Handbook of Clinical Neurology, Vol.

165 (3rd series)

Psychopharmacology of Neurologic Disease
V.I. Reus and D. Lindqvist, Editors
https://doi.org/10.1016/B978-0-444-64012-3.00003-4
Copyright © 2019 Elsevier B.V. All rights reserved

Chapter 3

Frontotemporal dementia
BRUCE MILLER1* AND JORGE J. LLIBRE GUERRA2,3
1
Memory and Aging Center and Global Brain Health Institute, University of California, San Francisco, CA, United States
2
Cognitive and Behavior Research Unit, National Institute of Neurology and Neurosurgery, Havana, Cuba
3
Global Brain Health Institute, University of California, San Francisco, CA, United States

Abstract
Recent research reveals an overlap between frontotemporal dementia (FTD) and a variety of primary psy-
chiatric disorders, challenging the artificial divisions between psychiatry and neurology. This chapter
offers an overview of the clinical syndromes associated with FTD while describing links between these
syndromes and neuroimaging. This is followed by a review of the neuropathology and genetic changes in
the brain. We will illustrate the syndromic overlap that exists between FTD and several primary psychiatric
disorders including bipolar affective disorder and schizophrenia. Emphasis will be placed on the behav-
ioral variant of FTD (bvFTD), which is the common clinical syndrome seen with degeneration of the fron-
tal lobes and is the most likely to be encountered in psychiatric settings.

The frontal lobes constitute about 40% of the human
cerebral cortex and are divided into three main anatomic
regions: primary motor cortex, premotor cortex, and
prefrontal cortex. Prefrontal cortex functions remain elu-
sive, but this cortical region plays a central role in the
control of personality, judgment, planning and multitask-
ing, drive, motivation, eating and other reward-related
behaviors, and social regulation. Hence, disorders that
affect this area usually overlap with primary psychiatric
conditions. Studies that probe clinical disorders of the
prefrontal cortex using MRI, EEG, transcranial magnetic
stimulation, and neuropathology offer a clearer under-
standing of frontal lobe functions and are transforming
clinical practice.
The term frontotemporal lobar degeneration (FTLD)
is a neuropathologic designation used to identify a group
of neurodegenerative diseases of the frontal and anterior
temporal lobes, associated with specific pathologies
(Rabinovici and Miller, 2010). The principal clinical syn-
dromes associated with FTLD are classified under the
rubric of FTD, an umbrella term for three clinical variants
distinguished by early and predominant symptoms:
bvFTD; semantic variant primary progressive aphasia
(svPPA); and nonfluent variant primary progressive
aphasia (nfvPPA) (Lanata and Miller, 2016).
The most common FTD syndrome is bvFTD, which is
characterized by early and often severely disabling
changes in personality and behavior that carry a huge
impact on the patient, family, and society. The full-blown
syndrome may be preceded by a long phase of subclinical
behavioral changes and social disruption, often occur-
ring in the absence of cognitive impairment (Pressman
and Miller, 2014). bvFTD shares many symptoms with
primary psychiatric disorders including schizophrenia,
obsessive–compulsive disorder, borderline personality
disorder and bipolar disorder (Manoochehri and Huey,
2012; Pressman and Miller, 2014).
Prevalence studies on bvFTD and the other FTD syn-
dromes are challenging because many cases are misclas-
sified, as the disease is largely unrecognized in the
communities to which these patients present, including
the courts, marriage counselors, addiction specialists,
and human resource departments. Furthermore, the med-
ical community is still unable to diagnose FTD in a
reliable fashion. Additionally, the related neurologic con-
ditions that involve movement, progressive supranuclear

*Correspondence to: Bruce Miller, M.D., Memory and Aging Center, University of California, San Francisco, CA, United States.
Tel: +1-415-476-5591, Fax: +1-415-353-8292, E-mail: bruce.miller@ucsf.edu
34 B. MILLER AND J.J. LLIBRE GUERRA
syndrome, corticobasal syndrome, and motor neuron dis-
ease (MND) often show FTLD pathology, yet are rarely
considered in epidemiologic studies (Knopman and
Roberts, 2011; Onyike and Diehl-Schmid, 2013). Knop-
man and Roberts report that the total number of cases
with FTLD syndromes ranges from 15 to 22 per
100,000 person and incidence rates are between 2.7
and 4.0 per 100,000 person/years. In the United States,
at the minimum, 20,000–30,000 persons live with FTD
(Knopman and Roberts, 2011; Onyike and Diehl-
Schmid, 2013).
bvFTD cases have been reported as early as the second
decade and as late as the tenth decade, although the mean
age at presentation for bvFTD is approximately 58 years.
There appears to be a slight male preponderance, although
this finding has varied between reports. It is remarkable
that about 40% of FTD patients present with a positive
family history for dementia. This frequency of genetic eti-
ology is higher when we compare it with most other neu-
rodegenerative diseases (Riedl et al., 2014).
bvFTD SYMPTOMS, ANATOMICAL
CORRELATES, AND OVERLAP WITH
PRIMARY PSYCHIATRIC DISORDERS
Patients with bvFTD demonstrate a gradual and progres-
sive but insidious decline in social conduct, apathy,emo-
tional blunting, and loss of insight. Some patients present
with a prodromal phase with marriage discourse, alienation
of friends and family, poor financial decisions, problems at
work, new addictions, and criminal activities. Furthermore,
the overlap with primary psychiatric conditions is high,
leading to a diagnosis of depression, bipolar disorder, or
a midlife crisis (Woolley et al., 2011; Wald€o et al., 2015).
For the purpose of this chapter, we will review the core
symptoms of bvFTD and its anatomical correlates.
Early behavioral disinhibition
Behavioral disinhibition is one the most classic and rec-
ognized symptoms in bvFTD patients, present in nearly
76% of the patients (Rascovsky et al., 2011). Within the
first years, patients tend to break social norms and rules.
As the disinhibition become more evident, patients
become more impulsive, addiction prone, irritable, and
likely to commit antisocial behaviors. The disinhibition
syndrome correlates with atrophy in the orbitofrontal
cortex (Rosen et al., 2005; Pressman and Miller, 2014).
Manoochehri and Huey (2012) note that one way dis-
inhibition manifests is that individuals become overly
friendly and start conversations that are inappropriately
explicit or personal. Offensive jokes, comments, or sex-
ual remarks; encroachment on the personal space of
others; childish behavior; and a general lack of etiquette
are common.
Early apathy
In bvFTD, approximately 85% of patients show early apa-
thy and inertia, and patients usually present with lack of
spontaneity and motivation. This may progress to mutism
and immobility in the end stages of the disease (Rascovsky
et al., 2011; Manoochehri and Huey, 2012; Pressman and
Miller, 2014). Rosen and Eslinger have related this symp-
tom anatomically with dysfunction of brain circuits that
involve the right anterior cingulate and caudate regions
(Rosen et al., 2005; Eslinger et al., 2012). Sometimes, it
is challenging to differentiate between apathy and depres-
sion, but the absence of sadness, hopelessness, and suicidal
ideas suggest that apathy is more likely than depression.
Early loss of sympathy or empathy
Patients may lose the ability to empathize with others,
become insensitive to loved ones’ emotional expressions
and needs (Bartchowski et al., 2018). They become dis-
tant, cold, and indifferent in relationships, even with close
friends and family. Often there is little or no concern for
the effect of their behavior on loved ones (Rankin, 2005).
In a voxel-based morphometry analysis, Rankin and col-
leagues showed that the loss of empathy correlated with
atrophy in the right anterior temporal and medial frontal
regions (Rankin et al., 2006). Similarly, Rosen and col-
leagues have shown related impairment in emotion recog-
nition with atrophy in the right lateral inferior temporal
and right middle temporal gyri (Rosen et al., 2006).
Early perseverative or compulsive behavior
Patients with bvFTD often display obsessive–compulsive
behaviors (71%). This varies from simple motor repetitive
movements, like foot tapping or pacing, to more complex
movements and language rituals. Repetition of stock
words or phrases becomes common. Patients tend to be
ritualistic around meals without any variation in the daily
diet. Hoarding is common (Pressman and Miller, 2014).
Some patients become more mentally rigid and resistant
to changes in scheduled routines or plans (Cerami and
Cappa, 2013). Obsessive–compulsive behavior has been
related with networks involving orbitofrontal and anterior
cingulate cortexes, basal ganglia, and thalamus.
Hyperorality and dietary changes
In bvFTD, changes in food preferences and habits are
usually present. In the clinic, we have seen patients that
become vegetarian or exclusively eat meat or sweets.
Others eat way beyond the point of satiety (Woolley
et al., 2007). Attempts to eat nondigestible objects are
also seen in later stages with relative frequency. The
exact anatomical correlation of this symptom is not clear,
 FRONTOTEMPORAL DEMENTIA 35
but Woolley has associated it with atrophy in the right bipolar disorder (Wald€o et al., 2015). For this reason,
orbitofrontal-insular-striatal brain network (Woolley misdiagnosis is seen in two directions, with some bvFTD
et al., 2007), while Piguet has correlated abnormal eating patients being initially misinterpreted as suffering from
with atrophy in the posterior hypothalamus (Piguet, a psychiatric disorder, while others with a primary
2011; Piguet et al., 2011b). psychiatric disorder being misdiagnosed as bvFTD.
Recent studies (Snowden et al., 2012; Shinagawa et al.,
Decline in executive function 2014; Wald€o et al., 2015) have pointed out the relative fre-
quency of psychotic symptoms in FTD patients, and the
In contrast to Alzheimer’s disease (AD), cognitive reports vary from 10% to 32%. These differences are
decline in bvFTD tends to be less dramatic in the early related to the instruments used for the evaluation of psy-
stages (Gregory et al., 1999). The cognitive symptoms chotic symptoms and the genetic and pathology profile
of bvFTD are mainly related to poor judgment, inatten- of the sample. A higher prevalence of psychotic symptoms
tiveness and distractibility, loss of planning ability, and in bvFTD seems to be associated with chromosome 9 open
disorganization. These patients are overly trusting and reading frame 72 (C9orf72) mutations where hallucina-
become susceptible to financial scams (Rabinovici and tions and delusions are reported as high as 50% (Sharon
Miller, 2010; Pressman and Miller, 2014). The executive et al., 2012; Snowden et al., 2012; Kertesz et al., 2013).
dysfunction correlates with atrophy in the dorsolateral Mahoney and colleagues hypothesize that thalamic
and medial prefrontal cortex (Rosen et al., 2005). and cerebellar projections could be related to the neuro-
psychiatric features associated with this mutation,
Pseudobulbar affect in FTD with MND including hallucinations and/or delusions (Takada and
Pseudobulbar affect (PBA) is a syndrome in which emo- Sha, 2012). These brain areas also seem to be particularly
tional or affective motor control becomes dysregulated as affected in C9orf72 carriers, possibly explaining the
a result of brain damage from a neurologic disease or as a higher prevalence of psychotic symptoms in patients
result of brain injury. This syndrome is often misdiag- with this genetic mutation (Mahoney et al., 2012).
nosed as a mood disorder caused by a primary psychiatric Recent studies have shown reduction of right medial pul-
disease. PBA among other causes may be seen in the vinar volume and neuron number in patients with schizo-
setting of FTD with MND (FTD-MND), which must phrenia, the same region affected in C9orf72 mutation
be distinguished from depression or other primary psy- carriers which may explain symptom overlap. Another
chiatric conditions. Laughter or crying are emotions that bvFTD subtype in which psychosis is high is FTLD with
are dysregulated with PBA (Olney et al., 2011). fused in sarcoma (FUS) pathology (Snowden et al.,
The cardinal feature of the PBA is the presence of epi- 2012) (Table 3.1).
sodes of laughter and/or crying, often triggered by a dis-
crete stimulus. These episodes present with paroxysm, Table 3.1
tend to be uncontrollable and involuntary, and may occur
Frequent symptoms in bvFTD patients and the anatomical
even in the absence of any congruent changes in the
correlates (Galimberti et al., 2015)
mood of the patient. The duration tends to be short. These
features help in the differentiation of PBA from mood Symptoms Frequency (%) Anatomical correlates
disorders, where the emotional state tends to last longer
and their emotional response is primarily a reflection of a Apathy 84 Right anterior cingulate,
specific situation or reaction. Several scales are available medial frontal lobe, and
to identify and characterize PBA (Newsom-Davis et al., caudate
1999; Smith et al., 2004). However, this is a clinical diag- Disinhibition 76 Right orbitofrontal cortex
nosis where the level of suspicion and clinical training Loss empathy 73 Right anterior temporal and
play important roles. This syndrome is effectively treated orbito-insular cortex
with a combination compound of dextromethorphan and Repetitive 71 Right supplementary motor
motor/ area and network
quinidine sulfate (Sauve, 2016).
compulsive involving orbitofrontal
behavior and anterior cingulate
Psychotic symptoms cortices, basal ganglia, and
thalamus
As discussed previously, bvFTD may present with prom-
Hyperorality 59 Network involving
inent neuropsychiatric symptoms and shares many and dietary orbitofrontal-insular-
symptoms with primary psychiatric disorders including changes striatal region and the
schizophrenia, obsessive compulsive disorder, border- posterior hypothalamus
line schizoid or antisocial personality disorder, and
36 B. MILLER AND J.J. LLIBRE GUERRA
The presence of overlapping symptoms between FTD
and specific psychiatric disorders can pose various prob-
lems related to differential diagnosis, prognosis, and
treatment, but neuropsychologic assessment may help
to differentiate the FTD profile from non-FTD patients.
During the neuropsychologic testing, some core
symptoms of bvFTD may be evident, as some patients
make inappropriate comments to their examiners, appear
cold or emotionally blunted, or appear inattentive and
disinterested. During the examination, these patients
often make rule violations and perseverate. The magni-
tude of these findings is usually greater in bvFTD than
in primary psychiatric disorders. Neuropsychologic test-
ing in bvFTD also frequently reveals executive dysfunc-
tion, which often correlates with tissue loss in the
dorsolateral prefrontal cortex. In bvFTD, patient memory
tends to be better than in AD, but some authors have
pointed out some degree of impairment in episodic mem-
ory in the early stages of FTD (Hodges et al., 2004). In
comparison with AD patients, bvFTD patients tend to
show higher scores of apathy, euphoria, disinhibition,
aberrant motor behavior, and eating abnormalities on
the Neuropsychiatric Inventory (NPI) (Levy et al.,
1996; Liscic et al., 2007). On the other hand, drawing
and other visuospatial functions are often relatively
spared in FTD clinical subtypes (Rabinovici and
Miller, 2010). With the progression of the disease,
changes in language, like stereotypy of speech, semantic
deficits, and progressive reduction, may occur as a result
of a disruption of dominant lobar language networks
(Pressman and Miller, 2014).
bvFTD DIAGNOSIS CRITERIA
The diagnosis of bvFTD requires a clinical and neurop-
sychologic approach supported by the use of neuroimag-
ing or genetics studies. Most of the patients with bvFTD
present with lack of insight and gradual onset. For this
reason, in the assessment of a patient with suspected
bvFTD, it is extremely important to interview caregivers
regarding changes in patient behavior and cognition
(Cerami and Cappa, 2013; Pressman and Miller, 2014).
Improper diagnosis prevents patients and families
from planning for the future and often leads to inappro-
priate and potentially harmful treatments, with FTD
caregivers reporting that the delay to proper diagnosis
is one of the most frustrating aspects of their experience.
In 2011, the International Behavioral Variant FTD
Consortium (FTDC) used pathologically confirmed cases
of FTLD to develop sensitive and specific clinical criteria
for diagnosing bvFTD, making possible a more accurate
diagnosis (see Table 3.2) (Rascovsky et al., 2011).
The international research criteria for bvFTD empha-
sized six core symptoms for the diagnosis, and the pres-
ence of any three of these is sufficient for a diagnosis of
Table 3.2
International consensus criteria for behavioral variant FTD
(Rascovsky et al., 2011)
I. Neurodegenerative disease
The following symptom must be present to meet criteria for
bvFTD:
A. Shows progressive deterioration of behavior and/or
cognition by observation or history (as provided by a
knowledgeable informant)
II. Possible bvFTD
Three of the following behavioral/cognitive symptoms (A–F)
must be present to meet criteria. Ascertainment requires that
symptoms be persistent or recurrent, rather than single or rare
events
A. Early* behavioral disinhibition [one of the following
symptoms (A.1–A.3) must be present]:
A.1. Socially inappropriate behavior
A.2. Loss of manners or decorum
A.3. Impulsive, rash or careless actions
B. Early apathy or inertia [one of the following symptoms
(B.1–B.2) must be present]:
B.1. Apathy
B.2. Inertia
C. Early loss of sympathy or empathy [one of the following
symptoms (C.1–C.2) must be present]:
C.1. Diminished response to other people’s needs and feelings
C.2. Diminished social interest, interrelatedness or personal
warmth
D. Early perseverative, stereotyped or compulsive/ritualistic
behavior [one of the following symptoms (D.1–D.3) must
be present]:
D.1. Simple repetitive movements
D.2. Complex, compulsive, or ritualistic behaviors
D.3. Stereotypy of speech
E. Hyperorality and dietary changes [one of the following
symptoms (E.1–E.3) must be present]:
E.1. Altered food preferences
E.2. Binge eating, increased consumption of alcohol or
cigarettes
E.3. Oral exploration or consumption of inedible objects
F. Neuropsychologic profile: executive/generation deficits
with relative sparing of memory and visuospatial functions
[all of the following symptoms (F.1–F.3) must be present]:
F.1. Deficits in executive tasks
F.2. Relative sparing of episodic memory
F.3. Relative sparing of visuospatial skills
 FRONTOTEMPORAL DEMENTIA
Table 3.2
Continued
III. Probable bvFTD
All of the following symptoms (A–C) must be present to meet
criteria.
A. Meets criteria for possible bvFTD
B. Exhibits significant functional decline (by caregiver report
or as evidenced by Clinical Dementia Rating Scale or
Functional Activities Questionnaire scores)
C. Imaging results consistent with bvFTD [one of the
following (C.1–C.2) must be present]:
C.1. Frontal and/or anterior temporal atrophy on MRI or CT
C.2. Frontal and/or anterior temporal hypoperfusion or
hypometabolism on PET or SPECT
IV. bvFTD with definite FTLD pathology
Criterion A and either criterion B or C must be present to meet
criteria
A. Meets criteria for possible or probable bvFTD
B. Histopathologic evidence of FTLD on biopsy or at
postmortem
C. Presence of a known pathogenic mutation
V. Exclusionary criteria for bvFTD
Criteria A and B must be answered negatively for any bvFTD
diagnosis. Criterion C can be positive for possible bvFTD but
must be negative for probable bvFTD
A. Pattern of deficits is better accounted for by other
nondegenerative nervous system or medical disorders
B. Behavioral disturbance is better accounted for by a
psychiatric diagnosis
C. Biomarkers strongly indicative of Alzheimer’s disease or
other neurodegenerative process
*As a general guideline “early” refers to symptom presentation within
the first 3 years.
possible bvFTD. Probable FTD will be considered in the
presence of significant functional decline and imaging
findings consistent with the disease or a known causal
genetic mutation. The diagnosis of definite bvFTD is
given if the possible and probable criteria are supported
by a finding of FTLD pathology.
CLINICAL AND PATHOLOGIC
CORRELATION: HISTOPATHOLOGY
AND GENETICS
Initially, FTLD was pathologically identified by the pres-
ence of frontotemporal atrophy and gliosis, with neurons
and glial cells containing inclusions of hyperphosphory-
lated τ protein. This was referred to as FTLD-τ. More
37
than 50% of the FTLD patients proved to be τ-negative
but ubiquitin staining positive, so two main groups were
identified FTLD-τ and FTLD-ubiquitin (FTLD-U) or
unknown molecular pathology (Cairns et al., 2007;
MacKenzie et al., 2010). Later on, 80%–95% of FTLD-
U inclusions were found to be composed of transactive
response (TAR) DNA binding protein 43kDa (TDP-43)
(Neumann et al., 2006). Most of the remaining 5% of
cases, who were τ- and TDP-43-negative, had inclusions
of FUS. Thus, they were referred to as FTLD-FUS.
Correlations have been noted between the clinical
FTLD subtypes and underlying proteinopathies, but a
strict one-to-one relationship is lacking. Nearly all
bvFTD cases fall within one of three histopathologic
groupings: τ, TDP-43, or FUS, each with a possibly
unique genetic contribution.
Positive family history is observed in 40%–50% of
the FTLD patients, and in the bvFTD phenotype, a pos-
itive family history could be present in 30% of the
patients when symptoms of MND are present (Lashley
et al., 2011; Goldman, 2012).
Molecular genetic studies have identified various
genes with specific pathogenic mutations in FTD:
e.g., the microtubule-associated protein τ gene (MAPT),
granulin (GRN), chromosome 9 open reading frame
72 (C9orf72), TARDBP, the gene encoding valosin-
containing protein (VCP), and the charged multivesicu-
lar body protein 2B gene (CHMP2B) (see Table 3.3).
Other genes appear to modify the susceptibility to dis-
ease, but this remains a new and active area for
investigation.
For the purpose of this chapter we focus our attention
on C9orf72, GRN, and MAPT mutations and their path-
ologic correlations in bvFTD. These three genes are the
most common and together explain at least 17%–40% of
the familial FTLD (DeJesus-Hernandez et al., 2011;
Gijselinck et al., 2012). C9orf72 and GRN mutations
are associated with TDP-43 deposits and MAPT with τ
deposition.
τ protein is involved in maintaining the microtubular
structure in the neuronal axon. Six isoforms have been
described, three of which have three microtubule binding
repeats (3R), and three of which have four repeats (4R).
τ is important in the pathogenesis of a variety of neuro-
degenerative conditions, including AD and FTLD.
Mutations in MAPT have been found to represent from
17% to 32% of patients with both FTD and a positive
family history (Rosso et al., 2003; Pressman and
Miller, 2014). MAPT mutations on chromosome 17q21
were the first to be linked to familial FTD. These muta-
tions were identified in families with an autosomal dom-
inant clinical syndrome of disinhibition, dementia, and
Parkinsonism. Now, more than 50 different MAPT muta-
tions have been reported in 134 FTLD families (Bang
et al., 2015).
Table 3.3
Genes related with FTLD

C9orf72 MAPT GRN TARDBP VCP FUS CHMP2B

Cr. Loc 9p21.2 17q21.32 17q21.32 1p36.22 9p13.3 16p11.2 3p11.2

Protein Unknown τ Progranulin TDP-43 ATP binding FUS protein deposits Multivesicular body
protein 2B
Function Unknown Microtubule Growth factor, DNA/RNA modulation Intracellular transport DNA repair/regulates ESCRT-III complex
stabilization inflammation transcription production
Age of onset 51 (36–68) 44 (21–63) 56 (47–87) Early ALS Variable Early ALS 50–60
20–60
Frequency in FTD 20%–50% 40%–50% 5%–25% Rare Rare 5% Rare
Syndrome FTD, ALS, FTD- FTD, PSP, CBD FTD, CBD, PD, AD ALS, rarely FTD Paget’s with IBM, FTD, ALS, FTD, essential FTD
ALS, ALS tremor
psychiatric
symptoms
Brain inclusion TDP A/B τ TDP A ? TDP D Unknown
 FRONTOTEMPORAL DEMENTIA
FTLD-τ is mainly associated with bvFTD and symp-
toms of MND tend to be rare. MAPT mutations present
with significant variability in clinical expression even
in the same family. In these families, symptoms are often
present by the age of 50; however, the range for age of
onset is wide and strongly overlaps with other types of
FTLD. It is remarkable that many carriers of MAPT
mutations present with a long psychiatric prodromal
phase (Bang et al., 2015).
TDP-43 protein is found in at least one half of all
bvFTD cases on histologic examination and is present
in nearly all cases with FTD with amyotrophic lateral scle-
rosis (FTD-ALS). MacKenzie et al. (2011), in the new
international FTLD classification, elicited four FTLD-
TDP subtypes, A–D, based on the cortical distribution,
intracellular location and morphology of the TDP inclu-
sions. Based on large clinicopathologic studies (Josephs
et al., 2011), the most common FTLD-TDP subtype is
type A accounting for 41%–49% of the cases, followed
by type B with 28%–34% and type C with 17%–25%,
while type D is rare (Sieben et al., 2012). FTLD-TDP-
43 type A is seen in patients with bvFTD or nfvPPA, type
B is typical for FTD-MND, and type C is seen with svPPA
and rarely with other FTD subtypes.
The two more common genetic mutations associated
with TDP-43 pathology are GRN and C9orf72 (Baker
et al., 2006; Cruts et al., 2006). In the case of the progra-
nulin gene (PGRN) more than 69 different GRN muta-
tions have been reported in 231 families (Cruts et al.,
2012). GRN mutations usually present by the age of
60 years, having an age of onset that is slightly higher
than for other forms of FTD. It is remarkable that vari-
ability in penetrance has been described, with 50%–
60% of the mutation carriers being affected by the age
of 60 years, and 90%–95% by the age of 70 years
(Sieben et al., 2012). GRN mutations are often associated
with asymmetric cerebral atrophy and, in addition to
bvFTD, may be associated with nfvPPA and Parkinson-
ism. Motor neuron symptoms are rare (Chen-Plotkin
et al., 2011).
C9orf72 encodes a ubiquitously expressed protein of
unknown function. In the normal population, the size of
the GGGGCC repeat ranges from 3 to 25 units; a noncod-
ing GGGGCC hexanucleotide expansion in this gene of
more than 400 base pairs is strongly associated with both
FTD and ALS (DeJesus-Hernandez et al., 2011; Renton
et al., 2011). At the University of California, San Fran-
cisco Memory and Aging Center, mutations in this gene
account for roughly 50% of familial FTD, other reports
give a range of 13%–26% among familial FTD cases
(Majounie et al., 2012).
C9orf72 hexanucleotide repeat expansion is the
most common known genetic cause of FTD and ALS
and most often presents with bvFTD, bvFTD with
39
MND (bvFTD-MND), or ALS, usually beginning at
the age of 55 (DeJesus-Hernandez et al., 2011; Sharon
et al., 2012; Snowden et al., 2012).
These differences in genetic and neuropathologic sub-
types suggest the need for different treatment approaches
based on differential target engagement in the future
management of the disease.
C9orf72, chromosome 9 open reading frame 72;
MAPT, microtubule-associated protein τ; GRN, granulin;
TARDBP, transactive response DNA binding protein
43 kDa; VCP, valosin-containing protein; FUS, fused
in sarcoma; CHMP2B, charged multivesicular body
protein 2B; IBM, inclusion body myositis; ESCRT, endo-
somal sorting complexes required for transport.
NEUROIMAGING IN bvFTD
In the diagnostic evaluation of bvFTD patients, fronto-
temporal atrophy or hypometabolism with structural
and/or functional neuroimaging transforms a diagnosis
from possible bvFTD into probable bvFTD
(Rascovsky et al., 2011; Pressman and Miller, 2014).
Furthermore, neuroimaging studies may help exclude
alternative disorders such as tumors, vascular dementia,
or normal pressure hydrocephalus.
FTLD is associated with diverse patterns of atrophy
of frontal and anterior temporal lobes. Different patterns
of atrophy have been described in correlation with the
clinical phenotypes. All of them are characterized by pro-
gressive cell loss, stereotypical spread, and abnormal
protein aggregation.
Patterns of neuroimaging findings can differentiate
bvFTD from other FTD syndromes, AD, and other
dementias (Muñoz-Ruiz et al., 2012), with important
results coming from Seeley and colleagues who have
demonstrated that bvFTD is associated with atrophy of
the orbitofrontal, anterior cingulate, anterior insular,
and anterior temporal cortices, particularly within the
right hemisphere (Lee et al., 2016). This group has also
shown that changes in the salience network, which is
comprised of the orbitofrontal cortex, anterior cingulate
cortex, anterior insula, and presupplementary motor area,
may underlie the selective vulnerability and the stereo-
typical spread of this neurodegenerative illness (Seeley
et al., 2009).
bvFTD is associated with frontal and temporal lobe
atrophy (Fig. 3.1) but also involves other structures like
the thalamus, striatum, and hypothalamus. Typically the
atrophy pattern is more pronounced on the right than left
frontotemporal areas (Lee et al., 2016; Muñoz-Ruiz
et al., 2012).
Patterns of atrophy differ slightly among the genetic
forms of FTLD. Anteromedial temporal atrophy has been
associated with mutations in MAPT (Rohrer et al., 2010),
40 B. MILLER AND J.J. LLIBRE GUERRA

Fig. 3.1. A T1 magnetic resonance image of the brain in sagittal, axial, and coronal cuts, shown in neurologic convention, showing
severe anterior predominant atrophy with hydrocephalus ex vacuo in a patient with advanced behavioral variant frontotemporal
dementia (bvFTD).

Syndrome-specific regional atrophy patterns: patients vs controls Atrophy max

= seed ROI
AD bvFTD SD PNFA CBS
L IFG R PMC
+35 +11 +14 +10 +40 6

R FI 4.4
A R Ang L TPole
Intrinsic functional connectivity networks: healthy controls
5

3.6
B
Structural covariance networks: healthy controls
6

4.6
C
Fig. 3.2. Convergent syndromic atrophy, healthy intrinsic connectivity networks (ICN), and healthy structural covariance (SC)
patterns (A) Five distinct clinical syndromes showed dissociable atrophy patterns, whose cortical maxima (circled) provided seed
ROIs for ICN and SC analyses. (B) ICN mapping experiments identified five distinct networks anchored by the five syndromic
atrophy seeds. (C) Healthy subjects further showed gray matter volume covariance patterns that recapitulated results shown in
(A and B). For visualization purposes, results are shown at P < 0.00001 uncorrected (A and C) and P < 0.001 corrected height
and extent thresholds (B). In (A–C), results are displayed on representative sections of the MNI template brain. In coronal and
axial images, the left side of the image corresponds to the left side of the brain. ANG ¼ angular gyrus; FI ¼ frontoinsula;
IFGoper ¼ inferior frontal gyrus, pars opercularis; PMC ¼ premotor cortex; TPole ¼ temporal pole (Seeley et al., 2009).

whereas mutations in GRN have been associated with
asymmetric temporoparietal atrophy, and C9orf72 muta-
tions tend to present symmetric atrophy, predominantly
involving dorsolateral, medial, and orbitofrontal lobes,
anterior temporal lobes, cerebellum, and medial thala-
mus. Sporadic forms usually present with frontal and
anterior temporal atrophy (Beck et al., 2008; Rohrer
et al., 2010).
Patterns of atrophy may also help in the differential
diagnosis, with Seeley et al. (2009) pointing out differen-
tial neuroimaging profiles in AD, bvFTD, svPPA,
nfvPPA, and CBD (Fig. 3.2). Even though these atrophy
 FRONTOTEMPORAL DEMENTIA 41
Table 3.4
Differential diagnosis of bvFTD

Psychiatric disorders Neurodegenerative disorders

Obsessive–compulsive Alzheimer’s disease

Fig. 3.3. Axial fluorodeoxyglucose positron emission tomog-
raphy (FDG-PET) images of a patient with advanced bvFTD,
demonstrating hypometabolism in the anterior lobes bilater-
ally, but right more so than left.
patterns in structural MRI are extremely helpful in the
diagnostic approach, it is important to note that early
in the disease, structural imaging can be normal. In these
early stages, functional neuroimaging studies such as
fluorodeoxyglucose positron emission tomography
(FDG-PET) may be slightly more sensitive than MRI
for the diagnosis (Womack et al., 2011). Characteristic
patterns of regional glucose hypometabolism on FDG-
PET, a marker of neuronal injury and neurodegeneration,
have been identified in association with the common
neurodegenerative dementias and can be clinically useful
with a sensitivity of 97% and a specificity of 86% for dis-
tinguishing AD from FTD (Foster et al., 2007). FDG-
PET reveals hypometabolism of frontal, anterior cingu-
late and anterior temporal regions in FTD, in contrast
to temporoparietal and posterior cingulate hypometabo-
lism in AD (Fig. 3.3).
A significant problem in bvFTD is predicting the
molecular subtype from the clinical syndrome. Amyloid
imaging is useful for distinguishing FTLD syndromes
from AD, and eventually, it is hoped that τ imaging will
help predict the risk of developing the disease, assess dis-
ease progression, and measure the efficacy of therapeu-
tics. In the last few years, the search for a sensitive and
specific τ binding ligand has intensified and τ neuroim-
aging agents are under development.
DIFFERENTIAL DIAGNOSIS
Lack of an early or clear diagnosis of bvFTD may lead to
delayed and inappropriate treatment, as well as family
and patient distress. bvFTD syndromes can be mistaken
for other neurodegenerative or psychiatric syndromes
(Table 3.4), and in early stages, the diagnosis is more
challenging, as it is important to exclude treatable condi-
tions that can mimic FTLD. A comprehensive clinical
and neuropsychologic evaluation, combined with labora-
tory studies and neuroimaging, are essential components
of the required workup.
Dementias are often mistaken for psychiatric disease,
and bvFTD patients are at highest risk for misdiagnosis.
disorder
Bipolar disorder Chronic traumatic encephalopathy
Depression Other FTD syndromes
Schizophrenia Movement disorders
Treatable conditions that can mimic FTD
Metabolic disturbances Cerebrovascular disease
Nutritional deficiencies CNS tumors
CNS infections Paraneoplastic conditions
Substance abuse Normal pressure hydrocephalus
Heavy metal toxicity Low intracranial pressure
bvFTD patients are often initially misdiagnosed with a
major depressive disorder, bipolar affective disorder, or
schizophrenia (Gálvez-Andres et al., 2007; Woolley
et al., 2007, 2011; Velakoulis et al., 2009).
In one study, 28% of patients had a prior psychiatric
diagnosis, and the mean delay between receiving psychi-
atric and neurodegenerative disease diagnoses was
33 months. Women with bvFTD received a psychiatric
diagnosis more often than men. This study suggests that
physicians should consider a more comprehensive eval-
uation in patients who present with new-onset behav-
ioral, emotional, or cognitive changes after age 40 in
order to rule out bvFTD or another neurodegenerative
condition (Woolley et al., 2011).
Others neurodegenerative disorders can be mistaken
for FTD-spectrum disorders, particularly AD, vascular
dementia, and dementia with Lewy bodies. Early age
of onset AD (EOAD) can be challenging to differentiate
from bvFTD because frequently it does not have the clas-
sical amnestic presentation of later onset AD. In some
cases, there may be a prominent executive or language
dysfunction as well.
It is also important to make reference to the FTD phe-
nocopy. This term was introduced by John Hodges and
Chris Kipps and may represent a diagnostic dilemma
(Kipps et al., 2010), describing patients who seem to
meet the bvFTD criteria but do not appear to progress
clinically and do not show atrophy on MRI.
FTD phenocopy pattern usually falls into four main
subtypes:
1. FTD by proxy
2. Self-diagnosed FTD
3. Primary psychiatric disorder
4. Slow FTD
42 B. MILLER AND J.J. LLIBRE GUERRA
In FTD by proxy, the caregiver becomes convinced
that their loved one has bvFTD. This idea is often rein-
forced by reading about the disease on the Internet or
though discussion with someone familiar with the
disease. A similar story is seen in self-diagnosed FTD.
Sometimes a psychiatric syndrome is misdiagnosed
as FTD. Usually, however, patients with primary psychi-
atric conditions like bipolar disorder have symptoms that
begin earlier in life, show relatively normal neuroimag-
ing, respond better to psychoactive compounds, and do
not progress to dementia. Finally, there are gene carriers
who may initially show normal imaging and progress
very slowly. In particular, some patients with C9 muta-
tions have been reported to have a very low progression
rate and long prodromal phase (Bang et al., 2015).
MANAGEMENT OF BEHAVIORAL
SYMPTOMS IN FTD
There is no treatment available that changes the course of
the bvFTD, so the focus of medical therapy is on symp-
tomatic relief. An individualized management plan, with
both nonpharmacologic and pharmacologic interven-
tions, should be created.
Nonpharmacologic interventions
Nonpharmacologic interventions should focus on the
safety and well-being of the patient. Discussion with fam-
ily around financial issues, such as limiting access to credit
cards and bank accounts, driving safety, and achieving an
environment that assures the physical safety of the patient
(Talerico and Evans, 2001; Piguet et al., 2011a) and early
retirement should be considered if the patient is currently
employed (Pressman and Miller, 2014).
Exercises and physical therapy may be also helpful in
patients with impending problems with movement. Chen
and colleagues (Cheng et al., 2014) have shown a benefit
in mood, cognition, and overall health in patients with
dementia when regular exercise routines are performed.
Physical therapy may be helpful in patients with mobility
problems such as Parkinsonism and may help to reduce
the risk of falls.
The presence of hyperorality in some patients may
require special care from caregivers to prevent excessive
weight gain or the dangerous placement of inedible
objects in the mouth (Manoochehri and Huey, 2012).
Pharmacologic interventions
Studies in the neurochemistry of bvFTD have shown a
serotoninergic network disruption, with decreased sero-
tonin levels and 5-HT1A and 5-HT2A receptors in fron-
totemporal regions and neuronal loss in the raphe nuclei
(Franceschi et al., 2005; Huey et al., 2006). Disruption in
the dopaminergic system, with low levels of dopamine
metabolites and severely reduced presynaptic dopamine
transporters in the putamen and caudate of FTD patients,
seems to be part of the FTD neuropharmacology
(Sj€ogren et al., 1998; Rinne et al., 2002). There is no evi-
dence supporting a deficit of acetylcholine in this disease
(Hansen et al., 1988). Consequently, the pharmacologic
management of neurobehavioral symptoms should ide-
ally suit the typical changes in neurotransmitter systems
occurring with the disease.
In 1997 Swartz and colleagues first treated 11 FTD
subjects with fluoxetine, sertraline, or paroxetine and
found improvement in disinhibition, apathy, carbohy-
drate cravings, and compulsive behaviors. In 2005 Men-
dez and colleagues described decreased verbal and motor
stereotypies when sertraline was used in this group of
patients. A meta-analysis of studies using serotonergic
drugs was conducted by Huey et al. in 2006, and signif-
icant decrease in behavioral symptoms as measured by
the NPI was observed (Huey et al., 2006). In total, the
evidence suggests that serotonin selective reuptake
inhibitors (SSRIs) (fluoxetine, sertraline, paroxetine, flu-
voxamine, and citalopram) are effective in helping with
various symptoms of FTD, including disinhibition,
impulsivity, repetitive behaviors, and eating disorders
(Sj€ogren et al., 1998; Huey et al., 2006; Manoochehri
and Huey, 2012).
Some patients with bvFTD will require the use of anti-
psychotic medications for the treatment of severe neuro-
behavioral symptoms. These compounds are usually
considered if there is no success with behavioral modifi-
cation or SSRIs. Diminished dopaminergic function in
these patients makes them vulnerable to extrapyramidal
side effects. Therefore, agents with relatively less D2
receptor antagonism, such as quetiapine, are preferred
if antipsychotics are needed (Pijnenburg et al., 2003;
Komossa et al., 2011; Asmal et al., 2013).
Acetylcholinesterase inhibitors are not recommended
in this group of patients, as they do not have a cholinergic
deficit like AD or DLB, and trials have not shown a con-
vincing benefit for cholinesterase inhibitors in cognition
or behavior (Mendez et al., 2007). AChIs are incorrectly
prescribed in approximately 40% of bvFTD patients
(Pressman and Miller, 2014). Memantine is an NMDA
receptor antagonist used for slowing cognitive decline
with moderate AD, but no significant difference in
behavioral or cognitive function was found in bvFTD
when compared with a placebo (Diehl-Schmid et al.,
2008; Boxer et al., 2009; Vercelletto et al., 2011). Several
other drugs, like lithium and some anticonvulsants, have
been tested in FTD with negative or inconclusive results.
Risks of toxicity are generally deemed to outweigh
theoretical benefits (Pressman and Miller, 2014).
 FRONTOTEMPORAL DEMENTIA
CONCLUSIONS
FTD is increasingly recognized as a leading cause of early-
onset dementia. bvFTD is the most common syndrome in
FTD and can be associated with behavior changes mim-
icking manic, depressive, obsessive–compulsive, or other
psychiatric syndromes, and causing social and family dis-
ruption. bvFTD can result from a number of different pro-
teinopathies, and some cases have a genetic etiology.
A comprehensive clinical and neuropsychologic evalua-
tion, combined with laboratory studies and neuroimaging,
can help in recognizing the core features of bvFTD and in
avoiding misdiagnosis. The pharmacologic management
of behavioral symptoms currently relies on the effect of
SSRIs, with some efficacy in reducing disinhibition, repet-
itive behaviors, and hyperorality. Small doses of atypical
antipsychotics may be required when there is no success
with SSRIs. There is no evidence supporting the use of
cholinesterase inhibitors or memantine. Promising areas
of research include PET imaging with τ ligands, which
may make it possible to identify subgroups that could
benefit from future therapies targeting the underlying
pathology with disease.
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