cerebral Blood Flow Alzheimers dementia. Psychiatry Research,
and Metabolism, 26, 12131221. 183, 4451.
Killiany, R.J., Gomez-Isla, T., Moss, M., Kikinis, Lustig, C., Snyder, A. Z., Bhakta, M., OBrien,
R., Sandor, T., Jolesz, F.,...Albert, M.S. (2000). K.C., McAvoy, M., Raichle, M.E.,...Buckner,
Use of structural magnetic resonance imaging R.L. (2003). Functional deactivations:Change
to predict who will get Alzheimers disease. with age and dementia of the Alzheimer type.
Annals of Neurology, 47, 430439. Proceedings of the National Academy of Science
Kircher, T., Weis, S., Freymann, K., Erb, M., USA, 100, 1450414509.
Jessen, F., Grodd, W.,...Leube, D. T. (2007). Machulda, M. M., Ward, H. A., Borowski, B.,
Hippocampal activation in MCI patients Gunter, J.L., Cha, R.H., OBrien, P.C.,...Jack,
is necessary for successful memory encod- C. R., Jr. (2003). Comparison of memory
ing. Journal of Neurology, Neurosurgery and fMRI response among normal, MCI, and
Psychiatry, 78(8), 812818. Alzheimers patients. Neurology, 61, 500506.
Klunk, W. E., Engler, H., Nordberg, A., Wang, Maruyama, M., Shimada, H., Suhara, T.,
Y., Blomqvist, G., Holt, D.P.,...Lngstrm, B. Shinotoh, H., Ji, B., Maeda, J.,...Higuchi, M.
(2004). Imaging brain amyloid in Alzheimers (2013). Imaging of tau pathology in a tauopa-
disease with Pittsburgh Compound-B. Annals thy mouse model and in Alzheimer patients
of Neurology, 55, 306319. compared to normal controls. Neuron, 79,
Knopman, D. S., DeKosky, S. T., Cummings, 10941108.
J. L., Chui, H., Corey-Bloom, J., Relkin, Mathis, C. A., Bacskai, B. J., Kajdasz, S. T.,
N.,...Stevens, J. C. (2001). Practice parame- McLellan, M. E., Frosch, M. P., Hyman,
ter:Diagnosis of dementia (an evidence-based B. T.,...Klunk, W. E. (2002). A lipophilic
review). Report of the Quality Standards thioflavin-T derivative for positron emis-
Subcommittee of the American Academy of sion tomography (PET) imaging of amyloid
Neurology. Neurology, 56, 11431153. in brain. Bioorganic and Medicinal Chemistry
Koedam, E. L., Lehmann, M., van der Flier, Letters, 12, 295298.
W. M., Scheltens, P., Pijnenburg, Y. A., Fox, McAllister, T. W., Saykin, A. J., Flashman,
N.,...Wattjes, M. P. (2011). Visual assess- L.A., Sparling, M.B., Johnson, S.C., Guerin,
ment of posterior atrophy development of S. J.,...Yanofsky, N. (1999). Brain activation
a MRI rating scale. European Radiology, 21, during working memory 1month after mild
26182625. traumatic brain injury: A functional MRI
Kordower, J. H., Chu, Y., Stebbins, G. T., study. Neurology, 53, 13001308.
DeKosky, S.T., Cochran, E.J., Bennett, D.,& McKeith, I.G., Dickson, D.W., Lowe, J., Emre,
Mufson, E.J. (2001). Loss and atrophy of layer M., O'Brien, J.T., Feldman, H.,...Yamada, M.
II entorhinal cortex neurons in elderly people (2005). Diagnosis and management of demen-
with mild cognitive impairment. Annals of tia with Lewy bodies. Third report of the DLB
Neurology, 49, 202213. consortium. Neurology, 65(12), 18631872.
Langbaum, J. B., Fleisher, A. S., Chen, K., McKhann, G. M., Knopman, D. S., Chertkow,
Ayutyanont, N., Lopera, F., Quiroz, H., Hyman, B. T., Jack, C. R., Jr., Kawas,
Y.T.,...Reiman, E.M. (2013). Ushering in the C. H.,...Phelps, C. H. (2011). The diagno-
study and treatment of preclinical Alzheimer sis of dementia due to Alzheimers dis-
disease. Nature Reviews Neurology, 9, 371381. ease: Recommendations from the National
558part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Institute on Aging and the Alzheimers Mosconi, L., Tsui, W. H., De Santi, S., Li, J.,
Association workgroup. Alzheimers and Rusinek, H., Convit, A.,...de Leon, M. J.
Dementia, 7(3), 263269. (2005). Reduced hippocampal metabolism in
Mega, M. S., Chu, T., Mazziotta, J. C., Trivedi, MCI and AD: Automated FDG-PET image
K. H., Thompson, P. M., Shah, A.,...Toga, analysis. Neurology, 64, 18601867.
A. W. (1999). Mapping biochemistry to Mueller, S. G., Schuff, N., Raptentsetsang, S.,
metabolism: FDG-PET and amyloid bur- Elman, J., & Weiner, M. W. (2008). Selective
den in Alzheimers disease. Neuroreport, 10, effect of Apo e4 on CA3 and dentate in nor-
29112917. mal aging and Alzheimers disease using
Mega, M.S., Cummings, J.L., OConnor, S.M., high resolution MRI at 4 T. Neuroimage
Dinov, I.D., Reback, E., Felix, J.,...Toga, A.W. 42:4248.
(2001). Cognitive and metabolic responses Mueller, S.G., Stables, L., Du, A.T., Schuff, N.,
to metrifonate therapy in Alzheimer dis- Truran, D., Cashdollar, N., & Weiner, M. W.
ease. Neuropsychiatry Neuropsychology and (2007). Measurement of hippocampal sub-
Behavioral Neurology, 14, 6368. fields and age-related changes with high
Miller, M. I., Priebe, C. E., Qiu, A., Fischl, B., resolution MRI at 4T. Neurobiology of Aging,
Kolasny, A., Brown, T.,...Morphometry, B. 28, 719726.
(2009). Collaborative computational anat- Mueller, S.G.,& Weiner, M.W. (2009). Selective
omy: An MRI morphometry study of the effect of age, Apo e4, and Alzheimers disease
human brain via diffeomorphic metric map- on hippocampal subfields. Hippocampus, 19,
ping. Human Brain Mapping, 30, 21322141. 558564.
Miller, S., Fenstermacher, E., Bates, J., Blacker, Mueller, S.G., Weiner, M.W., Thal, L.J., Petersen,
D., Sperling, R.A.,& Dickerson, B.C. (2006). R. C., Jack, C. R., Jagust, W.,...Beckett, L.
Hippocampal activation in MCI predicts sub- (2005). Ways toward an early diagnosis
sequent cognitive decline. Paper presented at in Alzheimers disease: The Alzheimers
the International Conference on Alzheimers Disease Neuroimaging Initiative (ADNI).
Disease, Madrid, Spain. Alzheimers and Dementia, 1, 5566.
Minoshima, S., Giordani, B., Berent, S., Frey, Mungas, D., Reed, B.R., Jagust, W.J., DeCarli,
K. A., Foster, N. L., & Kuhl, D. E. (1997). C., Mack, W. J., Kramer, J. H.,...Chui, H. C.
Metabolic reduction in the posterior cingu- (2002). Volumetric MRI predicts rate of cogni-
late cortex in very early Alzheimers disease. tive decline related to AD and cerebrovascu-
Annals of Neurology, 42, 8594. lar disease. Neurology, 59, 867873.
Mintun, M. A., Larossa, G. N., Sheline, Naidich, T. P., Daniels, D. L., Haughton,
Y. I., Dence, C. S., Lee, S. Y., Mach, V. M., Pech, P., Williams, A., Pojunas, K., &
R. H.,...Morris, J. C. (2006). [11C]PIB in Palacios, E. (1987b). Hippocampal forma-
a nondemented population: Potential tion and related structures of the limbic
antecedent marker of Alzheimer disease. lobe: Anatomic-MR correlation. Part II.
Neurology, 67, 446452. Sagittal sections. Radiology, 162, 755761.
Monchi, O., Petrides, M., Doyon, J., Postuma, Naidich, T.P., Daniels, D.L., Haughton, V.M.,
R.B., Worsley, K.,& Dagher, A. (2004). Neural Williams, A., Pojunas, K., & Palacios, E.
bases of set-shifting deficits in Parkinsons (1987a). Hippocampal formation and related
disease. Journal of Neuroscience, 24, 702710. structures of the limbic lobe: Anatomic-MR
Morgen, K., Kadom, N., Sawaki, L., Tessitore, correlation. Part I.Surface features and coro-
A., Ohayon, J., McFarland, H.,...Cohen, nal sections. Radiology, 162, 747754.
L.G. (2004). Training-dependent plasticity in Nakano, S., Asada, T., Matsuda, H., Uno, M.,&
patients with multiple sclerosis. Brain, 127, Takasaki, M. (2001). Donepezil hydrochlo-
25062517. ride preserves regional cerebral blood flow in
Morra, J. H., Tu, Z., Apostolova, L. G., patients with Alzheimers disease. Journal of
Green, A. E., Avedissian, C., Madsen, Nuclear Medicine, 42, 14411445.
S.K.,...Thompson, P.M. (2008). Validation of Neylan, T.C., Mueller, S.G., Wang, Z., Metzler,
a fully automated 3D hippocampal segmenta- T. J., Lenoci, M., Truran, D., ...
Schuff, N.
tion method using subjects with Alzheimers Insomnia severity is associated with a
disease mild cognitive impairment, and decreased volume of the CA3/dentate gyrus
elderly controls. Neuroimage, 43, 5968. hippocampal subfield. Biological Psychiatry,
Mosconi, L., Sorbi, S., de Leon, M. J., Li, Y., 68, 494496.
Nacmias, B., Myoung, P.S.,...Pupi, A. (2006). Nicolson, R., DeVito, T.J., Vidal, C.N., Sui, Y.,
Hypometabolism exceeds atrophy in pres- Hayashi, K. M., Drost, D. J.,...Thompson,
ymptomatic early-onset familial Alzheimers P. M. (2006). Detection and mapping of hip-
disease. Journal of Nuclear Medicine, 47, pocampal abnormalities in autism. Psychiatry
17781786. Research, 148, 1121.
CHAPTER 22. Neuroimaging, Cerebrospinal Fluid Markers, and Genetic Testing in Dementia 559
Nobili, F., Koulibaly, M., Vitali, P., Migneco, O., diagnostic criteria for the behavioural vari-
Mariani, G., Ebmeier, K.,...Darcourt, J. (2002). ant of frontotemporal dementia. Brain, 134,
Brain perfusion follow-up in Alzheimers 24562477.
patients during treatment with acetylcholin- Reddy, H., Narayanan, S., Arnoutelis, R.,
esterase inhibitors. Journal of Nuclear Medicine, Jenkinson, M., Antel, J., Matthews, P. M., &
43, 983990. Arnold, D. L. (2000). Evidence for adaptive
Nordberg, A. (2007). Amyloid imaging in functional changes in the cerebral cortex with
Alzheimers disease. Current Opinion in axonal injury from multiple sclerosis. Brain,
Neurology, 20, 398402. 123(Pt 11), 23142320.
OBrien, J. L., OKeefe, K. M., LaViolette, Reiman, E.M. (2007). Linking brain imaging and
P. S., DeLuca, A. N., Blacker, D., Dickerson, genomics in the study of Alzheimers disease
B. C., & Sperling, R. A. (2010). Longitudinal and aging. Annals of the NewYork Academy of
fMRI in elderly reveals loss of hippocampal Sciences, 1097, 94113.
activation with clinical decline. Neurology, 74, Reiman, E.M., Caselli, R.J., Chen, K., Alexander,
19691976. G.E., Bandy, D.,& Frost, J. (2001). Declining
OBrien, J.T., Erkinjuntti, T., Reisberg, B., Roman, brain activity in cognitively normal apolipo-
G., Sawada, T., Pantoni, L.,...DeKosky, S. T. protein E epsilon 4 heterozygotes:Afounda-
(2003). Vascular cognitive impairment. Lancet tion for using positron emission tomography
Neurology, 2, 8998. to efficiently test treatments to prevent
Posener, J.A., Wang, L., Price, J.L., Gado, M.H., Alzheimers disease. Proceedings of the National
Province, M. A., Miller, M. I.,...Csernansky, Academy of Science USA, 98, 33343339.
J. G. (2003). High-dimensional mapping of Reiman, E. M., Chen, K., Alexander, G. E.,
the hippocampus in depression. American Caselli, R.J., Bandy, D., Osborne, D.,...Hardy,
Journal of Psychiatry, 160, 8389. J. (2004). Functional brain abnormalities in
Post, S. G., Whitehouse, P. J., Binstock, R. H., young adults at genetic risk for late-onset
Bird, T.D., Eckert, S.K., Farrer, L.A.,...Zinn, Alzheimers dementia. Proceedings of the
A. B. (1997). The clinical introduction of National Academy of Science USA, 101, 284289.
genetic testing for Alzheimer disease. An Rombouts, S.A., Barkhof, F., Goekoop, R., Stam,
ethical perspective. Journal of the American C. J., & Scheltens, P. (2005). Altered resting
Medical Association, 277, 832836. state networks in mild cognitive impair-
Price, J. L., Ko, A. I., Wade, M. J., Tsou, S. K., ment and mild Alzheimers disease:An fMRI
McKeel, D.W.,& Morris, J.C. (2001). Neuron study. Human Brain Mapping, 26, 231239.
number in the entorhinal cortex and CA1 Rombouts, S. A., Barkhof, F., Veltman, D. J.,
in preclinical Alzheimer disease. Archives of Machielsen, W. C., Witter, M. P., Bierlaagh,
Neurology, 58, 13951402. M. A.,...Scheltens, P. (2000). Functional
Rabinovici, G. D., Furst, A. J., ONeil, J. P., MR imaging in Alzheimers disease dur-
Racine, C. A., Mormino, E. C., Baker, ing memory encoding. American Journal of
S.L.,...Jagust, W.J. (2007). 11C-PIB PET imag- Neuroradiology, 21, 18691875.
ing in Alzheimer disease and frontotemporal Rosas, H. D., Feigin, A. S., & Hersch, S. M.
lobar degeneration. Neurology, 68, 12051212. (2004). Using advances in neuroimaging to
Rabinovici, G. D., Rosen, H. J., Alkalay, A., detect, understand, and monitor disease pro-
Kornak, J., Furst, A.J., Agarwal, N.,...Jagust, gression in Huntingtons disease. NeuroRx, 1,
W. J. (2012). Amyloid vs FDG-PET in the 263272.
differential diagnosis of AD and FTLD. Rusinek, H., Brys, M., Glodzik, L., Switalski, R.,
Neurology, 77, 20342042. Tsui, W.H., Haas, F.,...de Leon, M.J. (2011).
Raichle, M. E., MacLeod, A. M., Snyder, A. Z., Hippocampal blood flow in normal aging
Powers, W. J., Gusnard, D. A., & Shulman, measured with arterial spin labeling at 3T.
G.L. (2001). A default mode of brain function. Magnetic Resonance Medicine, 65, 128137.
Proceedings of the National Academy of Science Ryan, N. S., & Fox, N. C. (2009). Alzheimer
USA, 98, 676682. disease: Visual rating of atrophy aids diag-
Rascovsky, K., Hodges, J. R., Kipps, C. M., nostic accuracy. Nature Reviews Neurology, 5,
Johnson, J. K., Seeley, W. W., Mendez, 243244.
M. F.,...Miller, B. M. (2007). Diagnostic cri- Salloway, S., Sperling, R., Gilman, S., Fox, N.C.,
teria for the behavioral variant of frontotem- Blennow, K., Raskind, M.,...Grundman, M.
poral dementia (bvFTD):Current limitations (2009). A phase 2 multiple ascending dose
and future directions. Alzheimers Disease and trial of bapineuzumab in mild to mod-
Associated Disorders, 21, S14S18. erate Alzheimer disease. Neurology, 73,
Rascovsky, K., Hodges, J. R., Knopman, D., 20612070.
Mendez, M. F., Kramer, J. H., Neuhaus, Saunders, A. M. (2000). Apolipoprotein E and
J.,...Miller, B.L. (2011). Sensitivity of revised Alzheimer disease:An update on genetic and
560part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Tepest, R., Wang, L., Miller, M. I., Falkai, P., & J. Q. (2011). The Alzheimers Disease
Csernansky, J.G. (2003). Hippocampal defor- Neuroimaging Initiative:Areview of papers
mities in the unaffected siblings of schizo- published since its inception. Alzheimers and
phrenia subjects. Biological Psychiatry, 54, Dementia. Epub ahead of print.
12341240. Weiner, M.W., Veitch, D.P., Aisen, P.S., Beckett,
Tomlinson, B.E., Blessed, G.,& Roth, M. (1968). L.A., Cairns, N.J., Green, R.C.,...Trojanowski,
Observations on the brains of non-demented J. Q. (2013). The Alzheimers Disease
old people. Journal of Neurological Sciences, 7, Neuroimaging Initiative:Areview of papers
331356. published since its inception. Alzheimers and
Tune, L., Tiseo, P.J., Ieni, J., Perdomo, C., Pratt, Dementia, 9, e111e194.
R. D., Votaw, J. R.,...Hoffman, J. M. (2003). Whitwell, J. L., Shiung, M. M., Przybelski,
Donepezil HCl (E2020) maintains functional S.A., Weigand, S.D., Knopman, D.S., Boeve,
brain activity in patients with Alzheimer B. F.,...Jack, C. R., Jr. (2008). MRI patterns
disease: Results of a 24week, double-blind, of atrophy associated with progression to
placebo-controlled study. American Journal of AD in amnestic mild cognitive impairment.
Geriatric Psychiatry, 11, 169177. Neurology, 70(7), 512520.
Van Leemput, K., Bakkour, A., Benner, T., Williamson, J., Goldman, J., & Marder, K. S.
Wiggins, G., Wald, L. L., Augustinack, (2009). Genetic aspects of Alzheimer disease.
J.,...Fischl, B. (2009). Automated segmenta- Neurologist, 15, 8086.
tion of hippocampal subfields from ultra-high Willis, M. W., Ketter, T. A., Kimbrell, T. A.,
resolution in vivo MRI. Hippocampus, 19, George, M. S., Herscovitch, P., Danielson,
549557. A.L.,...Post, R.M. (2002). Age, sex and later-
Vemuri, P., Whitwell, J. L., Kantarci, K., ality effects on cerebral glucose metabolism
Josephs, K. A., Parisi, J. E., Shiung, in healthy adults. Psychiatry Research, 114,
M.S.,...Jack, C.R., Jr. (2008). Antemortem 2337.
MRI based STructural Abnormality iNDex Wolfe, N., Reed, B.R., Eberling, J.L.,& Jagust,
(STAND)-scores correlate with postmor- W. J. (1995). Temporal lobe perfusion on
tem Braak neurofibrillary tangle stage. single photon emission computed tomogra-
Neuroimage, 42, 559567. phy predicts the rate of cognitive decline in
Vermersch, P., Leys, D., Scheltens, P.,& Barkhof, Alzheimers disease. Archives of Neurology, 52,
F. (1994). Visual rating of hippocampal atro- 257262.
phy: Correlation with volumetry. Journal of Wolk, D. A., & Dickerson, B. C. (2010).
Neurology, Neurosurgery and Psychiatry, 57, Apolipoprotein E (APOE) genotype has dis-
1015. sociable effects on memory and attentional-
Visser, P.J., Scheltens, P., Verhey, F.R., Schmand, executive network function in Alzheimers
B., Launer, L.J., Jolles, J.,& Jonker, C. (1999). disease. Proceedings of the National Academy of
Medial temporal lobe atrophy and memory Science USA, 107, 1025610261.
dysfunction as predictors for dementia in Womack, K. B., Diaz-Arrastia, R., Aizenstein,
subjects with mild cognitive impairment. H. J., Arnold, S. E., Barbas, N. R., Boeve,
Journal of Neurology, 246, 477485. B. F.,...Foster, N. L. (2011). Temporoparietal
Walsh, D.M.,& Selkoe, D.J. (2004). Deciphering hypometabolism in frontotemporal lobar
the molecular basis of memory failure in degeneration and associated imaging diag-
Alzheimers disease. Neuron, 44, 181193. nostic errors. Archives of Neurology, 68,
Walters, R.J., Fox, N.C., Crum, W.R., Taube, 329337.
D., & Thomas, D. J. (2001). Haemodialysis Wood, E. M., Falcone, D., Suh, E., Irwin, D. J.,
and cerebral oedema. Nephron, 87, 143147. Chen-Plotkin, A. S., Lee, E. B.,...Grossman,
Wang, L., Miller, J.P., Gado, M.H., McKeel, D.W., M. (2013). Development and validation of
Rothermich, M., Miller, M. I.,...Csernansky, pedigree classification criteria for fronto-
J. G. (2005). Abnormalities of hippocampal temporal lobar degeneration. Journal of the
surface structure in very mild dementia of the American Medical Association, Neurology,
Alzheimer type. Neuroimage. Epub ahead of 70(11), 14111417.
print. Xu, G., McLaren, D.G., Ries, M.L., Fitzgerald,
Wang, Z., Neylan, T.C., Mueller, S.G., Lenoci, M.E., Bendlin, B.B., Rowley, H.A.,...Johnson,
M., Truran, D., Marmar, C. R.,...Schuff, N. S.C. (2009). The influence of parental history
(2010). Magnetic resonance imaging of hip- of Alzheimers disease and apolipoprotein E
pocampal subfields in posttraumatic stress epsilon4 on the BOLD signal during recogni-
disorder. Archives of General Psychiatry, 67, tion memory. Brain, 132, 383391.
296303. Yushkevich, P.A., Avants, B.B., Pluta, J., Das, S.,
Weiner, M.W., Veitch, D.P., Aisen, P.S., Beckett, Minkoff, D., Mechanic-Hamilton, D.,...Detre,
L.A., Cairns, N.J., Green, R.C.,...Trojanowski, J.A. (2009). A high-resolution computational
562part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
atlas of the human hippocampus from post- Medical Image Computing and Computer-Assist
mortem magnetic resonance imaging at 9.4 T. Intervention, 11, 510517.
Neuroimage, 44, 385398. Yushkevich, P.A., Wang, H., Pluta, J., Das, S.R.,
Yushkevich, P.A., Avants, B.B., Pluta, J., Minkoff, Craige, C., Avants, B.B.,...Mueller, S. (2010).
D., Detre, J. A., Grossman, M., & Gee, J. C. Nearly automatic segmentation of hippocam-
(2008). Shape-based alignment of hippocam- pal subfields in in vivo focal T2weighted
pal subfields:Evaluation in postmortem MRI. MRI. Neuroimage, 53, 12081224.
23
Pharmacological Therapies
forAlzheimersDisease
Clinical Trials and Future Directions
The neuropathology of Alzheimers disease In 2011, the FDA approved a new formulation
(AD) is characterized by degeneration and loss of Aricept (donepezil hydrochloride), a 23 mg
of basal forebrain cholinergic neurons, lead- continuous release pill and in 2012, the FDA
ing to decreased cholinergic transmission and approved a 13.3 mg formulation of the Exelon
impaired memory and cognition (Bartus, Dean, (rivastigmine) transdermal patch. In 2013 a 28
Beer,& Lippa, 1982; Whitehouse etal., 1982). The mg extended-release formulation of Namenda
symptoms of AD dementia can be improved (memantine), Namenda XR, was introduced in
with acetylcholinesterase inhibitors (AChEIs) the United States.
(Birks, 2006). However, such pharmacologic In recent years, many drug candidates have
treatments merely afford palliative relief and do advanced into large, randomized controlled
not slow or reverse the progression of the dis- trials but have not demonstrated efficacy in
ease. Approved AChEIs include donepezil, riv- treating AD dementia. In part because of these
astigmine, and galantamine. Adysfunction of failures and in part because results from mul-
glutamatergic neurotransmission, manifested tiple longitudinal biomarker and clinicopatho-
as neuronal excitotoxicity, is also hypothesized logic studies have shown that the AD disease
to be involved in AD. Targeting the glutamater- process begins at least a decade before symp-
gic system, specifically NMDA receptors, offers toms of dementia develop, the field is moving
a novel approach to treatment in view of the toward earlier identification and treatment of
limited efficacy of existing drugs targeting the the disease (Weiner etal., 2012).
cholinergic system. Memantine is a low-affinity Major efforts are ongoing in academia
voltage-dependent uncompetitive antagonist and the pharmaceutical industry to develop
at glutamatergic NMDA receptors (Chen & drugs targeting the following mechanisms of
Lipton, 2005). Memantine is approved for treat- action in AD therapeutics:
ment of moderate-to-severe AD dementia. The
Food and Drug Administration (FDA) has not 1. Reduction of beta-amyloid (known as
approved any new drugs for the treatment of -amyloid, Abeta, or A) production,
AD since memantine was approved in 2003. notably secretase inhibitors
563
564part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
dementia began in late 2012. ACI-91 is a com- is necessary for Notch signaling and cell fate
pound that acts indirectly on beta-secretase determinations. These findings began to raise
and is currently being studied in a Phase II concerns about gamma secretase as a target
multicenter double-blind, placebo-controlled for AD:Inhibition of this protease, while low-
trial for the treatment of mild to moderate ering beta-amyloid production, might cause
AD dementia. The study will evaluate the severe toxicities due to blocking critical cell
compounds safety, tolerability, and efficacy differentiation events.
of 12months of treatment. A Phase II study evaluating the safety
and tolerability of the investigational oral
gamma secretase inhibitor avagacestat
Gamma-Secretase Inhibitors andModulators (BMS-708163) in patients with mild to mod-
erate AD dementia failed to reach its end-
Production of beta-amyloid is also regu- points. The compound is Notch-sparing,
lated by gamma secretase, a protease with and a single-ascending dose study suggested
numerous substrates. Gamma-secretase is a that it was tolerated at a single-dose range
membrane-embedded protease complex that of 0.3 to 800 mg, raising hopes that it would
cleaves the transmembrane region of APP to be suitable for further clinical development
produce beta-amyloid. In August 2010, devel- (Tong et al., 2012). Unfortunately, when a
opment of semagacestat, a gamma-secretase preliminary data from a Phase II study of
inhibitor, was halted when preliminary avagacestat in patients with prodromal AD
results from two ongoing long-term Phase III was examined, the company announced in
studies showed that it did not slow disease late 2012 that the results did not look favor-
progression and was, in fact, associated with able and thus development of this compound
worsening of clinical measures of cognition was halted.
and the ability to perform activities of daily
living. In addition, data showed semagace-
stat was associated with an increased risk Drugs to Prevent Beta-Amyloid Aggregation
of skin cancer compared with those who
received placebo. ELND005 (scyllo-inositol) is an oral
Tarenflurbil (r-flurbiprofen, Flurizan) was beta-amyloid antiaggregation agent. ELN005
the first gamma-secretase inhibitor that was is specifically designed to target the abnor-
stopped in Phase III clinical trials due to lack mal forms of beta-amyloid. In preclinical
of efficacy. Tarenflurbil (Flurizan), the enan- studies, ELND005 has been shown to slow
tiomer of the nonsteroidal anti-inflammatory the progression of AD pathology by neu-
drug flurbiprofen, is a modulator of tralizing beta-amyloid oligomers, inhibiting
gamma-secretase activity, and a Phase II their toxic effects on synaptic transmission,
trial of tarenflurbil for mild to moderate preventing the formation of beta-amyloid
AD indicated that the drug was well toler- fibrils, and breaking down existing fibrils
ated (Wilcock et al., 2008), while a post-hoc (Dasilva, Shaw,& McLaurin, 2010).
analysis suggested a potential signal of ben- A Phase II placebo controlled study was
efit on ADAS-Cog and the CDR-sb. However, completed in 351 patients with mild to mod-
in June 2008 a Phase III trial with over 1,700 erate AD who received study drug (250 mg
subjects failed to show efficacy, and further twice daily; 1,000 mg twice daily; 2,000 mg
development of tarenflurbil (Flurizan) for twice daily; or placebo) for up to 18months
treatment of AD was discontinued. (Salloway et al., 2011). The two higher dose
Gamma-secretase provides additional groups were discontinued in late 2009 due to
functions, besides contributing to the pro- greater rates of adverse events, including nine
duction of beta-amyloid in the brain, which deaths, in these dose groups. The study did
may explain some of the side effects expe- not achieve significance on primary outcome
rienced with semagacestat. The enzyme is measures. The 250 mg twice daily dose dem-
also critical for the processing of Notch, a onstrated a biological effect on beta-amyloid
protein that controls normal cell differentia- in the CSF and showed some effects on clini-
tion and communication (De Strooper etal., cal endpoints in an exploratory analysis,
1999). Notch, like APP, is cleaved within its particularly on the emergence of new neu-
transmembrane domain, and this proteolysis ropsychiatric symptoms. After reviewing
566part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
the final safety data, it was concluded that group of 27 patients, 22 received 150 g of
the 250 mg twice daily dose has acceptable CAD106 and 5 received the placebo. In the
safety and tolerability for further study, and first group, 67% of the patients receiving the
a Phase II study commenced in late 2012 of vaccine developed the antibody response.
this compound on agitation and aggression In the second higher dose group, 82% of the
in patients with moderate to severe AD. CAD106-treated participants had the anti-
body response (Winblad et al., 2012). The
Phase II trial, currently under way, is a ran-
Drugs to Promote Beta-Amyloid Clearance domized, double-blind, placebo-controlled,
parallel group study to evaluate the safety
Active Immunotherapy and tolerability of CAD106 when adminis-
tered as repeated subcutaneous injections in
The first human vaccination trial in AD, subjects with mild AD dementia.
AN-1792, was discontinued over a decade ACI-24, an active oligo-specific amyloid vac-
ago (in 2002). The vaccine used in that study cine, stimulates the patients immune system
activated T cells, which led to an unaccept- to produce beta-sheet conformation-specific
ably high incidence of meningoencephali- antibodies that prevent plaque deposition
tis (Orgogozo et al., 2003). Interestingly, in and enhance clearance of plaques (Pihlgren
long-term follow-up measurements, 20% etal., 2012). The vaccine is designed to break
of subjects had developed high levels of immune tolerance. During preclinical devel-
antibodies to beta-amyloid (Gilman et al., opment in animal models, ACI-24 has shown
2005). While placebo patients and nonan- high efficacy in vivo by memory restoration
tibody responders worsened, these anti- and plaque reduction. The vaccine is also
body responders showed relative stability characterized by a very high specificity due
in cognitive performance as assessed by the to generating a conformation-specific anti-
Neuropsychological Test Battery (although body response. The favorable safety profile of
not by other measures) and had lower lev- ACI-24 is underlined through the absence of
els of tau protein in their CSF. These results local inflammation in relevant models as well
suggest reduced disease activity in the as its T-cell-independent mechanism shown
antibody-responder group. Autopsies found in preclinical development.
that immunization resulted in clearance of
amyloid plaques, but it did not prevent pro-
gressive neurodegeneration (Vellas et al., Passive Immunotherapy
2009).
ACC-001 is a second-generation Solanezumab is a humanized monoclonal
beta-amyloid vaccine intended to induce antibody that recognizes the middle region of
a highly specific antibody response to beta-amyloid and binds soluble forms of the
beta-amyloid. ACC-001, an amino-terminal peptide (Farlow etal., 2012). Bapineuzumab,
immunoconjugate, was shown to be safe in a humanized monoclonal antibody against
a Phase Istudy and is currently being evalu- the N-terminus of beta-amyloid, is designed
ated in ongoing Phase II clinical studies. to bind and remove insoluble beta-amyloid
Another beta-amyloid vaccine clinical peptide (Salloway et al., 2009). Comparing
trial is CAD106, which is being evaluated in the two monoclonal antibodies, bapineu-
patients with mild AD dementia. CAD106 is zumab binds to aggregated beta-amyloid,
also designed to induce antibodies against the which is found primarily in the brain,
beta-amyloid. Results have been published while solanezumab binds to monomeric
from the Phase I clinical trial looking at the beta-amyloid oligomers, found throughout
safety, tolerability, and antibody response of the body. Solanezumab differs from bap-
active immunization with the CAD106 in 58 ineuzumab in several ways: It recognizes a
patients with AD dementia. The study par- distinct epitope in the central portion of the
ticipants, aged 50 to 80, had mild to moderate peptide, and whereas bapineuzumab binds
AD dementia and were split into two groups amyloid plaques more strongly than soluble
for a study period lasting a year. In one group beta-amyloid, solanezumab selectively binds
of 31 patients, 24 received 50g of CAD106 to soluble beta-amyloid with little to no affin-
and 7 received a placebo. In the second ity for the fibrillar form.
CHAPTER 23. Pharmacological Therapies for Alzheimers Disease 567
Bapineuzumab failed to meet its primary treatment of AD. The ADCS findings sug-
endpoints in two Phase III, multicenter, ran- gested that although the drug appeared to
domized, double-blind, placebo-controlled, slow cognitive decline, it did not slow func-
efficacy and safety trials in patients with mild tional impairment. The company announced
to moderate AD dementia. One of the trials in 2013 plans to conduct a confirmatory Phase
was in patients who are Apolipoprotein E 4 III clinical trial in patients with mild AD
(APOE 4) carriers and the second trial was dementia, diagnosed using more stringent
in patients who are APOE 4 noncarriers. In criteria, including amyloid imaging. Finally,
both trials, the primary outcome measures Solanezumab is being tested in the A4 trial
were cognitive and functional scales and were (Anti-Amyloid in Asymptomatic Alzheimers
evaluated at 18months. In the previous Phase Disease). The A4 trial is intended to bridge the
II trial, bapineuzumab had not met its pri- gap between trials for autosomal-dominant
mary efficacy endpoint in mild to moderate and sporadic AD.
AD dementia. Furthermore, amyloid-related Gantenerumab is a fully human anti-beta-
imaging abnormalities due to vasogenic amyloid antibody that has a high capac-
edema (ARIA-E) were observed in 0.8% of ity to specifically bind to cerebral amyloid
placebo and 15.8% of bapineuzumab-treated plaques (Bohrmann et al., 2012). Results
subjects overall. Risk factors for ARIA-E from Phase 1 clinical trials demonstrated
were dose, ApoE-4 allele, female gender, that gantenerumab treatment results in a
and baseline ARIA due to microhemorrhoage dose-dependent reduction of brain amy-
or hemosiderin deposits (ARIA-H), but not loid, possibly through phagocytosis via
age or disease severity. Symptoms associ- brain microglial cells, whereas amyloid load
ated with ARIA-E (e.g., headache, confusion, increased in patients receiving placebo treat-
and gait abnormalities) occurred in 2.5% of ment. APhase II study is currently recruiting
treated subjects overall but increased to 7.8% 770 patients in 15 countries to investigate the
in the 2.0 mg/kg group that had led to early efficacy and safety of gantenerumab in sub-
termination of the high-dose arm. Further jects with prodromal AD. The Phase II study
development of this compound has been is a multicenter, randomized, double-blind,
discontinued. placebo-controlled, parallel-group 2-year
The primary endpoints, both cogni- study to evaluate the effect of subcutaneous
tive and functional, were also not met in gantenerumab on cognition and function in
either of the two Phase III, double-blind, prodromal AD.
placebo-controlled solanezumab trials in Crenezumab, a humanized anti-amyloid
patients with mild to moderate AD demen- 1-40 and 1-42 antibody, is in a Phase II ran-
tia. However, a prespecified secondary analy- domized, double-blind, parallel group,
sis of pooled data across both trials showed placebo-controlled study clinical trial in
small but statistically significant slowing of mild to moderate AD dementia. In the Phase
cognitive decline in the overall study popu- I trial that concluded in 2010, crenezumab
lation of patients with mild to moderate AD demonstrated encouraging safety data in
dementia. In addition, prespecified second- patients with mild to moderate AD, with no
ary subgroup analyses of pooled data across signs of vasogenic edema in any of the sub-
both studies showed a statistically significant jects. Plasma beta-amyloid levels correlated
slowing of cognitive decline in patients with with serum crenezumab concentration. The
mild AD dementia, but not in patients with ongoing Phase II trial will enroll more than
moderate AD dementia. 370 patients in multiple centers globally. The
Adverse events with an incidence of at primary outcome measures are cognitive and
least 1% that occurred more frequently in the global function.
solanezumab group than in the placebo group Finally, another passive immunotherapy
were lethargy, rash and malaise, and angina. approach employed intravenous immu-
An independent analysis of the data from noglobulin (IVIG). Despite suggestions of
the solanezumab studies was performed by potential signals of benefit in earlier studies,
the Alzheimers Disease Cooperative Study the primary efficacy endpoints were not met
(ADCS), an academic national research con- in a 2013 report on the Phase III clinical trial
sortium that facilitates the discovery, devel- in 390 patients with mild to moderate AD
opment, and testing of new drugs for the over an 18-month period. Investigators are
568part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
continuing to analyze data from these trials, Beta-amyloid interacts with the signaling
given that several post-hoc analyses in sub- pathways that regulate the phosphorylation
groups of patients suggested the possibil- of tau. These two proteins and their associ-
ity of cognitive benefits, at least in APOE 4 ated signaling pathways therefore repre-
carriers. sent important therapeutic targets for AD.
Accordingly, a possible therapeutic strategy
for AD and related tauopathies is treatment
Nonimmunotherapy Clearance with MT-stabilizing anticancer drugs such as
ofBeta-Amyloid paclitaxel. However, paclitaxel and related
taxanes have poor bloodbrain barrier per-
Results of a study by researchers from Case meability and thus are unsuitable for dis-
Western Reserve University demonstrated eases of the brain. The MT-stabilizing agent,
that an oncology drug bexarotene (Targretin) epothilone D (EpoD), is brain penetrant and
reduced beta-amyloid plaques in the brains has been evaluated in tau transgenic mice
of a transgenic mouse model of AD (Cramer that develop forebrain tau inclusions, axonal
et al., 2012). Bexarotene activates retinoid degeneration, and MT deficits. In studies in
receptors on brain cells that increase produc- aged tauopathy mice, epothilone-treated ani-
tion of apolipoprotein E that helps rid excess mals retained more healthy axons, lost fewer
amyloid in the fluid-filled space between hippocampal neurons, and performed better
neurons (Mandrekar-Colucci, Karlo, & on memory tests compared to vehicle-treated
Landret, 2012). It also appears to enhance animals (Zhang etal., 2012). APhase Ib trial
another cleanup process, called phagocyto- of epothilone D in mild AD patients is cur-
sis. Bexarotene is FDA approved to treat cuta- rently enrolling patients.
neous T-cell lymphoma.
After 14days of treatment with bexarotene,
beta-amyloid plaque levels decreased by 75%. Tau Immunotherapy
In the study, transgenic mice treated with
bexarotene showed an improvement in their Tau-based immunotherapy is fairly new,
behavior based on several different behavioral but interest in the approach is growing.
and cognitive tests, such as ability to make Boutajangout et al. demonstrate that target-
nests and odor discrimination. The results ing phosphorylated tau by active immuniza-
of this animal study lend further support for tion prevents cognitive decline in the htau/
continued testing of the amyloid hypothesis as PS1 mouse model. This was the third study
a way to address this devastating illness. demonstrating the efficacy of active vaccina-
tion using phosphorylated tau fragments in
different animal models and confirmed pre-
Drugs to Prevent Tau Protein Phosphorylation vious findings (Boimel etal., 2010).
Many labs have generated antibodies
The second major target being pursued in the specific for tau oligomers. These polyclonal
quest for disease-modifying treatments for and monoclonal antibodies to tau oligomers
AD is the intracellular protein tau. Tau is a were prepared in vitro by seeding soluble tau
ubiquitous protein that binds to and stabilizes with oligomeric A (Lasagna-Reeves et al.,
microtubules (MT). Hyperphosphorylation 2010). The antibodies do not recognize tau
of tau disrupts its normal function in regu- monomers, but they do recognize both non-
lating axonal transport and leads to the accu- phosphorylated and phosphorylated tau in
mulation of neurofibrillary tangles and toxic neurofibrillary tangles. Elevated levels of tau
species of soluble tau (Iqbal etal., 1998). The oligomers have been quantified in postmor-
phosphorylation state of tau plays a critical tem AD brains, compared to control speci-
role in mediating tau mislocalization and mens. About 10% to 20% of total tau in AD
subsequent impairment of synaptic trans- brains is oligomeric, and the few tau struc-
mission (Rapoport, Dawson, Binder, Vitek,& tures found in control brains all appeared to
Ferreira, 2002). Furthermore, degradation of be neurofibrillary tangles.
hyperphosphorylated tau by the proteasome Finally, another tau-modulating compound
is inhibited by the actions of beta-amyloid, called tideglusib, an oral glycagen synthe-
further compounding the issue. tase kinase-3 (GSK-3) inhibitor, has been
CHAPTER 23. Pharmacological Therapies for Alzheimers Disease 569
evaluated for the treatment of AD. GSK-3 of 278 patients with moderate AD dementia
is the main enzyme involved in tau hyper- given the serotonin/5-hydroxytryptamine-6
phosphorylation (Takashima et al., 1998). (5-HT6) receptor antagonist Lu AE58054
Overexpression of GSK-3 leads to hyperphos- along with the donepezil suggested that Lu
phorylation of the tau protein (Sirerol-Piquer AE58054 in combination with donepezil pro-
et al., 2011). Tideglusib is a member of the vided added cognitive benefit, measured by
thiadiazolindindione family of the GSK-3 the ADAS-Cog, compared to placebo added
inhibitors. It is hypothesized that GSK-3 to donepezil.
may play a key role in the pathogenesis of Activation of the 5-HT6 receptor, a recep-
AD and possibly serve as the link between tor primarily expressed in the cerebral cortex
extracellular beta-amyloid and intracellular and hippocampus, usually represses cholin-
tau phosphorylation. Data from the Phase IIa ergic function (see Bentley etal., 1999), while
double-blind, placebo-controlled, escalating 5-HT6 antagonists elevate glutamatergic neu-
doses trial of tideglusib in 30 mild to mod- rotransmission (see Dawson et al., 2003). It
erate AD patients were reported showing a is posited that since Lu AE58054 selectively
trend toward cognitive benefit. A Phase IIb blocks serotonin from activating 5-HT6 recep-
clinical trial of tideglusib for the treatment of tors, it may result in an overall enhancement
AD dementia in 308 patients was reported in of acetylcholine and glutamate levels, thereby
2013 as not meeting primary endpoints. potentially producing beneficial effects on
attention, arousal, memory, learning, and
cognition.
Other Therapies Other 5-HT6 antagonists have been pre-
viously tested in AD dementia clinical tri-
Alpha-7 Nicotinic Acetylcholine Receptor als. Data from four Phase II clinical trials in
Agonist patients with mild to moderate AD demen-
tia treated with SB-742457 (NCT00348192,
EVP-6124, a selective alpha-7 nicotinic acetyl- NCT00224497, NCT00708552, and
choline receptor agonist, enhances synaptic NCT00710684) suggested a potential sig-
transmission and acts as a coagonist in com- nal for modest benefit on the Clinicians
bination with acetylcholine (ACh) to enhance Interview-Based Impression of Change with
cognition (Prickaerts et al., 2012). By sensi- Caregiver Input (CIBIC+) (Maher-Edwards
tizing the alpha-7 receptor, EVP-6124 makes etal., 2010), and similar benefits when com-
it possible for smaller amounts of naturally pared to donepezil (Maher-Edwards et al.,
occurring ACh to be effective in activating 2011). Several other 5-HT6 antagonists have
the alpha-7 receptor. This mechanism could completed or are in Phase Itrials. Dimebon,
potentially alleviate the undesirable side a drug that, among other things, antagonizes
effects caused by other systemic compounds, 5-HT6 receptors, showed cognitive benefits
such as AChEIs, which are dose limited by in Phase II trials, but it failed to show effi-
toxic side effects. Additionally, beta-amyloid cacy in larger Phase IIItesting. Alarge Phase
binds directly to alpha-7 receptors with high III clinical trial program with Lu AE58054
affinity (Wang et al., 2010). A multicenter, added to background stable therapy with
double-blind, placebo-controlled, 24-week donepezil and other cholinesterase inhibi-
Phase 2b study of EVP-6124 has been com- tors in patients with mild to moderate AD
pleted. In the trial of 409 people with mild to dementia begins enrollment in late 2013 and
moderate AD, the drug met seven of its nine early 2014.
endpoints with statistical and clinical sig-
nificance, with trends on the remaining two.
APhase III trial is reportedly being planned. Nerve Growth Factor
a neurotrophic protein that can enhance the people with mild cognitive impairment,
function of cholinergic neurons in the NBM, and 40 mild to moderate AD patients, were
prevent their death, and increase production given daily placebo or insulin (20 or 40
of ACh (Hefti, 1986). The drug has the poten- international units). The lower insulin dose
tial to induce sustained expression of NGF, improved delayed memory, and both doses
which may result in a long-lasting restoration staved off decline in general cognition (mea-
of function, protection of neurons, and slow- sured by ADAS-Cog) and functional abili-
ing the progression of AD. The Phase Iopen ties (measured by the Alzheimers Disease
label study in 10 patients with mild to moder- Cooperative Study Activities of Daily Living,
ate AD demonstrated that CERE-110 was safe i.e., ADCS-ADL).
and well tolerated (Rafii etal., 2014). Amul- A subset of participants consented to spi-
ticenter, placebo-controlled Phase II clinical nal taps for measuring cerebrospinal fluid
trial in collaboration with the Alzheimers AD biomarkers and to fluorodeoxyglucose
Disease Cooperative Study (ADCS) is under positron emission tomography (FDG-PET)
way. scans to assess brain glucose usage. On the
whole, CSF levels of A42, A40, tau, and
phosphorylated tau stayed the same in
Insulin treated participants over the 4-month study.
In exploratory analyses, correlations between
Diabetes increases the risk of developing CSF biomarker changes and cognitive mea-
any dementia by at least 100% and of AD by sures were observed in the treatment group
about 65%, with the risk increasing the lon- (low and high doses were pooled), but not in
ger the patient has had diabetes. According placebo participants. On FDG-PET, metab-
to a current hypothesis, learning takes place olism decreased in AD-affected regions
as a result of changes at synapses instigated (bilateral frontal, right temporal, bilateral
by convergent inputs from other neurons that occipital, and precuneus/cuneus) in the
stimulate various types of receptor on the placebo group more than in the treatment
neurons surface. The action of the main neu- groups (Craft et al., 2012). In collaboration
rotransmitter glutamate on its receptors is with the Alzheimers Disease Cooperative
amplified by intracellular signaling pathways Study group, a larger, 18-month Phase IIB
stimulated by insulin binding to the insulin multisite trial testing similar doses of intra-
receptor. An important enzyme activated by nasal insulin in MCI and mild AD patients is
these signals is protein kinase C (PKC), which under way. The study includes cognitive and
among other actions, promotes the release of functional tests, as well as CSF biomarker
calcium from intracellular stores. PKC seems and imaging endpoints.
to be central to the activation of synapses in
the hippocampus during learning tasks, as
well as stimulating the expression of genes for Aerobic Physical Exercise
receptors involved in learning, including the
insulin receptor. As the production of insulin The putative benefits of aerobic physical exer-
receptors declines with age, or as receptors cise for maximizing cognitive function and
become resistant to insulin, PKC is no longer supporting brain health have great potential
activated so strongly, weakening the increase for combating AD. Aerobic exercise offers a
in synaptic efficacy and the growth of new low-cost, low-risk intervention that is widely
synapses thought to be essential for learning available and may have disease-modifying
(de la Monte, 2012). Insulin stimulation also effects. Demonstrating that aerobic exercise
helps maintain healthy neuron infrastructure alters the AD process would have enormous
by preventing the activation of GSK3. This public health implications.
enzyme causes the hyperphosphorylation A wealth of animal research data sug-
of the tau protein, an abnormal modification gest that exercise positively impacts brain
leading to the formation of neurofibrillary health. Increased physical activity may
tangles. have a trophic effect on the brain, particu-
A Phase II trial of intranasal insulin for larly the hippocampus. Exercise appears to
AD has been completed (Craft etal., 2012). It stimulate neurogenesis, enhance neuronal
was a double-blind, 4-month trial. Sixty-four survival, increase resistance to brain insults,
CHAPTER 23. Pharmacological Therapies for Alzheimers Disease 571
and increase synaptic plasticity. Exercise pro- turn away from further investments in this
motes brain vascularization, mobilizes gene area. But the need for therapeutic progress in
expression profiles predicted to benefit brain the face of an exploding global epidemic is
plasticity, and maintains cognitive function. undeniable.
Additionally, exercise effects on the brain Despite the failures, the amyloid hypoth-
may reduce vascular risk factors (heart dis- esis has been strengthened by recent find-
ease, atherosclerosis, stroke, and diabetes) ings. While the solanezumab trials failed
that are believed to place an individual at to meet their primary endpoints, analysis
risk for dementia, vascular dementia, and of the pooled data provides the strongest
AD. Further, there is limited but compel- support yet for the therapeutic potential
ling animal data suggesting that exercise of targeting amyloid. This is further bol-
may have disease-modifying benefits in AD. stered by the discovery of a rare genetic
For instance, increased physical activity in polymorphisms associated with reduced
mouse models of AD reduces neuropatho- beta-secretase cleavage that affords dra-
logical burden and may promote hippocam- matic protection against sporadic AD. So,
pal neurogenesis. while other targets must be vigorously
In one recent study, Buchman and col- pursued, anti-amyloid treatments may still
leagues (2012) looked at how exercise affects hold the greatest promise in the treatment
cognition and risk of AD. All prior stud- of AD.
ies relied on self-reported exercise regi- Each of the negative pivotal trials of
men. None had prospectively measured the anti-amyloid agents has been conducted in
amount of exercise or activity. In this pro- individuals with AD dementia. As biomarker
spective, 4-year study, 716 subjects activ- findings have been incorporated into diag-
ity was measured using actigraphy for 10 nostic approaches and trial methodology,
hours per day. At the end of the observation academia and pharmaceutical companies
period, a total activity score was calculated have been moving therapies into earlier inter-
for each person using the information from ventional studies, particularly prodromal AD
the wrist device. During the study, each per- (mild cognitive impairment linked to AD by
son had at least two cognitive assessments. biomarkers). It is reasonable to anticipate that
At the beginning of the study, none of the clinical benefits will be greater with earlier
participants had AD dementia. On average, treatment.
each person wore the actigraphy monitor for But the neurobiology of the AD pathologic
just over 9 days to assess his or her activity cascade begins many years before prodro-
level. Cognitive testing was done, and it was mal AD symptoms develop. So presumably
repeated each year. The group was followed disease-modifying treatment, particularly
for an average of 3.5years. During that time, if targeting the amyloid accumulation that
9.9% of the group developed AD dementia. defines the earliest disease stage, should begin
At the end of the observation period, a strong prior to the onset of cognitive symptoms. We
association was observed between exercise now have diagnostic criteria for preclinical
and the risk for developing AD. If a person AD (see Chapter 18) based on imaging or
had a low overall physical activity, he or she cerebrospinal fluid biomarkers. As discussed
had a faster rate of cognitive decline. Subjects in detail in that chapter, these ideas have
with the lowest activity were most likely to now been incorporated into trial designs by
develop AD dementia. Compared to those several academic consortia, and trials will
with high rates of activity, the risk of devel- commence in 2013 and 2014. The ongoing
oping AD dementia was two times higher. ADCS Anti-Amyloid in Asymptomatic AD
(A4) trial should provide the strongest evi-
dence for or against beta-amyloids central
Future Directions role in driving AD pathology during preclini-
cal stage of the disease. Regulatory agencies
The overall failure of disease-modifying have been supportive of this strategy, despite
drug development for AD has led to frustra- the absence of clinically relevant outcomes
tion and even fatalism within industry and in such trials. The enormous need has gen-
academic research programs. Some fear that erated effective, precompetitive collabora-
the major pharmaceutical companies will tion that enables the launch of these studies.
572part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Despite the lack of success to date in identi- Dasilva, K.A., Shaw, J.E.,& McLaurin, J. (2010).
fying disease-modifying drugs for AD, opti- Amyloid-beta fibrillogenesis: Structural
mism is growing as new strategies continue insight and therapeutic intervention.
to be developed. Experimental Neurology, 223(2), 311321.
Dawson, L. A., Nguyen, H. Q., Li, P. (2003).
Potentiation of amphetamine-induced
References
changes in dopamine and 5-HT by a 5-HT(6)
Ballatore, C., Lee, V. M., & Trojanowski, J. Q. receptor antagonist. Brain Research Bulletin 15;
(2007). Tau-mediated neurodegeneration in 59(6), 513521.
Alzheimers disease and related disorders. de la Monte, S. M. (2012). Brain insulin resis-
Nature Reviews Neuroscience, 8(9), 663672. tance and deficiency as therapeutic targets
Bartus, R.T., Dean, R.L., III, Beer, B.,& Lippa, in Alzheimers disease. Current Alzheimers
A. S. (1982). The cholinergic hypothesis Research, 9(1), 3566.
of geriatric memory dysfunction. Science, De Strooper, B., Annaert, W., Cupers, P., Saftig,
217(4558), 408417. P., Craessaerts, K., Mumm, J. S.,...Kopan,
Bentley, J. C., Bourson, A., Boess, F. G., Fone, R. (1999). A presenilin-1-dependent
K.C., Marsden, C.A., Petit, N., Sleight, A.J. gamma-secretase-like protease mediates
(1999). Investigation of stretching behav- release of Notch intracellular domain. Nature,
iour induced by the selective 5-HT6 receptor 398(6727), 518522.
antagonist, Ro 04-6790, in rats. British Journal Farlow, M., Arnold, S. E., van Dyck, C. H.,
of Pharmacology, 126(7), 15371542. Aisen, P. S., Snider, B. J., Porsteinsson,
Birks, J. (2006). Cholinesterase inhibitors for A.P.,...Siemers, E.R. (2012). Safety and bio-
Alzheimers disease. Cochrane Database of marker effects of solanezumab in patients
Systematic Reviews, (1), CD005593. with Alzheimers disease. Alzheimers and
Bohrmann, B., Baumann, K., Benz, J., Gerber, Dementia, 8(4), 261271.
F., Huber, W., Knoflach, F.,...Loetscher, Gilman, S., Koller, M., Black, R. S., Jenkins, L.,
H. (2012). Gantenerumab: A novel human Griffith, S. G., Fox, N. C.,...Orgogozo, J. M.
anti-A antibody demonstrates sustained (2005). Clinical effects of Abeta immunization
cerebral amyloid- binding and elicits (AN1792) in patients with AD in an inter-
cell-mediated removal of human amyloid-. rupted trial. Neurology, 64(9), 15531562.
Journal of Alzheimers Disease, 28(1), 4969. Haass, C.,& Selkoe, D.J. (2007). Soluble protein
Boimel, M., Grigoriadis, N., Lourbopoulos, A., oligomers in neurodegeneration: Lessons
Haber, E., Abramsky, O., & Rosenmann, H. from the Alzheimers amyloid beta-peptide.
(2010). Efficacy and safety of immunization Nature Reviews Molecular and Cellular Biology,
with phosphorylated tau against neurofibril- 8(2), 101112.
lary tangles in mice. Experimental Neurology, Hefti, F. (1986). Nerve growth factor promotes
224(2), 472485. survival of septal cholinergic neurons after
Buchman, A.S., Boyle, P.A., Yu, L., Shah, R.C., fimbrial transections. Journal of Neuroscience,
Wilson, R. S., & Bennett, D. A. (2012). Total 6(8), 21552162.
daily physical activity and the risk of AD and Iqbal, K., Alonso, A.C., Gong, C.X., Khatoon, S.,
cognitive decline in older adults. Neurology, Pei, J.J.,& Wang, J.Z. (1998). Grundke-Iqbal
78(17), 13231329. I.Mechanisms of neurofibrillary degeneration
Chen, H. S., & Lipton, S. A. (2005). and the formation of neurofibrillary tangles.
Pharmacological implications of two distinct Journal of Neural Transmission Supplemental,
mechanisms of interaction of memantine 53, 169180.
with N-methyl-D-aspartate-gated chan- Jonsson, T., Atwal, J.K., Steinberg, S., Snaedal,
nels. Journal of Pharmacology and Experimental J., Jonsson, P. V., Bjornsson, S.,...Stefansson,
Therapeutics, 314(3), 961971. K. (2012). A mutation in APP protects against
Craft, S., Baker, L.D., Montine, T.J., Minoshima, Alzheimers disease and age-related cogni-
S., Watson, G. S., Claxton, A.,...Gerton, tive decline. Nature, 488(7409), 9699.
B. (2012). Intranasal insulin therapy for Lasagna-Reeves, C. A., Castillo-Carranza,
Alzheimer disease and amnestic mild cogni- D.L., Guerrero-Muoz, M.J., Jackson, G.R.,&
tive impairment:Apilot clinical trial. Archives Kayed, R. (2010). Preparation and char-
of Neurology, 69(1), 2938 acterization of neurotoxic tau oligomers.
Cramer, P.E., Cirrito, J.R., Wesson, D.W., Lee, Biochemistry, 49(47), 1003910041.
C. Y., Karlo, J. C., Zinn, A. E.,...Landreth, Maher-Edwards, G., Zvartau-Hind, M., Hunter,
G. E. (2012). ApoE-directed therapeutics A.J., Gold, M., Hopton, G., Jacobs, G., Davy,
rapidly clear -amyloid and reverse defi- M., Williams, P. (2010). Double-blind, con-
cits in AD mouse models. Science, 335(6075), trolled phase II study of a 5-HT6 recep-
15031506. tor antagonist, SB-742457, in Alzheimers
CHAPTER 23. Pharmacological Therapies for Alzheimers Disease 573
disease. Current Alzheimer Research, 7(5), Selkoe, D. J. (2011). Alzheimers disease. Cold
374385. Spring Harbor Perspectives in Biology, 3(7),
Maher-Edwards, G., Dixon, R., Hunter, J., pii:a004457.
Gold, M., Hopton, G., Jacobs, G., Hunter, Selkoe, D. J. (2008). Soluble oligomers of the
J., Williams, P. (2011). SB-742457 and done- amyloid beta-protein impair synaptic plas-
pezil in Alzheimer disease: a randomized, ticity and behavior. Behavior Brain Research,
placebo-controlled study. International Journal 192(1), 106113.
of Geriatric Psychiatry, 26(5), 536544. Sirerol-Piquer, M., Gomez-Ramos, P.,
Mandrekar-Colucci, S., Karlo, J.C.,& Landreth, Hernndez, F., Perez, M., Morn, M. A.,
G. E. (2012). Mechanisms underlying the Fuster-Matanzo, A.,...Garca-Verdugo, J. M.
rapid peroxisome proliferator-activated (2011). GSK3 overexpression induces neuro-
receptor--mediated amyloid clearance and nal death and a depletion of the neurogenic
reversal of cognitive deficits in a murine niches in the dentate gyrus. Hippocampus,
model of Alzheimers disease. Journal of 21(8), 910922.
Neuroscience, 32(30), 1011710128. Takashima, A., Murayama, M., Murayama,
Orgogozo, J. M., Gilman, S., Dartigues, J. F., O., Kohno, T., Honda, T., Yasutake,
Laurent, B., Puel, M., Kirby, L. C.,...Hock, K.,...Wolozin, B. (1998). Presenilin 1 asso-
C. (2003). Subacute meningoencephalitis in ciates with glycogen synthase kinase-3beta
a subset of patients with AD after Abeta42 and its substrate tau. Proceedings of the
immunization. Neurology, 61(1), 4654. National Academy of Science USA, 95,
Pihlgren, M., Madani, R., Hickman, D., 96379641.
Giriens, V., Chuard, N., ven der Auwera, Tanzi, R.E.,& Bertram, L. (2005). Twenty years
I.,...Stanco-Piorko, K. (2012). The safety of the Alzheimers disease amyloid hypoth-
profile of ACI-24, an oligo-specific amyloid esis: A genetic perspective. Cell, 120(4),
beta vaccine, demonstrated decrease of large 545555.
microbleedings in brain of aged Alzheimers Tong, G., Wang, J. S., Sverdlov, O., Huang,
disease mouse model. Alzheimers and S. P., Slemmon, R., Croop, R.,...Dockens,
Dementia, 5(4), Supplement, p425p426 R. C. (2012). Multicenter, random-
Prickaerts, J., van Goethem, N.P., Chesworth, ized, double-blind, placebo-controlled,
R., Shapiro, G., Boess, F. G., Methfessel, single-ascending dose study of the
C.,...Knig, G. (2012). EVP-6124, a novel oral -secretase inhibitor BMS-708163
and selective 7 nicotinic acetylcholine (Avagacestat), tolerability profile, pharmaco-
receptor partial agonist, improves memory kinetic parameters, and pharmacodynamic
performance by potentiating the acetyl- markers. Clinical Therapy, 34(3), 654667.
choline response of 7 nicotinic acetylcho- Vellas, B., Black, R., Thal, L. J., Fox, N. C.,
line receptors. Neuropharmacology, 62(2), Daniels, M., McLennan, G.,...Grundman,
10991110. M. (2009). Long-term follow-up of patients
Rafii, M. S., Baumann, T. L., Bakay, R. A., immunized with AN1792: Reduced func-
Ostrove, J. M., Siffert, J., Fleisher, tional decline in antibody responders. Current
A. S.,...Bartus, R. T. (2014). A phase1 study Alzheimers Research, 6(2), 144151.
of stereotactic gene delivery of AAV2-NGF Viswanathan, A., & Greenberg, S. M. (2011).
for Alzheimer's disease. Alzheimers Dementia, Cerebral amyloid angiopathy in the elderly.
pii:S1552-5260(13)02838-0. Annals of Neurology, 70(6), 871880.
Rapoport, M., Dawson, H. N., Binder, L. I., Wang, H.Y., Bakshi, K., Shen, C., Frankfurt, M.,
Vitek, M. P., & Ferreira, A. (2002). Tau is Trocm-Thibierge, C., & Morain, P. (2010). S
essential to beta-amyloid-induced neurotox- 24795 limits beta-amyloid-alpha7 nicotinic
icity. Proceedings of the National Academy of receptor interaction and reduces Alzheimers
Science USA, 99(9), 63646369. disease-like pathologies. Biological Psychiatry,
Salloway, S., Sperling, R., Gilman, S., Fox, N.C., 67(6), 522530
Blennow, K., Raskind, M.,...Grundman, M. Weiner, M.W., Veitch, D.P., Aisen, P.S., Beckett,
(2009). A phase 2 multiple ascending dose L.A., Cairns, N.J., Green, R.C.,...Trojanowski,
trial of bapineuzumab in mild to moder- J. Q. (2012). The Alzheimers Disease
ate Alzheimer disease. Neurology, 73(24), Neuroimaging Initiative: Areview of papers
20612070. published since its inception. Alzheimers and
Salloway, S., Sperling, R., Keren, R., Dementia, 8(1 Suppl), S1-68.
Porsteinsson, A. P., van Dyck, C. H., Tariot, Whitehouse, P. J., Price, D. L., Struble, R. G.,
P. N.,...Cedarbaum, J. M. (2011). A phase 2 Clark, A. W., Coyle, J. T., & Delon, M. R.
randomized trial of ELND005, scyllo-inositol, (1982). Alzheimers disease and senile
in mild to moderate Alzheimer disease. dementia: Loss of neurons in the basal fore-
Neurology, 77(13), 12531262. brain. Science, 215(4537), 12371239.
574part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Wilcock, G. K., Black, S. E., Hendrix, S. B., with CAD106 in patients with Alzheimers
Zavitz, K. H., Swabb, E. A., & Laughlin, disease: Randomised, double-blind,
M. A. (2008). Efficacy and safety of taren- placebo-controlled, first-in-human study.
flurbil in mild to moderate Alzheimers Lancet Neurology, 11(7), 597604.
disease:Arandomised phase II trial. Lancet Zhang, B., Carroll, J., Trojanowski, J.Q., Yao, Y.,
Neurology, 7(6), 483493. Erratum in Lancet Iba, M., Potuzak, J.S.,...Brunden, K.R. (2012).
Neurology 2008, 7(7), 575. Lancet Neurology The microtubule-stabilizing agent, epothilone
2011, 10(4), 297. D, reduces axonal dysfunction, neurotoxicity,
Winblad, B., Andreasen, N., Minthon, L., cognitive deficits, and Alzheimer-like pathol-
Floesser, A., Imbert, G., Dumortier, T.,...Graf, ogy in an interventional study with aged
A. (2012). Safety, tolerability, and antibody tau transgenic mice. Journal of Neuroscience,
response of active A immunotherapy 32(11), 36013611.
24
Worldwide, 35 million people suffer as hitting and biting others, and throwing
from dementia (Alzheimers Disease objects. These symptoms most commonly
International, 2008), the majority of whom manifest when people with AD are being
have Alzheimers disease (AD). It is a dev- assisted with personal care. Common symp-
astating illness, resulting in progressive toms of agitation include restlessness and
decline of cognitive ability and functional pacing, excessive fidgeting, motor activities
capacity and the emergence of behavioral associated with anxiety (such as hand wring-
and psychological symptoms of demen- ing and following a caregiver around the
tia (BPSDs). The progressive decline and house), and shouting/screaming. Common
the BPSDs can cause enormous distress to symptoms of psychosis include visual hal-
patients, their caregivers and families, and lucinations (most frequently of people or
have a major societal impact. More than 90% animals), auditory hallucinations, delusions
of people with dementia develop at least one (most often simple nonsystematized delu-
clinically significant behavioral or psychiat- sions of theft, harm, or infidelity or other
ric symptom (Steinberg etal., 2008)over the people living in the house) and delusional
course of their illness. BPSDs present as three misidentification (e.g., Capgras syndrome,
main syndromesagitation, psychosis, and believing that people on TV or in photo-
mood disordersalthough these syndromes graphs are real or believing that a mirror
frequently coexist. The overall frequency of reflection is someone else (Ballard, Gauthier,
BPSD, in particular agitation and aggres- etal., 2009).
sion, increases with the severity of demen- Aggression and nonaggressive agitation
tia (Aalten etal., 2003; see Chapter21). This occur in approximately 20% of people with
chapter focuses predominantly on treatment AD in contact with clinical services (Burns,
strategies for agitation, aggression, and psy- Jacoby, & Levy, 1990b) or living in the com-
chosis. Common symptoms of aggression in munity (Lyketsos etal., 2000)and in 40%60%
people with AD include verbal insults and of people in care facilities (Margallo-Lana
shouting, as well as physical aggression such et al., 2001). Delusions and hallucinations
575
576part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
than 200 participants and showed a sig- undertaken in 12 care homes with 347 resi-
nificant seven-point improvement on the dents and led to a significant reduction in
Cohen-Mansfield Agitation Inventory. It antipsychotic prescriptions for people with
should be noted that the absence of a control dementia, without increasing agitation or
treatment means that it is difficult to deter- disruptive behavior (Fossey et al., 2006).
mine the proportion of the benefit attrib- Similar benefits have also been demon-
utable to the intervention. Nevertheless, strated in a study that delivered a nursing
this study supports best practice guid- home liaison service to nine care homes,
ance for BPSDs, providing professionals involving a part-time old-age psychiatrist
with options for simple, first-line nondrug and a community psychiatric nurse. This
interventions and highlights the finding study was based on cognitive-behavioral
that most individuals experience improve- therapy as a first-line treatment choice
ment without pharmacologic treatment. (Ballard et al., 2002). Further evidence to
Reminiscence therapy also confers modest support training approaches includes an
but significant benefits in BPSDs and may excellent three-arm cluster RCT that dem-
be valuable as part of a personalized treat- onstrated the additional value of dementia
ment and care plan. care mapping to person-centered care in
People experiencing more severe or chal- 15 care homes with 289 participants with
lenging BPSDs still benefit from more intense dementia. The dementia care mapping was
individualized psychological interventions. used as a tool to improve person-centered
Evidence from large case series and a cou- care planning and substantially reduced
ple of small but well-designed clinical trials agitation by more than 10 points on the
supports the effectiveness of individualized, Cohen-Mansfield Agitation Inventory com-
comprehensive interventions delivered by pared with treatment as usual (standard-
a clinical psychologist and designed using ized effect size Cohens d > 0.5 for both
antecedent, behavior, consequence (ABC) treatments; Chenoweth etal., 2009).
charts.
For example, one cluster randomized trial
compared a clinical psychology model based Pharmacological TreatmentsAntipsychotics
on the ABC principles with a traditional
old-age psychiatry service in 55 referrals The first generation of antipsychotic drugs
of people with BPSD. Both groups showed (usually referred to as typical antipsy-
favorable responses to the interventions, but chotics) was introduced as a treatment for
the model led by the clinical psychologist schizophrenia in the 1950s and 1960s. By the
resulted in additional reduction of antipsy- 1970s these compounds were in frequent
chotic prescriptions and fewer hospital days clinical use as an off-license (off-label)
(Bird, 2002). treatment for BPSD. In the early 1990s, a
A different but equally important second generation of antipsychotic agents
approach is to improve the training and (usually referred to as atypical antipsy-
skill set of care staff to enable more effec- chotics) such as risperidone, olanzapine,
tive management of BPSDs and to improve aripirprazole, and quetiapine were intro-
the overall quality of care. Studies evaluat- duced for the treatment of schizophre-
ing this approach have reported variable nia. The adverse effect profiles of atypical
results, with many shorter studies indicat- agents are generally favorable in compari-
ing that initial benefits are not sustained son to those of typical agents in people
beyond the end of the training period. with schizophrenia and bipolar affective
However, more recent RCTs of intensive disorders. Consequently, atypical antipsy-
training packages and interventions to chotics also became the preferred option
develop practice have conferred substantial for the treatment of BPSDs in patients with
benefit over 4- to 12-month periods. One AD and other dementias by the mid-1990s
9-month cluster RCT analyzed the effec- because of the perceived better tolerability.
tiveness of a person-centered care train- However, several important safety issues
ing package delivered 2 days a week by a related to the use of these agents in patients
health care professional. The study was with dementia have become apparent.
578part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Typical antipsychotics 11 randomized, Early meta-analysis concluded significant Parkinsonism, dystonia, Adverse events associated with
placebo-controlled trials, but modest advantage over placebo in tardive dyskinesia typical antipsychotics make their
mostly small sample the treatment of behavioral symptoms. QTc prolongation use inadvisable in people with
sizes and of 412 weeks, Recent meta-analysis reports only one Significant increase in Alzheimers disease.
one up to 16 weeks placebo-controlled trial showed mortality risk compared
significant benefit of thioridazine. to atypical antipsychotics
Small thiothixine study suggested efficacy (180days, relative risk 1.37)
at low doses, but that symptoms return
after discontinuation.
Meta-analysis of haloperidol indicates
improvement in aggression, but not in
other symptoms of agitation.
Atypical 18 placebo-controlled Significant benefit in the treatment of Extrapyramidal symptoms Probably still the best option for the
antipsychotics trials over 612 weeks, aggression over 12 weeks. More limited Sedation short-term (612 weeks) treatment
only three trials of benefit for other symptoms and do Increased mortality of aggression that is severe,
612months not appear to be beneficial over longer (1.51.7-fold) persistent, and treatment resistant,
treatment periods Increased cerebrovascular but the serious adverse events
adverse events (3-fold) are a major caution to long term
therapy
580part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
CATIE study described no overall benefit dyskinesia appears to be less frequent than
(Schneider, Tariot, etal., 2006). However, the with typical antipsychotics, but Q-Tc prolon-
CATIE trial did indicate that antipsychotics gation has also been reported as a significant
were less likely to be discontinued because of problem with several atypical antipsychotics
perceived ineffectiveness over 9months than (Reilly et al., 2000). A recent meta-analysis
placebo (Schneider, Tariot, etal., 2006). also identified a significant increase in
respiratory and urinary tract infections and
peripheral edema among people treated with
Safety risperidone compared to placebo (Ballard &
Howard, 2006). These are likely to be class
Typical Antipsychotics effects for atypical antipsychotics. The lim-
ited trial data for other atypical antipsychot-
Typical antipsychotics are associated with ics precluded a comprehensive meta-analysis
numerous severe adverse effects in patients of adverse events.
with AD. These include parkinsonism (Tune, Over the last few years, the most seri-
Steele,& Cooper, 1991), dystonia, tardive dys- ous concerns regarding atypical antipsy-
kinesia, acceleration of cognitive decline, and chotics have related to emergent data
prolongation of the QTc interval on electro- suggesting an increase of cerebrovascu-
cardiogram (ECG), leading to added risk of lar events and increased mortality in AD
cardiac arrhythmias. Prolonged QTc has been patients. Observation of combined data
demonstrated with several typical antipsy- from placebo-controlled trials shows that
chotics which have been widely prescribed in risperidone has been associated with a
the past, including thioridazine and droperi- three-fold increased risk of serious cerebro-
dol (Reilly, Ayis, Ferrier, Jones, & Thomas, vascular adverse events compared to placebo
2000). Both have now either been withdrawn (37/1,175 vs. 8/779, OR 3.64, 95% CI 1.72 to
or are prescribed only very infrequently to 7.69, p = 0.0007; Ballard & Howard, 2006).
people with dementia. Furthermore, there is In the Mintzer trial of aripiprazole (Mintzer
a significant increase in mortality, which is et al., 2007), cerebrovascular adverse events
even greater than the mortality risk associ- were reported in four patients who were pre-
ated with atypical antipsychotics (reviewed scribed aripiprazole 10 mg/day but in none
in the next section). of the placebo-treated patients. Other sources
Until 2000, thioridazine, promazine, and of information, such as prescription event
haloperidol were all widely used in the clini- monitoring, would indicate that this is prob-
cal setting. However, prescribing practice has ably a class effect.
changed substantially in response to specific In 2005, the US Food and Drug
concerns related to the cardiac safety of thio- Administration published a warning high-
ridazine and general concerns regarding the lighting a significant increase in mortality
side effect profile of typical antipsychotics. risk (odds ratio [OR] = 1.7) for people with
The potential use of haloperidol remains con- AD treated with atypical antipsychotics
troversial, and it is still recommended and compared to individuals receiving placebo
widely prescribed as a treatment for aggres- in RCTs. Schneider has reviewed the evi-
sion and psychosis in some countries, despite dence from 15 of these trials and confirmed
higher risks of important side effects, includ- a significant increase in mortality (OR=1.54)
ing parkinsonism, gait disturbance, tardive with no difference between specific agents
dyskinesia, and mortality. (Schneider, Dagerman, & Insel, 2005). The
recent DART-AD RCT indicated that this
excess mortality risk continues over longer
Atypical Antipsychotics periods of prescribing, with an increasing
impact on the absolute number of attribut-
Widely reported side effects of atypical anti- able deaths (Ballard, Hanney, etal., 2009). An
psychotics include extrapyramidal symp- additional important study demonstrated an
toms, sedation, gait disturbances, and falls. even greater excess of mortality for typical
Many agents also lead to anticholinergic antipsychotics (Wang etal., 2005).
side effects, including delirium (Ballard & The most common cause of death in
Howard, 2006; Tune et al., 1991). Tardive people with dementia who are prescribed
CHAPTER 24. Management of Agitation, Aggression, and Psychosis Associated With Alzheimers Disease 581
that provide useful alternatives to pharmaco- score within 6 weeks (Holmes et al., 2004).
logical treatment. The guide provides medical However, there was no short-term benefit for
care plans and assessment tools to support treatment of clinically significant agitation
decisions regarding treatment, including the with donepezil over 12 weeks in a large RCT
prescription and discontinuation of antipsy- (Howard etal., 2007), or over 24 weeks with
chotics, and effective monitoring and review. rivastigmine in a smaller RCT (Ballard etal.,
Based upon the evidence base and current 2005), indicating that ChEIs do not appear to
drug licenses, risperidone is highlighted as be useful in the management of acute agita-
the preferred treatment if an antipsychotic is tion. A 5-month placebo-controlled RCT of
necessary. However, the guide emphasizes the galanthamine suggested that ChEI treatment
importance of considering the benefit of phar- may delay the emergence of overall BPSDs
macological and nondrug treatment of other (Tariot et al., 2000), and pharmacogenetic
general and mental health conditions before studies have suggested the possibility of a
resorting to an antipsychotic prescription. The preferential response to rivastigmine in the
limitations regarding the evidence base for treatment of overall BPSDs in people with the
other nonantipsychotic psychotropic drugs is wild-type Butyrylcholinesterase genotype
also highlighted. It particularly highlights the (Blesa etal., 2006). However, within the over-
importance of avoiding the practice of substi- all BPSD spectrum, ChEIs appear to have
tuting antipsychotics for other drugs with an their greatest effects on depression and dys-
even more limited evidence base which may phoria, apathy and indifference, and anxiety
be equally or more harmful. The guide is avail- (Gauthier etal., 2002).
able for professionals to use in clinical practice,
although it is not designed for use in acute
hospital settings. It is available as a download Memantine
from the Alzheimers Society (n.d.) and is
endorsed and promoted by the Department of Individual studies, meta-analyses, and pooled
Health, Royal College of General Practitioners analyses indicate that memantine may confer
and Royal College of Psychiatrists as a key benefit in the treatment of mild to moderate
tool in the drive to reduce antipsychotic drugs irritability and lability, agitation or aggression,
in people with dementia. and psychosis over 36 months in patients
with AD (Gauthier, Loft, & Cummings, 2008;
Gauthier, Wirth, & Mobius, 2005; McShane,
Other Pharmacological Treatments Areosa Sastre, & Minakaran, 2006; Wilcock,
Ballard, Cooper, & Loft, 2008). Although this
No pharmacological treatments other than evidence is potentially encouraging with
risperidone were considered to have a suf- respect to memantine as a useful adjunct to
ficient evidence base to recommend for the treatment of mild BPSD, there is limited RCT
treatment of agitation, aggression, or psycho- evidence regarding the use of memantine in
sis other than risperidone. Abrief review of the acute treatment of clinically significant
the emerging evidence regarding other can- BPSD. The recent MAGD trial compared
didate treatments is presented next. memantine and placebo over 6 and 12 weeks
in 153 people with AD and clinically signifi-
cant agitation. Memantine did not confer any
Cholinesterase Inhibitors significant benefit in the treatment of agitation
over 6 or 12 weeks in compared to placebo as
A meta-analysis demonstrated a small but measured by the Cohen-Mansfield Agitation
significant overall advantage of cholines- Inventory as the primary outcome measure.
terase inhibitors (ChEIs) over placebo with There was a significant benefit on the over-
regard to the treatment of BPSDs in AD (Trinh, all Neuropsychiatric Inventory score, but
Hoblyn, Mohanty,& Yaffe, 2003). Additional no advantage for memantine on the Clinical
support for beneficial effects of ChEIs on Global Impression of change as an overall
BPSDs comes from a randomized with- clinician-measured outcome, suggesting that
drawal study, in which cessation of donepezil overall benefits were not sufficient to recom-
was associated with a significant worsening mend memantine as a clinical therapy for acute
of the total Neuropsychiatric Inventory (NPI) agitation or aggression in people with AD (Fox
CHAPTER 24. Management of Agitation, Aggression, and Psychosis Associated With Alzheimers Disease 583
etal., 2012). Apost-hoc analysis (Wilcock etal., specific symptom clusters such as delusions,
2008), supported by a recent RCT (Howard hallucinations, aggression, and agitation to
et al., 2012), has, however, highlighted the develop more targeted therapies. One exam-
potential contribution of memantine to the ple is the potential use of muscarinic agonists
reduced emergence of overall BPSDs, with for the treatment of delusions:Anumber of
a 5.5 point significant advantage favoring postmortem studies have indicated an asso-
memantine over placebo at 6-month follow-up ciation between altered muscarinic receptor
on the total Neuropsychiatric Inventory in binding and delusions in dementia patients
the DOMINO trial (Howard etal., 2012). It is (Konovalov, Muralee, & Tampi, 2008), and
hoped that ongoing RCTs in Canada and in preliminary data from secondary analyses
the United Kingdom may clarify the role of of RCTs with muscarinic agonists such as
memantine in treating agitation and aggres- xanomeline (Ballard et al., 2000) indicate
sion in patients with AD in the near future. a potential treatment effect on psychosis.
Another example is the relationship between
altered adrenoceptors and agitation or
Antidepressants for Agitation aggression in postmortem studies in people
andAggression with AD (Bodick etal., 1997); a preliminary,
small RCT of the alpha-adrenoceptor blocker
In a 17-day trial in psychiatric inpatients with prazosin indicates potential benefit in the
severe BPSDs related to AD, Pollock and col- treatment of BPSDs in AD patients (Sharp,
leagues (2002) reported that citalopram was Ballard, Chen, & Francis, 2007). Targeted
superior to placebo, with the greatest efficacy drug development based upon the principles
for agitation or aggression, an effect not seen of evidence-based experimental medicine
with perphenazine. In a later study, citalo- is more likely to lead to the development of
pram was found to be comparable in efficacy effective therapies.
to risperidone, differentiated by its significant
effect on agitation symptoms and its superior
tolerability in the treatment of moderate to Conclusion
severe BPSDs (Pollock et al., 2007). RCTs of
sertraline (Finkel etal., 2004)and trazadone Agitation, aggression, and psychosis are fre-
(Teri etal., 2000)have been less promising. quent and distressing symptoms in people
with Alzheimers disease. Implementing the
best currently available evidence to optimize
Anticonvulsants safe and effective management is imperative.
These best practices include medical treat-
Two small parallel-group RCTs of carbamaze- ment of underlying conditions; treatment
pine for the treatment of agitation and aggres- of pain; routinely implementing effective
sion in AD, both conducted over a period of nonpharmacological care; and the judicious
6 weeks or less, suggested potential benefit short-term use of antipschotics, when appro-
(Olin, Fox, Pawluczyk, Taggart,& Schneider, priate, for severe symptoms that have not
2001; Tariot et al., 1998). A meta-analysis of responded to other approaches and pose sub-
the two trials (Gauthier etal., 2002)indicates stantial safety risk to the indiviudal or others.
significant improvement on both the Brief To move the field forward considerably, more
Psychiatric Rating Scale (mean difference focus is needed to evaluate potential phar-
5.5; 95% CI, 8.5 to 2.5) and on Clinical macological alternatives through adequately
Global Improvement (OR, 10.2; 95% CI, 3.1 powered RCTs.
33.1). Both studies also suggest good toler-
ability. In contrast, valproate has not shown
treatment benefits for BPSDs References
Aalten, P., de Vugt, M.E., Lousberg, R., Korten,
E., Jaspers, N., Senden, B.,...Verhey, F. R.
Other Treatments (2003). Behavioral problems in demen-
tia:Afactor analysis of the neuropsychiatric
It will also be important to use our best scien- inventory. Dementia and Geriatric Cognitive
tific understanding of the biological basis of Disorders, 15, 99105.
584part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Alzheimers Disease International. (2008). The in dementia among people in care envi-
prevalence of dementia worldwide. Retrieved ronments. Journal of Clinical Psychiatry, 62,
March 2014, from http://www.alz.co.uk/ 631636.
adi/pdf/prevalence.pdf. Ballard, C., Margallo-Lana, M., Juszczak, E.,
Alzheimers Society UK. (n.d.). Optimising treat- Douglas, S., Swann, A., Thomas, A.,...Jacoby,
ment and care for behavioural and psychological R. (2005). Quetiapine and rivastigmine
symptoms of dementia: A best practice guide. and cognitive decline in Alzheimers dis-
Retrieved March 2014, from http://www. ease:Randomised double blind placebo con-
alzheimers.org.uk/site/scripts/download_ trolled trial. British Medical Journal, 330, 874.
info.php?downloadID=609. Ballard, C. G., Patel, A., Solis, M., Lowe, K., &
Angelucci, F., Bernadini, S., Gravina, P., Wilcock, G. (1996). A one-year follow-up
Bellincampi, L., Trequattrini, A., Di Iulio, study of depression in dementia sufferers.
F.,...Spalletta, G. (2009). Delusion symptoms British Journal of Psychiatry, 168, 287291.
and response to antipsychotic treatment are Ballard, C., Piggott, M., Johnson, M., Cairns,
associated with the 5-HT2A receptor poly- N., Perry, R., McKeith, I.,...Perry, E. (2000).
morphism (102T/C) in Alzheimers dis- Delusions associated with elevated musca-
eases:A3-year follow-up longitudinal study. rinic binding in dementia with Lewy bodies.
Journal of Alzheimers Disease, 17, 203211. Annals of Neurology, 48, 868876.
Ballard, C., Brown, R., Fossey, J., Douglas, S., Ballard, C., Powell, I., James, I., Reichelt, K.,
Bradley, P., Hancock, J.,...Howard, R. (2009). Myint, P., Potkins, D.,...Barber, R. (2002).
Brief psychosocial therapy for the treat- Can psychiatric liaison reduce neuroleptic
ment of agitation in Alzheimer disease (The use and reduce health service utilization for
CALM-AD Trial). American Journal of Geriatric dementia patients residing in care facilities.
Psychiatry, 17, 726733. International Journal of Geriatric Psychiatry, 17,
Ballard, C., Creese, B., Corbett, A.,& Aarsland, 140145.
D. (2011). Atypical antipsychotics for the Banerjee, S., Smith, S. C., Lamping, D. L.,
treatment of behavioral and psychological Harwood, R.H., Foley, B., Smith, P.,...Knapp,
symptoms in dementia, with a particular M. (2006). Quality of life in dementia: More
focus on longer term outcomes and mortality. than just cognition. An analysis of associa-
Expert Opinion on Drug Safety, 10, 3543. tions with quality of life in dementia. Journal
Ballard, C. G., Eastwood, C., Gahir, M., & of Neurology, Neurosurgery and Psychiatry, 77,
Wilcock, G. (1996). A follow up study of 146148.
depression in the carers of dementia suffer- Bird, M. (2002). Psychosocial approaches to chal-
ers. British Medical Journal, 312, 947. lenging behavior in dementia: A controlled
Ballard, C. G., Gauthier, S., & Cummings, trial. In Report to the Commonwealth Department
J. L., Brodaty, H., Grossberg, G. T., Robert, of Health and Ageing (pp. 140). Canberra,
P., & Lyketsos, C. G. (2009). Management Australia:Office for Older Australians.
of agitation and aggression associated Blesa, R., Bullock, R., He, Y., Gambina, G.,
with Alzheimer disease. Nature Reviews Meyer, J., Rapatz, G., .
.
.
Lane, R. (2006).
Neuroscience, 5, 245255. Effect of butyrylcholinesterase genotype on
Ballard, C., Hanney, M. L., Theodoulou, M., the response to rivastigmine or donepezil in
Douglas, S., McShane, R., Kossakowski, younger patients with Alzheimers disease.
K.,...Jacoby, R. (2009). The demen- Pharmacogenetics and Genomics, 16, 771774.
tia antipsychotic withdrawal trial Bodick, N.C., Offen, W.W., Levey, A.I., Cutler,
(DART-AD): Long-term follow-up of a ran- N.R., Gauthier, S.G., Satlin, A.,...Paul, S.M.
domised placebo-controlled trial. Lancet (1997). Effects of xanomeline, a selective mus-
Neurology, 8, 151157. carinic receptor agonist, on cognitive function
Ballard, C., & Howard, R. (2006). Neuroleptic and behavioral symptoms in Alzheimer dis-
drugs in dementia:Benefits and harm. Nature ease. Archives of Neurology, 54, 465473.
Reviews Neuroscience, 7, 492500. Burns, A., Jacoby, R., & Levy, R. (1990a).
Ballard, C., Lana, M., Theodoulou, M., Douglas, Psychiatric phenomena in Alzheimers dis-
S., McShane, R., Jacoby, R.,...Juszczak, ease. III:Disorders of mood. British Journal of
E. (2008). A randomised, blinded, Psychiatry, 157, 8186, 9294.
placebo-controlled trial in dementia patients Burns, A., Jacoby, R., & Levy, R. (1990b).
continuing or stopping neuroleptics (the Psychiatric phenomena in Alzheimers dis-
DART-AD trial). PLoS Medicine, 5, 76. ease. IV: Disorders of behaviour. British
Ballard, C. G., Margallo-Lana, M., Fossey, Journal of Psychiatry, 157, 8694.
J., Reichelt, K., Myint, P., Potkins, D., & Chapman, F. M., Dickinson, J., McKeith,
O'Brien, J. (2001). A 1-year follow-up study I., & Ballard, C. (1999). Association among
of behavioral and psychological symptoms visual hallucinations, visual acuity, and
CHAPTER 24. Management of Agitation, Aggression, and Psychosis Associated With Alzheimers Disease 585
Cochrane Database of Systematic Reviews, (4), perphenazine, and placebo for the acute
2005. CD002852 treatment of psychosis and behavioral dis-
Lyketsos, C. G. (2007). Neuropsychiatric turbances in hospitalized, demented patients.
symptoms (behavioral and psychological American Journal of Psychiatry, 159, 460465.
symptoms of dementia) and the develop- Rabins, P.V., Mace, N.L.,& Lucas, M.J. (1982).
ment of dementia treatments. International The impact of dementia on the family. Journal
Psychogeriatrics, 19, 409420. of the American Medical Association, 248,
Lyketsos, C.G., Colenda, C.C., Beck, C., Blank, 333335.
K., Doraiswamy, M. P., Kalunian, D. A., & Reilly, J. G., Ayis, S. A., Ferrier, I. N., Jones,
Yaffe, K. (2006). Position statement of the S. J., & Thomas, S. H. (2000). QTc-interval
American Association for Geriatric Psychiatry abnormalities and psychotropic drug therapy
regarding principles of care for patients with in psychiatric patients. Lancet, 355, 10481052.
dementia due to Alzheimer disease. American Schneider, L.S., Dagerman, K.S.,& Insel, P. (2005).
Journal of Geriatric Psychiatry, 14, 561572. Risk of death with atypical antipsychotic
Lyketsos, C. G., Steinberg, M., Tschanz, J. T., drug treatment for dementia: Meta-analysis
Norton, M.C., Steffens, D.C.,& Breitner, J.C. of randomized placebo-controlled trials.
(2000). Mental and behavioral disturbances in Journal of the American Medical Association,
dementia: Findings from the Cache County 294, 19341943.
Study on Memory in Aging. American Journal Schneider, L. S., Dagerman, K., & Insel, P. S.
of Psychiatry, 157, 708714. (2006). Efficacy and adverse effects of atypical
Margallo-Lana, M., Swann, A., O'Brien, J., antipsychotics for dementia: Meta-analysis
Fairbairn, A., Reichelt, K., Potkins, D.,...Ballard, of randomized, placebo-controlled trials.
C. (2001). Prevalence and pharmacological American Journal of Geriatric Psychiatry, 14,
management of behavioural and psychological 191210.
symptoms amongst dementia sufferers living Schneider, L. S., Pollock, V. E., & Lyness, S. A.
in care environments. International Journal of (1990). A metaanalysis of controlled trials of
Geriatric Psychiatry, 16, 3944. neuroleptic treatment in dementia. Journal of
McShane, R., Areosa Sastre, A., & Minakaran, the American Geriatrics Society, 38, 553563.
N. (2006). Memantine for dementia. Cochrane Schneider, L. S., Tariot, P. N., Dagerman,
Database Systematic Reviews, (2), CD003154. K. S., Davis, S. M., Hsiao, J. K., Ismail,
Mintzer, J., Greenspan, A., Caers, I., Van Hove, M.S.,...Lieberman, J.A. (2006). Effectiveness
I., Kushner, S., Weiner, M.,...Schneider, L.S. of atypical antipsychotic drugs in patients
(2006). Risperidone in the treatment of psy- with Alzheimers disease. New England
chosis of Alzheimer disease: Results from a Journal of Medicine, 355, 15251538.
prospective clinical trial. American Journal of Sharp, S.I., Ballard, C.G., Chen, C.P.,& Francis,
Geriatric Psychiatry, 14, 280291. P. T. (2007). Aggressive behavior and neu-
Mintzer, J.E., Tune, L.E., Breder, C.D., Swanink, roleptic medication are associated with
R., Marcus, R.N., McQuade, R.D.,& Forbes, increased number of alpha1-adrenoceptors
A. (2007). Aripiprazole for the treatment of in patients with Alzheimer disease. American
psychoses in institutionalized patients with Journal of Geriatric Psychiatry, 15, 435437.
Alzheimer dementia:Amulticenter, random- Steele, C., Rovner, B., Chase, G.A.,& Folstein,
ized, double-blind, placebo-controlled assess- M. (1990). Psychiatric symptoms and nursing
ment of three fixed doses. American Journal of home placement of patients with Alzheimers
Geriatric Psychiatry, 15, 918931. disease. American Journal of Psychiatry, 147,
Olin, J. T., Fox, L. S., Pawluczyk, S., Taggart, 10491051.
N. A., & Schneider, L. S. (2001). A pilot ran- Steinberg, M., Shao, H., Zandi, P., Lyketsos,
domized trial of carbamazepine for behav- C.G., Welsh-Bohmer, K.A., Norton, M.C.,...
ioral symptoms in treatment-resistant Tschanz, J.T. (2008). Point and 5-year period
outpatients with Alzheimer disease. American prevalence of neuropsychiatric symptoms
Journal of Geriatric Psychiatry, 9, 400405. in dementia: The Cache County Study.
Pollock, B. G., Mulsant, B. H., Rosen, J., International Journal of Geriatric Psychiatry, 23,
Mazumdar, S., Blakesley, R.E., Houck, P.R.,& 170177.
Huber, K.A. (2007). A doubleblind compari- Tariot, P.N., Erb, R., Podgorski, C.A., Patel, S.,
son of citalopram and risperidone for the Jakimovich, L., & Irvine, C. (1998). Efficacy
treatment of behavioral and psychotic symp- and tolerability of carbamazepine for agita-
toms associated with dementia. American tion and aggression in dementia. American
Journal of Geriatric Psychiatry, 15, 942952. Journal of Psychiatry, 155, 5461.
Pollock, B.G., Mulsant, B.H., Rosen, J., Sweet, Tariot, P.N., Solomon, P.R., Morris, J.C., Kershaw,
R. A., Mazumdar, S., Bharucha, A.,...Chew, P., Lilienfeld, S.,& Ding, C. (2000). A 5-month,
M. L. (2002). Comparison of citalopram, randomized, placebo-controlled trial of
CHAPTER 24. Management of Agitation, Aggression, and Psychosis Associated With Alzheimers Disease 587
galantamine in AD. The Galantamine USA-10 elderly patients with behavioral disturbances.
Study Group. Neurology, 54, 22692276. Retrieved March 2014, from http://www.fda.
Teri, L., Logsdon, R.G., Peskind, E., Raskind, M., gov/drugs/drugsafety/postmarketdrug-
Weiner, M.F., Tractenberg, R.E.,...Thal, L.J. safetyinformationforpatientsandproviders/
(2000). Treatment of agitation in AD: A ran- drugsafetyinformationforheathcareprofes-
domized, placebo-controlled clinical trial. sionals/publichealthadvisories/ucm053171.
Neurology, 55, 12711278. htm.
Trinh, N.H., Hoblyn, J., Mohanty, S.,& Yaffe, K. Wang, P. S., Schneeweiss, S., Avorn J., Fischer,
(2003). Efficacy of cholinesterase inhibitors in M. A., Mogun, H., Solomon, D. H., &
the treatment of neuropsychiatric symptoms Brookhart, M. A. (2005). Risk of death in
and functional impairment in Alzheimer dis- elderly users of conventional vs. atypical anti-
ease:Ameta-analysis. Journal of the American psychotic medications. New England Journal of
Medical Association, 289, 210216. Medicine, 353, 23352341.
Tune, L. E., Steele, C., & Cooper, T. (1991). Wilcock, G.K., Ballard, C.G., Cooper, J.A.,& Loft,
Neuroleptic drugs in the management of H. (2008). Memantine for agitation/aggres-
behavioral symptoms of Alzheimers disease. sion and psychosis in moderately severe to
Psychiatric Clinics of North America, 14, 353373. severe Alzheimers disease:Apooled analy-
US Food and Drug Administration. (2005). Public sis of 3 studies. Journal of Clinical Psychiatry,
Health Advisory: Deaths with antipsychotics in 69, 341348.
25
In the care of a person with Alzheimers dis- Among the BPSDs that complicate the care
ease (AD) or another dementia, management of demented people, whether at home or
of behavioral disturbances can present even in an institutional setting, depression, apa-
greater practical difficulties than manage- thy, and sexualized inappropriate behavior
ment of diminished memory. The majority present particularly important concerns. In
of demented individuals will at some time this chapter, we will address these behav-
manifest behavioral and psychological symp- ioral syndromes. After reviewing the nature
toms of dementia (BPSDs), such as agitation, of these behaviors and the evidence-based
sometimes resulting in a crisis for caregivers approaches to their management, we will
(Tractenberg, Weiner, Patterson, Teri,& Thal, suggest practical management guidelines for
2003; see Chapter21). Depression, aggression, clinicians and caregivers.
or sexualized inappropriate behavior can dis-
turb and endanger not only the demented
person but also others in their vicinity. BPSDs Depressive Symptoms
are often the source of stress that precipitates
institutionalization. The diagnostic criteria Depressive symptoms frequently accompany
for AD and other dementias have not focused the cognitive symptoms of dementia (Jost&
on behavioral aspects of these disorders, yet Grossberg, 1996). Some 30%50% of indi-
BPSDs make an undeniable contribution to viduals with AD display depression, though
the morbidity of dementia. Perhaps even the number or severity of symptoms in
the hospitalization of Alzheimers index about half of these falls below the threshold
dementia patient, Auguste D, would have required for a diagnosis of major depressive
been delayed had her memory difficulties disorder (Lyketsos, Steinberg, et al., 2000).
not been accompanied by pathological jeal- The presence of depressive symptoms in AD
ousy, paranoid delusions, auditory halluci- does not depend upon the severity of cogni-
nations, screaming, and agitation (Graeber& tive symptoms, and depressive symptoms
Mehraein, 1999). can appear even before AD is diagnosed
588
CHAPTER 25. Management of Depression, Apathy, and Sexualized Inappropriate Behavior in Dementia 589
(Jost & Grossberg, 1996). In some cases, an depressive affect that is expressed behavior-
individuals awareness of cognitive decline ally. In one study, the presence of depres-
can initiate a depressive reaction; however, sion appeared responsible for the weight
it is likely that the pathophysiologic changes loss in about one third of the 19% of nursing
inherent in AD, which include loss of norad- home residents who lost 5 pounds or more
renergic and serotonergic neurons, contribute (Morley& Kraenzle, 1994).
to depressive symptoms in AD (Lyketsos & As with depression among the cognitively
Olin, 2002). intact, treatment interventions include both
Self-assessment of depressive symptoms psychosocial and pharmacologic approaches.
demands a level of cognitive and emotional Early in the course of dementia, the value
awareness that may erode early in the course of insight-oriented interventions is more
of dementia. Depression that is comorbid with apparent. The progression of dementia inevi-
dementia has an independently deleterious tably brings with it greater need for assis-
effect on functioning and quality of life, so it tance from others, and this forced increase
can be valuable to recognize its presence even in dependency can be very unwelcome and
when the sufferer cannot articulate an eas- even quite frightening. Adults who have
ily recognizable set of diagnostic clues. For been especially autonomous and self-reliant
this reason, a more lenient set of criteria has may find it helpful to grieve their loss of
been proposed for use in diagnosing depres- independence. Others, who have taken pride
sion among AD patients (Olin et al., 2002). in intellectual achievements, may be deeply
The suggested criteria, which are in unoffi- pained when experiencing an increasing dif-
cial but common clinical usage, require only ficulty in cognitive performance. Inability to
three rather than five depressive symptoms to complete a project of personal significance,
be present in order to justify the diagnosis of such as the writing of a book planned before
major depressive disorder. Depressed mood is significant cognitive decline had begun, may
listed among the depressive symptoms, but its undermine self-esteem and become a focus of
presence is not a prerequisite for the diagnosis. self-deprecation.
Masked expressions of depression in Later during the course of dementia, when
dementia are often encountered, perhaps a persons insight contributes less to the relief
because dysphoric feelings that cannot of distress or the production of behavioral
be put into words may find their expres- change, behavioral interventions can still be
sion in actions. The presence of delusions useful for alleviating depressive symptoms.
in a demented patient, and perhaps espe- Many patients with milder depressive symp-
cially delusions with a depressive tone, toms appear to enjoy engaging in activities
should raise a clinicians suspicion that such as listening to music of their choice or
depression might be present. In one patient participating in appropriate levels of physi-
cohort, the presence of depression among a cal exercise. An important principle in such
community-dwelling group of patients with activities is to recognize the patients limita-
probable AD was associated with a 1.8-fold tions and avoid making functional or cogni-
increase in the likelihood of delusions, tive demands that are excessively frustrating.
an increased likelihood that became even Given the clinical significance of depres-
greater with control of potential confounding sive symptoms in dementia, it is truly
variables (Bassiony et al., 2002). Aggressive unfortunate that no specific medication
verbal or physical behaviors, too, may be an has been designated by the Food and Drug
expression of emotional distress originating Administration (FDA) as safe and effective
in depression (Menon et al., 2001). In some in treating dementia-associated depression.
cases, patients may direct aggression toward The cognitive-enhancing cholinesterase
themselves, resulting in self-destructive or inhibitors have not proven effective in treat-
suicidal behavior. Verbal outbursts or disrup- ing established depressive symptoms in
tive vocalizations can reflect the presence of demented subjects (McDermott & Gray,
depression that is difficult for a demented 2012). Memantine, a cognitive enhancer that
patient to describe in more understandable exerts its effects through the glutamatergic
language (Dwyer& Byrne, 2000). Resistance system, lacks data supporting or refuting
to care, refusal to eat, and resulting loss antidepressant effects. Stimulants have not
of weight, too, can indicate dysphoric or been studied in recent years as a treatment
590part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
open study has suggested that depressive (Howland, 2011a, 2011b), but it is none-
symptoms in frontotemporal dementia may theless reasonable to assess cardiac risk
benefit from treatment with a serotonin reup- factors and to obtain an electrocardio-
take blocking antidepressant (Swartz, Miller, gram as part of the workup of any older
Lesser,& Darby, 1997). For the clinician, the adult for whom antidepressant treatment
choice of whether to prescribe an antidepres- is planned. Although the adverse effects
sant to a demented person can be confusing, of the newer antidepressants are often
though the relatively good toleration of anti- quite mild, appropriate psychoeducation
depressant treatment in demented patients should be given to the patient and/or
(Nelson& Devanand, 2011), as compared to authorized health care representative. The
poorer tolerance of cholinesterase inhibitors prescribing clinician should review the
or antipsychotics, encourages consideration reasons for prescribing, the limited data
of a potentially beneficial clinical trial despite supporting the use of antidepressants in
the limited evidence supporting specific demented patients, the available treat-
effectiveness of antidepressants in target- ment alternatives, and the most common
ing AD patients depressive symptoms. We and most serious potential adverse effects.
suggest the following approach, taking into 4. Depressive symptoms should be mea-
account the limitations of availabledata: sured at baseline using an appropri-
ate instrument. For patients with
1. In any demented patient with behavioral higher scores on the Mini-Mental State
disturbances, treatment interventions Examination (>15/30 points), the
should be preceded by a differential diag- Geriatric Depression Scale is often an
nostic assessment process that takes into efficient measure (Yesavage, 1988). For
account environmental and medical fac- patients with greater cognitive impair-
tors, past psychiatric history, and family ment, the Cornell Scale for Depression
psychiatric history. in Dementia can be used (Alexopoulos,
2. The more clearly the patients symptoms Abrams, Young,& Shamoian, 1988).
resemble major depressive disorder, the 5. Eventual discontinuation of the phar-
more appropriate it may be to consider macotherapy should be an objective of
an antidepressant trial. Post-hoc analysis treatment, although in some cases that
of the DIADS-2 results, for example, indi- will prove inadvisable. Periodic monitor-
cated that a subgroup of AD patients who ing of depressive and other BPSD symp-
met baseline criteria for major depressive toms will inform the decision whether to
disorder showed a noticeable trend toward taper and stop antidepressant treatment.
achieving superior results with sertra- As yet, there are no standard guidelines
line, although the outcome was still not for antidepressant discontinuation in
statistically superior to placebo. Patients demented patients with depressive dis-
with symptoms suggesting a masked orders. A reasonable standard might be
depression, too, could be considered for to begin gradual dose reduction after
treatment. Along these lines, it should be 6months of continuous depressive remis-
noted that some antidepressants (e.g., cita- sion. However, a recent double-blind
lopram) have demonstrated a potential antidepressant discontinuation study in
signal of benefit in treating nondepressive demented patients documented a sub-
BPSDs (see Chapter24). sequent increase in depressive symp-
3. The serotonin reuptake inhibitors, and toms supporting that clinicians who
particularly sertraline or citalopram, may discontinue a demented patients anti-
be considered first-line antidepressants depressant should watch for subsequent
in treating depression in AD patients. re-emergence of depressive symptoms
Caution should be exercised with citalo- (Bergh, Selbaek,& Engedal, 2012).
pram dosing, given the recent FDA warn-
ing regarding prolonged QTc interval
and the suggestion that older adults not Apathy
be dosed higher than 20 mg/d. Clinical
data have not entirely supported this Apathy has been defined as diminished
level of specific caution about citalopram motivation not attributable to diminished
592part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
finding was more pronounced in those with Cameron, 2002). Galantamine, in two
less severe apathy (Ferrero-Arias etal., 2011). double-blind studies and other open-label
Positive benefits from pharmacotherapy trials, has been associated with improvement
in the treatment of apathy among demented in apathy in subjects with AD dementia and
subjects have been documented for several in vascular dementia (Berman et al., 2012).
classes of medications: cognitive enhancers, In one double-blind placebo-controlled trial,
stimulants, and antidepressants (Berman, the emergence of apathy in subjects with
Brodaty, Withall, & Seeher, 2012). By con- AD dementia was reduced (Cummings,
trast, two groups of medications often used Schneider, Tariot, Kershaw, & Yuan, 2004).
to treat BPSD in demented patients, the anti- An effect on apathy with memantine treat-
psychotics and the anticonvulsants, have ment has been less consistently supported.
demonstrated little or no value as treatments Two brief, randomized, double-blind,
for apathy in demented cohorts (Berman placebo-controlled studies showed signifi-
et al., 2012). The studies that have assessed cant improvements in apathy compared to
pharmacotherapy of apathy in demented placebo in subjects with AD dementia or
subjects are limited in duration and power, vascular dementia, while several other stud-
and focus primarily on AD. More needs to be ies have supported nonsignificant a trend
learned about prevention of apathy, longer toward benefit (Berman etal., 2012). The data
term pharmacologic management of apathy, on memantine as a treatment for apathy in
and pharmacotherapy of apathy in non-AD patients with frontotemporal dementia have
dementias. produced mixed results; two small case series
Based on the results of several double-blind (Swanberg, 2007)or case reports (Links etal.,
trials, and consistent with the findings of 2013)suggest benefit, but a small open-label
open-label trials, cognitive enhancers appear study was negative (Diehl-Schmid, Forstl,
to reduce apathy in AD patients. The cholin- Perneczky, Pohl,& Kurz, 2008).
esterase inhibitors have been studied more Dolder and colleagues recently reviewed
extensively than memantine in this regard. the literature on stimulant medications in
Standard doses of donepezil, in two ran- treating apathy among demented patients
domized controlled trials, were associated (Dolder, Davis, & McKinsey, 2010). While
with a decreased likelihood of the emergence there are scarce data to reach conclusions
of apathy during the 24 weeks of assess- about the potential benefits of stimulants
ment (Waldemar et al., 2011). In a series of among patients with different types of
other trials, mostly open-label studies in dementia or with regard to specific types of
which apathy was one of multiple behaviors stimulants, the little available data appear to
measured, treatment was associated with be strongest for treatment of patients with
reduced behaviors in groups of patients with AD dementia and for the use of methylphe-
AD dementia (Berman et al., 2012) and also nidate. Divided daily doses of methylphe-
in small case series with patients with Lewy nidate between 10 and 40 mg/d have been
body dementia (Lanctot& Herrmann, 2000). used in the reviewed studies. Yet clinicians
Greater levels of apathy at study baseline who prescribe stimulants in elderly patients
were associated with a greater likelihood of must carefully consider and monitor cardiac
response, but apathy was noted to increase in effects, as the use of these medications can be
some subjects (Mega, Masterman, OConnor, associated with increases in heart rate and
Barclay, & Cummings, 1999; Tanaka et al., blood pressure.
2004). While rivastigmine has been reported The use of antidepressants in treating
to reduce apathy in subjects with AD demen- apathy has been explored to only a limited
tia and in Lewy body dementia, small and degree, and authorities have questioned
perhaps underpowered studies have failed to whether their effects reduce or, perhaps in
show significant treatment benefits in fron- some cases, exacerbate apathy (Benoit etal.,
totemporal dementia and vascular dementia 2008). The SSRIs may be of particular con-
patients (Berman etal., 2012). Apathy is very cern as potential contributors to apathy. Yet,
common in the dementia of Parkinsons dis- on the other hand, measures of psychomo-
ease (Aarsland etal., 2007), and the usefulness tor retardation were improved in a trial with
of rivastigmine in treating this apathy was demented hospitalized patients with behav-
suggested in a small case series (Bullock & ioral disturbances treated with citalopram
594part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
(Nyth & Gottfries, 1990). Bupropion, which Caution is warranted before labeling sex-
possesses stimulant properties, has also been ual or other behaviors as inappropriate, since
reported to be useful in the management of in some cases the behaviors may actually be
apathy in patients with organic brain disease appropriate or at least acceptable. A cogni-
(Corcoran, Wong,& OKeane, 2004). tively impaired individual can remain capa-
ble of sexual interest, excitement, and activity
that is appropriate within certain contexts,
Sexualized Inappropriate Behavior such as clearly consensual sexual involve-
ment with a relationship partner. An inap-
Sexualized inappropriate behavior, which propriate and apparently sexualized grab at
is estimated to occur among 7% to 25% of an attendant sometimes represents a poorly
demented patients, is less frequent than modulated request for attention and affec-
either depression or apathy, yet it presents tion. The engagement of the limbic system
one of the most challenging management does not necessarily deteriorate in tandem
dilemmas (Stubbs, 2011). To begin with, many with that of more recently evolved cortical
caregivers are uncomfortable with expres- areas, and there are circumstances in which
sions of sexuality among these older and offering a demented person a nonsexual hug
cognitively impaired individuals; this can or a relaxing hand massage is both welcome
result in a focus on the sexual content rather and appropriate.
than the inappropriate quality of the behav- Thinking beyond SIB as normal behav-
ior. Relabeling these behaviors as sexualized ior or an expression of the wish for contact
inappropriate behavior (SIB), a small seman- and affection, there are other psychosocial
tic change that refocuses attention on disin- considerations. Our currently aging group
hibition rather than sexuality as the target of gay, lesbian, bisexual, and transgendered
of our treatment interventions, can in some individuals may express sexuality in a way
cases reduce caregiver shock, disgust, or that caregivers in institutional settings will
aversion in the presence of behaviors that are find unfamiliar (Benbow & Beeston, 2012).
socially unacceptable among the cognitively Cognitive impairment may modulate sexual
intact. Males are more likely than females to behavior that is intended to be appropri-
show this variety of BPSD, and disinhibited atefor example, through misidentification
sexualized behavior is more characteristic of of another person as a spouseleading to
frontotemporal dementia than of AD. behaviors that would be appropriate in the
SIB usually consists of masturbation in correct context. Delusional misinterpreta-
areas that lack privacy or sexualized intru- tion of anothers behavior as an invitation
sions upon others using words or actions to intimacy can lead to unwanted advances.
that are unacceptable for a variety of rea- Sexual behavior in some demented individu-
sons (Stubbs, 2011). Unwanted consequences als may merely represent manifestation of a
can include embarrassment, disruption of a preexisting mental disorder such as mania or
milieu or home setting, psychic or physical paraphilia or continuation of habitual inap-
trauma to others, transmission of a commu- propriate behavior that predated cognitive
nicable sexual disease, and reactions of vari- impairment.
ous sorts that may range from inappropriate A neurological explanation of SIB should
participation in sexual activity to aggressive take into account the possibilities both of
responses. In some cases, SIB can result in decreased inhibition and increased drive.
legal allegations and liability. To the conster- Black and colleagues, in a comprehensive
nation of family caregivers, SIB can occur in review of SIB, suggest that four brain sys-
public places such as health clubs or restau- tems are potential contributors to SIB (Black,
rants. In the home, it represents a potential Muralee,& Tampi, 2005). Failure of inhibition
hazard for children who spend time with and social judgment suggests impairment of
an older, demented relative. In institutional the frontal executive systems restraining
settings, it can represent a reason for hospi- capacity. An increase in sexual drive, similar
talization or even expulsion. Inpatient units to the hypersexuality seen in the Kluver-Bucy
often encounter great difficulty finding resi- syndrome, has been invoked and may be of
dential placements for demented patients particular importance in frontotemporal
whose disinhibited behavior is sexualized. dementias. Striatal involvement is suggested
CHAPTER 25. Management of Depression, Apathy, and Sexualized Inappropriate Behavior in Dementia 595
by a compulsive quality to some SIBs. Finally, open-label trials. As with the other off-label
hypothalamic involvement, through disor- uses described in this chapter, it is necessary
dered hormonal control, has also been con- that the competent patient or the authorized
sidered a possible contributor to some cases health care representative be informed about
of SIB. the use of a medication for this nonindicated
As with other BPSDs, SIB should initially purpose and be educated about the poten-
be addressed behaviorally. Psychoeducation tial risks, benefits, and alternative treatment
of the caregiving system is an important ini- approaches. As a prelude to pharmacother-
tial step. Spouses, children of sufficient age apy of SIB, it may be appropriate to discon-
and capacity to understand, and caregiving tinue medications that increase sexual drive
institutional staff may initially fail to under- or expression such as androgens, levodopa,
stand that the SIB is a symptom of neurode- or disinhibiting sedative-hypnotics. When
generation rather than the unmasking of an using one of the medications suggested
evil or aggressive character. Reframing the helpful for managing SIB, it is advisable to
SIB as a common symptom of dementia can follow the universal guideline for geriatric
diminish the moral stigmatization that might pharmacotherapy, which is to start low, go
otherwise occur and can facilitate behavioral slow, but do not undertreat or declare failure
management that may include more accept- prematurely.
able ways of responding to whatever needs Pharmacologic management of SIB has
the patient is expressing through sexualized aimed to reduce sexual drive or to diminish
behaviors. Sex education is an important disinhibition. Evidence is not available to
aspect of training for institutional care staff assess the effects of cognitive-enhancing cho-
who may lack experience in distinguishing linesterase inhibitors or memantine on sexu-
acceptable and inappropriate behaviors from alized behavior, though one letter describes a
those that are not tolerable within an institu- case in which rivastigmine alleviated sexually
tional setting. aggressive behavior of a demented woman
Behavioral interventions often suffice (Alagiakrishnan, Sclater, & Robertson,
in managing SIB and should in general 2003). The libido-reducing and antiorgasmic
be employed prior to pharmacotherapeu- effects of serotonergic antidepressants, some-
tic approaches because their effectiveness times a cause of treatment nonadherence in
may be as great and the hazard of potential younger adults, may serve advantageously
adverse medication effects can be avoided. in managing SIB in some demented patients.
To begin with, overstimulating external cues Paroxetine (Stewart & Shin, 1997), cita-
such as sexually exciting television shows lopram (Chen, 2010; Tosto, Talarico, Lenzi,&
or movies should be eliminated. Although Bruno, 2008), and clomipramine (Leo& Kim,
confrontation of inappropriate behavior may 1995)each have been prescribed at standard
fail to have lasting beneficial consequences, a antidepressant doses and claimed to be help-
sexualizing person may be responsive to dis- ful in reducing sexualized behaviors in case
traction and redirection toward involvement reports. Trazodone, though in other con-
in a more acceptable activity. Sexualized texts occasionally a cause of hypersexuality,
intrusions on a roommate or family member has also been used in this way. The famil-
may necessitate a room change or avoidance iar adverse effects of these antidepressants,
of unchaperoned time together. Public mas- and especially of clomipramine, can under-
turbation or undressing can sometimes be mine their use in managing SIB. Cimetidine
managed by use of clothing modifications (Wiseman, McAuley, Freidenberg, &
that make it more difficult to remove clothing Freidenberg, 2000)(600 to 1,600 mg/d), per-
without assistance, such as pants that fasten haps through its secondary effect on testos-
in the back rather than the front and do not terone levels resulting from hepatic enzyme
have a zipper. induction, has been used to lower libido
Although not yet supported by random- and manage SIB. As an unwanted conse-
ized, controlled, double-blind clinical tri- quence of its use, blood levels of hepatically
als, many different medications have been metabolized coadministered medications
tried in the management of SIB. Clinical may also be diminished. Nonspecific seda-
practice to date appears to rely primarily on tion or increased impulse control is a treat-
the reported results of small case series or ment objective when using antipsychotics
596part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
to manage SIB, and these medications are term management of these symptoms in both
therefore often used in an effort to affect SIB patients with AD dementia and in those with
despite an evidence base apparently limited other neurodegenerative disorders.
to a couple of case reports describing the use
of haloperidol (Jensen, 1989) or quietiapine References
(MacKnight & Rojas-Fernandez, 2000) and
a post-hoc analysis supporting risperidones Aarsland, D., Bronnick, K., Ehrt, U., De Deyn,
use at low doses in a Korean nursing home P. P., Tekin, S., Emre, M., & Cummings,
cohort (Suh, Greenspan, & Choi, 2006). The J. L. (2007). Neuropsychiatric symptoms
in patients with Parkinsons disease and
adverse effects of the antipsychotics are
dementia: frequency, profile and associ-
described in detail in Chapter 24, including ated care giver stress. Journal of Neurology,
the increase in overall mortality risk that Neurosurgery, and Psychiatry, 78, 3642.
is associated with their long-term use in Alagiakrishnan, K., Sclater, A., & Robertson,
demented older adults. Pindolol (40 mg/d), D. (2003). Role of cholinesterase inhibitor
through adrenergic antagonism or perhaps in the management of sexual aggression in
through its serotonergic effects, was reported an elderly demented woman. Journal of the
to manage SIB successfully in one patient American Geriatrics Society, 51, 1326.
(Jensen, 1989). There is also a case report of Alexopoulos, G. S., Abrams, R. C., Young,
gabapentins use in managing SIB (Miller, R. C., & Shamoian, C. A. (1988). Cornell
Scale for Depression in Dementia. Biological
2001).
Psychiatry, 23, 271284.
In more severe or treatment-resistant Apostolova, L. G., Akopyan, G. G., Partiali,
cases, hormonal agents have been used N., Steiner, C. A., Dutton, R. A., Hayashi,
to lower libido through effects on the K. M.,...Thompson, P. M. (2007). Structural
hypothalamic-pituitary-gonadal hormonal cir- correlates of apathy in Alzheimers disease.
cuit. Medroxyprogesterone (Light& Holroyd, Dementia and Geriatric Cognitive Disorders, 24,
2006) (doses of 100 to 300 mg/d given as an 9197.
intramuscular injection), diethylstilbesterol Bassiony, M. M., Warren, A., Rosenblatt,
(Kyomen, Nobel, & Wei, 1991) (1 mg/d), or A., Baker, A., Steinberg, M., Steele,
leuprolide acetate (Ott, 1995)(7.5mg/month C. D.,...Lyketsos, C. G. (2002). The relation-
ship between delusions and depression in
given as an intramuscular injection) have
Alzheimers disease. International Journal of
been reported in one or more cases to manage Geriatric Psychiatry, 17, 549556.
SIB. Estrogen (Lothstein, Fogg-Waberski, & Benbow, S.M.,& Beeston, D. (2012). Sexuality,
Reynolds, 1997)(0.625 mg/d), used in a larger aging, and dementia. International
sample of patients, was also reported effec- Psychogeriatrics, 24(7), 10261033.
tive in managing SIB. The side effects of these Benoit, M., Andrieu, S., Lechowski, L.,
hormonal agents include weight changes, diz- Gillette-Guyonnet, S., Robert, P. H., &
ziness, nausea, insomnia, pain, edema, and Vellas, B. (2008). Apathy and depression in
depression. Alzheimers disease are associated with func-
tional deficit and psychotropic prescription.
International Journal of Geriatric Psychiatry, 23,
409414.
Conclusion Bergh, S., Selbaek, G., & Engedal, K. (2012).
Discontinuation of antidepressants in people
In the management of demented patients in with dementia and neuropsychiatric symp-
home or institutional settings, BPSDs present toms (DESEP study): Double blind, ran-
challenges that often exceed those of reduced domised, parallel group, placebo controlled
memory capacity. Preventive management of trial. British Medical Journal, 344, e1566.
the environment, early recognition of BPSDs, Berman, K., Brodaty, H., Withall, A., & Seeher,
and monitoring of the safety of patient and K. (2012). Pharmacologic treatment of apa-
caregivers are important steps in providing thy in dementia. American Journal of Geriatric
Psychiatry, 20, 104122.
optimal care. Behavioral interventions should
Black, B., Muralee, S., & Tampi, R. R. (2005).
generally precede pharmacologic treatment Inappropriate sexual behaviors in dementia.
approaches, and sometimes the combina- Journal of Geriatric Psychiatry and Neurology,
tion is optimal. Further research must seek 18, 155162.
a fuller understanding of BPSDs neuropsy- Branconnier, R. J., & Cole, J. O. (1980). The
chiatric mechanisms and explore the longer therapeutic role of methylphenidate in
CHAPTER 25. Management of Depression, Apathy, and Sexualized Inappropriate Behavior in Dementia 597
senile organic brain syndrome. Proceedings Journal of Psychosocial Nursing and Mental
of the Annual Meeting of the American Health Services, 49, 1316.
Psychopathological Association, 69, 183196. Howland, R. H. (2011b). A critical evaluation
Bullock, R.,& Cameron, A. (2002). Rivastigmine of the cardiac toxicity of citalopram: Part 2.
for the treatment of dementia and visual hal- Journal of Psychosocial Nursing and Mental
lucinations associated with Parkinsons dis- Health Services, 49, 1316.
ease: A case series. Current Medical Research Jensen, C. F. (1989). Hypersexual agitation in
and Opinion, 18, 258264. Alzheimers disease. Journal of the American
Chen, S. T. (2010). Treatment of a patient with Geriatrics Society, 37, 917.
dementia and inappropriate sexual behav- Jost, B.C.,& Grossberg, G.T. (1996). The evolu-
iors with citalopram. Alzheimers Disease and tion of psychiatric symptoms in Alzheimers
Associated Disorders, 24(4), 402403. disease:Anatural history study. Journal of the
Corcoran, C., Wong, M.L.,& OKeane, V. (2004). American Geriatrics Society, 44, 10781081.
Bupropion in the management of apathy. Kyomen, H.H., Nobel, K.W.,& Wei, J.Y. (1991).
Journal of Psychopharmacology, 18, 133135. The use of estrogen to decrease aggres-
Cummings, J. L., Schneider, L., Tariot, P. N., sive physical behavior in elderly men with
Kershaw, P.R.,& Yuan, W. (2004). Reduction dementia. Journal of the American Geriatrics
of behavioral disturbances and caregiver Society, 39, 11101112.
distress by galantamine in patients with Lanctot, K.L.,& Herrmann, N. (2000). Donepezil
Alzheimers disease. American Journal of for behavioural disorders associated with
Psychiatry, 161, 532538. Lewy bodies: A case series. International
David, R., Koulibaly, M., Benoit, M., Garcia, Journal of Geriatric Psychiatry, 15, 338345.
R., Caci, H., Darcourt, J.,& Robert, P. (2008). Landes, A. M., Sperry, S. D., Strauss, M. E., &
Striatal dopamine transporter levels correlate Geldmacher, D. S. (2001). Apathy in
with apathy in neurodegenerative diseases Alzheimers disease. Journal of the American
ASPECT study with partial volume effect cor- Geriatrics Society, 49, 17001707.
rection. Clinical Neurology and Neurosurgery, Leo, R. J., & Kim, K. Y. (1995). Clomipramine
110, 1924. treatment of paraphilias in elderly demented
de Vasconcelos Cunha, U. G., Lopes Rocha, F., patients. Journal of Geriatric Psychiatry and
Avila de Melo, R., Alves Valle, E., de Souza Neurology, 8, 123124.
Neto, J. J., Mendes Brega, R.,...Sakurai, E. Light, S. A., & Holroyd, S. (2006). The use of
(2007). A placebo-controlled double-blind medroxyprogesterone acetate for the treat-
randomized study of venlafaxine in the treat- ment of sexually inappropriate behaviour in
ment of depression in dementia. Dementia and patients with dementia. Journal of Psychiatry
Geriatric Cognitive Disorders, 24, 3641. and Neuroscience, 31, 132134.
Diehl-Schmid, J., Forstl, H., Perneczky, R., Pohl, Links, K. A., Black, S. E., Graff-Guerrero, A.,
C.,& Kurz, A. (2008). A 6-month, open-label Wilson, A. A., Houle, S., Pollock, B. G., &
study of memantine in patients with fronto- Chow, T. W. (2013). A case of apathy due
temporal dementia. International Journal of to frontotemporal dementia responsive to
Geriatric Psychiatry, 23, 754759. memantine. Neurocase, 19(3), 256261.
Dolder, C. R., Davis, L. N., & McKinsey, J. Lothstein, L.M., Fogg-Waberski, J.,& Reynolds,
(2010). Use of psychostimulants in patients P. (1997). Risk management and treatment
with dementia. Annals of Pharmacotherapy, 44, of sexual disinhibition in geriatric patients.
16241632. Connecticut Medicine, 61, 609618.
Dwyer, M., & Byrne, G. J. (2000). Disruptive Lyketsos, C. G., & Olin, J. (2002). Depression
vocalization and depression in older nursing in Alzheimers disease: Overview and treat-
home residents. International Psychogeriatrics, ment. Biological Psychiatry, 52, 243252.
12, 463471. Lyketsos, C. G., Sheppard, J. M., Steele,
Ferrero-Arias, J., Goni-Imizcoz, M., C. D., Kopunek, S., Steinberg, M., Baker,
Gonzalez-Bernal, J., Lara-Ortega, F., da A. S.,...Rabins, P. V. (2000). Randomized,
Silva-Gonzalez, A.,& Diez-Lopez, M. (2011). placebo-controlled, double-blind clinical
The efficacy of nonpharmacological treat- trial of sertraline in the treatment of depres-
ment for dementia-related apathy. Alzheimers sion complicating Alzheimers disease:Initial
Disease and Associated Disorders, 25, 213219. results from the Depression in Alzheimers
Graeber, M.B.,& Mehraein, P. (1999). Reanalysis Disease study. American Journal of Psychiatry,
of the first case of Alzheimers disease. 157, 16861689.
European Archives of Psychiatry and Clinical Lyketsos, C. G., Steinberg, M., Tschanz, J. T.,
Neuroscience, 249(Suppl 3), 1013. Norton, M.C., Steffens, D.C.,& Breitner, J.C.
Howland, R. H. (2011a). A critical evaluation (2000). Mental and behavioral disturbances in
of the cardiac toxicity of citalopram: Part 1. dementia: Findings from the Cache County
598part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Study on Memory in Aging. American Journal Ott, B. R. (1995). Leuprolide treatment of sex-
of Psychiatry, 157, 708714. ual aggression in a patient with Dementia
MacKnight, C., & Rojas-Fernandez, C. (2000). and the Kluver-Bucy syndrome. Clinical
Quetiapine for sexually inappropriate Neuropharmacology, 18, 443447.
behavior in dementia. Journal of the American Oudman, E. (2012). Is electroconvulsive ther-
Geriatrics Society, 48, 707. apy (ECT) effective and safe for treatment
Magai, C., Kennedy, G., Cohen, C. I., & of depression in dementia? A short review.
Gomberg, D. (2000). A controlled clinical Journal of ECT, 28, 3438.
trial of sertraline in the treatment of depres- Padala, P.R., Padala, K.P., Monga, V., Ramirez,
sion in nursing home patients with late-stage D. A., & Sullivan, D. H. (2012). Reversal
Alzheimers disease. American Journal of of SSRI-associated apathy syndrome
Geriatric Psychiatry, 8, 6674. by discontinuation of therapy. Annals of
Marin, R. S. (1991). Apathy: A neuropsychiat- Pharmacotherapy, 46, e8.
ric syndrome. Journal of Neuropsychiatry and Petracca, G., Teson, A., Chemerinski, E.,
Clinical Neurosciences, 3, 243254. Leiguarda, R., & Starkstein, S. E. (1996). A
Marshall, G. A., Fairbanks, L. A., Tekin, S., double-blind placebo-controlled study of
Vinters, H. V., & Cummings, J. L. (2006). clomipramine in depressed patients with
Neuropathologic correlates of apathy in Alzheimers disease. Journal of Neuropsychiatry
Alzheimers disease. Dementia and Geriatric and Clinical Neurosciences, 8, 270275.
Cognitive Disorders, 21, 144147. Petracca, G. M., Chemerinski, E., &
McDermott, C. L., & Gray, S. L. (2012). Starkstein, S. E. (2001). A double-blind,
Cholinesterase inhibitor adjunctive therapy placebo-controlled study of fluoxetine in
for cognitive impairment and depressive depressed patients with Alzheimers disease.
symptoms in older adults with depression. International Psychogeriatrics, 13, 233240.
Annals of Pharmacotherapy, 46, 599605. Reifler, B. V., Teri, L., Raskind, M., Veith,
Mega, M. S., Masterman, D. M., OConnor, R., Barnes, R., White, E., & McLean, P.
S.M., Barclay, T.R.,& Cummings, J.L. (1999). (1989). Double-blind trial of imipramine in
The spectrum of behavioral responses to cho- Alzheimers disease patients with and with-
linesterase inhibitor therapy in Alzheimer out depression. American Journal of Psychiatry,
disease. Archives of Neurology, 56, 13881393. 146, 4549.
Menon, A. S., Gruber-Baldini, A. L., Hebel, Roth, M., Mountjoy, C.Q.,& Amrein, R. (1996).
J.R., Kaup, B., Loreck, D., Itkin Zimmerman, Moclobemide in elderly patients with cogni-
S.,...Magaziner, J. (2001). Relationship tive decline and depression:An international
between aggressive behaviors and depression double-blind, placebo-controlled trial. British
among nursing home residents with demen- Journal of Psychiatry, 168, 149157.
tia. International Journal of Geriatric Psychiatry, Starkstein, S.E., Mizrahi, R., Capizzano, A.A.,
16, 139146. Acion, L., Brockman, S.,& Power, B.D. (2009).
Miller, L. J. (2001). Gabapentin for treatment Neuroimaging correlates of apathy and
of behavioral and psychological symptoms depression in Alzheimers disease. Journal of
of dementia. Annals of Pharmacotherapy, 35, Neuropsychiatry and Clinical Neurosciences, 21,
427431. 259265.
Morley, J. E., & Kraenzle, D. (1994). Causes of Stewart, J. T., & Shin, K. J. (1997). Paroxetine
weight loss in a community nursing home. treatment of sexual disinhibition in dementia.
Journal of the American Geriatrics Society, 42, American Journal of Psychiatry, 154, 1474.
583585. Stubbs, B. (2011). Displays of inappropriate sex-
Nelson, J. C., & Devanand, D. P. (2011). A ual behaviour by patients with progressive
systematic review and meta-analysis of cognitive impairment:The forgotten form of
placebo-controlled antidepressant studies in challenging behaviour? Journal of Psychiatric
people with depression and dementia. Journal and Mental Health Nursing, 18, 602607.
of the American Geriatrics Society, 59, 577585. Suh, G.H., Greenspan, A.J.,& Choi, S.K. (2006).
Nyth, A.L.,& Gottfries, C.G. (1990). The clini- Comparative efficacy of risperidone versus
cal efficacy of citalopram in treatment of emo- haloperidol on behavioural and psycho-
tional disturbances in dementia disorders. logical symptoms of dementia. International
ANordic multicentre study. British Journal of Journal of Geriatric Psychiatry, 21, 654660.
Psychiatry, 157, 894901. Swanberg, M.M. (2007). Memantine for behav-
Olin, J. T., Schneider, L. S., Katz, I. R., Meyers, ioral disturbances in frontotemporal demen-
B. S., Alexopoulos, G. S.,...Lebowitz, B. D. tia: A case series. Alzheimers Disease and
(2002). Provisional diagnostic criteria for Associated Disorders, 21, 164166.
depression of Alzheimer disease. American Swartz, J. R., Miller, B. L., Lesser, I. M., &
Journal of Geriatric Psychiatry, 10, 125128. Darby, A. L. (1997). Frontotemporal
CHAPTER 25. Management of Depression, Apathy, and Sexualized Inappropriate Behavior in Dementia 599
dementia: Treatment response to serotonin Waldemar, G., Gauthier, S., Jones, R., Wilkinson,
selective reuptake inhibitors. The Journal of D., Cummings, J., Lopez, O.,...Mackell, J.
clinical psychiatry, 58, 212216. (2011). Effect of donepezil on emergence of
Tanaka, M., Namiki, C., Thuy, D. H., Yoshida, apathy in mild to moderate Alzheimers
H., Kawasaki, K., Hashikawa, K.,...Kita, T. disease. International Journal of Geriatric
(2004). Prediction of psychiatric response to Psychiatry, 26, 150157.
donepezil in patients with mild to moderate Weintraub, D., Rosenberg, P. B., Drye, L. T.,
Alzheimers disease. Journal of the Neurological Martin, B. K., Frangakis, C., Mintzer,
Sciences, 225, 135141. J. E.,...Lyketsos, C. G. (2010). Sertraline for
Tosto, G., Talarico, G., Lenzi, G.L.,& Bruno, G. the treatment of depression in Alzheimer dis-
(2008). Effect of citalopram in treating hyper- ease: Week-24 outcomes. American Journal of
sexuality in an Alzheimers disease case. Geriatric Psychiatry, 18, 332340.
Neurological Sciences, 29. 269270. Wiseman, S. V., McAuley, J. W., Freidenberg,
Tractenberg, R. E., Weiner, M. F., Patterson, G. R., & Freidenberg, D. L. (2000).
M. B., Teri, L., & Thal, L. J. (2003). Hypersexuality in patients with dementia:
Comorbidity of psychopathological domains Possible response to cimetidine. Neurology,
in community-dwelling persons with 54, 2024.
Alzheimers disease. Journal of Geriatric Yesavage, J.A. (1988). Geriatric depression scale.
Psychiatry and Neurology, 16, 9499. Psychopharmacology Bulletin, 24, 709711.
26
And as with age his body uglier grows, It was the seminal work of Alois Alzheimer
So his mind cankers. that provided the first clear understanding
Shakespeare, The Tempest (act IV, of a disease that is now named after him
scene1,213214) (Berchtold& Cotman, 1998).
Increase in global life expectancy and con-
sequent aging of the population has resulted
Last scene of all, in an unprecedented increase in the inci-
That ends this strange eventful history, dence and prevalence of dementia. This shift
Is second childishness and mere oblivion, will continue to pose increasing demands
Sans teeth, sans eyes, sans taste, sans on global health care resources. In 2006, the
everything. worldwide prevalence of Alzheimers dis-
Shakespeare, As You Like It (act II, ease was 26.6million. It is projected that by
scene7, 143170) 2030, the number of persons suffering from
dementia worldwide will rise to nearly 1 bil-
lion. By 2050, the prevalence will quadruple,
The contemporary history of dementia by which time 1 in 85 persons worldwide will
begins in 1906 with the report at a conference be living with the disease. The impact of these
in Tubingen, Germany, by Alois Alzheimer demographic changes requires us to consider
On a peculiar disease process of the cerebral carefully the means by which we manage
cortex. However, the awareness of (senile) this epidemic while we await the discovery
dementia and the cognitive and behavioral of an agent or agents that can effectively
disturbances that result from this disease alter the course and outcome of dementia.
dates back thousands of years. Medical lit- Despite the very significant advances over
erature and fiction are replete with descrip- the past 100 years in our understanding of
tions of the personal and social consequences the pathogenesis of dementia, we still lack
of the illness. Older descriptions of demen- any effective intervention that can provide
tia largely attributed the development of any more than modest slowing of the inexo-
dementia to the cognitive decline that was rable cognitive and functional decline. We
believed to inevitably accompany old age. are a long way from preventing or reversing
600
CHAPTER 26. Nonpharmacological Approaches to Managing Behavior Symptoms in Dementia 601
the process. It is estimated that about 43% prevalence rates for these symptoms vary
of prevalent cases will need a high level of widely depending on the study population
care, equivalent to that of a nursing home. If and the criteria used to ascertain symptoms
effective interventions could delay disease (Okura etal., 2010). Between 56% and 74% of
onset and progression by a modest 1 year, persons with moderately advanced dementia
there could be nearly 9.2million fewer cases exhibit at least one BPSD (Geda et al., 2008;
of the disease by 2050, with nearly the entire Lyketsos etal., 2002). Most studies show that
decline attributable to decreases in persons the frequency and severity of BPSDs increase
needing a high level of care (Brookmeyer, with dementia severity. For example, depres-
Johnson, Ziegler-Graham,& Arrighi, 2007). sion, social withdrawal, and anxiety dis-
The appropriate management of dementia orders are seen more commonly in early
needs to focus on two main issues: slowing dementia while agitation, disinhibition, and
the deficits imposed by cognitive decline aggression are more common in advanced
and managing the behavioral and psycho- dementia (Jost& Grossberg, 1996). Although
logical symptoms (BPSDs) that develop as generalizable patterns can be seen in some
the disease progresses (Cohen-Mansfield, aspects of behavioral symptoms across
1994; Finkel, Costa e Silva, Cohen, Miller,& groups of patients with dementia, they may
Sartorius, 1996; Tariot, 1996). Although cli- vary substantially in intensity and severity
nicians are more knowledgeable about from person to person and from time to time
pharmacological interventions that treat the in the same person. For the most part, these
cognitive deficit, less is understood about forms of variability are not well understood.
the appropriate management of the BPSDs. Although cognitively intact persons may
For the most part, the dominant approach respond to sources of distress in the environ-
has been pharmacological, yet there are ment (e.g., uncertainty, unpredictability) or in
increasing questions being raised about the themselves (e.g., pain or other physical dis-
appropriateness of this approach. The US comfort) in a variety of ways, they are gen-
Department of Health and Human Services erally able to communicate their distress in
Office of the Inspector General reported that ways that are understandable by others and
99.5% of nursing facilities in the United States socially acceptable. In persons with demen-
were noncompliant regarding the regulations tia, however, communication abilities and
concerning the use of antipsychotic agents insight are often impaired, which may cause
in nursing homes. The Center for Medicare forms of distress experienced by all of us to be
Services implemented an initiative to reduce expressed in ways we describe as BPSDs. In
the use of antipsychotic agents in nursing addition, premorbid personality traits likely
homes by 15% by 2013. As a result, increasing color how distress is expressed as BPSDs.
emphasis is being placed on developing and This may explain, in part, why one person
utilizing nonpharmacological interventions. exhibits aggressiveness and another exhib-
its apathy. Just as nondemented people are
different, so also are people suffering from
A Conceptual Overview of Behavioral dementia. Aone-size-fits-all approach to this
and Psychological Symptoms problem fails to account for the tremendous
variations seen in BPSDs.
As detailed in Chapters21, 24, and 25, BPSDs One way to explain this behavioral variation
are a varied group of symptoms that com- is to draw a parallel with normal human devel-
plicate the course of dementia to varying opment. Human growth and development
degrees in many patients with dementia. unfolds along a predictable sequence of events
These disturbances result in immense dis- from birth to adult life. The ability to manage
tress to patient and caregiver alike (Cerejeira, basic and instrumental activities of daily living
Lagarto, & Mukaetova-Ladinska, 2012). (ADLs and IADLs) independently is acquired
Symptoms such as apathy, agitation, aggres- hierarchically as the nervous system matures.
siveness, depression, and psychosis are Normal aging is often accompanied by a grad-
associated with substantial personal and ual loss of some previously acquired motor,
caregiver distress, increased health care costs cognitive, and psychosocial abilities. The ensu-
both direct and indirect, and a greater risk ing functional decline is modulated by adap-
for institutional placement. Estimates of the tive capacity and coping skills. When late life
602part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
the reptilian brain. From birth, humans learn There is no consensus on the most appro-
(to varying degrees) to tolerate frustration, priate and effective way of ameliorating the
delay gratification, and act in accordance BPSDs that complicate management at differ-
with social norms. This is largely a function ent stages of the illnessthis is likely because
of the prefrontal and other parts of the neo- there is no one-size-fits-all method that
cortex, and the process takes about 20years applies to each individual. General and per-
to complete. Disruption of higher cortical sonalized nonpharmacological approaches,
functions can occur following cortical dam- sometimes combined with pharmacology,
age, states of intoxication, and in dementia. are generally recommended. While in the
Depending on the degree of damage, there past, pharmacological treatment has been a
can be disinhibition, a disregard for social mainstay of treatment efforts, there has been
norms, disruption of language fluency, and increasing concern raised about the efficacy
a regression to a less developed or childlike and appropriateness of these interventions,
state. The unacceptable behaviors that result especially the use of antipsychotic drugs.
can broadly be classified as either disturbed Nearly one in three nursing-home residents
and dangerous, or disturbing and troubling in the United States received antipsychotic
(see Table26.1). drugs in 2007, which is the highest reported
level of use in more than a decade (Chen etal.,
2010). Twenty-eight percent of all Medicare
To Medicate or Not beneficiaries in nursing homes received
at least one prescription for antipsychot-
The management of BPSDs remains largely ics during the study period: 20.3% received
empiric and inconsistent. When confronted atypicals only; 3.7%, conventionals only;
with distressing BPSDs, the clinician is con- and 3.6%, both atypicals and conventionals.
fronted with the dilemma of whether to Less than half (41.8%) of treated residents
drug or not to drug. The disruptive behav- received antipsychotic therapy in accordance
iors often exhibited by infants, children, and with prescribing guidelines. Almost one in
adolescents are tolerated as normal and, four (23.4%) patients had no appropriate
rightly, few would resort to the use of phar- indication for antipsychotic treatment, 17.2%
macological agents to contain the average had daily doses exceeding recommended
episode of bad behavior. Yet, when con- levels, and 17.6% had both inappropriate
fronted with similar behavior in demented indications and high dosing. Patients receiv-
elderly, there has often been a rush to treat- ing antipsychotic therapy within guidelines
ment with psychotropics. A survey by the were no more likely to achieve stability or
Office of the Inspector General in May 2011 improvement in behavioral symptoms than
examined the use of atypical antipsychotic were those taking antipsychotics outside the
drugs in nursing homes and found that guidelines (Briesacher etal., 2005).
off-label conditions were associated with 83% Few clinicians would deny the useful-
of claims for atypical antipsychotic drugs for ness of nonpharmacological interventions
elderly nursing home residents; 88% were for BPSDs. However, the relative paucity of
associated with the condition specified in the high-quality studies that demonstrate the
FDA boxed warning. effectiveness of many nonpharmacological
604part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
treatments for BPSDs have made many clini- drugs are vastly superior in efficacy and side
cians reluctant to use them for all but the most effect profile to the older drugs. That being
trivial disturbances. Additionally, despite said, they are not entirely free of serious car-
many nonpharmacological treatments being diac, metabolic, and central nervous system
both effective and well tolerated, reluctance effects, especially in the elderly in whom the
to institute them in the long-term care setting use of these drugs, as a class, has been associ-
has been influenced by the fact that they often ated with increased risk of death, stroke, and
require a dedicated and trained staff with cognitive decline (Narang etal., 2010; Vigen
time and patience to try different modalities. et al., 2011). Before utilizing these agents, a
Having said that, it must be added that there careful workup must be completed. The pres-
are situations in which patients are refractory ence of a psychosis or serious mood disorder
to nonpharmacological interventions or pose should be the only acceptable indication for
serious risk to themselves and others that prescribing first- and second-generation anti-
necessitate the acute use of pharmacological psychotic medications. To date, however, not
interventions. To deny a distressed patient one of these agents has been granted FDA
any appropriate treatment is unacceptable approval for use in dementia and, if used, is
and unethical. Pharmacology must be consid- used off label. (In the United Kingdom, the
ered when the safety of the patient or others is only drug licensed for the treatment of per-
at risk or when the benefits of pharmacology sistent and refractory agitation and psychosis
clearly outweigh the risks. Pharmacotherapy in dementia is risperidonefor short-term
should always be employed in conjunction treatment 12 mg daily for only up to 6
with nonpharmacological methods. In all weeks.) Suffice it to say that the prescription
such instances the drug should be used for of antipsychotics for older demented individ-
approved indications, in the lowest possible uals is coming under increased scrutiny and
effective dose and for a limited period of regulation in both the lay and professional
time. All interventions must be documented press. Some have gone so far as to say that
in terms of risk benefit and rationale, and The way antipsychotic drugs are used in
they must be appropriately monitored. nursing homes is a form of elder abuse (as
As matters stand today, the question is not stated by Patricia McGinnis, executive direc-
to drug or not to drug but rather how to tor of California Advocates for Nursing Home
use both modalities effectively in conjunc- Reform, to the Senate Special Committee on
tion. No single modality works for all situ- Aging in 2010)and that Instead of providing
ations or persons; it is up to the treatment individualized care, many homes indiscrimi-
team to decide which modality is most nately use these drugs to sedate and subdue
effective in a particular situation. Until the residents.
advent of atypical antipsychotic drugs in
the early 1990s, conventional agents were
the most commonly prescribed agents for Developing Nonpharmacological
BPSDs, despite the fact that these drugs were Approaches
developed and approved for the treatment
of psychosis. Most cases of dementia do not The ensuing section is based on experience
exhibit frank psychosis. In addition, these gained over the past 7 years at Briarwood
conventional antipsychotic drugs were asso- Nursing and Rehabilitation in Needham,
ciated with serious side effects that limited Massachusetts. The program is based on the
their use in older patients. Concern with the Eden Alternative model and provides care
overuse of these drugs led to the Omnibus for 40 residents. Over the prior 7 years, the
Budget Reconciliation Act of 1987, which use of antipsychotic drugs on the dementia
mandated that these drugs be used only as service has been reduced to about 5% with-
a last resort to treat BPSDs. The atypical or out any noticeable increase in distress to
second-generation antipsychotic drugs were patients or staff or increase in use of other
initially believed to be free of most of the psychotropic drugs. The process of achieving
side effects that limited the use of conven- this goal is discussed in the ensuing section
tional antipsychotics. Two decades of clinical to provide practical suggestions on develop-
experience and data have proved otherwise. ing nonpharmacological interventions. These
Unquestionably, these second-generation suggestions are offered as general guidelines
CHAPTER 26. Nonpharmacological Approaches to Managing Behavior Symptoms in Dementia 605
with the understanding that each facility has for patients. This training had an immedi-
its own patient and caregiver demographics ate impact on the understanding, confidence,
and characteristics, as well as staff and milieu and ability of the staff to deal effectively with
strengths and limitations. BPSDs without reflexively resorting to use of
pharmacotherapy.
Interdisciplinary Teamwork
Modification of the Physical
Long-term care and more so, dementia care is Environment
effective when it becomes an interdisciplin-
ary effort. It takes a team to care for a person There is no perfect environment for patients
with dementia. Traditional hospital-based with dementia. Unless one has the luxury of
care is directed at cure and the lead clini- designing a facility from scratch, most facili-
cian, often a physician, is the coordinator ties have to work within the limitation of the
of care. On the other hand, dementia care is existing structure. Yet within these constraints
directed at the maintenance of function and a lot can be done to modify the environment.
quality of life. The most effective model is Color and visuals were extensively used.
one in which the roles of nursing, social work, Doors to rooms were painted in different col-
family, and rehabilitation services become ors, and display boxes outside every room
central. The lead clinician assumes a less help cue patients to their own environment.
central role in the decision-making process. Room occupancy is limited to single or dou-
Perhaps the most important member of the ble occupancy, and hallways are brightly lit.
team is the nursing assistant. This is the per- Floors are not polished to a high gloss and
son that provides most of the care and in turn the area was conditioned to prevent echo and
absorbs the brunt of the BPSDs. In addition sound distortion. Most important, ambient
to the nursing staff, social worker, and, when noise is kept to a minimum.
feasible, the nursing attendant, a nutritionist
and physical therapist meet with a psychia-
trist to coordinate care. The core team con- Proposed Models of Care
sisting of a nurse, social worker, psychiatrist,
and geriatric internist meet twice a week to No single model of care fits all situations.
review problem patients. Whenever possible, Staff are encouraged to attempt different
the appropriate certified nursing assistant, models of care based on the perceived needs
occupational therapist, physical therapist, of the individual resident. These include the
speech therapist, and the consulting pharma- following:
cist join the group.
1. Cognitive/emotion-oriented interven-
tions (reminiscence and life review,
Staff Education simulated presence therapy, validation
therapy)
With significant support from the facility 2. Sensory stimulation interventions (aro-
administrator and the director of nursing, matherapy, light therapy, massage/touch,
all staff in groups of three or four, attended a music therapy)
6-week program (The Oasis Program) led by 3. Behavior management techniques
a nurse educator who educates all members 4. Psychotherapy (cognitive-behavioral
of the team about patient-centered care. therapy, psychoeducation)
The objective of this program is to get staff 5. Other psychosocial interventions such as
to understand how to communicate effec- animal-assisted therapy and exercise
tively with demented individuals at differ-
ent stages of the illness with an emphasis Unfortunately, consistent and reliable data
on attempting to appreciate the needs of the about the efficacy of the various psycho-
resident. Staff learn to distinguish between social therapies are lacking. Before opt-
disturbed and disturbing behaviors. ing for any intervention in relation to
They learn that it is often possible to redirect agitation and aggressive behavior, and
the behavior and remain flexible in caring before opting for any intervention, it is
606part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
important to carefully analyze the poten- pertinent to the residents care. Asignificant
tial causes for the disruptive behavior (e.g., part of this discussion focuses on gathering
antecedents-behaviors-consequences) and to information about the residents premorbid
attempt to minimize the antecedent. These personality, including likes and dislikes and
causes may include pain, medical illness, responses to frustration. Another area of dis-
fatigue, depression, loneliness, under or cussion is devoted to the family and the resi-
overstimulation, and social or environmental dents stated desire for limitations in care and
stressors. No single intervention can work end-of-life choices. Families are encouraged
to manage the disruption caused by differ- to meet with members of the team informally
ent types of BPSD. Our experience suggests as and when the need arises as well as for-
that the key to managing disruptive behav- mally for a monthly support group meeting.
iors using psychosocial interventions is flex-
ibility and an institutional commitment to
limiting pharmacological intervention. If the End-of-Life Care for Severely
tenets of the conceptual model for BPSDs Demented Persons
described earlier in this chapter are consid-
ered valid and are entertained, then it helps No discussion of dementia care can be con-
staff to understand that many disruptive sidered complete without some appreciation
behaviors are no different than those that of end-of-life care. Caring for terminally ill
they have experienced as parents of young persons is always a complex process in which
childrenand they did not resort to phar- clinicians are confronted with their own reli-
macology to control them. The limbic system gious and ethical beliefs, their clinical judg-
interprets change as chaos, and many of the ment, and their interpretation of the legal
symptoms of BPSDs are primitive attempts boundaries within which to practice. What
at restoring order to the environment. To this defines quality of care at the end of life for
end, it helps to remember that pharmacologi- persons suffering from dementia is not well
cal interventions should be resorted to only understood. In 2009 Alzheimers disease was
when the safety and well-being of the patient the sixth leading cause of death in the United
or others is at risk. Persons suffering from States. Dementia-related deaths are the most
dementia need to feel safe and experience a rapidly increasing cause of mortality in the
sense of control. This becomes most evident United States. Despite the fact that 70% of
when very personal activities such as bath- dementia-related deaths occur in the nursing
ing and toileting are met with resistance and home, the provision of hospice care remains
agitation. Whenever possible, these activities significantly limited (Kiely, Givens, Shaffer,
should be provided by same-sex caregivers. Teno,& Mitchell, 2010). This is mainly because
The environment should remain constant; dementia is, erroneously, not considered by
routine is very important. Noise should many to be a terminal illness, and therefore
be kept to a minimum. When language is persons with advanced dementia often do not
impaired and communication becomes dif- receive optimal palliative care. Areview of the
ficult, it becomes important to be sensitive to literature on this subject indicates that many
nonverbal cues. As in communicating with patients with dementia die without adequate
nonverbal infants, touch and body language pain control, with feeding tubes in place,
become key methods of communication. and without the benefits of hospice care.
Caregivers have to appreciate that it is not Only about 6% of nursing home residents
what you say but how you say it that is most are admitted to hospice (Mitchell, Kiely, &
applicable to patients with dementia. Hamel, 2004; Mitchell, Morris, Park,& Fries,
2004; Sachs, Shega,& Cox-Hayley, 2004. There
are many myths that confound decision mak-
Family Involvement ing in the ambiguity surrounding the end of
life. One of the more common myths is that
A key component is the involvement of the forgoing life-sustaining treatment and pre-
residents family at every stage of the resi- scribing high doses of opiates to relieve pain
dents stay on the unit through discharge and distress will lead to criminal prosecution
or death. Family members meet with the (Meisel, Snyder, & Quill, 2000). Although it
team at admission and provide information has been shown that the health care needs of
CHAPTER 26. Nonpharmacological Approaches to Managing Behavior Symptoms in Dementia 607
patients dying from dementia are comparable and Alzheimers disease: Greco-Roman
to those of persons dying from cancer, these period to the 1960s. Neurobiology of Aging,
needs are not well articulated. Respecting 19(3), 173189.
patient preferences is key to quality care at the Box, G. E. P., & Draper, N. R. (1987). Empirical
model-building and response surfaces. NewYork,
end of life, but by virtue of severe cognitive
NY:Wiley.
and functional deficits, these patients can-
Briesacher, B. A., Limcangco, M. R.,
not participate in treatment decisions at late Simoni-Wastila, L., Doshi, J.A., Levens, S.R.,
stages of illness. Shea, D. G., & Stuart, B. (2005). The quality
As the numbers of persons dying with of antipsychotic drug prescribing in nursing
advanced dementia continue to increase, more homes. Archives of Internal Medicine, 165(11),
attention needs to be directed to this aspect of 12801285.
health policy. Median survival in advanced Brookmeyer, R., Johnson, E., Ziegler-Graham,
dementia is between 3 and 6 years, during K., & Arrighi, M. H. (2007). Forecasting
which time any number of clinical crises can the global burden of Alzheimers disease.
Alzheimers and Dementia, 3(3), 186191.
complicate the clinical course of the illness.
Cerejeira, J., Lagarto, L.,& Mukaetova-Ladinska,
Palliative care could allow for care to be deliv-
E. B. (2012). Behavioral and psychologi-
ered according to previously stated wishes cal symptoms of dementia. Frontiers in
and appropriately involve family members. Neuroscience, 3, 73.
Hospice care can limit medical interventions Chen, Y., Briesacher, B., Field, T., Tjia, J., Lau,
that provide little or no benefit. Is it reasonable D., & Gurwitz, J. (2010). Unexplained varia-
to continue therapy for issues such as hyper- tion across U.S. nursing homes in antipsy-
cholesteremia and osteoporosis? Is it kind chotic prescribing rates. Archives of Internal
or cruel to subject a person with advanced Medicine, 170(1), 8995.
dementia to repeated laboratory investiga- Cohen-Mansfield, J. (1994). Reflections on the
assessment of behavior in nursing home
tions, radiological procedures, and endosco-
residents. Alzheimers Disease and Associated
pies? Is it ethical to undertreat pain to avoid
Disorders, 8(Suppl 1), S217S222.
addicting someone? Do antibiotics amelio- Finkel, S.I., Costa e Silva, J., Cohen, G., Miller,
rate distress? Or is it wiser and more humane S., & Sartorius, N. (1996). Behavioral and
to exercise clinical restraint, practice mas- psychological signs and symptoms of
terly inactivity, and to let thy will be done dementia: A consensus statement on cur-
(Meisel, Snyder,& Quill, 2000)? Can such an rent knowledge and implications for research
approach, practiced in long-term care facili- and treatment. International Psychogeriatrics,
ties and community settings, provide a better 8(Suppl 3), 497500.
quality of life and facilitate a good death? Geda, Y. E., Roberts, R. O., Knopman, D. S.,
Petersen, R. C., Christianson, T. J., Pankratz,
There are no clear answers to these ques-
V. S.,...Rocca, W. A. (2008). Prevalence of
tions. There are moral, legal, and religious
neuropsychiatric symptoms in mild cog-
convictions that inevitably influence the cli- nitive impairment and normal cognitive
nicians consideration in end-of-life demen- aging: Population based study. Archives of
tia care. In the final analysis every clinician General Psychiatry, 65(10), 11931198.
has to revisit the sacred covenant entered Jost, B.C.,& Grossberg, G.T. (1996). The evolu-
into with each patient and to do no harm tion of psychiatric symptoms in Alzheimers
primum non nocere. disease:Anatural history study. Journal of the
American Geriatric Society, 44(9), 10781081.
Kiely, D.K., Givens, J.L., Shaffer, M.L., Teno,
Acknowledgments J.M.,& Mitchell, S.L. (2010). Hospice utili-
zation and outcomes among nursing home
residents with advanced dementia. Journal
The author wishes to acknowledge the help
of the American Geriatric Society, 58(12),
and cooperation of the team of care providers
22842291.
at the Briarwood Nursing and Rehabilitation Lyketsos, C.G., Lopez, O., Jones, B., Fitzpatrick,
in Needham, Massachusetts. A. L., Breitner, J., & DeKosky, S. (2002).
Prevalence of neuropsychiatric symptoms
References in dementia and mild cognitive impair-
ment: Result from the cardiovascular
Berchtold, N. C., & Cotman, C. W. (1998). health study. Journal of the American Medical
Evolution in the conceptualization of dementia Association, 288(12), 14751483.
608part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Meisel, A., Snyder, L.,& Quill, T. (2000). Seven (2010). Prevalence of neuropsychiatric symp-
legal barriers to end-of-life care:Myths, reali- toms and their association with functional
ties, and grains of truth. Journal of the American limitations in older adults in the United
Medical Association, 284, 24952507. States:The aging, demographics and memory
Mitchell, S. L., Kiely, D. K., & Hamel, M. B. study. Journal of the American Geriatric Society,
(2004). Dying with advanced dementia in the 58, 330337.
nursing home. Archives of Internal Medicine, Sachs, G. A., Shega, J. W., & Cox-Hayley, D.
164(3), 321326. (2004). Barriers to excellent end-of-life care
Mitchell, S.L., Morris, J.N., Park, P.S.,& Fries, for patients with dementia. Journal of General
B. E. (2004). Terminal care for persons with Internal Medicine, 19(10), 10571063.
advanced dementia in the nursing home Tariot, P. N. (1996). Behavioral manifestations
and home care settings. Journal of Palliative of dementia:Aresearch agenda. International
Medicine, 7(6), 808816. Psychogeriatrics, 8(Suppl 1), 3138.
Narang, P., El-Refai, M., Parlapalli, R., Danilov, Vigen, C. L. P., Mack, W. J., Keefe, R., Sano,
L., Manda, S., Kaur, G.,& Lippmann, S. (2010). M., Sultzer, D., Stroup, S., & Schneider,
Antipsychotic drugs: Sudden cardiac death L. S. (2011). Cognitive effects of atypi-
among elderly patients. Psychiatry (Edgmont), cal antipsychotic medications in patients
7(10), 2529. with Alzheimers disease: Outcomes from
Okura, T., Plassman, B. L., Steffens, D. C., CATIE-AD. American Journal of Psychiatry,
Llewellyn, D.J., Potter, G.G.,& Langa, K.M. 168(8), 831839.
27
The cognitive, functional, and behavioral order to facilitate care provision. To better
decline experienced by individuals diag- address the needs of both the patient and
nosed with dementia can be severe and the caregiver, the public and health care pro-
debilitating, leading to a significant need of viders must recognize the caregiverpatient
support from family caregivers beginning dyad as two distinct people, not just one.
early in the course of the disease. As such, Early identification of caregiver stress, bur-
there is an increasing sense of burden, as den, and grief allows for optimum medi-
spouses and adult children often take on a cal and psychosocial interventions, as well
multitude of new responsibilities previously as access to community resources, such as
managed by the person with dementia, often caregiver support groups and online caregiv-
beginning prior to when a dementia diagno- ing communities. The goal of this chapter is
sis is made. In conjunction with increasing to review the nature of caregiving, identify
burden, there is often an accompanying sense some of its positive and negative aspects,
of grief and loss as the disease progresses. and provide practical guidance for dementia
A number of adverse outcomes for the caregivers.
dementia caregiver, such as stress, depres-
sion, and diminishing health status of
the caregiver, directly lead to increases in What Is Caregiving?
(1) institutionalization of the person with
dementia and (2)declines in quality of life for Caregiving scenarios can be represented in
both the patient and the caregiver. Additional many waysfor example, the wife that cares
caregiver burden comes from for her husband who suffered a stroke; the
(1) inadequate understanding of the dis- daughter who from a distance supervises
ease for which they are providing care, and the care of her aging parents; or the neigh-
(2) a delay in recognition, diagnosis, and bor who helps the woman next door who is
treatment of symptoms related to dementia dealing with cancer. The definition of care-
(Galvin etal., 2010a, 2010b). giving relates to all the activities performed
It is critical to increase the understanding by a concerned individual who contributes
about the dementia caregivers stressors in to the well-being of another individual. At
609
610part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
times, this definition can be confounded training is necessary for the informal care-
with the provision of direct care or assistance giver. Relatives and friends provide care
with activities of daily living (ADLs); how- without receiving specific training to assist
ever, caregiving can be performed in differ- their loved ones. Experience is developed
ent forms and at different levels. Caregiving over a period of years as caregivers learn
responsibilities do not necessarily have to from their interactions while providing care.
be fulfilled by individuals with specialized There are many factors that exert influence
training. As long as there is a special interest during the informal caregiving process; for
or a caring attitude toward others, caregiv- instance, the nature of the relation between
ing responsibilities can be fulfilled. A care- the caregivers and their loved ones, their
giver is therefore defined as an individual history, and how their interactions evolved.
who oversees the welfare of another person. Caregivers usually play different roles in
This individual can provide basic assistance their families and social networks besides
and care for someone who is frail, disabled, being caregivers. They can simultaneously be
ill, and/or needs help in one or more aspects spouses, daughters, siblings, friends, neigh-
of life. Caregivers perform a variety of tasks bors, and so on. In part because of the variety
to assist someone in his or her daily life, for of roles played at the same time, caregivers
example, balancing a checkbook, shopping, may become overwhelmed attempting to ful-
visiting doctors offices, giving medication fill the goals of their variety of roles. In many
reminders, or helping someone to eat, take instances, family dynamics are disturbed
a bath, or dress. For many caregivers, this when the time to assume caregiving respon-
assistance and care are not considered care- sibilities arrives. Additionally, the caregiving
giving. According to Carol Levine, caregiv- process is affected by the cultural and ethnic
ers do not think of what they do in terms of background of the caregiver and the person
performing tasks related to activities of daily receiving the care.
living (ADLs) and instrumental activities To fulfill their role, caregivers do not need
of daily living (IADLs); they do whatever to live in the same household as the indi-
needs to be done. Then they watch and wait vidual for whom they are caring. They can
until the next thing needs to be done, and be in the vicinity or just supervise the care of
the next and the next (Levine, 2003, p.117). someone from a distance. A2004 study from
Caregivers are often ready to take care of the Alzheimers Association and National
their loved one when needed, regardless of Alliance for Caregiving noted that only one
their own circumstances. This means that, at quarter of dementia caregivers actually lived
times, caregivers can suffer or even sacrifice with the person for whom they were pro-
themselves while caring for others. viding care (Alzheimers Association, 2013).
In general, caregivers are divided into for- Other caregivers, particularly adult children
mal or paid caregivers and informal or and friends, can reside quite a distance from
unpaid (often family) caregivers (Alzheimers the patient with dementia. The Alzheimers
Association, 2013). All professionals who Disease Facts and Figures Report from the
receive a financial reimbursement for directly Alzheimers Association reported that 10%
caring or in some form supervising the care of the nearly 10 million family and other
of other(s) are considered formal caregiv- informal caregivers lived more than 2 hours
ers, including home health aides, geriatric from the patient with dementia (Alzheimers
care managers, social workers, and so on. Association, 2013).
All individuals who provide care or over- Whether it is from far away or close by, an
see someones care without receiving finan- individual can be the source of care or the
cial reimbursement are considered informal focus of care. According to the Alzheimers
caregivers, for instance, family members and Association, most people will become care-
friends. In this chapter we are specifically giversor need one at some point in their
addressing informal, family caregivers of lives. To foresee who will play the caregiver
patients with dementia. role or the care receiver role is not easy to
Considering the professional context in determine. For example, caregiving can occur
which formal caregivers carry out their gradually over time, or it can occur over-
tasks, specialized training is required. night. In some cases, caregivers anticipate
However, no experience or formalized taking on the caregiving role and know in
CHAPTER 27. The Role of the Family in the Care and Management of Patients With Dementia 611
advance what is expected of them (Sheets& Family caregivers assist older relatives in
Mahoney-Gleason, 2011). Some relatives can dealing with the physical and psychosocial
see themselves performing specific tasks that consequences of dementia. Cognitive impair-
they might feel comfortable doing or because ment impacts the patients ability to live
it is their area of expertise. In other cases, it is independently. The care provided by family
more difficult to be prepared due to the unan- caregivers encompasses emotional support,
ticipated nature of caregiving. Similarly, it is financial aid, and provision of services rang-
difficult to think about receiving assistance ing from instrumental aid and personal care
from others without feeling that ones inde- assistance to health care tasks and mediation
pendence and dignity are jeopardized. with formal care providers. Dementia care-
Caregivers may play their caregiving role giving can involve a substantial expenditure
on a full-time or part-time basis. Fulfilling the of time over a long-lasting period (Schulz&
responsibilities of caregiving demands time, Martire, 2004). The consequences to caregiv-
and this can constitute a job within itself for ers are widespread and include financial,
the caregiver. Whether it is full time or part health, and psychosocial burdens (Cucciare,
time, the value of caregiving is great at all Gray, Azar, Jimenez,& Gallagher-Thompson,
levels. The value of the services that family 2010). Cultural beliefs and expectations
caregivers provide for free, while caring for may inform families interpretation of the
older adults, is estimated at $375 billion a signs, symptoms, causes, and management
year. This amount is almost twice as much as of dementia and their commitment to care
what is actually spent on homecare and nurs- provision (Napoles, Chadiha, Eversley, &
ing home services combined ($158 billion) Moreno-John, 2010; Sayegh& Knight, 2010).
(National Alliance for Caregiving, 2009). The For example, Hispanic cultural beliefs
cost of care for patients with dementia is esti- regarding Alzheimers disease etiology view
mated at $172 billion annually (Alzheimers it as part of the normal aging process, so
Association, 2013). when behavioral and psychological symp-
As previously noted, caregivers can be cat- toms emerge, their loved one is stigmatized
egorized as formal or informal. Many persons as gone crazy (Gray, Jimenez, Cucciare,
with dementia have more than one caregiver Tong, & Gallagher-Thompson, 2009). There
at the same time:a formal caregiver, such as is also the concept of La Tercera Edad (the
a home attendant or home health aide, who third and final cycle of life) with a need for
provides assistance with daily living activi- increased family assistance and transition of
ties; and an informal caregiver, such as a rela- responsibilities across generations as elderly
tive or friend, who oversees matters like mail family members undergo normal aging
and bills. Informal caregiving is considered (Flores, Hinton, Barker, Franz, & Velasquez,
the most common form of providing com- 2009). In Asian cultures, illness events are
munity care to frail older persons (Toseland, family focused, with elderly relatives trust-
1995). Regardless of the type of caregiving ing that family members will make the treat-
provided, self-identification as a caregiver ment decisions that are in their best interest
facilitates access to services. It is important (University of Washington Medical Center,
to educate and empower informal caregivers 2007).
to recognize their role and the importance of
this role. In the United States, there are ser-
vices designed to assist caregivers specifi- Personal Challenges Faced by the
cally, but if the individual does not identify Family Caregiver
himself or herself as a caregiver, the opportu-
nity to access such services diminishes. Caregiving is a responsibility that requires
strength and support as dementia pro-
gresses, robbing the memories, energy, and
The Family Caregiver freedom of loved ones. Any type of caregiv-
ing, especially for people with dementia, can
There is widespread recognition of the criti- have serious physical and emotional effects.
cal disease management and care provision Caregivers may be too overwhelmed, frus-
tasks performed by family members of per- trated, or depressed to seek the help they
sons with dementia (Talley & Crews, 2007). need. It is important for caregivers to seek
612part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
help to cope with the strains of caregiving as the disease progresses, from finances and
well as to make sure they attend to their own legal matters to the daily household chores
health. Caregivers play a critical role and (Gallagher-Thompson et al.,2003). As previ-
should be empowered to speak freely to their ously mentioned, caring for a relative with
loved ones health care providers with any dementia is linked to negative psychosocial
questions or concerns about caring for some- and physical consequences for the caregiver
one with dementia. It is essential to have (Pinquart & Sorensen, 2003). The negative
open discussions to maintain the well-being health effects caused in some caregivers can
of the caregiver and health of the patient. severely diminish their quality of life and, in
Working with a team of care providers who some cases, accelerate the need for institu-
are connected in some way allows the provi- tionalization of the patient (Gaugler, Leitsch,
sion of quality care. An alliance developed Zarit,& Pearlin, 2000). Caregiving can be very
between the caregiver and patients provid- difficult, full of challenges, and very taxing at
ers can only be advantageous. the spiritual, emotional, physical, social, and
Chronic progressive diseases such as economic levels (Sheets& Mahoney-Gleason,
dementia result in increasingly severe func- 2011).
tional limitations that last indefinitely.
Subsequently, these will require long-term
caregiving by family members, while trig- Benefits of Caregiving
gering stress reactions associated with
altered relationship dynamics (Saban, Much of the caregiving literature assumes
Sherwood, DeVon, & Hynes, 2010), result- a view of the caregiver as being burdened
ing in growing caregiver burden and depres- without consideration of the caregivers
sion (Schoenmakers, Buntinx,& DeLepeleire, expectations and experiences (Flores et al.,
2010). Caregivers of individuals with chronic 2009). Yet within the caregiving journey, indi-
disease are at elevated risk for depression; viduals can experience a variety of emotions
anxiety; poor quality of life; and health prob- that are not solely negative. The 2009 Report
lems such as heart disease (Lee, Colditz, of Findings on the Aging Services Network
Berkman, & Kawachi, 2003), headaches noted that while caregiving can be stressful,
(Kreutzer et al., 2009), digestive problems there are also benefits and rewards (Levine,
(Thompson etal., 2004), and disturbed sleep Halper, Peist, & Gould, 2010). Caregivers
(Brummett et al., 2006). Biological marker have reported positive feelings about care-
abnormalities among caregivers include giving (e.g., family togetherness and the
increased cortisol secretion (Bremner, 2006), satisfaction of helping others) while simulta-
abnormal glucose regulation (Altuna, Lelli, neously reporting high levels of stress during
San Martn de Viale, & Damasco, 2006), the care provision (Alzheimers Association,
inflammation (Hamer, Gibson, Vuononvirta, 2013). Thus, in addition to the detrimental
Williams, & Steptoe, 2006), and abnormal aspects of caregiving, there are a number of
immunologic function (Kavelaars& Heijnen, perceived benefits associated with caregiv-
2006). The personal implications of caregiv- ing, such as (a)the opportunity to give back;
ing can involve feelings of grief and depres- (b) improved relationships; (c) feeling good
sion. Caregivers are not only responsible for about the quality of care; (d)serving as a role
supervising the care of another person but model for others; (e) increased self-esteem;
also for caring for themselves in order to be (f)an enhanced sense of purpose; and (g)feel-
better prepared to provide care. ings of pleasure and satisfaction (Coon etal.,
According to researcher and caregiver 2004).
Carol Levine, Dementia caregivers struggle
with particularly difficult responsibilities and
wrenching losses (Levine, 2003, p.116). The Cultural Differences in Knowledge,
negative impact associated with caregiving Attitudes, and Caregiving
is likely to be greater for dementia caregiv-
ers than caregivers of frail nondemented The older adult population in the United
elders (Ory, Hoffman, Lee, Tennstedt, & States is becoming more diverse. In 2006,
Schulz, 1999). The dementia caregiver starts 81% of adults age 65+ were Caucasian; by
assuming more and more responsibilities as 2050 this is estimated to decrease to 61%
CHAPTER 27. The Role of the Family in the Care and Management of Patients With Dementia 613
(Napoles etal., 2010). Given that the number Pacific Islander American Health Forum,
of Americans from minority backgrounds is 2006). It is important to consider that these
predicted to increase at a rate greater than groups might be deprived from accessing
Caucasians, studies of cross-cultural differ- caregiving services because of their linguistic
ences in caregiving experiences and out- barriers rather than a lack of need for such
comes are needed (Sayegh & Knight, 2010), services.
particularly since minorities may bear a dis- Family members require education and
proportionate burden of Alzheimers disease knowledge about dementia, treatment, and
caregiving (Napoles et al., 2010). Increased services to cope effectively with caregiving
stress, strain, and burden associated with (Gray, 2003). Substantial evidence suggests
caregiving may increase risk of psychologi- that caregiving experiences of minority care-
cal and physical morbidities (Napoles etal., givers differ significantly from those of White
2010). There are five important themes when caregivers (Aranda & Knight, 1997). To bet-
considering caregiving in a multicultural ter understand caregiver help-seeking and
community:(1)the perceived role of the fam- help-accepting perspectives and actions, it
ily in care (a term known as familism) (Flores is critical to learn about cultural values and
et al., 2009; Losada et al., 2010; (2) gender expectations (Valle, 1998). Minority elders,
roles (Del Gaudio et al., 2012); (3) family especially Latinos, are a growing and diverse
traditions and cultural identity (Gray et al., population that tends to delay entry into care
2009); (4) expectations about caregiving until the moderate and late stages of the dis-
(Flores etal., 2009); and (5)role of faith and ease. Consequently, this makes advance care
religion (Herbert etal., 2007). planning more challenging to implement and
Cultural beliefs and influences can shape caregiving more stressful. Insufficient knowl-
health care choices and service use and edge about dementia, especially prognosis
impact the ways in which patients and their and progression, obstructs efforts to plan
families both view and manage Alzheimers and prepare. Ethnic minorities may lack the
disease (Knight& Sayegh, 2010; Livney etal., necessary information or hold to culturally
2011). Asignificant challenge in establishing influenced beliefs that delay accessing the
an Alzheimers disease diagnosis in diverse help needed.
populations is to validate and standardize Ethnic differences at intrapersonal, inter-
assessments across different ethnic and racial personal, and environmental levels are pres-
groups. This includes not only differences in ent across multiple psychosocial domains.
symptom presentation across groups but also For example, compared with non-Hispanic
cultural perceptions about cognitive health Caucasians, Hispanics make less use of
and attitudes and beliefs about care. For long-term care institutions and report more
example, it is common for Korean Americans positive appraisals of coping, increased spiri-
to consider themselves in good health if tuality, and beliefs in filial responsibility and
they are symptom free, sometimes delay- familism, while at the same time reporting
ing seeking care until symptoms become higher levels of burden and depression and
severe (Han, Kang, Kim, Ryu,& Kim, 2007). diminished psychosocial health (Napoles
Hispanic older adults are more likely to et al., 2010). A study of African American
believe memory changes are part of normal family caregivers found that caregiving
aging and that Alzheimers disease is due to was viewed as a traditional family value
experiencing a difficult life, loneliness, stress, (Sterritt & Pokorny, 1998). A study pub-
trauma and family problems, or attribute it lished by Gelman and colleagues suggests
to external forces such as Gods will or el mal that general beliefs about aging and memory
de ojo (evil eye). Hispanics also include more loss among Latinos are a significant barrier
emotional and behavioral symptoms as part to early diagnostic evaluations for memory
of the spectrum of Alzheimers disease symp- loss (Gelman et al., 2010). Minority fam-
toms compared with Caucasians (Hinton, ily caregivers may feel too overwhelmed to
Franz, Yeo,& Levkoff, 2005; Karlawish etal., participate in available community services
2011). Groups with high linguistic isolation and may even experience them as intrusive
have greater difficulty accessing basic health and unwelcome. Regardless of the percep-
and social services, requiring outreach and tions minority caregivers may have about
services in their native language (Asian and community services, if they are presented
614part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
strategically with cultural sensitivity, care- more than two decades. The NYUCI dem-
givers often welcome the assistance. onstrated the value of social support and
counseling for spouse caregivers, alleviat-
ing some deleterious effects of care pro-
Impact of Providing Caregiver Support vision on the spouse-caregivers mental
health, and postponing nursing home place-
The stress associated with caring for an older ment of their Alzheimers disease patient
relative suffering from Alzheimers disease spouses by 557 days compared with usual
or another dementing illness is often con- care (Mittelman et al., 2004a, 2004b, 2006,
siderable (Mittelman, Haley, Clay, & Roth, 2007). Moreover, the interventions effects
2006; Mittelman, Roth, Clay, & Haley, 2007; on spouse caregivers depression were
Mittelman, Roth, Coon, & Haley, 2004a; long-lasting, continuing through nursing
Mittelman, Roth, Haley, & Zarit, 2004b). home placement and the death of the patient
Caregivers frequently neglect their own (Mittelman et al., 2004a, 2004b, 2006, 2007).
needs as they focus on satisfying the patients A mediation analysis demonstrated that a
needs. Many authors have acknowledged the substantial proportion of effect on change
importance of providing encouragement to in these outcomes could be attributed to
caregivers to take better care of themselves, intervention-induced increases in the spouse
as they can become so involved in care provi- caregivers satisfaction with their social sup-
sion that they may delay or forget to attend port (Roth, Mittelman, Clay, Madan,& Haley,
to their own personal needs. According to 2005; Roth, Perkins, Wadley, Temple,& Haley,
Shaw, caregiver support groups have been 2009). The fundamental message underlying
developed as a treatment response to the NYUCI was that real and perceived social
obvious need for relief from the stress asso- support improves spouse caregivers ability
ciated with caregiving (Shaw, 1997, p.165). to withstand the difficulties of caregiving and
The stress-coping paradigm (Pearlin, defers the need for nursing home placement.
Mullin, Semple, & Skaff, 1990) has been
adopted by many researchers to explain
caregiver response to interventions (Brodaty, Family-Centered Care in Dementia
2007). When caregivers feel well supported,
they report reduced burden, stress, and The family has a dual status in care of indi-
depression. Research suggests that social viduals with dementia. In their caregiving
support resources can reduce the conse- capacity, family members are viewed by the
quences of stressful life experiences and health care and social service system as part
contribute to preservation of psychological of the care team. In this status, family care-
well-being (Fiore, Coppel, Becker, & Cox, givers experience a variety of burdens and
1986; House, Landis, & Umberson, 1988; strains that may compromise family function-
Keyes, Shmotkin,& Ryff, 2002; Krause, 1995). ing, compete with day-to-day role respon-
Social support may be effective in part by sibilities, adversely impact their health, and
increasing the perception that resources are generate a variety of emotional sequelae.
available to handle stress, thereby decreasing Involvement in care also negatively impacts
appraisals of stressors as potentially harm- caregivers own health promotion activi-
ful (Cohen, 2004). Individuals with greater ties, including delaying or canceling routine
social support report more positive affect health care, screening exams, or other pre-
and a greater sense of control (Ferguson & ventive health activities (Schulz & Martire,
Goodwin, 2010). Regarding support groups, 2004). However, family caregivers can be
Toseland said:During group meetings, care- further impacted by dementia, apart from
givers can gain valuable information about the strains and burdens they experience from
the processes of aging and the progression of care provision. When learning of their rela-
specific ailments. Understanding disease pro- tives dementia diagnosis, family members
cesses helps caregivers to anticipate and plan may be simultaneously confronted by fears
for future caregiving demands (Toseland, for their own susceptibility due to genetic
1995, p.33). risk (Raveis, 2004; Raveis, Pretter,& Carrero,
The NYU Caregiver Intervention (NYUCI) 2010), particularly in families in which more
was a longitudinal, controlled trial spanning than one person has developed dementia. In
CHAPTER 27. The Role of the Family in the Care and Management of Patients With Dementia 615
these situations, involvement in care provi- services he or she would like to access. It is
sion can impose additional stress, for as care- not always easy for caregivers to verbalize or
givers, they are afforded firsthand exposure clarify their needs, and subsequently, to iden-
to their relatives experience. While this can tify the resources available to satisfy such
serve to normalize or demystify dementia, needs. It is essential for the clinician to assist
the witnessing of their relatives difficulties the caregiver in articulating needs and to
may intensify caregivers own health-related respect caregiver preferences. Most caregiv-
fears and concerns. It can be very challenging ers benefit from discussing their needs with
for caregivers to address concerns about their a social worker or a geriatric care manager.
loved ones condition while coming to terms Once the specific needs of the patient and
with their own uncertain future. caregiver are identified, it is imperative to facil-
Over the last few decades, an expanding itate the exploration of services, programs, and
body of family-based research has docu- benefits offered in their community. It is also
mented the ramifications of illness on the vital to remember that benefits are different
family system (Bachner, Karus, & Raveis, according to location. Furthermore, availabil-
2009; Beard, Sakhtah, Imse, & Galvin, 2012; ity of programs and services varies from state
Galvin et al., 2010b; Raveis, 2004; Raveis to state and from community to community.
etal., 2010). These efforts have informed the After the identification and exploration has
growing paradigm shift from a biomedi- taken place, a plan of action has to be imple-
cal model of care to one that is patient and mented to satisfy caregiver and patient needs.
family centered and have led policy makers Assimilating and adjusting to a demen-
and the health professions to acknowledge tia diagnosis is a difficult task, for both the
that family caregivers must be recognized as patient and the family. For most individuals
partners in care (Reinhard, Brooks-Danso, affected by dementia, receiving the diag-
Kelley, & Mason, 2008) and be supported nosis is just the first step of the journey.
in their care responsibilities (Raveis, 2004; Unfortunately, many patients and family
Talley & Crews, 2007). Nearly half of infor- members leave the physicians office mis-
mal family caregivers are performing medi- informed or lacking information about the
cal and nursing tasks in addition to helping diagnosis. Assuming that a probable diagno-
with activities of daily living for patients sis has been given in a clear and informative
with dementia. The landmark State of the manner, people can still use terms incorrectly
Science Symposium: Professional Partners and interchangeably, have misconceptions
Supporting Family Caregivers issued a primary about what a dementia diagnosis means, and
recommendation to develop and promote do not have a clear treatment plan. In addi-
a patient and family-centered service para- tion to all the questions that might be gener-
digm (Kelley, Reinhard, & Brooks-Danso, ated after receiving a dementia diagnosis, the
2008, p.11). Family-centered care recognizes question of what to do next also rises.
that supporting family members in their criti- Here we provide a practical list of activi-
cal role is integral to the patients medical ties each caregiver should consider to better
and psychosocial health. Although families prepare for his or her caregivingrole:
are directly involved in health care, caregiv-
ing, treatment decision making, and health 1. After the diagnosis is given, take time to
advocacy, a comprehensive attempt to attend discuss what the diagnosis means to you
to their concerns and information needs is and your loved one. Write down ques-
not routinely targeted. tions you have about the diagnosis, prog-
nosis, treatment plan, and so on. Then
make a follow-up appointment with the
Developing an Individualized Care Plan diagnosis provider to ask those questions.
2. Consider getting a second opinion from a
Although caregivers of dementia patients specialist (neurologist, psychiatrist, geri-
typically deal with a partially predictable atrician) if there are still questions about
set of issues, every caregiver, and thus every the diagnosis and treatment plan.
caregiving experience, is unique. For a vari- 3. Consider any special needs of the patient.
ety of reasons, a caregiver may have particu- Does the patient have difficulties with
lar preferences for the type of programs and walking and balance? If so, he or she may
616part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Although every case is different, here are some key points that might be helpful after a diagnosis of mild
cognitive impairment or dementia is given:
1. Learn as much as possible about the diagnosis (Internet, books, or support groups)
2. Learn how to monitor the progression of symptoms and their response to therapies (see Table27.2)
3. Identify and contact organizations associated with the diagnosis (see Table27.3)
4. Participate in physically and mentally stimulating activities (exercising, dancing, museum visits, or
computer access)
5. Join social gatherings (YMCA, local clubs, or senior groups, etc.)
6. Eat a healthy diet (consulting with a dietitian or nutritionist, if necessary)
7. Learn about the following:
a. Transportation services (Access-A-Ride, local transit organizations, or services through Medicaid)
b. Safety devices/alert systems at home (Comfort zone or personal response services)
c. Meals options (home-delivered meals through Meals on Wheels or cooking assistance)
d. Home care services or companionship services (home care agencies)
e. Housing options:
Independent living
Senior housing
Naturally occurring retirement communities (NORCs)
Assisted living
Nursing homes
Continuum care retirement communities
8. Consider registering for the MedicAlert + SAFE Return Program (Alzheimers Association)
9. Plan and organize legal and financial matters (using an elder law attorney, if necessary):
Designate a health care proxy
Plan to complete a living will and a durable power of attorney
Consider obtaining Social Security Disability, if applicable
Apply for early retirement if applicable
Add a cosigner to financial accounts
TABLE27.2 The Healthy Aging Brain Care Monitor (HABC-Monitor) Caregiver Assessment
Tool
Cognitive Domain Functional Domain Behavioral Domain Caregiver Domain
Judgment or decision Planning, preparing, or Feeling down, depressed, Your quality of life
making serving meals or hopeless
Less interest or pleasure in Taking medications in Being stubborn, agitated, Your financial future
doing things, hobbies, or the right dose at the aggressive, or resistant
activities right time to help from others
Repeating the same things Walking or physical Feeling anxious, nervous, Your mental health
over and over such as ambulation tense, fearful, or
questions or stories panicked
Learning how to use a tool, Bathing Believing others are Your physical health
appliance, or gadget stealing from them or
planning to harm them
Forgetting the correct Shopping for personal Hearing voices, seeing
month or year items such as things, or talking to
groceries people who are not
there
Handling complicated Housework or Poor appetite or
financial affairs such as household chores overeating
balancing checkbook,
filing income taxes, and
paying bills
Remembering Leaving her/him alone Falling asleep, staying
appointments asleep, or sleeping too
much
Thinking or memory Her/his safety Acting impulsively,
without thinking
through the
consequences of her or
his actions
Her/his quality of life Wandering, pacing, or
doing things repeatedly
Falling or tripping
Note. The Healthy Aging Brain Care Monitor is a copyrighted instrument by Drs. Malaz Boustani, James Galvin and
Christopher Callahan and the Indiana University School of Medicine. The HABC-Monitor and scoring rules are available
at http://www.wishard.edu/our-services/senior-care/healthy-aging-brain-center/resources
Dementia-Related Sites
Alzheimers Association http://www.alz.org/
Alzheimer Disease Education and Referral Center http://www.nia.nih.gov/alzheimers
Alzheimers Foundation of America http://www.alzfdn.org/AFAServices/tollfreehotline.
html
American Parkinsons Disease Association http://www.apdaparkinson.org/
Association for Frontotemporal Degeneration http://www.ftd-picks.org/
Creutzfeldt-Jacob Disease Foundation http://www.cjdfoundation.org/
Lewy Body Dementia Association http://www.lbda.org/
US Department of Health and Human Services http://www.alzheimers.gov
Health-Related Sites
American Heart Association http://www.heart.org/HEARTORG/
American Stroke Association http://www.strokeassociation.org/STROKEORG/
American Diabetes Association http://www.diabetes.org/
General Information Sites
AARP http://www.aarp.org/
Administration on Aging http://www.aoa.gov/AoARoot/Elders_Families/
index.aspx
Caregiver Action Network http://caregiveraction.org/
Department of Health& Human Services:Eldercarehttp://www.eldercare.gov/Eldercare.NET/Public/
Index.aspx
Elder Care Lawyers http://www.elderlawanswers.com/Default.aspx
Family Caregiver Alliance http://www.caregiver.org/caregiver/jsp/home.jsp
Federation Employment and Guidance Services http://www.fegs.org/fegs-services/
Healthcare Proxy http://www.health.ny.gov/professionals/patients/
health_care_proxy/index.htm
Leading Age (How to tour a Nursing Home) http://www.leadingage.org/How_to_Tour_a_
Nursing_Home.aspx
Long Term Care Information http://longtermcare.gov/
Medicaid http://medicaid.gov/index.html
Medicare http://www.medicare.gov/index.html
Medline Plus http://www.medlineplus.gov/
National Academy of Elder Law Attorney http://www.naela.org
National Association of Geriatric Care Managers http://www.caremanager.org/
National Institute on Aging http://www.nia.nih.gov/
National Institutes of Health:Senior Health http://nihseniorhealth.gov/index.html
Social Security Administration http://www.ssa.gov/
caregiver stress and coping process:Asocio- for adjustment. American Journal of Community
cultural review and analysis. Gerontologist, 37, Psychology, 14, 93111.
342354. Flores, Y.G., Hinton, L., Barker, J.C., Franz, C.E.,&
Bachner, Y., Karus, D., & Raveis, V. H. (2009). Velasquez, A. (2009). Beyond familism:Acase
Examining the social context in the caregiving study of the ethics of care of a Latina caregiver
experience: Correlates of global self-esteem of an elderly parent with dementia. Health Care
among adult daughter caregivers to an older for Women International, 30, 10551072.
parent with cancer. Journal of Aging and Health, Gallagher-Thompson, D., Coon, D. W., Solano,
21, 10161039. N., Ambler, C., Rabinowitz, Y.,& Thompson,
Beard, R.L., Sakhtah, S., Imse, V.,& Galvin, J.E. L. W. (2003). Change in indices of distress
(2012). Negotiating the joint career: Couples among Latino and Anglo female caregivers of
adapting to Alzheimers and aging in place. elderly relatives with dementia: Site-specific
Journal of Aging Research, 2012, 797023. results from the REACH national collabora-
Bremner, J. D. (2006). Traumatic stress: Effects tive study. Gerontologist, 43, 580591.
on the brain. Dialogues in Clinical Neuroscience, Galvin, J. E., Duda, J. E., Kaufer, D. I., Lippa,
8, 445461. C.F., Taylor, A.,& Zarit, S.H. (2010a). Lewy
Brodaty, H. (2007). Meaning and measure- body dementia:Caregiver burden and unmet
ment of caregiver outcomes. International needs. Alzheimers Disease and Associated
Psychogeriatrics, 19, 363381. Disorders, 24, 177181.
Brummett, B. H., Babyak, M. A., Siegler, I. C., Galvin, J. E., Duda, J. E., Kaufer, D. I., Lippa,
Vitaliano, P.P., Ballard, E.L., Gwyther, L.P.,& C.F., Taylor, A.,& Zarit, S.H. (2010b). Lewy
Williams, R. B. (2006). Associations among body dementia: The caregiver experience of
perceptions of social support, negative affect, clinical care. Parkinsons and Related Disorders,
and quality of sleep in caregivers and non- 16, 388392.
caregivers. Health Psychology, 25, 220225. Gaugler, J., Leitsch, S.A., Zarit, S.H.,& Pearlin,
Cohen, S. (2004). Social relationships and health. L. (2000). Caregiver involvement following
American Psychologist, 59, 676684. institutionalization: Effects of preplacement
Coon, D. W., Rubert, M., Solano, N., stress. Research in Aging, 22, 337359.
Mausbach, B., Kraemer, H., Argulles, Gelman, C.R. (2010). Learning from recruitment
T.,...Gallagher-Thompson, D. (2004). challenges: Barriers to diagnosis, treatment,
Well-being, appraisal, and coping in Latina and research participation for Latinos with
and Caucasian female dementia caregiv- symptoms of Alzheimers disease. Journal of
ers: Findings from the REACH study. Aging Gerontological Social Work, 53, 94113.
and Mental Health, 8, 330345. Gray, H. L., Jimenez, D. E., Cucciare, M. A.,
Cucciare, M. A., Gray, H., Azar, A., Jimenez, Tong, H. Q., & Gallagher-Thompson, D.
D., & Gallagher-Thompson, D. (2010). (2009). Ethnic differences in beliefs regard-
Exploring the relationship between physical ing Alzheimer disease among dementia fam-
health, depressive symptoms, and depression ily caregivers. American Journal of Geriatric
diagnoses in Hispanic dementia caregivers. Psychiatry, 17, 925933.
Aging and Mental Health, 14, 274282. Gray, L. (2003). Caregiver depression: A growing
Del Gaudio, F., Hichenberg, S., Eisenberg, mental health concern. Policy Brief. Family
M., Kerr, E., Zaider, T. I., & Kissane, D. W. Caregiver Alliance, San Francisco, CA.
(2012). Latino values in the context of pal- Hamer, M., Gibson, E. L., Vuononvirta,
liative care:Illustrative cases from the family R., Williams, E., & Steptoe, A. (2006).
focused grief therapy trial. American Journal Inflammatory and hemostatic responses to
of Hospice and Palliative Care. Epub ahead of repeated mental stress: Individual stability
print. and habituation over time. Brain Behavior and
Feinberg, L., Horvath, J., Hunt, G., Plooster, L., Immunity, 20, 456459.
Kaga, J., Levine, C.,...Wilkinson, A. (2003). Han, H. R., Kang, J., Kim, K. B., Ryu, J. P., &
Family caregiving and public policy principles for Kim, M. T. (2007). Barriers to and strate-
change. Retrieved March 2014, from http:// gies for recruiting Korean Americans for
www.caregiving.org/data/principles04.pdf. community-partnered promotion research.
Ferguson, S. J., & Goodwin, A. D. (2010). Journal of Immigrant and Minority Health, 9,
Optimism and well-being in older adults:The 137146.
mediating role of social support and per- Hebert, R. S., Dang, Q., & Schulz, R. (2007).
ceived control. International Journal of Aging Religious beliefs and practices are associated
and Human Development, 71, 4368. with better mental health in family caregivers
Fiore, J., Coppel, D.B., Becker, J.,& Cox, G.B. of patients with dementia:Findings from the
(1986). Social support as a multifaceted con- REACH study. American Journal of Geriatric
cept: Examination of important dimensions Psychiatry, 15, 292300.
620part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Hinton, L., Franz, C.E., Yeo, G.,& Levkoff, S.E. (2010). Psychosocial factors and caregivers
(2005). Conceptions of dementia in a multi- distress: Effects of familism and dysfunc-
ethnic sample of family caregivers. Journal of tional thoughts Aging and Mental Health, 14,
the American Geriatric Society, 53, 14051410. 193202.
House, J. S., Landis, K. R., & Umberson, D. Manly, J.J.,& Mayeux, R. (2004). Ethnic differ-
(1988). Social relationships and health. ences in dementia and Alzheimers disease.
Science, 241, 540545. In N. B.Anderson, R. A.Bulatao,& B. Cohen
Karlawish, J., Barg, F. K., Augsburger, D., (Eds.), Critical perspectives on racial and eth-
Beaver, J., Ferguson, A., & Nunez, J. (2011). nic differences in health in late life (pp. xxxx).
What Latino Puerto Ricans and non-Latinos Washington, DC:National Research Council,
say when they talk about Alzheimers dis- the National Academies Press.
ease. Alzheimers and Dementia, 7, 161170. Mittelman, M. S., Haley, W. E., Clay, O. J., &
Kavelaars, A., & Heijnen, C. J. (2006). Stress, Roth, D. L. (2006). Improving caregiver
genetics, and immunity. Brain Behavior and well-being delays nursing home placement of
Immunity, 20, 313316. patients with Alzheimer disease. Neurology,
Kelley, K., Reinhard, S. C., & Brooks-Danso, 67, 15921599.
A. (2008). Executive summary:Professional Mittelman, M. S., Roth, D. L., Clay, O. J., &
partners supporting family caregivers. Haley, W. E. (2007a). Preserving health of
American Journal of Nursing, 108(9 Suppl), Alzheimer caregivers: Impact of a spouse
612. caregiver intervention. American Journal of
Keyes, C.L., Shmotkin, D.,& Ryff, C.D. (2002). Geriatric Psychiatry, 15, 780789.
Optimizing well-being: The empirical Mittelman, M. S., Roth, D. L., Coon, D. W., &
encounter of two traditions. Journal of Personal Haley, W.E. (2004a). Sustained benefit of sup-
and Social Psychology, 82, 10071022. portive intervention for depressive symptoms
Knight, B. G., & Sayegh, P. (2010). Cultural in caregivers of patients with Alzheimers
values and caregiving: The updated socio- disease. American Journal of Psychiatry, 161,
cultural stress and coping model. Journal of 850856.
Gerontology, Psychology and Social Science, 65B, Mittelman, M. S., Roth, D. L., Haley, W. E., &
513. Zarit, S. H. (2004b). Effects of a caregiver
Krause, N. (1995). Negative interaction and intervention on negative caregiver apprais-
satisfaction with social support among older als of behavior problems in patients with
adults. Journal of Gerontology, Psychology and Alzheimers disease:Results of a randomized
Social Science, 50B, 5973. trial. Journals of Gerontology B: Psychological
Kreutzer, J. S., Rapport, L. J., Marwitz, J. H., Sciences Social Sciences, 59, P27P34.
Harrison-Felix, C., Hart, T., Glenn, M., & Monahan, P.O., Boustani, M., Alder, C., Galvin,
Hammond, F. (2009). Caregivers well-being J. E., Perkins, A., Healy, P.,...Callahan, C.
after traumatic brain injury: A multicenter (2012). A practical clinical tool to monitor
prospective investigation. Archives of Physical dementia symptoms: The HABC-Monitor.
Medicine and Rehabilitation, 90, 939946. Clinical Interventions in Aging, 7, 143157.
Lee, S., Colditz, G. A., Berkman, L. F., & Napoles, A. M., Chadiha, L., Eversley, R., &
Kawachi, I. (2003). Caregiving and risk of Moreno-John, G. (2010). Developing cultur-
coronary heart disease in U.S.women:Apro- ally sensitive dementia caregiver interven-
spective study. American Journal of Preventive tions: Are we there yet? American Journal of
Medicine, 24, 113119. Alzheimers and Other Dementias, 25, 389406.
Levine, C. (2003). Family caregiving: Current Evercare. (2009). The Evercare Survey of the
challenges for a time-honored practice. Economic Downturn and Its Impact on Family
Generations, 27, 58. Caregiving. National Alliance for Caregiving,
Levine, C., Halper, D., Peist, A.,& Gould, D.A. Bethesda, MD
(2010). Bridging troubled waters: Family National Institutes of Health. (2010). Caring
caregivers, transitions, and long-term care. for a person with Alzheimers disease. [NIH
Health Affairs, 29, 116124. Publication # 09-6173]. March 2010. Bethesda,
Livney, M. G., Clark, C. M., Karlawish, J. H., MD: US Department of Health and Human
Cartmell, S., Negrn, M., Nuez J.,...Arnold, Services.
S.E. (2011). Ethnoracial differences in the clin- Ory, M., Hoffman, R., Lee, J., Tennstedt, S., &
ical characteristics of Alzheimers disease at Schulz, R. (1999). Prevalence and impact of
initial presentation at an urban Alzheimers caregiving: A detailed comparison between
disease center. American Journal of Geriatric dementia and non-dementia caregivers.
Psychiatry, 19, 430439. Gerontologist, 39, 177185.
Losada, A., Marquez-Gonzalez, M., Knight, B.G., Pearlin, L.I., Mullin, J.T., Semple, S.J.,& Skaff,
Yanguas, J., Sayegh, P.,& Romero-Moreno, R. M. M. (1990). Caregiving and the stress
CHAPTER 27. The Role of the Family in the Care and Management of Patients With Dementia 621
process: An overview of concepts and their Schoenmakers, B., Buntinx, F.,& DeLepeleire, J.
measures. Gerontologist, 30, 583594. (2010). Supporting the dementia family care-
Pinquart, M.,& Sorensen, S. (2003). Differences giver:The effect of home care intervention on
between caregivers and non-caregivers in general well-being. Aging and Mental Health,
psychological health and physical health: 14, 4456.
A meta-analysis. Psychology and Aging, 18, Schulz, R.,& Martire, L.M. (2004). Family care-
250267. giving of persons with dementia:Prevalence,
Raveis, V.H. (2004). Psychosocial impact of spou- health effects, and support strategies.
sal caregiving at the end-of-life: Challenges American Journal of Geriatric Psychiatry, 12,
and consequences. Gerontologist, 44(Special 240249.
Issue 1), 191120. Shaw, S. A. (1997). Modern psychoanalytic
Raveis, V. H., Pretter, S., & Carrero, M. (2010). approach to caregiver support group. Group,
It should have been happening to me:The 21, 159174.
psychosocial issues older caregiving mothers Sheets, C., & Mahoney-Gleason, H. (2011).
experience. Journal of Family Social Work, 13, Caregiver support in the Veterans Health
131148. Administration: Caring for those who care.
Reinhard, S.C., Brooks-Danso, A., Kelley, K.,& Generations, 34, 9298.
Mason, D. J. (2008). Editorial: How are you Sterritt, P. F., & Pokorny, M. E. (1998).
doing? American Journal of Nursing, 108(9 African-American caregiving for a relative
Suppl), 45. with Alzheimers disease. Geriatric Nursing,
Roth, D.L., Mittelman, M.S., Clay, O.J., Madan, 19, 127128, 133134.
A., & Haley, W. E. (2005). Changes in social Talley, R.C.,& Crews, J.E. (2007). Framing the
support as mediators of the impact of a psy- public health of caregiving. American Journal
chosocial intervention for spouse caregiv- of Public Health, 97, 224228.
ers of persons with Alzheimers disease. Thompson, R. L., Lewis, S. L., Murphy,
Psychology and Aging, 20, 634644. M. R., Hale, J. M., Blackwell, P. H., Acton,
Roth, D.L., Perkins, M., Wadley, V.G., Temple, G. J.,...Bonner, P. N. (2004). Are there sex
E.M.,& Haley, W.E. (2009). Family caregiv- differences in emotional and biological
ing and emotional strain: Associations with responses in spousal caregivers of patients
quality of life in a large national sample of with Alzheimers disease? Biological Research
middle-aged and older adults. Quality of Life for Nursing, 5, 319330.
Research, 18, 679688. Toseland, R. W. (1995). Group work with the
Saban, K.L., Sherwood, P.R., DeVon, H.A.,& elderly and family caregivers. New York,
Hynes, D.M. (2010). Measures of psychologi- NY:Springer.
cal stress and physical health in family care- University of Washington Medical Center.
givers of stroke survivors:Aliterature review. (2007). Culture clues. Retrieved April 2013,
Journal of Neuroscience Nursing, 42, 128138. from http://depts.washington.edu/pfes/
Sayegh, P., & Knight, B. G. (2010). The effects CultureClues.htm.
of familism and cultural justification on the Valle, R. (1998). Caregiving across cul-
mental and physical health of family care- tures: Working with dementing illnesses and
givers. Journal of Gerontology: Psychological ethnically diverse populations. Washington,
Sciences, 66B, 314 DC:Taylor& Francis.
28
Ultimately, all patients with dementing ill- The lack of certainty about the underlying
nesses will lose their mental competence. diagnosis and rate of progression should not
Competence for more subtle and demanding deter the physician from beginning the dia-
tasks and decisions will be lost first. At the logue about competency. The mere fact that
same time, patients with dementing illnesses there is a substantial risk of losing compe-
usually will lose many elements of self- tency should be sufficient to raise the issue.
awareness, including awareness of their areas At the outset the physician should clarify
of incompetence, and will lose their ability his or her role in the process of diagnos-
to conform their behavior to adjust even for ing and managing each specific patient and
those deficits they acknowledge. This con- should resolve any ambiguity about that
flict can lead to significant challenges for role. The physician should know (1)whether
physicians and other professionals involved the patient will authorize him or her to talk
in dementia care. Competency issues can with family members, which ones he or she
be extremely emotional ones for patients may talk with, and whether any subjects are
and caregivers; clinicians must remain calm off limits; (2)whether other professionals are
and rational in the face of families emo- involved, including lawyers and others who
tions. Basing assessments and recommenda- might provide counsel and advice to family
tions on clear principles helps; a particularly members; and (3)whether there are any legal
important principle is beginning the discus- proceedings contemplated or already under
sion of competency issues as early as possible way. If other professionals are involved, the
after the diagnosis of a dementing disease physician must know whether the patient
preferably before critical competencies are will allow all professionals involved to com-
lost and while the patient retains sufficient municate freely with one another about the
metacognition, executive function, and cred- patients case. If there are legal proceedings
ibility within the family to participate fully in in the offing, the physician should know
the process. At this stage the patient may be whether he or she will be expected to provide
diagnosed as having mild cognitive impair- testimony, in what context, and on whose
ment or questionable/very mild dementia. behalf.
622
CHAPTER 28. Mental Competence and Legal Issues in Dementia Care 623
When a patient with acute appendicitis agrees Competency is a legal judgment that is based
to surgery, the patients consent (or even pas- in large part on clinical observations and
sive assent) will be accepted as valid even if their interpretation. Neuropsychological
the patient suffers from delirium or demen- test results supplement clinical observations
tia. In the same situation, refusal of surgery and aid in their interpretation, but they do
would be presumed incompetent unless it not substitute for a clinical inquiry more
could be shown that the patient understood specific to the individual patients situation.
the proposed surgery and its alternatives, Moreover, the context of neuropsychologi-
understood the potential consequences of cal testing is standardized, but the context of
refusing surgery, understood the implica- real-life decision making is not; real decisions
tions of those consequences, and could are made in a context that can have more cues
explain how, considering the implications, but also more stress and potential distraction
his or her decision was rational. A patient than a neuropsychologists office. Benefits of
giving competent refusal might point out neuropsychological testing in assessing and
that although untreated appendicitis could managing competency issues are discussed
lead to life-threatening peritonitis, he or she later in the chapter.
had had severe adverse reactions to anesthe-
sia in the past that made surgery especially
dangerous, that initial treatment with antibi- Competency-Related Issues Should
otics might obviate the need for surgery, and Be Addressed as Early as Possible
so on. The ability to assemble such facts and
marshal such arguments would be unneces- When a patient is diagnosed with mild cogni-
sary if the recommendation for surgery were tive impairment or mild dementia, it is likely
accepted. that he or she is still competent in many areas.
In particular, patients may be competent to
designate who they would like to make deci-
sions for them if they become incompetent
Competency Can Fluctuate later. Designating proxy decision makers
through health care proxies, durable pow-
Fluctuating deficits are the rule in demen- ers of attorney, and provisions in trust docu-
tia. Drugs, acute general medical illness, ments can avoid legal emergencies in which
pain, lack of sleep, stress, and depression the medical or financial decisions are press-
all can exacerbate deficits that impair ing and there is no one with clear authority
decision-making competence. Fluctuating to act on the patients behalf. Also, as will be
cognitive deficits can lead to intermittent or discussed further, patients with professional
state-dependent decision-making incompe- responsibilities should be advised to relin-
tence. When they do, the physician should quish them before their cognitive deficits
seek informed consent for medical proce- lead to expensive, embarrassing, and some-
dures during intervals of better function, times tragic mistakes.
designing the consent to be durable if the
patient subsequently becomes delirious or
otherwise incapable of making a rational Communication Should Be Clear,
decision. Soon after a diagnosis of dementia Redundant, and Multimodal
or mild cognitive impairment is made, the
potential for fluctuating competency should Issues of competency can be subtle for phy-
be pointed out; it may help patients and fami- sicians and lawyers, even more so for lay
lies recognize the importance and urgency of people. Results of a competency assessment
executing a durable power of attorney and a should be communicated in writing as well
health care proxy. as explained orally, and patients and families
CHAPTER 28. Mental Competence and Legal Issues in Dementia Care 625
can be directed to a range of resources, includ- command is given in a soft voice and slowly
ing support groups, Websites, and books. if the command is given in a loud voice). The
An individual practice can develop hand- Executive Interview Test (Royall, Mahurin,&
outs customized for the specific populations Gray, 1992; Royall et al., 2004) is a concise,
served by the practice and for the approaches practical survey of executive function that
to testing and evaluation the practice most is intermediate in length between a typical
often uses. office examination and neuropsychological
testing; it takes 1015 minutes to do and can
be administered by a nurse or technician.
Formal Legal Proceedings to Establish Metacognition and awareness of noncogni-
Incompetence Are Not Always Necessary tive functional deficits involve the same brain
systems. Both can be assessed by compar-
When medical, financial, or practical deci- ing the patients self-reported performance
sions can be made for the patient, the substi- with the performance observed on exami-
tute decision maker is benign and trusted, the nation and the performance reported by
decision is a reasonable one, and the patient family members or other collateral sources.
assents (or does not object), the patients A review of instrumental activities of daily
competency to decide or to agree is rarely living such as shopping, transportation, tak-
challenged. When any of these factors is not ing medications, keeping appointments, and
present, or when the decision involves a great managing money may yield markedly differ-
deal of money or substantial medical risk, a ent answers when asked of the patient than
formal legal proceeding should be consid- when asked of a caregiver.
ered. Clinicians practicing in a hospital setting Metacognition has two dimensions: the
can consult the hospitals risk management feeling of knowing and confidence in ones
department or hospital counsel for assistance knowledge. Metacognition requires func-
with making the judgment. Greater formality tioning of the dorsomedial frontal region,
and rigor in competency assessment is neces- especially in the right hemisphere, and the
sary when there is disagreement, conflict, or right parietal lobe. In general, metacognition
mistrust between concerned parties. is more impaired in cortical dementias than
in subcortical dementias. Certainty about
wrong answers and gross denial of deficits is
Executive Function and Metacognition a great threat to competent decision making;
it is more likely to occur early in cases with
Adequate executive function is a prerequisite prominent right hemisphere involvement.
for successful goal-directed activity, for safe Office cognitive testing affords a natural
independent living, and for acceptable per- opportunity to assess the patients awareness
formance of complex activities like driving, of his or her cognitive deficits. Comparison of
managing money, or practicing a profession. directly measured and self-assessed deficits
Dementias of several different etiologies, can be quantitated (Williamson et al., 2010),
including Alzheimers disease but most but a more qualitative approach provides
consistently frontotemporal dementia, can additional information useful in competency
impair executive function disproportionately assessment. Before testing, ask the patient
early their clinical course. It is thus important how he or she thinks he or she will do on tests
to assess executive function adequately at the of memory and concentration and other cog-
time dementia or mild cognitive impairment nitive abilities. Separately, ask family mem-
is diagnosed. If neuropsychological testing bers whether the patients behavior reflects
is not done, the office-based testing done by any adjustment for cognitive impairments.
the neurologist or psychiatrist should screen After the test but before telling the patient the
for executive dysfunction using procedures results, ask the patient again to assess his or
like the Clock Drawing Test, the Luria hand her performance. After giving the results, ask
sequence, Trail Making B, or presentation of the patient if he or she agrees or disagrees,
conflicting stimuli (e.g., asking the patient and note whether the patient acknowledges a
to raise his or her right arm quickly if the poor performance but excuses it or minimizes
626part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
its import. If the patient does not accept the to environmental changes and the use of
presence of a cognitive deficit during the cues and mnemonic aids. They also will be
office visit, he or she should be given a written open to accepting help with activities and
report to review at home and be asked again decisions they find difficult. Patients who
about awareness of deficits on the next visit. deny deficits are at the highest risk for unsafe
In this way patients can be placed on a con- or self-destructive actions. These relation-
tinuum of self-awareness that progresses from ships apply at all levels of overall cognitive
full appreciation of deficits to frank denial. impairment, but they deserve special atten-
Some points on the continuum are as follows: tion in the earlier stages of dementia, when
the patients life makes frequent demands on
1. Knowing they have cognitive deficits, cognitive functions that have declined.
appreciating their implications, and
making adjustments to their behavior to
account for them; The Role of Neuropsychological Testing
2. Knowing they have cognitive deficits,
appreciating their implications, but not Neuropsychological testing is not required to
modifying their behavior; establish competency or lack of competency
3. Knowing they have cognitive deficits but to make a specific decision in a specific con-
not appreciating their implications; text. However, results of neuropsychological
4. Acknowledging cognitive deficits after testing can be useful in several important
failing a test but before being told of the ways in managing competency-related issues
test results, and then showing apprecia- in dementiacare:
tion of their implications;
5. Acknowledging cognitive deficits after 1. Clear-cut abnormalities on neuropsycho-
failing a test but before being told of the logical testing can be used in conjunction
test results, but excusing their perfor- with imaging results and other biomark-
mance or regarding the results as insig- ers in convincing a patient or his or her
nificant or irrelevant; family that the patient is indeed cogni-
6. Acknowledging cognitive deficits only tively impaired, that competencies even-
after being confronted with test results tually will be lost, and that the problems
and their significance by the physician; associated with a loss of competency
7. Acknowledging deficits after extensive should be anticipated and mitigated by
persuasion and review of a written report preventive actions.
of performance; and 2. Serial neuropsychological testing indicat-
8. Completely denying deficits despite ing the pace of dementia progression can
efforts at persuasion and confrontation aid in suggesting a time frame for action
with evidence. in advance of incompetence to perform
a specific function or make a specific
Metacognition can be formally tested by decision.
neuropsychologists and by occupational 3. A neuropsychological profile suggesting
therapists. Some neuropsychological tests disproportionate loss of executive func-
of memory explicitly incorporate questions tion and/or lack of awareness of cognitive
about how sure the patient is of his or her deficits can be helpful in explaining why
answer. In addition, the neuropsychologist a patient who looks relatively intact may
can make and record systematic observations already lack competency to make major
of the patients comments and behavior as the financial decisions, to drive safely, or to
testing proceeds and deficits are uncovered. validly change his or her will. Test results
Occupational therapists can perform struc- carry weight in legal proceedings; when
tured assessments of performance in instru- conflicting opinions of experts appear to
mental activities of daily living and compare cancel one another, evidence from testing
them with patients self-assessments of the can tip the balance.
same functions. 4. A neuropsychological profile can sug-
Patients with higher levels of self-awareness gest specific areas of potential incom-
will be more open to memory training and petency. Some neuropsychological tests
other cognitive rehabilitation activities and are face valid and persuasive in this
CHAPTER 28. Mental Competence and Legal Issues in Dementia Care 627
this situation the physician should point out the neuropsychological deficits that might
that the patient has an illness that gradually affect the patients financial judgments, tes-
will affect his or her financial ability and sug- tamentary capacity, and susceptibility to
gest that changes be made before the patient undue influence. It would be within those
loses his or her money. The specific emphasis professionals scope to elicit and implement
in the appeal to the patient can take advan- the patients broader intentions for his or her
tage of the patients expressed concerns; assets while addressing the patients needs
either a fear of being cheated or a concern to to pay for his or her care and provide for
leave a legacy can motivate reconsideration of dependents. If the physician suspects that the
financial arrangements. The changes must be patients advisers are not sufficiently familiar
made while the patient is competent to make with the nuances of dementiain particular,
them; since the dementing illness is progres- the potential for disproportionate impair-
sive, there is no time to lose. Competence ment of executive function and metacog-
to change financial arrangements requires a nition, and the potential for a new onset of
basic understanding of what ones assets are, paranoid thinking or depression that might
what bills one is responsible for paying, who further impair judgmenthe or she should
would control the assets following a change, seek an opportunity to educate the advisers.
and an appropriate rationale for choosing
that person. Apatient can retain this compe-
tence even after he or she has lost the abil- Dementia and Driving
ity to handle financial details such as paying
bills on time and not paying the same bills Patients with moderate or severe demen-
twice. tia cannot drive safely, and if they are cur-
When a reasonable prediction can be made rently driving, they should be unequivocally
about the needs for care in the future and advisedboth orally and in writingto
what they might cost, and when the patient stop driving immediately. In states where
and family have some combination of assets reporting of such patients to the licensing
and insurance that could cover the costs, they authority is mandatory, this should be done
can be advised to set aside the money that without delay. When reporting the patient is
will probably be needed for care and protect not permitted without the patients consent,
it from unplanned withdrawals. Legal coun- the physician should ask the patients con-
sel usually will be needed to do this. sent to make the report and should, unless
As soon as possible after the demen- the patient objects, advise family members or
tia diagnosis, the patient should be asked other caregivers of the recommendation.
whether there is someone, typically a family Since failing to make a required report on
member, whom they would trust to handle a driver with dementia is a major legal risk,
his or her money when the patient is no lon- physicians should know whether their state
ger able to do so. If the answer is other than has mandatory reporting of dementia and, if
an unqualified yes, someoneoften a social so, what the criteria are for making the report.
worker or family therapistshould investi- In some states the diagnosis of Alzheimers
gate the reason and determine whether the disease would trigger mandatory report-
trust issue within the family is resolvable or ing, even if the disease process were at an
whether an external trustee might be needed early stage and causing only mild cogni-
to protect the patients assets. tive impairment. The contemporary view of
When the patient has substantial assets separating the clinical syndrome from the
well beyond those needed to ensure his or presumed neuropathology has not yet pen-
her own care, it is likely that there is already etrated motor vehicle licensing agencies. For
a lawyer, banker, and/or other professional the physicians legal protection the patients
involved in creating and implementing an medical records must make such distinctions
estate plan. Here the physician can per- clearly, in the unfortunate event that a patient
formas always with the patients con- with mild cognitive impairment continues to
senta valuable service by explaining to the drive and is involved in a crash.
patients advisers the patients current men- Advising patients with mild cognitive
tal capabilities, the diagnosis of a degenera- impairment or mild dementia about driving
tive disease, the probable clinical course, and is especially challenging because for many
630part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
medication side effect. In that case the patient 3. Testing of driving performance in the vir-
should be advised to abstain from driving tual reality of a driving simulator. Driving
until further evaluation of his or her driving simulation can present the patient with
ability can be done. Falls getting into or out unexpected events and emergency situ-
of a car suggest problems with weakness or ationsthings a patient with dementia
coordination of the legs that could interfere may find difficult to manage, and things
with a timely response to a traffic situation. that cannot be incorporated into an
There are several ways in which the extent on-road test. The best validated and most
of increased crash risk can be estimated: widely researched driving simulator is
the STSIM system (see the developers
1. Office-based testing or neuropsychologi- Web site, http://www.stsimdrive.com,
cal testing of cognitive functions known to for details). The base configuration of the
be associated with driving performance and system includes 80 different driving sce-
crash risk, such as reaction time, visual per- narios; the software counts crashes and
ception, and ability to read and interpret road near misses as well as driving irregulari-
signs. A few of the specific test perfor- ties such as lane departures.
mances that have been explicitly linked to 4. Automated analysis of black box (telematics)
increase crash risk include recalling two recordings of actual driving behavior. Systems
or fewer of four words on delayed recall, for recording and analyzing driver behav-
a Trails B time of greater than 180 seconds, ior currently are used by some automobile
and a time outside of normal limits for insurance carriers for rate setting, and by
navigating a maze on a computer screen motor vehicle fleet operators to monitor
(Anderson et al., 2012; Emerson et al., their professional drivers. Current tech-
2012; Ott etal., 2008). The Clock Drawing nology can detect and record several of
Test, scored on a 7-point scale with a cut- the driving problems commonly seen in
off for abnormality of four or less, may be patients with dementia, including lane
a highly specific screening test for unsafe departures, excessive variation in speed,
driving (Freund, Gravenstein, Ferris, inappropriately slow driving, sudden
Burke,& Shaheen, 2005). In a study of 119 stops, and abrupt turns. Units with GPS
older drivers evaluated with a driving functionality can establish whether the
simulator, the test was 64.2% sensitive and driver got lost on a familiar route, even if
97.7% specific in identifying unsafe driv- the driver eventually found his or her way
ers. The interrater reliability of the 7-point home. Specialized black box recording
scale for scoring the CDT was 0.95 in their analysis for evaluating drivers with mild
study. The combination of low cost, brief cognitive impairment or early dementia
administration time, and high reliability is not yet commercially available, but it is
is impressive, but the results need to be likely to appear given the ever-increasing
confirmed on a larger and more diverse scale of the issue.
sample of older drivers. 5. On-road testing by an examiner specializing
2. Testing of the Useful Field of View (UFoV), in assessing the safety of older drivers and
a standardized, computer-administered test people with diseases that can affect driving
of visual attention. It measures the visual ability. Aroad test by a specialized exam-
information that can be acquired in a brief iner will be more sensitive than a road test
glance, with or without a distracting con- for drivers license renewal; the former
dition. The developers of the test present will look for potentially risky behavior that
evidence that a reduction of 40% or more would not in itself cause the driver to fail
in UFoV is associated with a seven-fold the test for licensure.
increase in crash risk. The same criterion
is 89% sensitive and 81% specific in pre- In addition, the patient should have tests of
dicting that an older individual will have hearing and vision if these were not recently
one or more motor vehicle crashes if he done and passed. However, it has been estab-
or she continues to drive. (See the devel- lished that poor visual acuitythe visual func-
opers Web site, http://www.visuala- tion tested for licensing of driversdoes not
wareness.com, for a summary of research predict motor vehicle crashes in older drivers.
findings and bibliography.) Glare sensitivity, loss of peripheral vision, and
632part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
diminished useful field of view all are associ- For those patients who continue to drive,
ated with a significant increase in crash risk. crash risk can be mitigated somewhat by
The evidence for these relationships is direct; specifying circumstances under which the
it comes from a study where baseline visual patient should not drive. Also, patients
testing was performed in 1,801 drivers aged should be strongly cautioned against using
6584years; state motor vehicle crash records a mobile phone while driving. Crash risk
were then reviewed a specific time point for any driver increases with mobile phone
24years later, by which point 120 drivers had use. The incremental risk for drivers with
been involved in crashes (Rubin etal., 2007). mild cognitive impairment or mild dementia
On-road testing is not the gold standard of is greater because of their difficulty dealing
driving evaluation. While failing a road test with distractions, redirecting attention, and
implies impaired driving performance under processing conflicting stimuli.
the conditions of the test, road test perfor-
mance can be worsened by anxiety or fatigue
and may not be representative of the patients Testamentary Capacity
performance in the particular situations in
which he or she usually drives. On the other When patients with dementia make wills
hand, passing a road test does not imply that disinherit natural heirs or give large
that a patient could cope with the additional sums to unrelated caregivers, their wills are
demands of night driving, bad weather, or often contested. When the assets involved
heavy traffic, and it does not imply that the are substantial, the contests can lead to
patient will respond appropriately and in expensive and emotionally stressful litiga-
time to an unexpected event like a child run- tion. In this litigation physicians are called
ning across the street in front of the car. The to testify regarding the patients mental
assessment of these capabilities is better done state at the time of writing (or rewriting) his
in a driving simulator. The special value of or her will. There are two implications for
road tests is that failing one can get the unsafe physicians treating patients with dementia.
driver off the road immediately. The first is that shortly after the diagnosis
The expense and inconvenience of road of dementia (or even a dementing disease
testing or testing in a driving simulator can be with the current syndrome of mild cognitive
avoided if the results of cognitive testing or impairment) the physician should encourage
UFoV testing are sufficiently bad to be highly the patient to review his or her willor to
specific for unsafe driving. When it becomes make a will if one is not on fileand make
widely available, black box recording and any desired changes before the disease pro-
automated analysis of actual driving behav- gresses. If there already are obvious defi-
ior may be an efficient method for evaluating cits in memory or judgment, special pains
driving competence that offers the advantage should be taken to establish and document
of not requiring a testa situation that may the ingredients of testamentary capacity.
evoke the patients anxiety or potentially his This activity can beand usually should
or her resistance. bea separately scheduled patient encoun-
In persuading a patient to discontinue ter, carried out either by the principal phy-
driving, it is useful to identify any noncogni- sician or by a neurologist or psychiatrist
tive reason why the persons driving might with an interest in dementia or experience
be unsafe. In addition to impaired hear- with competency assessment. The interview
ing or vision (especially peripheral vision, should establish that the patient:
glare intolerance, or UFoV), decreased neck
mobility, diminished limb strength, and falls 1. Knows what a will is;
getting into and out of a car should be con- 2. Knows what his or her assets are;
sidered. As to the importance of leg strength 3. Knows the people who have a reasonable
and balance, patients who require more than claim to be beneficiaries;
10 seconds to walk 10 feet, turn around, and 4. Understands the impact of a particular
come back have double the rate of crashes. distribution of assets;
Driving cessation for a noncognitive reason is 5. Does not have delusions or other psy-
face saving for the patient and may be more chotic phenomena that would affect the
readily accepted. decisions made; and
CHAPTER 28. Mental Competence and Legal Issues in Dementia Care 633
6. Can express his or her wishes clearly and the prevalence of dementia increases, reflect-
consistently. ing changes in the age distribution of the
population. A study of voting-related com-
If the patients decisions seem likely to evoke petency in patients with Alzheimers disease
family conflict, video recording of the inter- suggested that a general understanding of
view is advised. If the assets are modest and the nature and effect of voting and the abil-
there is nothing unusual about the will, it is ity to express a choice usually are preserved
sufficient to document these basic criteria for in mild dementia and often are preserved
testamentary capacity in the clinical record. in moderate dementia. However, as demen-
As with other competencies, criteria for tes- tia progresses, patients are less able to rea-
tamentary capacity are interpreted more lib- son about political issues or to understand
erally when less is at stake and the choices the likely personal implications of election
made are typical ones. results (Appelbaum, Bonnie, & Karlawish,
The retrospective signs of potential testa- 2005). While in practice citizens compe-
mentary incapacity include the following: tency to vote is not verified, the issues are
similar to those of testamentary capacity.
1. Radical change from previous wills; One might grant a lifelong Democrat or life-
2. Changes that disinherit natural heirs such long Republican a right to vote for the party
as a spouse or a child; he or she has always supported. A sudden
3. Changes made reflecting prob- change in voting behavior inconsistent with
able delusions, misperceptions, or long-held opinions would raise the issue of
misunderstandings; competency to vote (or perhaps of dyslexia
4. Changes that disregard the testators per- or dyspraxia interfering with marking a bal-
sonal history and reflect only the persons lot or operating a voting machine in a way
current circumstances; and consistent with the patients intentions).
5. Changes suggesting undue influence, such
as an unusually large bequest to a recent
caregiver who is not related and who was Dementia and Firearm Safety
not named at all in the previous will.
In the United States 17 million people
When these signs are present, a judge might over the age of 65 own one or more guns
invalidate the will unless there is positive evi- (Mertens & Sorenson, 2012). Eighty percent
dence that the testator was fully competent at of all homicides committed by persons over
the time of making the new will. If the phy- 65 are committed using guns, as are more
sician learns that the patient with dementia than half of all suicides. Impairments in
plans to revise his or her willor that the judgment and impulse control, mood dis-
patient has recently done sothe physician turbances, and paranoid thinking associated
should suggest a special interview assessing with dementia increase the risk of violence
the elements of testamentary capacity, point- in general and gun violence in particular.
ing out that given the diagnosis the patients For this reason patients with dementiaor
will might be challenged and that such an even mild cognitive impairment thought to
interview will be helpful in ensuring that be due to a progressive degenerative brain
the patients valid intentions are carried out. diseaseshould not have access to firearms;
Gutheil (2007) offers advice regarding pitfalls at the very least firearms in their possession
in the assessment of testamentary capacity, should be disabled.
specifically emphasizing that neither a neu- A study conducted in a university hospi-
rological or psychiatric diagnosis nor the tal memory clinic found that 60% of patients
presence of cognitive impairment is in itself with dementia had a firearm in the home. In
evidence for testamentary incapacity. 45% of cases the family knew that the fire-
arm was kept loaded and in another 38% the
family did not know whether the gun was
Dementia and Voting loaded (Spangenberg, Wagner, Hendrix, &
Bachman, 1999). These statistics do not only
Participation of people with mild to moderate imply a risk of gun violence perpetrated by
dementia in voting has increasing salience as the patient; for example, an unlocked and
634part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
loaded gun might be appropriated and mis- sides in a legal dispute. Also, some clinicians
used by a visiting grandchild. have strongly held biases toward a more pro-
The first step in mitigating gun-related tective attitude or a more libertarian one.
risk is recognizing the problem. Every ini-
tial evaluation of a dementia patient should
include inquiry about firearms in the home. Dementia and End-of-Life Planning
If patients are not able or willing to answer
questions about firearms, they should be Ultimately patients with dementia will die,
asked of their caregivers. Interventions to either because they develop a general medi-
remove, disable, or securely lock up guns are cal condition such as pneumonia or because
more likely to succeed early in the course of they stop eating and drinking. If patients with
illness when some insight and judgment are dementia receive aggressive treatment for
preserved, or late in the course where impair- general medical conditions, and receive tube
ments in memory and praxis would make it feedings when they stop eating and drink-
hard for a patient to defeat simple measures ing, they can live on for months or even years
like locking the weapon in a gun safe and after they have lost the ability to participate
securing the key, or removing ammunition actively in life. Many people say that if they
from the home. lose their basic mental capacities, they would
In situations where there is immediate prefer not to live and not to be kept alive by
danger related to gunsas when a patient artificial means. However, confronted with
with dementia has paranoid delusions and a very specific and treatable condition like
threatens to use the gun against an alleged pneumonia, the patients spouse or child may
persecutor, or when a gun-owning patient find it hard to direct that treatment be with-
with dementia is depressed and suicidal held, and the patients physician may find it
state mental health laws can be invoked. difficult to withhold the treatment. For such
A physician with knowledge of the situa- reasons patients write living wills and desig-
tion, not necessarily a psychiatrist, can call nate health care proxies. When a patient with
upon the police to remove the patient from mild cognitive impairment or mild dementia
the home for emergency psychiatric evalua- chooses a health care proxy, or reviews his or
tion. A caregiver can remove the guns from her choice of a health care proxy, the physi-
the home and secure them while the patient cian should advise the patient to choose a
is away being evaluated. proxy who would feel comfortable about
implementing the patients advance direc-
tive. In some cases the spouse, who is the
Why Assessors of Competence May Disagree default substitute decision maker, would be
a poor choice for health care proxy, because
Skilled evaluators may disagree about the spouse may know in advance that he or
whether a particular patient is competent she would be unwilling to say no to treating
to make a particular decision or undertake an infection or to giving tube feedings even if
a specific activity. Such disagreements arise it was the patients expressed wish.
for several reasons. Competence itself is con- When implementing advance directives,
text dependent and can fluctuate over time, it is worth considering that what patients
so two assessments at different time points think they would want under a given set of
may begin with different data. Context circumstances is not necessarily what they
dependency is more important when there would want if those circumstances came to
is greater impairment of executive func- pass and they were competent to decide at
tion. Assessors may differ in the way they the time. A health care proxy tasked with act-
test competence. They may apply different ing in the interest of the patient might in fact
thresholds for determining that a patient is determine that the choices indicated in the
competent. advance directive do not accurately reflect
Differences between assessors conclusions what the patient would want at the given
usually can be resolved when the reason for time if he or she were competent to say. In
them is understood. In exceptional cases dis- that case is the proxys obligation to follow
agreements are driven by conflicting motives, the patients advance directive or to use his
as when two experts are engaged by opposite or her judgment based on full knowledge of
CHAPTER 28. Mental Competence and Legal Issues in Dementia Care 635
the patients pre-illness personality and the the patient a deep thinker who was concerned
current medical and social circumstances? about the meaning of life and would regard
In many jurisdictions law permits a health years spent in a nursing home as empty and
care proxy to make decisions contrary to the meaningless even if they were pleasant? Did
patients advance directives, i.e., the latter are the patient prefer to spend his remaining
not binding. One resolution is for the health assets putting his grandson through college
care proxy to follow the advance directive and medical school rather than paying for
unless there is a compelling reason to do long-term care in a facility? Would his view
otherwise, and for the proxy to discuss the of paying for his nursing home care change if
deviation from the advance directive with a the grandson inherited money from someone
disinterested (and unprejudiced) third party. else and no longer needed help with tuition?
Consider the following situation. A The decision to disregard an advance
90-year-old widower with mild dementia directive is a weighty one. In a situation
would prefer to die rather than live in a nurs- where a health care proxy thinks the patients
ing home and no longer be able to manage advance directive no longer makes sense, the
his own affairs. He designates his son as his physician should direct the health care proxy
health care proxy and completes an advance to a third party to help with thinking through
directive stating he wants no extraordinary the issues. It is always helpful, and it is essen-
measures to be taken to keep him alive, spe- tial if the health care proxy has a financial
cifically mentioning ventilators. Over the next interest in the decision to be made.
year his dementing illness proceeds. He must The considerations just outlined can be
relinquish control over his assets to a trustee. anticipated in the design of an advance direc-
He can no longer maintain his apartment. He tive. The patient can state the assumptions
loses weight because he eats poorly, and he behind the advance directive and ask the
becomes incontinent and confused at night. health care proxy to reconsider the directive
Finally he grudgingly accepts admission to a if those assumptions are no longer true. The
nursing home after intensive lobbying by his health care proxy can be directed to discuss
children. He is admitted to a nursing home, any potential deviation from the directive
where to his surprise he is happy:He makes a with a disinterested third party such as a
couple of friends. He likes the food and gains family friend or clergyman.
weight. He is relieved to be rid of oppressive
responsibilities and does not care about los-
ing control over many aspects of his life. Finding and Developing Resources
A few months later he develops severe
pneumonia with respiratory failure. He needs Physicians who see a significant number
intubation and ventilation along with antibi- of patients with dementia in their practice
otics to have a good chance of survival. He often will find that they need the help of
is delirious from fever and hypoxia. Should other professionals with specific expertise.
his son honor his prior directive or contradict Developing a panel of such professionals and
it by opting for aggressive treatment on the using them consistently makes care more
grounds that the patient was happy with his efficient. Periodic conversations with them
life in the nursing home immediately prior to can touch on the issues of several different
the acute illness, and that the patient would patients. Also, physicians can make sure
have written a different advance directive if that they are up to date on dementia and its
he knew at the time how life in the nursing care, and aware of any special features of the
home was going to turn out? patient population they treat (e.g., cultural
In this case the health care proxy should or religious issues). A physician who regu-
draw on his full knowledge of the patient and larly refers patients to the same lawyer for
not just his expressed intentions at the time help with estate planning can educate that
he signed the advance directive. At that time lawyer about such things as executive func-
was the patient depressed and passively sui- tion and metacognition, and the lawyer can
cidal? Did he have a realistic idea about life educate the physician about such things as
in a nursing home, or was his idea based on how trusts operate when a trustee or benefi-
frightening newspaper stories about neglect ciary develops impaired judgment in finan-
and abuse in long-term care institutions? Was cial matters.
636part iii Assessment, Diagnosis, and Comprehensive Treatment:From Principles to Practice
Martin, R., Griffith, H. R., Belue, K., Harrell, Rubin, G. S., Ng, E. S. W., Bandeen-Roche, K.,
L., Zamrini, E., Anderson, B.,...Marson, Keyl, P. M., Freeman, E. E., & West, S. K.
D. (2008). Declining financial capacity in (2007). A prospective population-based study
patients with mild Alzheimer disease:Aone of the role of visual impairment in motor
year longitudinal study. American Journal of vehicle crashes among older drivers: The
Geriatric Psychiatry, 16, 209219. SEE study. Investigations in Ophthalmology and
Mertens, B., & Sorenson, S. B. (2012). Current Visual Science, 48, 14831491.
considerations about the elderly and fire- Spangenberg, K. B., Wagner, M. T., Hendrix,
arms. American Journal of Public Health, 103(3), S., & Bachman, D. L. (1999). Firearm
396400. presence in households of patients with
Ott, B. R., Festa, E. K., Amick, M. M., Grace, Alzheimers disease and related demen-
J., Davis, J. D., & Heindel, W. C. (2008). tias. Journal of the American Geriatric Society,
Computerized maze navigation and on-road 47(10), 11831186.
performance by drivers with dementia. Journal Vaughan, L.,& Giovanello, K. (2010). Executive
of Geriatric Psychiatry Neurology, 21(1), 1825. function in daily life: Age-related influences
Royall, D.R., Mahurin, R.K.,& Gray, K. (1992). of executive processes on instrumental activi-
Bedside assessment of executive dyscon- ties of daily living. Psychology and Aging,
trol:The Executive Interview (EXIT25). Journal 25(2), 343355.
of the American Geriatric Society, 40, 12211226. Williamson, C., Alcantar, O., Rothlind, J.,
Royall, D.R., Palmer, R., Chiodo, L.K.,& Polk, Cahn-Weiner, D., Miller, B. L., & Rosen,
M. J. (2004). Declining executive control in H. J. (2010). Standardized measurements of
normal aging predicts change in functional self-awareness deficits in FTD and AD. Journal
status: The Freedom House study. Journal of of Neurology, Neurosurgery and Psychiatry,
the American Geriatric Society, 52, 346352. 81(2), 140145.
Index
posterior cortical atrophy (PCA), 212 fragile X-associated tremor ataxia syndrome
progressive multifocal leukoencephalopathy (FXTAS), 337
(PML), 322 Herpes Simplex Encephalitis, 306
progressive supranuclear palsy (PSP), 224 limbic encephalitis, 307
rapid onset of late-life neurodegenerative Niemann-Pick Disease Type C, 339340
disorders, 346 in paramedian artery infarction, 50
subacute sclerosing panencephalitis (SSPE), polycystic lipomembranous osteodysplasia
324 with sclerosing leukoencephalopathy
Susac Syndrome, 327 (PLO-SL), 345
vascular cognitive impairment (VCI), 264 PSP-RS (Richardsons Syndrome), 222
X-linked adrenoleukodystrophy (X-ALD), qualitative evaluation by, 468469
332 sarcoidosis, 317
malaise, 316 Susac Syndrome, 327
mammillothalamic tract (MMT), 41, 53 Wilsons Disease, 345
management X-linked adrenoleukodystrophy (X-ALD),
Alzheimers disease and dementia, 390392, 332
391t Memory Impairment Screen (MIS), 476t,
dementia with Lewy bodies (DLB), 238240 477478
Parkinsons Disease Dementia (PD-D), memory systems, 108121, 109t
249251 about, 108
posterior cortical atrophy (PCA), 214217 disruptions in, 110t
Manes, F., 186 episodic memory, 108117
mania improving memory in dementia, 120121
meningoencephalitis, 315 priming, 119
neurosyphilis, 314, 315 procedural memory, 118119
MAPT gene, 223 semantic memory, 117118
Marchiafava Bignami Disease, 303304 simple classical conditioning, 118
Marcuse, H., 137138 working memory, 119120
Marsden, C.D., 133, 134135 meningoencephalitis, 315
Martin, A., 25 meningovascular syphilis, 315
mathematical skills, 339 Menon, V., 90
Mattis Dementia Rating Scale, 244 mental activity
McKhann, G.M., 177, 383 inhibiting or stopping, 8283
McKone, E., 17, 23 initiating and sustaining, 82
Meador, K.J., 136137 mental competence and legal issues, 622636
measurement tools, 522t about, 622
mechanisms, examples of, 7f, 8f disagreements in, 634
medial dorsal (MD) nucleus, 47 driving, 629632
medial geniculate nucleus (MGN), 44 end-of-life planning, 634635
medial pulvinar (PM), 4748 executive function and metacognition,
medial temporal lobe, 112f, 113f, 532534 625626
Medication Drift syndrome, 421422 financial management, 628629
medications, differential diagnosis, 303 firearm safety, 633634
See also specific medications neuropsychological testing, 626627
melatonin, 251 principles, 623625
memantine, 417t professional competence and dementia,
BPSDs, 582583 627628
efficacy and effectiveness of, 405406t resources for, 635636
mechanisms of action, 404 road maps for, 636
pharmacological management, 397398, testamentary capacity, 632633
403408 voting, 633
memory deficit mental status examination. See screening and
Alzheimers disease and dementia, 371373 mental status examination
Creutzfeldt-Jakob Disease (CJD), 320 meprobamate, 387t
dementia with Lewy bodies (DLB), 233 Mesulam, M.M., 26, 84, 176177
656Index
Religious Orders cohort Study, 280 Sagging Brain Syndrome (SBS), 343344
REM sleep behavior disorder (RBD), 238, 245, sagittal stratum (SS), 4041
518 salience, early, 199
repetitive behavior, 183 salience network, 75, 75f, 86
representation, 4 sarcoidosis, 317
response/behavioral selection SCales for Outcomes of PArkinsons
about, 82 disease-cognition (SCOPA-Cog), 244
inhibiting or stopping motor and mental schizophrenia-like psychosis with paranoia,
activity, 8283 340
initiating and sustaining motor and mental Schmahmann, J.D., 61
activity, 82 scope of problem, 292
response criteria thresholds, setting, 28n4 scrapie, 320
response maintenance, 82 screening and mental status examination,
resting state functional connectivity magnetic 461482
resonance imaging (rs-fcMRI), 55, 537538 about, 461462
rest tremor, 223 appearance and indicators of functional
reticular thalamic nucleus, 44 status, 462463
retinal degeneration, 345 arousal and orientation, 463464
retinotropic objects, 67 attention, working memory, processing
retrograde amnesia, 115116 speed, and psychomotor function, 464465
reversal learning and extinction test, 94 executive function, 465466
Ribot, 115116 functional status and dementia symptom
Richardson, E.P., 145 questionnaires, 472474
Richardson, J.C., 220, 223 language, 466467
Richardson PSP phenotype, 221 measures of psychological function, 474482
rigidity memory function, 468469
delayed posthypoxic leukoencephalopathy, mood and psychological functioning, 463
328 multimodal cognitive operations, 469,
PSP-P (Parkinsonism), 223 471472
risk factors qualitative evaluation by domain, 462472
Alzheimers disease and dementia, 363366, specialized mental functions, 469, 471472
363t tools, 476477t
Parkinsons Disease Dementia (PD-D), 241t visuospatial function, 467468
ritualistic behavior, 183 Seeley, W.W., 7475, 90, 179, 487
rivastigmine, 417t seizures
apathy, 592 central nervous system vasculitis, 317
dementia with Lewy bodies (DLB), 239 epilepsy, 340
Parkinsons Disease Dementia (PD-D), 249 Hashimotos Encephalopathy (aka. Steroid
relationship with sleep disturbances, 518 Responsive Encephalopathy associated
Robots law, 110, 110t with Autoimmune Thyroiditis (SREAT)),
Roe, A.W., 19 310
rofecoxib, 443 intravascular lymphoma, 323
Rosenfeld, M., 198 limbic encephalitis, 307
rostral head, lesions of, 42 MELAS, 319
Rothi, L.J.G., 133 Niemann-Pick Disease Type C, 340
Rountree, S., 415 sarcoidosis, 317
Roussy, G., 50 systemic lupus erythematosus (SLE), 317318
rubral tremor, 53 X-linked adrenoleukodystrophy, 299
ruminative behaviors, 334 selective regional vulnerability of the aging
brain, 147
Sabattoli, F., 235 self, representations of the, 8485
safety issues self-knowledge, 85
BPSDs, 580581 self-mutilation, 340
posterior cortical atrophy (PCA), 217 self-referential processing, 85
CHAPTER . Index 663
word meanings, relationship with concepts and qualitative evaluation by, 464465
categories, 1012 Sagging Brain Syndrome (SBS), 344
working memory, 109t, 115f, 119120 task setting, 7677
about, 72, 76 World Health Organization (WHO), 364
attentional control and processing priorities,
7778 X-linked adrenoleukodystrophy (X-ALD),
fragile X-associated tremor ataxia syndrome 332
(FXTAS), 337
Parkinsons Disease Dementia (PD-D), 244 Zlokovic, B.V., 369
About the Editors
Brad C. Dickerson, MD, is a behavioral Alireza Atri, MD, PhD, is a cognitive neurolo
neurologist and neuroscientist at Harvard gist/neuroscientist and clinical-educator at
Medical School and Massachusetts Gen Harvard Medical School, ENRM Bedford VA
eral Hospital in Boston, Massachusetts. Medical Center, and Massachusetts General
Dr.Dickerson runs a busy weekly clinic car Hospital in Boston, Massachusetts, dedicated
ing for patients with various forms of cog to improving awareness, early diagnosis, treat
nitive impairment and dementia, as well as ment, and clinical practice regarding cognitive
providing training for clinical and research aging and dementia syndromes, particularly
fellows. His research focuses primarily on Alzheimers disease (AD). Dr. Atri special
the use of quantitative structural and func izes in providing care to patients and families
tional neuroimaging techniques to under affected by cognitive impairment, AD, espe
stand the neurobiology of Alzheimer's cially early-onset AD, and unusual dementias.
disease, primary progressive aphasia, fron His research involves integrating pharamaco
totemporal dementia, and other dementias, logical, functional neuroimaging, mathemati
and on the relationships between imaging cal, neuropsychometric, and clinical methods
measures and behavior. He also investigates to improve the design, implementation, inte
the neural substrates of changes in memory, gration, and analysis of multimodal studies
affect, and other abilities in healthy young to better risk stratify, detect, track, and pre
adults and in normal aging. He has pub dict clinical trajectory, and to assess treatment
lished widely and has won a number of responses in individuals along the cognitive
awards, including the prestigious American agingimpairmentAD spectrum. Dr.Atri has
Academy of Neurology Norman Geschwind published, and lectures widely, on AD-related
Award in Behavioral Neurology. research and clinical practice, directs integrated
memory clinics and undergraduate and gradu
ate medical courses, and teaches nationally and
internationally on best evidence and practices
in AD and dementia evaluation and care.