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 CONTEMPORARY NEUROLOGY SERIES

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Multiple Non-Motor Features

ROGER L. ALBIN
OXFORD
PARKINSON DISEASE
SERIES EDITOR
Eva L. Feldman, MD, PhD
Russell N. DeJong Professor of Neurology
University of Michigan

Contemporary Neurology Series

74 NEUROLOGIC COMPLICATIONS OF CRITICAL ILLNESS
Third Edition
Eelco F.M. Wijdicks, MD, PhD, FACP
75 CLINICAL NEUROPHYSIOLOGY
Third Edition
Jasper R. Daube, MD, and Devon I. Rubin, MD, Editors
76 PERIPHERAL NEUROPATHIES IN CLINICAL PRACTICE
Steven Herskovitz, MD, Stephen N. Scelsa, MD, and Herbert H. Schaumburg, MD
77 CLINICAL NEUROPHYSIOLIOGY OF THE VESTIBULAR SYSTEM
Fourth Edition
Robert W. Baloh, MD, FAAN, and Kevin A. Kerber, MD
78 THE NEURONAL CEROID LIPOFUSCINOSES (BATTEN DISEASE)
Second Edition
Sara E. Mole, PhD, Ruth D. Williams, MD, and Hans H. Goebel, MD, Editors
79 PARANEOPLASTIC SYNDROMES
Robert B. Darnell, MD, PhD, and Jerome B. Posner, MD
80 JASPER’S BASIC MECHANISMS OF THE EPILEPSIES
Jeffrey L. Noebels, MD, PhD, Massimo Avoli, MD, PhD, Michael A. Rogawski, MD, PhD, Richard W. Olsen, PhD, and Antonio V.
Delgado-Escueta, MD
81 MYASTHENIA GRAVIS AND MYASTHENIC DISORDERS
Second Edition
Andrew G. Engel, MD, Editor
82 MOLECULAR PHYSIOLOGY AND METABOLISM OF THE NERVOUS SYSTEM
Gary A. Rosenberg, MD
83 SEIZURES AND EPILEPSY
Second Edition
Jerome Engel, Jr., MD, PhD
84 MULTIPLE SCLEROSIS
Moses Rodriguez, MD, Orhun H. Kantarci, MD, and Istvan Pirko, MD
85 FRONTOTEMPORAL DEMENTIA
Bruce L. Miller, MD
86 AUTONOMIC NEUROLOGY
Eduardo E. Benarroch, MD
87 EVALUATION AND TREATMENT OF MYOPATHIES
Second Edition
Emma Ciafaloni, MD, Patrick F. Chinnery, FRCP, FMedSci, and Robert C. Griggs, MD, Editors
88 MOTOR NEURON DISEASE IN ADULTS
Mark Bromberg, MD
89 HYPERKINETIC MOVEMENT DISORDERS
Roger M. Kurlan, MD, Paul E. Green, MD, and Kevin M. Biglan, MD, MPH
90 THE NEUROLOGY OF EYE MOVEMENTS
Fifth Edition
R. John Leigh, MD, FRCP, and David S. Zee, MD
91 MIGRAINE
Third Edition
David W. Dodick, MD, and Stephen D. Silberstein, MD, FACP, FAHS, FAAN
92 CLINICAL NEUROPHYSIOLOGY
Fourth Edition
Devon Rubin, MD and Jasper Daube, MD, Editors
93 PLUM AND POSNER’S DIAGNOSIS AND TREATMENT OF STUPOR AND COMA
Fifth Edition
Jerome B. Posner, MD, Clifford B. Saper, MD, PhD, Nicholas D. Schiff, MD, and Jan Claassen, MD, PhD
94 NEUROIMMUNOLOGY
Bibiana Bielekova, MD, Gary Birnbaum, MD, and Robert P. Lisak, MD, FRCP
95 CLINICAL NEUROPHYSIOLOGY
Fifth Edition
Devon I. Rubin, MD, Editor
PARKINSON DISEASE
Roger L. Albin, MD
Department of Neurology, University of Michigan
Geriatrics Research, Education, and Clinical Center; VA Ann Arbor Health System
Oxford University Press is a department of the University of Oxford. It furthers the University’s objective of excellence in research,
scholarship, and education by publishing worldwide. Oxford is a registered trade mark of Oxford University Press in the UK and certain other
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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
Names: Albin, Roger L., author.
Title: Parkinson disease / Roger L. Albin. Other titles: Contemporary neurology series ; 96.
Description: New York, NY : Oxford University Press, 2023. |
Series: Contemporary neurology series ; 96 | Includes bibliographical references and index.
Identifiers: LCCN 2022006295 (print) | LCCN 2022006296 (ebook) |
ISBN 9780190843014 (hardback) | ISBN 9780190843038 (epub) | ISBN 9780190843045
Subjects: MESH: Parkinson Disease
Classification: LCC RC382 (print) | LCC RC382 (ebook) | NLM W1 CO769N v.96 2023 |
DDC 616.8/33—dc23/eng/20220525
LC record available at https://lccn.loc.gov/2022006295
LC ebook record available at https://lccn.loc.gov/2022006296
DOI: 10.1093/med/9780190843014.001.0001
This material is not intended to be, and should not be considered, a substitute for medical or other professional advice. Treatment for the
conditions described in this material is highly dependent on the individual circumstances. And, while this material is designed to offer accurate
information with respect to the subject matter covered and to be current as of the time it was written, research and knowledge about medical
and health issues is constantly evolving and dose schedules for medications are being revised continually, with new side effects recognized and
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For Maurice and Marguerite Albin
Men pass, examples abide.
—Tacitus
As you speak comes an avalanche of artillery fire
it’s that bastard Parkinson who is taking so long
he caught up with us at last when we took a walk
on an irregular route our collars loose at the chin
our hands in our pockets we were on leave already
when Parkinson suddenly reminded us that it was
not the end yet that this blasted war isn’t over yet
—From The Last Attack. To Klaus Zbigniew Herbert (trans. Alissa Valles)
Contents

Preface
1. DEFINITION, HISTORY, NOSOLOGY, AND CLASSIFICATION
INTRODUCTION AND DEFINITION
BRIEF HISTORY OF PD
NOSOLOGY AND CLASSIFICATION SCHEME
CLASSIFICATION LEVEL 1: PISM—DIVISION INTO COMPLEX PISM AND SIMPLE PISM
CLASSIFICATION LEVEL 2: SPECIFIC DIAGNOSIS BASED ON ETIOLOGY
AMBIGUITIES AND FUTURE DIRECTIONS
CONCLUSION
2. EPIDEMIOLOGY
INTRODUCTION
PREVALENCE
INCIDENCE
MORTALITY
RISK FACTORS
IMPLICATIONS FOR UNDERSTANDING ETIOPATHOGENESIS AND ANTICIPATING THE
FUTURE BURDEN OF PD
3. PATHOLOGY
INTRODUCTION
THE AGING BRAIN
GROSS PATHOLOGY, LEWY PATHOLOGY, AND Α-SYNUCLEINOPATHY
SUBSTANTIA NIGRA PARS COMPACTA PATHOLOGIES
INCIDENTAL LEWY BODY DISEASE
THE BRAAK ET AL. STAGING SYSTEM
SYNUCLEINOPATHY OUTSIDE THE BRAIN
NON-SYNUCLEINOPATHY PATHOLOGIES
4. PATHOPHYSIOLOGY I: BASAL GANGLIA ARCHITECTURE AND THE STANDARD
MODEL
INTRODUCTION
BASIC BASAL GANGLIA ARCHITECTURE
THE “STANDARD” MODEL OF BASAL GANGLIA PATHOPHYSIOLOGY
COMPLEXITIES OF BASAL GANGLIA ARCHITECTURE
CONCLUSION
5. PATHOPHYSIOLOGY II: NEUROTRANSMITTER SYSTEM DYSFUNCTIONS
INTRODUCTION
NIGROSTRIATAL DOPAMINE SIGNALING FUNCTIONS
HABIT FORMATION AND CHUNKING
CHOLINERGIC PROJECTION SYSTEM DYSFUNCTIONS
SEROTONINERGIC SYSTEM DYSFUNCTIONS
CONCLUSION AND FUTURE CHALLENGES
 6. GENETICS OF PARKINSON DISEASE
INTRODUCTION
DOMINANT FORMS OF PD
RECESSIVE FORMS OF PD
GLUCOCEREBROSIDASE (GBA)
PD GENETIC RISK FACTORS
IMPLICATIONS OF PD GENETIC RESEARCH
7. PATHOGENESIS
NEURONAL VULNERABILITY
Α-SYNUCLEIN
THE PRION-LIKE HYPOTHESIS
MITOCHONDRIAL DYSFUNCTION
OXIDATIVE STRESS
ENDOLYSOSOMAL DYSFUNCTION
NEUROINFLAMMATION
NEUROPROTECTION TRIALS
CONCLUSION
8. PRODROMAL PARKINSON DISEASE
INTRODUCTION
REM SLEEP BEHAVIOR DISORDER
OBSERVATIONAL STUDIES
REM SLEEP BEHAVIOR DISORDER COHORT STUDIES
GENETIC COHORT STUDIES
PURE AUTONOMIC FAILURE
CONCLUSION
9. CLINICAL FEATURES I: INITIAL EVALUATION
PRESENTATION FEATURES
NATURE OF DIAGNOSIS AND DIAGNOSTIC CRITERIA
HISTORY
EXAMINATION
DIFFERENTIAL DIAGNOSIS
TREATMENT RESPONSIVENESS
DIAGNOSTIC ACCURACY
10. CLINICAL FEATURES II: NON-MOTOR FEATURES
INTRODUCTION
COGNITIVE IMPAIRMENTS
NEUROPSYCHIATRIC DISORDERS
SLEEP DISORDERS AND EXCESSIVE DAYTIME SOMNOLENCE
PAIN AND AKATHISIA
FATIGUE
AUTONOMIC DISORDERS
VISUAL DISORDERS
ORAL HEALTH
CONCLUSION
11. CLINICAL FEATURES III: NATURAL HISTORY
INTRODUCTION
ASSESSING PD PROGRESSION
PD PROGRESSION: CLINICALLY SALIENT FEATURES
SUBGROUPS
NATURAL HISTORY SUMMARY
CONTINUING CARE
END-OF-LIFE CARE
12. PHARMACOLOGY I: L-DOPA PHARMACOKINETICS AND PHARMACODYNAMICS
INTRODUCTION
DOPAMINERGIC NEUROTRANSMISSION
L-DOPA PHARMACOKINETICS
L-DOPA PHARMACODYNAMICS
PEAK DOSE DYSKINESIAS
INTERACTIONS OF L-DOPA PHARMACOKINETICS, PHARMACODYNAMICS, AND
DISEASE PROGRESSION
CONCLUSION AND FUTURE DIRECTIONS
13. PHARMACOLOGY II: TREATING PARKINSON DISEASE
INTRODUCTION
USING L-DOPA
WHEN THE HONEYMOON IS OVER
L-DOPA ADJUNCTS
DOPAMINE AGONISTS
CHOLINERGIC AGENTS
OTHER SYMPTOMATIC THERAPIES
FUTURE DIRECTIONS
14. SURGERY
INTRODUCTION
DEEP BRAIN STIMULATION: RATIONALE AND POSSIBLE MECHANISMS
DEEP BRAIN STIMULATION: INDICATIONS
DEEP BRAIN STIMULATION: PROCEDURES
DEEP BRAIN STIMULATION: STN DBS BENEFITS
DEEP BRAIN STIMULATION: GPI DBS BENEFITS AND STN VERSUS GPI DBS
DEEP BRAIN STIMULATION: ADVERSE EVENTS
LESIONAL PROCEDURES
CELL-BASED AND GENE THERAPIES
FUTURE DIRECTIONS
CODA: LOOKING AHEAD
DISEASE HETEROGENEITY
EPIDEMIOLOGY
TREATMENTS
BASIC AND CLINICAL RESEARCH SYNERGIES

Index
Preface

The literature related to Parkinson disease (PD) is immense. Why write something that doesn’t make an
original contribution to our understanding of PD? This book is aimed at filling a perceived gap in the
literature. There are a number of excellent general neurology textbooks and several fine movement
disorders textbooks. At the other end of spectrum is the enormous and expanding primary research
literature on PD, accompanied by many useful critical reviews of specific topics in the PD field. What is
missing is a useful overview bridging the gap between general textbooks and specific topical reviews.
The target audience for this monograph is neurologists in training, residents and fellows, and non–
movement disorder neurologists seeking a useful introduction to the many facets of PD clinical practice
and research. In a number of ways, I’ve tried to write the book I would have liked to have read when I
was in training. I’m hopeful also that this monograph will be useful for scientists seeking an introduction
to PD. Whether my effort is successful is for readers to decide.
Many individuals contributed both directly and indirectly to this book. I am grateful to Eva Feldman
and Craig Panner for providing the opportunity to write this book. The Provost’s office at the University
of Michigan granted me 6 months of sabbatical leave that was crucial for the initiation of this project.
Important direct contributions came from colleagues willing to critically evaluate individual chapters.
Thanks to Jon Stoessl, Bill Dauer, Ray Dorsey, Andy Lieberman, Dan Leventhal, and Kelvin Chou. I thank
anonymous reviewers tapped by Oxford University Press for encouragement and helpful comments.
Special thanks to the gracious and supremely competent Kara Wyant for covering my clinics during the 6
months that I initiated this project. The talented Patricia Ferrer Beals created several of the figures.
Indirect contributors were even more important. My colleagues in the Movement Disorders Division
and the Department of Neurology at the University of Michigan provide a truly collegial environment. As
a resident, I benefited greatly from the instruction and example of several excellent physician-scientists,
including Bob Macdonald, Jim Albers, and Ken Casey.
My former Department Chairs, Sid Gilman and David Fink, were exemplars of academic leadership
who promoted scholarship and expected clinical excellence. I’ve benefited considerably from support
from the Department of Veteran’s Affairs through the VA Ann Arbor Health System Geriatrics Research,
Education, and Clinical Center (GRECC). I’m grateful to the former and current GRECC Directors, Mark
Supiano and Neil Alexander, for their support. I’ve had the considerable luxury of being able to
collaborate with a number of very talented investigators, mainly at the University of Michigan: Nico
Bohnen, Pete Detloff, Bob Koeppe, Bill Dauer, Martin Sarter, Martijn Muller, Vikas Kotagal, Hank
Paulson, Dan Leventhal, Kelvin Chou, and Cathie Spino. My thanks to all of them. I’m particularly
grateful to Kirk Frey, not only for his intellectual partnership, but also for his friendship over the period
of many years. My greatest professional debt is to my former mentors, Anne Young and the late Jack
Penney, two superb scientists, excellent clinicians, and exceptional friends who guided me in both
movement disorder research and clinical practice.
My greatest, and unrepayable, debt is described in the dedication.
Chapter 1
Definition, History, Nosology, and Classification

INTRODUCTION AND DEFINITION

The description and discussion of the many aspects of Parkinson disease (PD) is dogged by the fact that
PD is an ambiguous concept. What we call PD is an etiologically and clinically heterogeneous
metasyndrome overlapping a number of other disorders. Definitions, diagnostic criteria, and
classification schema provide essential common vocabularies for communication among clinicians and
researchers. Definitions, diagnostic criteria, and classification schemes for PD, however, are constructs
imposed on variable and imperfectly understood disease biology. Difficulties with the formulation of PD
definitions, diagnostic criteria, and classification schemes include historical and contemporary use of
competing definitions of PD, disease heterogeneity, the existence of disorders with overlapping clinical
and pathological features, and ambiguous use of the terms “disease” and “syndrome.” For the purposes of
exposition and discussion in this volume, the following inclusive—perhaps vague—definition of PD is
employed:
Parkinson disease is an age-related neurodegenerative syndrome characterized primarily by clinical features of parkinsonism, notably
bradykinesia, consequent to relatively selective, early degeneration of dopaminergic nigrostriatal terminals. It is gradually progressive over
the course of several years. Its early clinical features are driven by striatal dopaminergic denervation with prominent later clinical features
secondary to extrastriatal pathologies.

The defining features of parkinsonism and bradykinesia are discussed below.

This definition incorporates several features common to most definitions of PD. These include the
requirement for typical clinical manifestations, typical onset later in life, the underlying presence of
neurodegeneration, and a slowly progressive course secondary to neurodegeneration. This definition also
includes the concept that defining initial clinical manifestations are driven by preferential and gradual
loss of dopaminergic nigrostriatal terminals, the implicit corollary that some clinical features will
improve with dopamine replacement therapy (DRT), and the implicit corollary that neurologic features
secondary to dysfunction of other central nervous system (CNS) systems (e.g., spasticity due to
corticospinal tract dysfunction or dystaxia) are absent, particularly in the early phase of disease. To be
clinically useful, diagnostic classifications should predict natural history, and this definition incorporates
an element of natural history by describing defining motor features, progressive course, and later clinical
features. This definition also points to the importance of evolving pathologies outside the nigrostriatal
system that dominate the later course of PD. This definition is silent with respect to specific features of
underlying histopathology or specific etiologies. Since it is based on clinical manifestations, this
definition doesn’t address prodromal features that are the subject of considerable research interest and
likely reflect dysfunction and/or neurodegeneration that likely precedes nigrostriatal neuron degeneration
(see Chapter 8, “Prodromal Parkinson Disease”).
The age-related component of this definition addresses the fact that the great majority of PD occurs
late in life, with incidence and prevalence increasing markedly in the last decades of life (see Chapter 2,
“Epidemiology”). PD and parkinsonism occur, however, at earlier ages. Earlier onset PD has been
fractionated conventionally as juvenile onset PD (JOPD; <20 years of age) and young onset PD (YOPD;
20–40 years [sometimes 20–45 or 50 years]). What has been termed JOPD, however, almost invariably
does not meet the criteria described above because it typically presents with additional major CNS
features (see below). Other than age of onset, the considerable majority of YOPD patients resemble
typical, late age of onset PD patients. So-called JOPD is highly likely, and YOPD somewhat likely, to be
caused by monogenic defects.

BRIEF HISTORY OF PD
In its reliance on major clinical features, this PD definition is a direct descendent of the original 19th-
century characterizations of PD. While descriptions of what was likely PD are documented in some
premodern Western and non-Western medical writings, the description that established PD as a distinct
entity is James Parkinson’s famous treatise of 1817, “An Essay on the Shaking Palsy.”1,2,3 Based on
evaluation of a small number of subjects, Parkinson’s concise and articulate essay identified key clinical
features of PD and differentiated PD from other tremulous conditions. “On the Shaking Palsy” is notable
also for Parkinson’s suggestion that the cervical spinal cord was the site of pathology, thoughtful
discussion of the limitations of clinical characterization of disease entities, and the need for pathologic
examination of PD patients. Political radical and pioneering paleontologist, the polymath Parkinson was a
typical figure of the Enlightenment. “On the Shaking Palsy” reflects the preoccupation with accurate
description and classification typical of much Enlightenment science.
Following Parkinson’s initial description, a number of 19th-century neurologists, including Marshall
Hall, Charcot, and Gowers, expanded knowledge of the clinical features of PD. Charcot emphasized the
key feature of bradykinesia, was responsible for the eponym “Parkinson’s disease,” and noted the
tremorolytic effects of what we now know were antimuscarinic preparations. The underlying pathology of
PD remained unclear into the 20th century. An influential 1893 case report by Blocq and Marinesco
described hemiparkinsonism secondary to a tuberculoma that affected the right substantia nigra (SN). In
1919, the Russian neuropathologist Tretiakoff, working in France, published his doctoral thesis of an
autopsy series of PD patients. Tretiakoff described loss of pigmented SN neurons and Lewy bodies within
surviving SN neurons. The German neurologist and pathologist Friedrich Lewy had previously described
neuronal inclusion pathology in PD but not within the SN. Tretiakoff’s assignment of SN pathology with
intraneuronal Lewy bodies as the key feature of PD neuropathology was initially controversial but
subsequently supported by the detailed work of the German neuroscientist Rolf Hassler in the late 1930s
and with further confirmation published by British neuropathologists in the early 1950s.
Subsequent advances in understanding of PD were characterized by fruitful interactions between
directed studies of PD and expanding basic neurobiology research, something that continues to be an
important feature of PD research. Work on catecholamine neurotransmitters led to Arvid Carlsson’s 1957
demonstration that reserpine-induced bradykinesia was reversed by the dopamine precursor L-dopa and
his suggestion that L-dopa would be an effective treatment for PD. Considerable subsequent basic and
clinical research by several investigators, notably that of Oleh Hornykiewicz and George Cotzias,
established dopamine as the neurotransmitter of the nigrostriatal projection, demonstrated dopamine
deficits in PD, and demonstrated that L-dopa is an effective symptomatic therapy for PD. By 1970, the
modern era of PD treatment and PD research had begun.

NOSOLOGY AND CLASSIFICATION SCHEME

Ambiguities regarding the classification of and diagnostic criteria for PD and related disorders start with
the terms “disease” and “syndrome.” As pointed out in thoughtful discussions by Weiner and Kempster et
al., this is a recurrent theme in PD-related nosology.4,5 “Disease” is commonly defined as impairment(s)
of normal function or structure leading to characteristic signs and symptoms.6,7 This definition is silent as
to specific etiologies, with alternative definitions and common usage incorporating identification of
disease with specific etiologies or specific pathologic features (e.g., pneumococcal pneumonia).
“Syndrome” is similarly ambiguous. Strictly speaking, it refers to consistently co-occurring clinical signs
and symptoms (e.g., fibromyalgia syndrome) but is often used with the implication of common
pathophysiology and/or organ dysfunction resulting from several potential etiologies (e.g., the syndrome
of acute hepatic failure).
PD and its related disease terminology exemplifies ambiguous use of “disease” and “syndrome.”
There are three partly contradictory approaches to PD diagnostic criteria. The first, used by several
clinical criteria, including the recent Movement Disorders Society (MDS) Clinical Diagnostic criteria, is
the clinical construct of dopamine replacement therapy–responsive parkinsonism.8,9,10,11,12,13 The second
is the clinicopathologic construct of clinical parkinsonism accompanied by neuropathologic
identification of SN neuronal loss and α-synucleinopathy.14 The third is the clinicogenetic construct of
clinical parkinsonism secondary to an identified mutation causing nigrostriatal degeneration.
Clinically defined levodopa-responsive parkinsonism, however, may be secondary to other entities such
as multiple system atrophy (MSA). Some clinicogenetically defined PD, notably that associated with
homozygous PRKN mutations, some homozygous PINK1 mutations, and some dominant LRRK2 mutations,
lack α-synucleinopathy and would not be classified as PD by clinicopathologic criteria (see Chapter 6,
“Genetics of Parkinson Disease”).15,16 Confounding features of the clinicogenetic approach are
incomplete penetrance and the phenomenon of mutations within a single gene causing variable
phenotypes. Mutations in C9orf72, for example, cause amyotrophic lateral sclerosis and frontotemporal
dementia but are also implicated as causes of a variety of other neurodegenerative disorders and even
some psychiatric disorders.17 Ambiguities of clinicogenetic classification of PD spill over into other
classification approaches. The recent MDS Clinical Diagnostic criteria are aimed at maximizing clinical
identification of PD associated with α-synucleinopathy and are ambiguous with respect to the
classification of parkinsonism associated with Pink1, PRKN, and some LRRK2 mutations.8
The most precise use of the term “disease” would be to use it to only label conditions with specific
etiologies (e.g., Huntington disease). Assignment of specific etiology should carry with it the critical
feature of specifically describing natural history. The most precise use of “syndrome” would be to use it
only to describe distinctive clinical features with common underlying pathophysiology but several
potential etiologies. Both the clinical and clinicopathologic construct definitions of PD are typical uses of
the term “disease” but are actually syndromic descriptors. An alternative suggested by some authors is to
abandon the term PD and refer to all these entities as “Parkinson syndrome.”18,19 While logically
coherent, this approach is probably not practical. The term “Parkinson disease” is probably too strongly
embedded to be uprooted easily, and clinicians and researchers are already using another term as a
syndrome descriptor. The term “parkinsonism” (Pism) is widely used to describe the constellation of
clinical signs and symptoms associated with abnormal nigrostriatal dopaminergic neurotransmission. This
syndromic descriptor is silent about not only etiology but also about natural history.
Another problem is classification of disorders that exhibit parkinsonism and other prominent
neurologic features as part of their initial presentations. What has historically been termed “juvenile onset
PD” is in this category. Some of these disorders (e.g., Kufor-Rakeb syndrome, caused by mutations of the
ATP13A2 gene) may have pathogenetic mechanisms that overlap with some forms of PD.20 Including these
disorders in a classification scheme may provide useful perspectives on the pathogenesis of PD and
related disorders.
The problems of ambiguous definitions and heterogeneous disease are hardly unique to PD clinical
care and research. Other fields deal with this problem in different ways. The highly diverse ataxic
disorders, whose unifying feature is some form of cerebellar dysfunction, are classified exclusively on the
basis of etiologies. This is clumsy given the varied pathologic processes affecting the cerebellar system
and the remarkable number of inherited cerebellar disorders. Another approach is the hierarchic
multilevel classification approach adopted by the International League Against Epilepsy (ILAE).21,22 The
ILAE system incorporates clinical and laboratory data at different levels—seizure type, epilepsy type,
and epilepsy syndrome type—in parallel with the search for specific etiologies. This multilevel approach
has the advantage of usefully restricting classification and diagnostic choices at each level. This largely
semiology-based approach is easier to use than the “flatter” etiologic classification of ataxic disorders,
particularly for clinical care. A third approach is the classification system developed recently for
evaluation of dystonias.23 This is a biaxial scheme using an axis of clinical characteristics and a second
axis based on etiologies, where the latter are defined by pathologic findings and/or genetic data.
Incorporating etiology into a classification scheme is relevant for clinical research where subject
stratification and subtype identification may be important.
An overarching classification scheme that attempts to reduce ambiguities secondary to terminology and
disease heterogeneity may be useful. Because the terms “Parkinson disease” and “parkinsonism” are
already embedded in the field, I suggest adapting and clarifying them rather than abandoning them.
Following the lead of the ILAE classification scheme for epilepsies and the recognition that what we call
PD has multiple etiologies, I suggest retaining the term “parkinsonism” as a syndrome descriptor (as it is
most commonly used now) in the strict sense of a constellation of signs and symptoms resulting from a
common underlying pathophysiologic substrate; in this case, striatal dopaminergic signaling dysfunction.
PD is then used to define a more specific entity (see below).
I suggest a bilevel hierarchic approach to classification and diagnosis of PD and related disorders
based on clinical features supplemented by other investigations. This approach may be clinically useful,
incorporates etiology to the extent possible, and is aimed at providing guidance for subject
characterization in clinical research (Figure 1.1).
Figure 1.1 Two-level classification approach for Parkinson disease.

CLASSIFICATION LEVEL 1: PISM—DIVISION INTO COMPLEX PISM AND SIMPLE PISM

As with existing approaches, classification and diagnosis begins with the recognition of the syndrome of
Pism. In most prior schemes, designation as Pism is usually the presence of 2 of 4 so-called cardinal
features: bradykinesia, rigidity, resting tremor, postural instability. The simpler approach used in the MDS
Clinical Diagnostic Criteria is adopted for this classification scheme. Limb bradykinesia is seen as the
critical core feature of Pism and is defined as slowness of movement accompanied by decrements of
movement speed and/or amplitude. Bradykinesia accompanied by either rigidity or rest tremor (or both)
constitutes Pism.8 The MDS Clinical Diagnostic Criteria approach is based on recognition that these key
clinical features stem from disrupted nigrostriatal dopaminergic neurotransmission. Postural instability is
excluded as a core feature as it may result from non–dopaminergic system pathologies. The MDS Clinical
Diagnostic Criteria stress the role of expert clinical evaluation in assigning the designation of Pism.
Given the presence of unequivocal Pism, the first level of classification is between complex Pism
(CPism) and simple Pism (SPism). The designation of CPism indicates Pism in the presence of other
clinically significant neurologic features not due to nigrostriatal dopaminergic dysfunction. Examples
include significant early cognitive or autonomic dysfunction, pyramidal tract motor deficits, cerebellar
dysfunction, and other neurologic disorders. Examples of disorders that would sort into this category
include dementia with Lewy bodies (DLB), Kufor-Rakeb syndrome, POLG-related syndromes, 22q11.2
syndromes, polyglutamine disorders such as the spinocerebellar ataxias, and frontotemporal dementias.
The remaining, and great majority, of patients with parkinsonism would then be classified in the category
of SPism.

CLASSIFICATION LEVEL 2: SPECIFIC DIAGNOSIS BASED ON ETIOLOGY

The next level of classification is the assignment of a specific diagnostic entity reflecting, to the extent
feasible, identification of specific etiologies (Table 1.1 and Table 1.2). I suggest a Linnaean-type
binomial designation for each specific diagnosis: CPism– or SPism–diagnosis (e.g., SPism–LRRK2; see
below). Given incomplete knowledge of the etiologies of both SPism and CPisms, the present criteria for
assignment of specific etiologies vary from clinical criteria to detection of specific mutations, with
pathological classifications occupying a middle position. Presently used clinical criteria are placeholders
for more definitive etiologic assessments. Though pathologic criteria are more specific, they may not be
definitive because more than one etiology may give rise to identical or highly similar pathologic features.
Genetic etiologies may be the most definitive, but at this point only characterize a minority of individuals
with Pism.

Table 1.1 List of complex parkinsonism entities

Etiology Criteria
CPism: Dementia with Lewy Bodies Clinical criteria32
Pathologic criteria33
CPism: Progressive supranuclear palsy Clinical criteria34
Pathologic criteria35,36
CPism: Frontotemporal dementia Clinical criteria37
Pathologic criteria38 Genetic testing (MAPT, PRGN, C9orf72, etc.)
CPism: Multiple system atrophy Clinical criteria39
Pathologic criteria40
CPism: Corticobasal syndrome Clinical criteria41
Pathologic criteria42
CPism: POLG Genetic testing: OMIM 174763
CPism: 22q11.2 Genetic testing43
CPism: SCA2 Genetic testing: OMIM 601517
CPism: SCA3 Genetic testing: OMIM 109150
CPism: ATP13A2 (Kufor-Rakeb) Genetic testing: OMIM 606693
CPism: NBIAs (PKAN, PLA2G6) Genetic testing: OMIM 234200 and 612953
Not intended to be exhaustive. Additional entities, particularly genetic entities, can be added.
OMIM, Online Mendelian Inheritance in Man.
Table 1.2 List of simple parkinsonism entities
Etiology Criteria
SPism: Idiopathic Clinical criteria: MDS Criteria8 Pathologic criteria14
SPism: Vascular Clinical criteria24
SPism: Drug-induced Clinical criteria26
SPism: GBA (glucocerebrosidase) Genetic testing: OMIM 606463
SPism: LRRK2 (leucine repeat rich kinase 2) Genetic testing: OMIM 609007
SPism: PRKN (Parkin; RBR E3 ubiquitin protein ligase) Genetic testing: OMIM 602544
SPism: PINK1 (PTEN-induced putative kinase 1) Genetic testing: OMIM 608309
SPism: DJ1 (parkinsonism-associated deglycase) Genetic testing: OMIM 602533
SPism: SNCA (α-synuclein) Genetic testing: OMIM 163890
SPism: VPS35 (VPS35, retromer complex component) Genetic testing: OMIM 601501
Not intended to be exhaustive. Additional entities, particularly genetic entities, can be added.
Movement Disorders Society (MDS); OMIM, Online Mendelian Inheritance in Man.

Methods for establishing etiologies include clinical assessments, laboratory and imaging assessments,
genetic analyses, and pathologic evaluations. Where feasible, conventional diagnostic criteria are
incorporated. Examples of specific diagnoses include progressive supranuclear palsy (PSP), as defined
by established clinical and clinicopathologic criteria (CPism–PSP), PRKN mutation associated PD
(SPism–PRKN) and LRRK2 mutation associated PD (SPism–LRRK2) as defined by genetic studies, and
drug-induced PD (SPism–Drug-Induced), as defined by clinical (and potentially molecular imaging)
evaluations (Tables 1.1 and 1.2).
The broadest and most common diagnosis in the SPism category is SPism–Idiopathic, essentially what
is conventionally classified as PD via MDS Clinical Diagnostic criteria but excluding entities with a
specific genetic etiology. As in the MDS Clinical Diagnostic Criteria, good response to treatment is an
additional cardinal feature of SPism–Idiopathic. This is clearly a heterogeneous group. The hope is that
as the pathogenesis of SPism–Idiopathic becomes understood better, it will be possible to fractionate
SPism–Idiopathic on the basis of defined etiologies or pathogenic mechanisms.

AMBIGUITIES AND FUTURE DIRECTIONS

Additional problems impede etiologic classifications. Some disorders lack well-defined diagnostic
criteria. There are proposed clinical criteria for SPism–Vascular, but no generally accepted or validated
clinical or pathologic criteria for this entity.36,37,38 The Diagnostic and Statistical Manual of Mental
Disorders (DSM-5) contains only vague criteria for SPism–Drug-Induced.39 These criteria, for example,
don’t specify bradykinesia as the core feature of parkinsonism. Genetic classification is not always
straightforward. In individuals with potential mutations not previously associated with Pism, there can be
considerable uncertainty about the significance of genetic results. In some cases, a specific form of
mutation may lead to different phenotypes. Individuals with triplications of the SNCA gene (encoding the
protein α-synuclein) can present with either typical Pism (SPism–SNCA) or as DLB, which would then
be classified as CPism–SNCA.
A controversial aspect of this classification approach is the separation of currently defined DLB
(CPism–DLB) and SPism–Idiopathic.40,41 At end stage, these entities exhibit strongly overlapping, if not
wholly identical pathology. DLB and SPism–Idiopathic exhibit differing natural history. Whether this is
due to comorbid pathologies, differences in the depositions or distributions of α-synuclein, or other
factors is unclear. Levy et al. present a sophisticated argument that preserving the distinction between
DLB and SPism–Idiopathic is clinically useful, will facilitate research, and offers a cogent alternative to
the simple “1-year rule” used presently to differentiate DLB and SPism–Idiopathic.42 Further research
will be needed to clarify the relationship of DLB and currently defined SPism–Idiopathic.
 Because SPism-Idiopathic is heterogeneous, I anticipate that future research will fractionate this
population. It is plausible that differences in clinical phenotype and natural history could be secondary to
different pathogenetic mechanisms. One possibility is that SPism–Idiopathic is an “oligogenic” disorder
driven by combinations of individually harmless but cumulatively damaging mutations in several genes.43
Different combinations of genes/mutations might produce different subtypes. It is also plausible that much
of the clinical heterogeneity of SPism–Idiopathic is due to the effects of comorbid conditions such as
vascular brain injury and amyloidopathy.
This classification approach is flexible in that it can be modified easily as new data clarify the
etiologies and pathogenesis of SPisms and CPisms. There is the possibility that some forms of SPism
result from dysfunction of common pathogenic pathways. In some genetic forms of SPism (e.g., SPism–
PRKN or SPism–PINK1), mitochondrial dysfunction is likely at the heart of pathogenesis (see Chapter 6,
“Genetics of Parkinson Disease” and Chapter 7, “Pathogenesis”). In SPism–GBA, endolysosomal
dysfunction may be the basis of neurodegeneration (see Chapters 6 and 7). SPism–Idiopathic might sort
into subgroups based on relatively discrete biochemical-cellular mechanisms of neurodegeneration.
Differing mechanisms of pathogenesis may ultimately have therapeutic implications, and common
pathogenetic mechanisms could be incorporated into the second stage of this classification scheme or
form the basis of a third level of classification as a way of subtyping SPisms.

CONCLUSION
To return to the conventional definition of PD presented in the introductory section of this chapter, PD
encompasses SPism–Idiopathic and several of the genetic disorders that produce SPism. In clinical
practice, it is impossible to differentiate SPism–Idiopathic and these genetic SPisms. The former is much
more common than any of the genetic SPisms, and, in subsequent chapters, term “Parkinson disease” is
largely used as a substitute for SPism–Idiopathic PD. The genetic SPisms will be discussed specifically
in a later chapter (Chapter 6, “Genetics of Parkinson Disease”).

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13. Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: A clinico-pathological study
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14. Dickson DW, Braak H, Duda JE, et al. Neuropathological assessment of Parkinson’s disease: Refining the diagnostic criteria. Lancet
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15. Poulopoulos M, Levy OA, Alcalay RN. The neuropathology of genetic Parkinson’s disease. Mov Disord. 2009;27:831–842.
16. Wider C, Skipper L, Solida A, et al. Autosomal dominant dopa-responsive parkinsonism in a multigenerational Swiss family.
Parkinsonism Relat Disord. 2008;4:465–470.
17. van der Ende EL, Jackson JL, White A, Seelor H, van Blitterswijk M, Van Swieten JC. Unravelling the clinical spectrum and the role of
repeat length in C9ORF79 repeat expansions. J Neurol Neurosurg Psychiatr. 2021;92:502–509.
18. Titova N, Padmakumar C, Lewis SJG, Chaudhuri KR. Parkinson’s: A syndrome rather than a disease? J Neural Transm (Vienna).
2017;124:907–914.
19. Albin RL, Dauer WT. Parkinson syndrome: Heterogeneity of etiology; heterogeneity of pathogenesis? Neurology. 2012;79:202–203.
20. Kett LR, Dauer WT. Endolysosomal dysfunction in Parkinson’s disease: Recent developments and future challenges. Mov Disord.
2016;31:1433–1443.
21. Fisher RS, Cross JH, French JA, et al. Operational classification of seizure types by the International League Against Epilepsy: Position
Paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58:522–530.
22. Scheffer IE, Berkovic S, Capovilla G, et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for
Classification and Terminology. Epilepsia. 2017;58:512–521.
23. Albanese A, Bhatia K, Bressman SB, et al. Phenomenology and classification of dystonia: A consensus update. Mov Disord.
2013;28:863–873.
24. McKeith IG, Boeve BF, Dickson DW, et al. Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the
DLB Consortium. Neurology. 2017;89:88–100.
25. McKeith IG, DW Dickson, J Lowe, et al. Diagnosis and management of dementia with Lewy bodies: Third report of the DLB
Consortium. Neurology. 2005;65:1863–1872.
26. Hoglinger GU, Respondek G, Stamelou M, Movement Disorder Society-endorsed PSP Study Group. Clinical diagnosis of progressive
supranuclear palsy: The Movement Disorder Society criteria. Mov Disord. 2017;32:854–864.
27. Litvan I, Hauw JJ, Barktko JJ, et al. Validity and reliability of the preliminary NINDS neuropathological criteria for progressive
supranuclear palsy and related disorders. J Neuropathol Exp Neurol. 1996;55:97–105.
28. Hauw JJ, Daniel SE, Dickson D, et al. Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome
(progressive supranuclear palsy). Neurology. 1994;44:2015–2019.
29. Olney NT, Spina S, Miller BL. Frontotemporal dementia. Neurol Clin. 2017;35:339–374.
30. Cairns NJ, Bigio EH, Mackenzie IR, et al. Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration:
Consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol. 2007;114:5–22.
31. Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology.
2008;71:670–676.
32. Trojanowski JQ, Revesz T, Neuropathology Working Group on MSA. Proposed neuropathological criteria for the post mortem diagnosis
of multiple system atrophy. Neuropathol Appl Neurobiol. 2007;33:615–620.
33. Armstrong MJ, Litvan I, Lang AE, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013;80:496–503.
34. Dickson DW, Bergeron C, Chin SS, et al.; Office of Rare Diseases of the National Institutes of Health. Office of Rare Diseases
neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol. 2002;61:935–946.
35. Fung WL.Butcher NJ, Costain G. Practical guidelines for managing adults with 22q11.2 deletion syndrome. Genet Med. 2105;17:599–
609.
36. Zijlmans JC, Daniel SE, Hughes AJ, et al. Clinicopathological investigation of vascular parkinsonism, including clinical criteria for
diagnosis. Mov Disord. 2004;19:630–640.
38. Kaira S, Grosset DG, Benamer HT. Differentiating vascular parkinsonism for idiopathic Parkinson’s disease: A systematic review. Mov
Disord. 2010;25:149–156.
37. Rektor I, Bohnen NI, Korczyn AD, et al. An updated diagnostic approach to subtype definition of vascular parkinsonism:
Recommendations from an expert working group. Parkinson Rel Disord. 2018;49:9–16.
39. DSM Library. Accessed May 5, 2021. http://dsm.psychiatryonline.org/doi/full/10.1176/appi.books.9780890425596.MedicationInduced
40. Boeve BF, Dickson DW, Duda JE, et al. Arguing against the proposed definition changes of PD. Mov Disord. 2016;31:619–1622.
41. Postuma RB, Berg D, Stern M, et al. Abolishing the 1-year rule: How much evidence will be enough? Mov Disord. 2016;31:1623–
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Chapter 2
Epidemiology

INTRODUCTION
While Parkinson disease (PD) was identified as a distinct clinical entity in the 19th century and its
pathology clarified in the first half of the 20th century, it is likely that it was during and after the mid-20th
century that it emerged as a major medical problem. PD was probably a rare condition in the 19th century
and earlier periods. The insightful discussion of PD in the 1892 edition of William Gowers’s textbook, A
Manual of Diseases of the Nervous System, is based on his personal series of 115 patients evaluated
over more than two decades at what was then the National Hospital for the Paralyzed and Epileptics,
Queen Square, London.1 Working primarily as clinician in the equivalent of a tertiary referral center in the
middle of the most densely populated part of Britain, Gowers saw approximately five new PD patients
per year, a rate that will strike contemporary neurologists as remarkably low. It is likely that population
growth and increased life expectancy accompanying modernization gradually drove up both the absolute
number of PD patients and the prevalence of PD in industrialized nations. More recently, declines in
competing causes of age-related mortality are probably also contributing to an increasing burden of PD.
General improvements in medical care likely extended the life expectancy of PD patients, further
increasing prevalence. It is possible also that improved symptomatic treatment of PD with dopamine
replacement therapies (DRTs) also increased life expectancy in PD and contributed to rising prevalence
(see “Mortality” below). There are also suggestions that products of our industrial civilization are hazard
factors for PD and contributed to increased PD prevalence in the 20th century (see “Risk Factors”
below).
Epidemiologic research on PD is one of many areas hampered by the metasyndromic nature of PD.
Leaving aside all the difficulties inherent in consistent ascertainment, classification, and follow-up of
participants, the intrinsically heterogeneous nature of what we label as PD is a major obstacle to
interpreting the results of many epidemiologic studies. As epidemiologic studies often provide clues to
the etiopathogenesis of disease, identify modifiable risk factors, and are critical to estimating the current
and future social impacts of disease, limitations of PD epidemiologic studies have adverse scientific and
policy consequences.
Recent analyses suggest that the global burden of PD has increased to a considerable extent. Data from
the Global Burden of Disease, Injuries, and Risk Factors Study (GBD) suggest that PD is the neurological
disorder with the most rapid, recent increases in prevalence, disability, and deaths.2,3 The estimated
number of those affected worldwide in 1990 was 2.5 million. The estimated number of those affected
worldwide in 2015 was 6.1 million. While much of this impressive increase is attributable to population
aging, the GBD analyses suggest that this marked increase was not due solely to population aging because
age-standardized prevalence rates were estimated to have increased by approximately 22%.3 A more
recently published GBD analysis of neurologic disease trends in the United States is consistent with the
earlier global assessment.4 Potential contributors to PD prevalence increase above what would be
predicted for population aging are better ascertainment, increasing incidence, and longer survival of PD
patients. The available data (see “Incidence” below) doesn’t permit reliable assessment of which of these
variables is changing. Regardless, with continued world population growth and world population aging,
the global PD burden is likely to increase markedly, particularly in low- and middle-income nations
undergoing demographic transitions (Figure 2.1). Some authors describe this as the “Parkinson
pandemic,” another manifestation of the civilization-wide transition from a human world strongly
influenced by acute infectious disease to one characterized by high levels of chronic, age-related
illnesses.5,6

Figure 2.1 Projected global burden of Parkinson disease accounting for changes in aging, longevity, smoking rates, and industrialization, 1990–
2040. Reprinted with permission from Dorsey et al. J Parkinson Dis. 2018;8(S1):s3–s8.5 Copyright (2018) with permission from IOS Press.
Permission obtained also from Prof. Ray Dorsey.

It is likely that there was another significant change in the epidemiology of parkinsonism (Pism) during
the 20th century. The post-encephalitic parkinsonism (PEP) described as a consequence of the great
Influenza pandemic at the end of World War I was probably a major source of patients with Pism during
the mid-20th century. More than 10% of the large case series (802 patients; seen at Columbia University
from 1949–1964) forming the basis of the important 1967 Hoehn and Yahr paper on the natural history of
PD carried a diagnosis of PEP.7 In the century-long (1914–2010) autopsy series of Pism patients (N = 261
from 9,359 total autopsies) from the University Hospitals of Geneva, approximately 3% were found to
have PEP, with the last PEP autopsy case in 1962.8 The relatively high prevalence of PEP in the mid-20th
century led to Poskanzer and Schwab’s daring hypothesis, since unequivocally falsified, that virtually all
PD was actually a form of PEP and a sequel of the 1918–1919 influenza pandemic, with the corollary that
PD incidence would decline in the second half of the 20th century.9
The great majority of epidemiologic studies, reviewed here, of PD were performed in the modern
(after the introduction of DRT) period. While all agree about the contemporary relatively high prevalence
of PD, there is less agreement about specific prevalence and incidence rates, trends in prevalence and
incidence, trends in mortality and the effects of treatments, and the existence and nature of putative
environmental risk factors. Some aspects of PD epidemiology will be addressed in other chapters.
Proximate causes of death in PD patients differ somewhat from those experienced in age-matched controls
and will be discussed in Chapter 11, “Clinical III: Natural History.” Aspects of genetic epidemiology of
PD will be covered in Chapter 6, “Genetics of Parkinson Disease.”

PREVALENCE
Prevalence estimates for PD vary significantly due in part to methodological differences between studies.
Definitions of PD, case ascertainment methods, and types of study cohorts all vary considerably. Studies
in different nations or regions may also produce differing results due to differences in population age
structures. In general, more rigorously performed studies produce higher prevalence estimates. Three
recent papers summarize much of the prevalence literature. Pringsheim et al. performed a systematic
review and meta-analysis of prevalence studies from 1985 to 2010.10 Meta-analysis of the worldwide
data showed the expected increase in prevalence with age, rising from 41/100,000 in individuals aged
40–49 years to 1903/100,000 in individuals older than 80 years. Comparisons of male and female
differences in prevalence by decade did not reveal many significant differences, a result different from
clinical practice and what is generally seen in clinical research, where male predominance is the rule.
The GBD study gave somewhat different results, suggesting prevalence peaking in the mid-80s and
consistently higher prevalence among men (Figure 2.2).4 Marras et al. recently combined data from five
cohort studies in North America to estimate combined prevalence in Canada and the United States.11
Standardized to the US population by 2010 Census estimates, for men and women older than 45,
prevalence was 572/100,000; for women older than 45, prevalence was 488/100,000; and for men older
than 45, 667/100,000. These prevalence estimates translate to approximately 700,000 affected
individuals in the United States in 2010. This is similar to the GBD estimate for the United States in 2016.
Marras et al. indicate that their estimates are likely minimum estimates of PD prevalence in the United
States. A more recent prevalence study based on US administrative data suggests that there were
approximately 1,000,000 individuals affected by PD in the United States with a male to female ratio of
approximately 60:40 in 2017.12 This approximates an overall prevalence rate of 300/100,000 in the
United States.
Figure 2.2 Worldwide prevalence of Parkinson disease by age and sex in 2016. Reprinted from GBD 2016 Parkinson’s Disease
Collaborators. Lancet Neurol. 2017;17:939–963.3

Prevalence studies suggest ethnicity-based differences in PD prevalence. Pringsheim et al. suggested

that standardized PD prevalence rates were lower in Asian than European North American populations. A
subsequent systematic review and meta-analysis by Abbas et al. supports this inference.13 Other studies
suggest also that African Americans exhibit significantly lower PD prevalence, on the order of a 50%
reduction, compared with Americans of European descent.14,15,16 Within the United States, there may also
be significant regional differences in PD prevalence (Figure 2.3).14 Possible ethnic and regional
prevalence differences point toward significant and varying genetic and environmental factors influencing
PD risk.
Figure 2.3 County-level incidence of Parkinson disease in the United States (2003) estimated from Medicare data. Band of increased
incidence across lower Great Lakes, Ohio River Valley, and Mississippi River Valley. Reprinted with permission from Willis AS, et al.
Neuroepidemol. 2010;34:143–151.14 Permission from Karger AG, Basel.

INCIDENCE
As with prevalence studies, there is considerable variation in methods and outcomes of incidence studies.
Systematic reviews from Twelves et al. (2003) and Hirsch et al. (2016) nicely cover the available studies
in this area, and Hirsch et al. provided some formal meta-analysis of the accumulated studies.17,18 Hirsch
et al. report PD incidence of 38/100,000 person years in women over the age of 40 and 61/100,000
person years in men over the age of 40. Meta-analysis indicated a strong increase in PD incidence with
age. Incidence in both men and women increased approximately 35-fold from the fifth to the eighth decade
of life. Incidence appeared to peak in eighth decade (70–79), consistent with prevalence results from the
worldwide GBD study.3 Incidence was greater in men than in women in the seventh and eighth decades of
life. A prior meta-analysis of prevalence studies by this group indicated sex differences in PD prevalence
only in the sixth decade of life.10 Hirsch et al. suggested that male incidence may be higher but men may
experience higher mortality rates, and this inference is consistent with accumulated data suggesting that
PD is less aggressive in women.19 On the other hand, the worldwide GDB study analysis indicates higher
PD prevalence in men than in women at virtually all ages.3
An important but unresolved issue is whether PD incidence is changing over the past few decades.
Some data from the United States and Canada suggest stable incidence in recent decades.20,21 Other
studies, however, return discrepant results. Using a large United Kingdom primary care database (The
Health Improvement Network), Horsfall et al. reported a modest, 1% per year decline in incident PD
diagnoses over the period from 1999 to 2009.22 Goldacre et al. reported parallel results from death
certificate data in the United Kingdom over the period from 1979 to 2006.23 A recent analysis of Finnish
data over the past quarter century suggests no changes in PD incidence.24 Using data collected in the
Rochester Epidemiology Project (Olmsted County, Minnesota), Savica et al. evaluated incident PD over
the period from 1976 to 2005.25 Incidence increased markedly in men but not in women, from
approximately 40/100,000 person-years to approximately 56/100,000 person-years over the study period.
Increased PD incidence was most marked in men older than 70. Savica et al. speculated that the rising PD
male incidence was linked to declining rates of smoking in American men (see “Risk Factors” below).
The recent GBD study of neurologic disease trends in the United States suggests rising age-specific
incidence of PD in the country.4 Very different results were reported by Darweesh et al. in an analysis of
data from the Rotterdam Study, a prospective, community-based cohort study of age-related disease.26
Comparison of Pism and PD incidence between the 1990 and 2000 cohorts at 10-year follow-up revealed
marked declines in Pism (~40%) and PD (~60%) incidence. While this study has the strengths of a
prospective, community-based study with excellent participant characterization and follow-up, the
number of incident Pism and PD cases was relatively small. Evaluation of Taiwanese administrative data
from 2004 to 2011 suggests declining PD incidence in that nation.27
At this time, whether there are any recent trends in PD incidence is unclear. All studies to date have
significant limitations. The most interesting and potentially impactful outcome would be to establish that
there are different trends in PD incidence in different communities. This would point toward important
environmental risk factors for PD, something that has been elusive.

MORTALITY
There is general agreement that PD is associated with excess mortality, with varying estimates of the
magnitude of PD effects. Whether DRT modifies mortality is also unclear. There is considerable variation
in studies examining mortality in PD. Some were based on clinic samples, some on clinical trial cohorts,
some are community-based studies, and some are based on administrative data. Ascertainment of PD
varies from study to study, and there are varying follow-up durations. Almost all relevant data were
generated in the post-DRT period. In their major case series of pre-DRT era patients, Hoehn and Yahr
estimated that the standardized mortality ratio (SMR) was approximately 3, indicating that PD
significantly diminished life expectancy in the pre-DRT era.7 Nobrega et al., however, reported a lower
SMR of 1.6 based on a retrospective analysis of roughly contemporaneous PD patient data in Olmsted
County, Minnesota.28 Reconstructing the life expectancy of PD patients prior to the development of DRT
is now impossible. Even if suitable datasets were available, there are many other improvements in public
health and medical care that would confound analysis.
In a conventional review of PD mortality studies, Ishihara et al. describe a range of individual study
SMRs, from 1.0 to 3.6 with a mean of approximately 1.9.29 Later reviews report similar assessments of
mortality studies.30 In a systematic review and meta-analysis of mortality in PD, Macleod et al. described
mortality ratios varying from 0.9 to 3.79 with considerable heterogeneity in individual study results. In
inception cohort studies, where participants were enrolled at or around time of diagnosis, the mean
mortality ratio was 1.52.31 Noninception cohort studies tended to produce higher mortality ratios, likely
closer to a mortality ratio of 2.0, though Macleod et al. did not compute a mean mortality ratio because of
marked study heterogeneity. It is possible that SMRs of 1.5 and greater may be overestimates of PD-
associated mortality. One rigorous, community-based study that enrolled only incident PD patients in
Cambridgeshire, United Kingdom (CamPaIGN) reported a relatively low SMR of 1.29 at 10-year follow-
up.32 This was not statistically different from the general UK population although CamPaIGN may have
been underpowered to detect a significant difference of this magnitude. On the other hand, in another
careful population-based study in Northern Sweden, Backstrom et al. describe an SMR of 1.58 for PD.33
Poortvliet et al. reported an interesting analysis of a PD registry in Queensland, Australia.34 Using data
spanning two decades, they describe increased mortality risk in PD, but varying as a function of disease
duration. In the first decade following diagnosis, mortality risk was approximately equivalent to the
reference population. Beyond the first decade after diagnosis, relative mortality rose significantly and
relative mortality continued to increase with increasing duration of disease.
Ishihara et al. performed a useful analysis by applying the Gompertz function, which accounts for
accelerating mortality with aging, in conjunction with varying SMR values to estimate life expectancy in
PD.29 They estimated changes in life expectancies as a function of age of onset, sex, and SMR. Not
surprisingly, diminishing life expectancy was a function of SMR and also a function of age of onset, with
younger-onset individuals estimated to experience longer duration of disease but also the greatest loss of
life expectancy. With an SMR of 2, for example, an individual with PD onset at age 40 would lose
approximately 7 years of life. At the same SMR, an individual with PD onset at age 80 would lose
approximately 3 years of life. Even assuming a relatively low SMR of 1.5, individuals with PD onset
later in life are predicted to experience diminished lifespan. At this SMR, PD onset at age 90 is
associated with a loss of 1 year of life.
In their review of mortality studies, Ishihara et al. also comment that SMRs of cohorts enrolled after
the 1970s may be lower than the SMRs of those enrolled earlier. The data do not allow rigorous test of
this suggestion, but the 1970s was the period when DRT was introduced and initially widely used. In the
Geneva autopsy series, the mean age of death of PD patients between 1914 and 1959 was approximately
75 years, while mean age of death in the interval from 2000 to 2010 was approximately 80 years.8 The
concept that DRT increases life expectancy in PD is controversial. In their meta-analysis of mortality
studies, Macleod et al. state that there are no robust data indicating an effect of DRT on survival.31 Some
studies examining PD patient cohorts shortly after the introduction of DRT suggested improvements in
mortality. In a review published in the mid-1990s, Clarke suggested that this effect reflected delay in
death due to DRT in a cohort of frail, elderly PD patients who received DRT shortly after its
introduction.35 After a few years, this cohort expired and mortality risk in PD re-equilibrated, with SMRs
similar to those in the pre-DRT era. Analysis of death certificate data from England and Wales over the
period from 1993 to 2006 suggests declining PD-related mortality, particularly in men.36 This effect, if
valid, cannot be attributed to the introduction of DRT but does suggest increasing life expectancy in PD.
This may be attributable to better PD care but may also reflect general improvements in medical care.
Recent data from the Rochester Epidemiology Project (Olmsted County, Minnesota) suggest a survival
benefit of DRT. Savica et al. reported survival rates for incident synucleinopathies (PD, PD with
dementia [PDD], Lewy body dementia [LBD], multiple system atrophy [MSA]) from 1991 to 2010,
compared with reference participants.37 The survival curve for PD patients diverges from that of
reference participants approximately 5 years after PD onset. This 5-year period corresponds with the
typical 4–5 year duration of the “honeymoon” period when PD patients often exhibit robust and relatively
side-effect free responses to DRT. The survival curves for the other and less treatable synucleinopathies
appear to diverge earlier, also suggesting a survival benefit of DRT in PD. The Rochester data are
consistent with the Queensland registry data indicating no increase in mortality risk in the first decade
after diagnosis of PD.34 The concept that DRT modifies survival in PD is consistent also with data
suggesting that neurologist care significantly reduces the mortality rates of PD patients.38 Neurologists
tend to be more aggressive in use of DRTs.39 It is plausible that life expectancy of PD has improved in the
DRT era and that appropriate use of DRT is a candidate for increasing survival of PD patients although
disentangling the effects of DRT on survival from general improvements in care is difficult.

RISK FACTORS
While the descriptive epidemiology (prevalence, incidence, mortality) of PD lacks precision, the basic
story of an increasingly prevalent age-related disease is clear. The epidemiology of risk factors, however,
is murky, with many risk factors described on the basis of relatively weak associations and interpretation
problems surrounding some apparently solid findings. Perhaps reflecting the general lack of clarity about
risk factors, the literature in this area is immense. Formal meta-analysis methods allow aggregation of
multiple study results, simplifying assessment of the literature. Noyce et al., for example, used formal
meta-analysis of 200-plus studies to describe 19 factors that may significantly influence PD risk.40 The
remainder of this chapter relies heavily on recent meta-analyses of risk factors. It is a truism that risk
factor epidemiologic studies describe associations. Interpretation of the significance of described
associations depends not only on the methodological quality of individual studies but also on a number of
features. Some, such as the strength or specificity of the associations or the presence of a dose-response
relationship, are intrinsic to the described association. Others, such as biological plausibility or
coherence with other known disease features, are extrinsic to the described associations.41 One
reasonable generalization is that none of the described risk factors for PD is highly potent. In the Noyce et
al. meta-analysis, for example, the most powerful risk factor of PD was having a PD-affected relative,
with an odds ratio (OR) of 4.45 (95% CI 3.395.83). This is certainly significant but contrasts markedly
with the tobacco abuse–associated risk of squamous cell lung cancer, where the OR for current, heavy
male smokers is estimated at greater than 100.42
In addition to relying primarily on recent meta-analyses, the following discussions focus on possible
environmental risk factors (Table 2.1). The roles of genetic risk factors are discussed in Chapter 6,
“Genetics of Parkinson Disease.” Some described risk factors, such as idiopathic rapid eye movement
(REM) sleep behavior disorder or mid-life constipation, are more likely features of prodromal PD and
are discussed in Chapter 8, “Prodromal Parkinson Disease.” Potentially protective risk factors are
discussed first, followed by hazardous risk factors.
Table 2.1 Parkinson disease environmental-modifiable risk factors
Risk factor Protective or Odds Comment
hazardous ratio
Smoking, tobacco abuse Protective ~0.4– Possible reverse causation
0.6
Coffee, tea, caffeine Protective ~0.7 Possible reverse causation
Serum urate Protective ~0.7 Biologically plausible, negative major clinical trial, negative mendelian
randomization study
Medications Associations mainly based on pharmacoepidemiologic studies prone to
CCBs Protective ~0.8– confounders
0.9
NSAIDs Protective ~0.8–
0.9
Statins Unclear
Immunosuppressives Protective ~0.4–
0.6
Pesticides, herbicides, fungicides Hazardous ~1.4– Supported by some experimental data
1.6
Rural living, agricultural Hazardous ~1.2– Lack of specific associations
employment, well water 1.5
Solvents Hazardous ~1.4 No clear compound-specific associations, supported by some
experimental data
Traumatic brain injury Hazardous ~1.5 Possible recall bias, reverse causation
Heavy metals Hazardous ~1.6 Best data for lead exposure, other metal associations unclear, Role of low
level Mn toxicity unclear
Cardiovascular disease risk factors Hazardous ~1.2– Hazard ratios vary with specific risk factor
1.65
Type 2 diabetes Hazardous ~1.2 Accelerates disease progression
Air pollution Hazardous ~1.1– Requires further study
1.2
Hepatitis C Hazardous ~1.1– Requires further study
1.2
CCB, calcium channel blocker; NSAID, nonsteroidal anti-inflammatory drug; T2DM, type 2 diabetes mellitus.

Smoking-Tobacco Abuse
The relationship of smoking-tobacco abuse to PD risk is particularly cloudy. One of the most consistent
observations in PD epidemiology is that current or past cigarette smoking is associated with substantially
lower risk of PD. Interpretation of this finding is contested. Several meta-analyses converge on 40–60%
(OR around 0.6–0.4) reductions in PD risk.40,43,44,45,46 There are two major interpretative possibilities.
One is that there is something in tobacco that impedes the neurodegenerative processes of PD. The second
is that this is an example of reverse causation. Rather than a causal association between tobacco abuse
and reduced risk of PD, this association indicates some biological feature of PD-prone individuals that
reduces risk of tobacco abuse.
A causal association between tobacco abuse and reduced PD risk is plausible. In some toxin models of
PD, nicotine reduces neurodegeneration.47 Putting nicotine aside, tobacco smoke contains hundreds of
compounds, and it is possible that one or more of them has neuroprotective effects. The case for reverse
causation, however, is strong. As with other drugs of abuse, the addictive effects of nicotine are likely
mediated to a large extent by perversion of nigrostriatal dopaminergic reward signaling (Chapter 5,
“Pathophysiology II”). It is plausible that PD-prone individuals have life-long, perhaps congenital, but
subtle differences in nigrostriatal dopaminergic signaling that renders them less susceptible to the
reinforcing effects of nicotine. Some data support this hypothesis. PD patients appear to find it easier to
quit smoking.48 Though controversial, there are data indicating that there is no decrease of PD risk
associated with second-hand tobacco smoke exposure.49 The basis of the reduced PD risk associated with
tobacco abuse is the topic of continuing research and may be an area where study of gene–environment
interactions resolves interpretive uncertainties.

Coffee, Tea, and Caffeine

The relationship of coffee, tea, and caffeine consumption to PD risk is analogous to the uncertainty
surrounding tobacco abuse. A number of studies associate coffee consumption with reduced PD risk.
Meta-analyses report that coffee consumption is associated with an approximately 30% reduction in PD
risk.40,45,50,51,52 Fewer data are available for tea consumption but meta-analyses indicate similar results,
with an approximately 30% reduction in PD risk.51,53 Caffeine is suggested to be the critical component as
individual studies examining the effects of decaffeinated coffee or teas with lower caffeine content did not
show reduced risk associations. Caffeine is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP) model of nigrostriatal neurodegeneration.54 On the other hand, caffeine and
some of its metabolites are adenosine receptor antagonists. Adenosine A2a receptors are expressed at
uniquely high levels by an important subpopulation of striatal neurons, and adenosine A2a antagonists
have reinforcing properties in rodent models of addiction. As with smoking-tobacco abuse, it is plausible
that the reduced PD risk associated with coffee, tea, or caffeine consumption is due to reverse causation.
On the other hand, adenosine receptors play roles in synaptic development and maintenance, a plausible
substrate for a neuroprotective effect of adenosine antagonists.55

Serum Urate
A number of studies suggest that serum uric acid levels are inversely related to PD risk. Meta-analyses
describe significant reductions in PD risk, approximately by 33%, in individuals with higher serum urate
levels.56,57,58 Similarly, there are reports of reduced PD risk in gout victims.59 Urate may act as an
intracellular antioxidant, leading to suggestions that the inverse relationship between serum urate levels
and PD risk is due to less resistance to cellular oxidative stress in individuals with lower urate
production. As with a number of other possible risk factors, reverse causation is also plausible. The
inverse relationship between PD risk and serum urate levels, and the accompanying concept of higher
urate levels as protective against oxidative stress, were the basis for the phase III Safety of Urate
Elevation in PD trial (SURE-PD3), which aimed to assess if raising serum urate levels with oral inosine
produces disease-modifying effects. The outcome of this study was negative, which does not definitively
exclude the possibility that lower serum urate increases risk of PD.60 A recent mendelian randomization
study also argues against serum urate as a protective factor for PD.61

Medications
Pharmacoepidemiologic studies suggest that some medications influence PD risk. This has been most
thoroughly explored for calcium channel blockers (CCBs) and nonsteroidal anti-inflammatory drugs
(NSAIDs). Aggregation of data in meta-analyses suggests modest reductions in PD risk with ORs around
0.8–0.9.40,62,63 In conjunction with preclinical experiments, these findings, notably those with CCBs, were
used as clues to the mechanisms of pathogenesis and experiments aimed at repurposing existing agents as
disease-modifying treatments for PD.64 This very well done work led to a major clinical trial of the CCB
isradipine as a disease-modifying treatment for PD (Safety, Tolerability and Efficacy evaluation of
Dynacirc in PD; STEADY-PD). The results of this trial were negative; however, there are concerns that
the isradipine dosing schedule used in STEADY-PD, derived from a well-executed phase II tolerability
study, did not produce adequate inhibition of the target L-type calcium channel.65,66
Conflicting data have been reported for statins, with several studies describing risk reduction but some
data describing no effects or increased PD risk with statin exposure.40,67 A phase II trial exploring the
efficacy of simvastatin as a disease-modifying therapy is apparently completed but no results reported.68
Recent intriguing observations suggest that immunosuppressive agents reduce PD risk, perhaps
substantially, on the order of 40–50% risk reductions.69 These observations emerge from studies of large
administrative databases and may be contaminated by confounders but are consistent with data suggesting
that the inflammatory processes play a role in neurodegeneration in PD (see Chapter 7, “Pathogenesis”).

Pesticides, Herbicides, Fungicides

Exposure to a variety of agriculturally used compounds has long been suspected to increase PD risk.
Meta-analyses suggest ORs on the order of 1.4–1.6 for PD risk for pesticides and herbicides but less-
strong associations for fungicides.40,44,70,71,72 A meta-analysis by Breckenridge et al. employed
corrections for publication bias and suggested that the ORs for increased PD risk with exposure to these
compounds, while still significant, are somewhat lower.44 Unlike the apparently beneficial associations
with tobacco abuse or caffeine consumption, there are no suggestions of reverse causation for the
associations of increased risk of PD with pesticide or herbicide exposures. It is plausible that the toxic
effects of some of these compounds, superimposed on normal age-related decline in nigrostriatal
dopaminergic neuron integrity (Chapter 3, “Pathology”), contribute to PD incidence. Rotenone, for
example, is potent broad-spectrum insecticide whose primary mechanism of action is inhibition of
mitochondrial complex I function. Genetic evidence and a large body of animal model work implicates
mitochondrial dysfunction in PD pathogenesis (Chapter 7, “Pathogenesis”). Systemic rotenone exposure
with the correct administration schedule produces relatively selective degeneration of nigrostriatal
dopaminergic neurons in rodents.73 Paraquat is a widely used herbicide whose mechanism of action
involves generation of superoxide free radicals and has been used in in vitro and in vivo models of
neurodegeneration.
The concept that pesticide-herbicide exposure increases risk of PD is mechanistically plausible, with
an abundance of supporting epidemiologic data. Nonetheless, these are not very powerful associations, it
is not clear what specific agents are responsible, whether some individuals are particularly susceptible,
or, given the heterogeneity of PD, if these agents are responsible for a subspecies of PD. This is another
area where gene–environment interaction studies may prove rewarding.

Rural Living, Agricultural Employment, Well Water

Possibly, but not definitely, related to pesticide-herbicide exposure are a number of studies describing
increased PD risk associated with rural residence, farm work, and well water consumption. ORs in meta-
analyses range from around 1.2 to 1.5.40,44 The relative non-specificity of these potential risk factors
makes it difficult to assess their significance.

Solvents
Industrial solvents are linked to increased PD risk. One meta-analysis describes an OR of approximately
1.4 for increased risk of PD associated with solvent exposure.72 These studies generally lump together a
variety of solvents. A twin study suggested that exposure to trichloroethylene (TCE) and
perchloroethylene substantially increase risk of PD.74 The chlorinated solvent TCE was widely used for
much of the 20th century and is a persistent and widespread environmental contaminant. TCE
administration to rodents is reported to reproduce neurochemical and pathologic features of PD.75 In a
recent interesting study, De Miranda et al. reported that TCE administration to rats produced nigrostriatal
dopaminergic neuron injury and increased the activity of the protein kinase leucine repeat risk kinase 2
(LRRK2), a mechanism implicated in some genetic forms of PD (simple Pism [SPism]–LRRK2; see
Chapters 6 and 7).76 As with pesticide-herbicide exposures, solvent toxicity is a plausible risk factor for
PD, but the specific compounds involved and whether individual susceptibilities vary remains unclear.

Traumatic Brain Injury

Traumatic brain injury (TBI), particularly with loss of consciousness, is associated with increased risk of
PD. In one meta-analysis, the OR for increased PD risk was approximately 1.5.77 Interpretation of these
results is complex. It is certainly plausible the TBI could increase PD risk through two nonexclusive
mechanisms. First, TBI could magnify or accelerate whatever pathogenic processes underlie PD. Second,
TBI could independently cause a degree of brain injury, which when added to the effects of pathogenic
processes underlying PD, results in cumulative pathologies exceeding a threshold for clinical expression
of parkinsonism. Interpretation of TBI study data is clouded by two factors. One may be recall bias, with
PD patients more likely to recall TBI events as salient. The second may be reverse causation. Subtle
motor problems in the prodromal phase of PD may result in falls or other causes of TBI. It is conceivable
also that some combination of actual pathogenic effects of TBI, recall bias, and reverse causation could
contribute to the apparent increased risk of PD associated with TBI.78
A special case of TBI potentially increasing risk of PD or Pism is the consequences of repetitive, very
often subconcussive TBI associated with contact sports. A recent analysis of causes of death among
former professional soccer players in Scotland suggests that this form of TBI is a risk factor for PD or
Pism, with the latter potentially secondary to chronic traumatic encephalopathy (CTE).79 While well
done, this study is retrospective and could not take some potentially relevant confounders into account.
Assuming they are valid, whether these results generalize to recreational or casual players is uncertain.

Heavy Metals
Heavy metals exposure is another potential risk factor for the development of PD. The literature in this
area is broad and conflicting, with epidemiologic studies both supporting and refuting roles of heavy
metals exposure as a PD risk factor.80,81 Iron, copper, lead, and mercury have all been studied, as have
joint exposures to several potentially toxic heavy metals. A recent meta-analysis by Gunnarsson and
Bodin identified only a small number of good-quality studies.81 This meta-analysis suggested that lead
exposure (hazard ratio of ~1.6) but not exposure to other heavy metals is a risk factor for PD. The role of
manganese exposure as a PD risk factor is particularly controversial. Manganese neurotoxicity was well
described as a serious occupational hazard in the early 19th century. As historically described,
manganism exhibits Pism but has other clinical features that distinguish it clearly from PD (complex Pism
[CPism]–Mn). More recently, there are data that occupational manganese exposures at levels
considerably lower than those producing typical manganism may give rise to PD or a PD-like syndrome.82
Some molecular imaging data are consistent with low-level manganese exposure producing nigrostriatal
dopaminergic terminal degeneration but in a pattern different from that seen in PD (see Chapter 3,
“Pathology”).82 As with other potential environmental toxic risk factors, there are numerous uncertainties.
If low-level exposure to manganese is a risk factor for PD, is manganese toxicity exacerbating pathologic
processes underlying PD, or is clinical expression the consequence of multiple accumulating brain
pathologies? Further research is needed to resolve this issue.

Air Pollution
Recent studies suggest that air pollution, particularly exposure to atmospheric particulate matter particles
smaller than 2.5 μm (PM2.5), is a risk factor for PD.83,84 The estimated ORs are modest, on the order of
1.1–1.2, but the broad exposures to these levels of PM2.5 would drive the population attributable risk
fraction secondary to air pollution to relatively high levels. This association was described in North
American regions with relatively good control of air pollution, and air pollution could be a more
powerful risk factor in regions with worse air pollution.84 A plausible mechanism for air pollution as a
PD risk factor is enhanced neuroinflammation, which encompasses processes increasingly linked to PD
pathogenesis (see Chapter 7). PM2.5 particles have the ability to penetrate into tissues throughout the body
and elicit inflammatory processes. These effects are not specific to PD as air pollution exposure is also
implicated as a risk factor for primary dementias.85 If this effect is real, it is plausible that air pollution
exposure could contribute to PD via cumulative brain injury, lowering thresholds for expression of
parkinsonism.

Hepatitis C
Hepatitis C (HepC) is a highly prevalent infection in many regions. Several studies report increased PD
associated with prior HepC infection. A recent meta-analysis suggests ORs in the range of 1.2–1.3.86 This
is not a large increase in risk, but, as with air pollution, the large number of exposed individuals suggests
that increased risk of PD associated with HepC could constitute a significant contributor to PD incidence
around the world.

Cardiovascular Disease Risk Factors

A recent large-scale analysis of US Medicare administrative data from Kummer et al. suggests that
several cardiovascular disease risk factors increase the risk of developing PD.87 This work follows a
considerable amount of prior epidemiologic work establishing that cardiovascular risk factors are
associated with risk of another common age-related brain disorder, dementia. Kummer et al. describe
ORs in the range of 1.2–1.65 with obstructive sleep apnea exhibiting the highest OR. In a parallel analysis
of the same dataset, Kummer et al. studied risk of dementia as a positive control and found that
cardiovascular disease risk factors were also associated with incident dementia, though with somewhat
higher ORs. The concept that cardiovascular disease risk factors influence PD risk is indirectly supported
by some prior studies. Cardiovascular disease risk factor load is associated with DRT-refractory clinical
features.88 Mediterranean-like diets, widely accepted to reduce cardiovascular disease risk, are reported
to decrease PD risk.89,90
For one important and increasingly prevalent cardiovascular risk factor, type 2 diabetes mellitus
(T2DM), the relationship to PD risk is somewhat unclear.91 Some studies suggest increased risk of PD
associated with T2DM with others suggesting diminished risk of PD in individuals with T2DM. A
suggested explanation for these discrepancies is that studies suggesting reduced risk of PD in T2DM are
case-control studies susceptible to differential mortality effects, with cohort studies tending to show
increased risk of PD in T2DM. A recent meta-analysis and mendelian randomization analysis indicates
that T2DM is associated with increased PD risk, with an estimated hazard ratio of 1.21.92 It is generally
agreed that T2DM is associated with more severe clinical features in PD.
There are at least two general mechanisms through which cardiovascular risk factors could influence
PD risk. One is a direct interaction with whatever pathogenic processes drive neurodegeneration in PD.
Analogous interactions are speculated to play a role in the pathogenesis of Alzheimer disease.93 A second
and perhaps more likely possibility is that cardiovascular risk factors independently drive
cerebrovascular brain injury in parallel with whatever processes produce PD. The cumulative effect of
these (and other age-related) pathologies contributes to clinical expression of PD.

IMPLICATIONS FOR UNDERSTANDING ETIOPATHOGENESIS AND ANTICIPATING THE

FUTURE BURDEN OF PD
Epidemiologic work in PD is motivated by desires to achieve three goals. Perhaps the most important
motivation is the desire to obtain clues about the etiopathogenesis of PD, followed by the closely related
goal of identifying modifiable PD risk factors, and, finally, to assist in understanding the social impacts of
PD. The latter goal includes using epidemiologic data to understand the present financial and resource
impacts imposed by PD and also to make reasonable projections about future social demands. One recent
study estimated the total economic burden of PD in the United States at approximately $52 billion
annually (in 2017 dollars) and projected a total economic burden in excess of $80 billion annually in two
decades.12 These projections inevitably involve assumptions about prevalence and incidence rates, with
the latter, in particular, exhibiting considerable uncertainty.
To date, epidemiologic work has accomplished relatively little in terms of understanding the
etiopathogenesis of PD. One of the strongest risk factors for PD is family history. This suggests an
important role for genetic factors in PD incidence, a conclusion supported by emerging genetic data (see
Chapter 6). While a small fraction of PD is due to monogenic disorders, the role of genetic contributions
to more typical, “sporadic” PD is likely complex. Some identified risk factors, such as idiopathic REM
sleep behavior disorder or mid-life constipation, are not properly risk factors but likely manifestations of
prodromal PD (see Chapter 8, “Prodromal Parkinson Disease”). These phenomena may provide clues
about the etiopathogenesis of PD, but likely only indirectly because they are markers for periods during
which early pathogenic processes are occurring. The status of other identified risk factors, such as the
well-characterized inverse relationship between tobacco abuse and PD risk, is problematic as they may
represent examples of reverse causation. Other risk factors, such as exposure to heavy metals or the
effects of some medications, are controversial.
Relatively little attention, however, has been paid to some of the most prominent features of PD
epidemiology. The strongest risk factors for PD are age, sex, and possibly ancestry. We know surprisingly
little about how aging effects the brain and increases susceptibility to neurodegenerative syndromes such
as PD. The role of sex in influencing features of PD has been investigated to a modest degree (see
Chapter 11, “Clinical III”) but what aspects of sex influence PD risk are not understood. Gonadal steroid
effects are an obvious candidate. Recent preliminary findings suggest that earlier menopause or
ovariectomy increases PD risk, observations consistent with the concept that female gonadal steroids
have neuroprotective effects.94,95 The potential roles of ancestral differences in PD risk, which suggests a
significant role for genetic effects and is consonant with family history as a risk factor, have hardly been
researched. The relative lack of large-scale genomic data in non-European populations is a significant
obstacle to this type of research.
The lack of success in identifying unequivocal and actionable risk factors is an obstacle to efforts to
modify PD risk. No one is going to recommend taking up cigarette smoking to reduce PD risk. The
concept of gene–environment interactions with genetically different subsets of individuals differentially
susceptible to specific environmental hazards is very attractive but also very difficult to validate. Twin
studies of PD incidence generally support the gene–environment interaction concept for PD risk because
existing studies suggest a significant degree of heritability and environmental risk components.96,97
The lack of success in clarifying risk factors also affects efforts to forecast the increasing burden of
PD. It’s very likely that PD incidence and prevalence will increase significantly in the coming decades.
Population aging is a worldwide phenomenon, occurring in high-, middle-, and low-income nations. The
absolute numbers of individuals older than 65 is expected to soar in South America, China, India, and
Africa. Population aging by itself will substantially increase the burden of PD, though if there are
significant ancestry differences in PD risk, these increases may be blunted in Asia and Africa. Uncertainty
about the roles of risk factors, however, complicates projections of future PD prevalence and burden.
Rossi et al., for example, demonstrated that assuming a protective role of smoking significantly affects
projections of PD prevalence in the United States.98 If HepC and PM2.5 air pollution are PD risk factors,
there will be previously unanticipated benefits to eradicating HepC and controlling air pollution.99
More definitive PD epidemiologic data would be very useful for PD research, clinical care, and health
policy planning. Better analyses, however, will likely require very large datasets with good clinical and
risk factor data and substantial genetic analysis. This will be difficult to obtain, although large-scale
efforts such as the United Kingdom Biobank project may ultimately provide some useful data. Studies in
non-European populations will be crucial.

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Chapter 3
Pathology

INTRODUCTION
Discussions of Parkinson disease (PD) pathology are dogged by the same problems of definition and
metasyndromic heterogeneity that arise in other contexts of PD biology. Pathologic evaluations are often
regarded as “gold standards” for disease definition, but the PD pathology literature is characterized by
notable ambiguities. These ambiguities likely contribute to the absence of specific formal neuropathologic
criteria and recommended standardized pathologic assessment for PD.1,2,3 First, histopathologic evidence
of α-synucleinopathy is conventionally defined as essential for pathologic diagnosis of PD, yet
parkinsonism (Pism) associated with some genetic disorders, notably Parkin (simple Pism [SPism]–
PRKN) mutations, classified as clinicogenetic causes of PD and phenotypically indistinguishable from
sporadic PD (SPism–Idiopathic), lack α-synucleinopathy.4 To complicate matters further, some LRRK2
mutations associated with PD (SPism–LRRK2) may or may not exhibit histopathologic evidence of α-
synucleinopathy.4 Second, dementia with Lewy bodies (DLB; complex Pism [CPism]–DLB), whose
natural history differs from the natural history of PD, is usually histopathologically indistinguishable from
more advanced PD. Third, conventional pathologic classifications for PD do not take into account the
impact of other age-related pathologies that might contribute to the clinical expression of Pism (see
below). This is best illustrated by the fact that some apparently normal elderly individuals exhibit
significant α-synucleinopathy, a phenomenon termed incidental Lewy body disease (iLBD). Fourth, there
are no criteria differentiating iLBD from PD. Finally, standard descriptions of neuropathologic
assessment of PD implicitly assume the presence of Pism in the patients under examination, and, in this
sense, neuropathologic definition of PD is not independent of clinical evaluation and has a somewhat
circular quality.
It is worth emphasizing strongly that PD, like many other neurodegenerative syndromes, affects many
components of the nervous system. Some regions and pathways are preferentially affected, and there are
likely spatiotemporal patterns in the progression of regional–subregional pathology, but multiple parts of
the nervous system are affected, contributing to the many different clinical features of PD (see also
Chapter 10, “Clinical II”).

THE AGING BRAIN

As with all common and many uncommon neurodegenerative disorders, age is the major risk factor for
PD, indicating that changes accompanying aging of the nervous system are a critical substrate for the
expression of the pathogenetic mechanisms that produce PD. So-called normal aging of the nervous
system is poorly understood but is likely complex and heterogeneous, with varying underlying
mechanisms and impacts in different brain regions and types of cells. Some data point directly to age-
related changes relevant to the pathogenesis and pathologies of PD. The best documented is age-related
degeneration of nigrostriatal dopaminergic neurons. Described originally in postmortem studies, this
phenomenon was definitively characterized in vivo using molecular imaging methods. Each decade after
the age of 20 is accompanied by an approximate 5% per decade and apparently linear decline in
nigrostriatal dopaminergic terminal density (Figure 3.1).5 Nigrostriatal dopaminergic perikaryal numbers
exhibit age-related declines of approximately the same magnitude per decade.6,7,8,9 The precise
relationships of terminal and perikaryal declines are unclear as there may be nonlinear relationships
between nigrostriatal dopaminergic neuron perikaryal loss and terminal density changes, with terminal
loss preceding perikaryal degeneration.10,11,12 The existence of iLBD, α-synucleinopathy in apparently
normal elderly individuals (see below), suggests prodromal degeneration of nigrostriatal dopaminergic
neurons. The precise relationship between the apparently presymptomatic α-synucleinopathy in
nigrostriatal dopaminergic neurons of iLBD and age-related degeneration of dopaminergic nigrostriatal
neurons is unclear. It is unlikely that α-synucleinopathy per se is the cause of all age-related dopaminergic
nigrostriatal neuron degeneration. The latter appears to start shortly after the conclusion of brain
maturation in the third decade of life. Fearnley and Lees, and other investigators, analyzed the subregional
pattern of age-related nigrostriatal dopaminergic neuron loss in the absence of α-synucleinopathy and
describe a distribution of age-related neuronal loss different from that seen in PD.8,13 Nonetheless, the
existence of age-related nigrostriatal dopaminergic neuron degeneration suggests that this population of
neurons has some underlying age-related changes that increase susceptibility to the pathogenic processes
causing PD (see Chapter 7, “Pathogenesis”).
Figure 3.1 In vivo molecular imaging demonstration of age-related decline in nigrostriatal dopaminergic terminals. Posterior putamen
[11C]dihydrotetrabenazine (DTBZ) binding to the type 2 vesicular dopamine transporter (BP, binding potential) versus age in normal (filled
circles, men; open circles, women) and PD patients (filled squares, men; open squares, women). The line is the regression of posterior
putamen DTBZ BP versus age in normal research participants using a declining exponential model. Within the normal group, there is a
significant age-related decline in DTBZ BP, approximately 5% per decade. Note complete separation of normal and PD participant groups.
Reprinted with permission from Bohnen et al., J Cereb Blood Flow Metab. 2006;26:1198–1212.

It is plausible that other normal age-related changes contribute to the pathophysiology and/or
pathogenesis of PD. Molecular imaging data suggest age-related changes in other neurochemically defined
brain systems affected in PD. There are age-related declines in cholinergic systems known to be affected
in PD (see below).14 These include some basal forebrain corticopetal projections, striatal cholinergic
interneuron terminals, and cholinergic projections from the brainstem pedunculopontine-lateral
dorsotegmental complex (PPN-LDT) to the thalamus. There is also evidence of age-related declines in
serotoninergic terminal density in multiple brain regions.15 Other age-related changes may be relevant.
Significant age-related changes in striatal projection neuron dendrite morphology are documented in both
rodents and felines.16 It is likely that analogous age-related changes occur in primates. Age-related
changes in human nigrostriatal neuron dendritic architecture are also reported.17 The interactions of
changes that appear to accompany healthy brain aging and the pathologies characteristic of
neurodegenerative disorders are almost completely unknown, a major gap in our understanding of
neurodegeneration.
GROSS PATHOLOGY, LEWY PATHOLOGY, AND Α-SYNUCLEINOPATHY

Gross Pathology
The gross pathology of PD is largely unremarkable, with little obvious change in the great majority of
brain regions, though reduced brain weight is seen in patients with long-standing PD and dementia. The
important exception is macroscopically visible depigmentation of the substantia nigra pars compacta and
locus ceruleus, reflecting degeneration of neuromelanin containing neurons within these structures (Figure
3.2).

Figure 3.2 Gross pathology of the substantia nigra pars compacta in Parkinson disease subject (A) versus unaffected control (B). Marked
depigmentation of the substantia nigra secondary to loss of neuromelanin containing dopaminergic neurons. Image courtesy of Dr. Andrew
Lieberman, Department of Pathology, University of Michigan.

Histopathology
Pathologic diagnosis of PD requires neuronal loss within the substantia nigra pars compacta accompanied
by the characteristic cellular histopathologic feature: LBs within the perikarya of affected neurons (LBs;
Figure 3.3).1 Neuron loss and LBs are generally accompanied by astrocytic gliosis and accumulated
neuromelanin within resident macrophages. Neuronophagia (apparent phagocytosis of neurons by
macrophages) and pigmentary incontinence (apparent spilling of neuromelanin from breached neurons)
are sometimes seen. Similar phenomena are seen in other affected pigmented brainstem nuclei, such as the
locus ceruleus and dorsal motor nucleus of the vagus. This bare description is only the starting point for
the complex pathology of PD.
Figure 3.3 Photomicrographs of Lewy pathology. (A) Neuron containing multiple hematoxylin and eosin (H&E) stained Lewy bodies in
eosinophilic cores and pale haloes. (B) Intraneuritic Lewy body. (C) Lewy body immunostained for α-synuclein, showing pale core, dense rim.
(D) Pale body. (E) Pale body (star) with associated Lewy body (arrowhead). (F) Pale body immunostained for α-synuclein. Scale bars = 10
microns. (G) Lewy neurites and cortical Lewy body (asterisk) in neocortex. α-Synuclein immunostain. A–F, reprinted from Wakabayashi et al.
Parkinsonism Rel Disord. 2006;12(S2):S92–98; G, by Jensflorian, own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?
curid=11788792

Lewy Bodies and Related Pathologies

LBs and related structures are the defining positive cellular histopathologic features of PD.18,19 LBs are
intracellular proteinaceous inclusions defined traditionally by unique staining patterns with dye-based
methods. The discovery that a major constituent of LBs is the protein α-synuclein (aSyn) had a major
impact on the study of PD pathology.20 This advance was inspired by the discovery that aSyn gene
mutations, both point mutations and gene duplications-triplications, cause a dominant form of PD (SPism–
SNCA; though also manifesting as DLB in members of some pedigrees) leading to the designation of PD
as a “synucleinopathy.”21,22 α-Synucleinopathy is also present in Multiple Systems Atrophy, though with
different regional and cellular distributions. As mentioned above, DLB is also an α-synucleinopathy.
Normal aSyn is a presynaptic protein, and localization in neurites and perikarya is abnormal.
Application of immunohistochemical methods with specific antisera against aSyn revealed a spectrum
of pathology previously only glimpsed by relatively insensitive dye-based methods. LBs are part of a
spectrum of aSyn immunoreactive neuronal inclusion pathology that includes “classic” or “brainstem”
LBs, “cortical” LBs, neuritic proteinaceous aggregates called Lewy neurites (LNs), and “pale bodies”
that may be precursors to LBs and LNs (Figure 3.3). Most of these neuronal abnormalities were detected
with traditional dye-based methods, but, by enhancing detection sensitivity, aSyn immunohistochemistry
allowed identification of the regional extent of these pathologies and made possible efforts to reconstruct
the possible spatiotemporal sequence(s) underlying the emergence of regional pathologies (see below).
With traditional dye-based methods, brainstem LBs are 8–30 μm cytoplasmic inclusions with
eosinophilic cores, concentric lamellae surrounding cores, and pale haloes (Figure 3.3). With aSyn
immunohistochemistry, halo regions are more densely stained with relatively less immunoreactive cores
(Figure 3.3).18,19 Cortical LBs have less sharply defined borders, lack halos, exhibit more uniform aSyn
immunoreactivity, and tend to occur in amygdala, hippocampal formation, and some neocortical regions.
Cortical LBs and the core regions of brainstem LBs exhibit strong ubiquitin immunoreactivity. Most likely
occurring in both dendrites and axons, LNs have varying morphology, described as “thread-like,”
“spindle-like,” or “club-shaped,” and exhibit aSyn and often ubiquitin immunoreactivity (Figure 3.3).
aSyn immunohistochemistry also detects smaller, immunoreactive “dots” within the neuropil, likely
smaller aggregates of aSyn that may be precursors to the larger aSyn inclusions. Pale bodies are more
amorphous, weakly eosinophilic, aSyn immunoreactive structures within neurons (Figure 3.3). Also
occurring within perikarya are punctate or “dust-like” aSyn immunoreactive inclusions. A plausible
sequence of LB formation is that the initial forms are small inclusions followed by the formation of pale
bodies and then more mature LBs and LNs. This process is suggested to be driven by the formation,
expansion, and propagation of intracellular aSyn multimers with amyloid features (see Chapter 7,
“Pathogenesis”).
Unlike the amyloid precursor protein (APP) fragment (amyloid β [Aβ] fragment) containing plaques or
some neurofibrillary tangles of Alzheimer disease (AD), LBs are generally intracellular. Extracellular
LBs may be seen, presumably after neuronal death, but these are infrequent. Some data suggest that the
percentage of LB-containing neurons within the substantia nigra is not related to disease duration and may
be constant at all disease stages.23 This implies turnover of LBs with destruction of LBs as LB-containing
neurons perish.
LBs have a complex structure. Ultrastructure studies of both LBs and LNs reveal that a major
component is aSyn filaments, approximately 200–600 nm long and 5–10 nm wide.18,19 Normal aSyn is an
unfolded protein, but aSyn filaments are aggregates of aSyn monomers with amyloid-β pleated sheet
structural features.24 Electron microscopy of brainstem LBs reveals that they are not membrane-bounded
and exhibit densely packed filaments in their cores, with radially arranged filaments around the core. The
filaments of cortical LBs appear to have less organized structure. Other constituents visualized by
electron microscopy include granular material and vesicular structures, including what may be degraded
organelles.25 Proteomic analyses demonstrate that while aSyn is a major constituent of LBs, hundreds of
other proteins are present.19
The direct pathogenic significance of LBs and LNs is unclear. It is tempting to think that these
intracellular inclusions physically disrupt intracellular functions. LNs, for example, are suggested to
accumulate at axonal branches and retard axonal transport.26 LBs and LNs might also disturb cellular
homeostasis by sequestering or injuring proteins and organelles necessary for essential functions. On the
other hand, there are indications that much smaller aSyn oligomers possess greater cytopathic effects than
Another random document with
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Diocletian, inasmuch as it shews his profound reluctance to disturb
the internal peace which his own wise policy had established. As a
propitious day, the Festival of the Terminalia, February 23, 303, was
chosen for the inauguration of the anti-Christian campaign. The
church at Nicomedia was levelled to the ground by the Imperial
troops and, on the following day, an edict was issued depriving
Christians of their privileges as full Roman citizens. They were to be
deprived of all their honours and distinctions, whatever their rank;
they were to be liable to torture; they were to be penalised in the
courts by not being allowed to prosecute for assault, adultery, and
theft. Lactantius well says[12] that they were to lose their liberty and
their right of speech. The penalties extended even to slaves. If a
Christian slave refused to renounce his religion he was never to
receive his freedom. The churches, moreover, were to be destroyed
and Christians were forbidden to meet together. No bloodshed was
threatened, as Diocletian had stipulated, but the Christian was
reduced to the condition of a pariah. The edict was no sooner posted
up than, with a bitter jibe at the Emperors, some bold, indignant
Christian tore it down. He was immediately arrested, tortured,
racked, and burnt at the stake. Diocletian had been right. The
Christians made willing martyrs.
Soon afterwards there was an outbreak of fire at the palace.
Lactantius accuses Galerius of having contrived it himself so that he
might throw the odium upon the Christians, and he adds that
Galerius so worked upon the fears of Diocletian that he gave leave
to every official in the palace to use the rack in the hope of getting at
the truth. Nothing was discovered, but fifteen days later there was
another mysterious outbreak. Galerius, protesting that he would stay
no longer to be burnt alive, quitted the palace at once, though it was
bad weather for travelling. Then, says Lactantius, Diocletian allowed
his blind terrors to get the better of him, and the persecution began
in earnest. He forced his wife and daughter to recant; he purged the
palace, and put to death some of his most powerful eunuchs, while
the Bishop of Nicomedia was beheaded, and crowds of less
distinguished victims were thrown into prison. Whether there was
incendiarism or not, no one can say. Eusebius, indeed, tells us that
Constantine, who was living in the palace at the time, declared years
afterwards to the bishops at the Council of Nicæa that he had seen
with his own eyes the lightning descend and set fire to the abode of
the godless Emperor. But neither Constantine nor Eusebius was to
be believed implicitly when it was a question of some supernatural
occurrence between earth and heaven. The double conflagration is
certainly suspicious, but tyrants do not, as a rule, set fire to their own
palaces when they themselves are in residence, however strong
may be their animus against some obnoxious party in the State.
A few months passed and Diocletian published a second edict
ordering the arrest of all bishops and clergy who refused to
surrender their “holy books” to the civil officers. Then, in the following
year, came a third, offering freedom to all in prison if they consented
to sacrifice, and instructing magistrates to use every possible means
to compel the obstinate to abandon their faith. These edicts
provoked a frenzy of persecution, and Gaul and Britain alone
enjoyed comparative immunity. Constantius could not, indeed,
entirely disregard an order which bore the joint names of the two
Augusti, but he took care that there was no over-zealousness, and,
according to a well-known passage of Lactantius, he allowed the
meeting-places of the Christians, the buildings of wood and stone
which could easily be restored, to be torn down, but preserved in
safety the true temple of God, viz., the bodies of His worshippers.[13]
Elsewhere the persecution may be traced from province to province
and from city to city in the mournful and poignant documents known
as the Passions of the Martyrs. Naturally it varied in intensity
according to local conditions and according to the personal
predilections of the magistrates. Where the populace was fiercely
anti-Christian or where the pagan priests were zealous, there the
Christians suffered severely. Their churches would be razed to the
ground and the prisons would be full. Some of the weaker brethren
would recant; others would hide themselves or quit the district;
others again would suffer martyrdom. In more fortunate districts,
where public opinion was with the Christians, the churches might not
be destroyed, though they stood empty and silent.
The fiercest persecution seems to have taken place in Asia Minor.
There had been a partial revolt of the troops at Antioch, easily
suppressed by the Antiochenes themselves, but Diocletian
apparently connected it in some way with the Christians and let his
hand fall heavily upon them. Just at this time, moreover, in the
neighbouring kingdom of Armenia, Saint Gregory the Illuminator was
preaching the gospel with marvellous success, and the Christians of
Cappadocia, just over the border, paid the penalty for the uneasiness
which this ferment caused to their rulers. We hear, for example, in
Phrygia of a whole Christian community being extirpated.
Magistrates, senators, and people—Christians all—had taken refuge
in their principal church, to which the troops set fire. Eusebius, in his
History of the Church, paints a lamentable picture of the persecution
which he himself witnessed in Palestine and Syria, and, in his Life of
Constantine, he says[14] that even the barbarians across the frontier
were so touched by the sufferings of the Christian fugitives that they
gave them shelter. Athanasius, too, declares that he often heard
survivors of the persecution say that many pagans risked the loss of
their goods and the chance of imprisonment in order to hide
Christians from the officers of the law. There is no question of
exaggeration. The most horrible tortures were invented; the most
barbarous and degrading punishments were devised. The victim who
was simply ordered to be decapitated or drowned was highly
favoured. In a very large number of cases death was delayed as
long as possible. The sufferer, after being tortured on the rack, or
having eyes or tongue torn out, or foot or hand struck off, was taken
back to prison to recover for a second examination.
Even when the victim was dead the law frequently pursued the
corpse with its futile vengeance. It was no uncommon thing for a
body to be thrown to the dogs, or to be chopped into fragments and
cast into the sea, or to be burnt and the ashes flung upon running
water. He was counted a merciful judge who allowed the friends of
the martyr to bear away the body to decent burial and lay it in the
grave. At Augsburg, when the magistrate heard that the mother and
three servants of a converted courtesan, named Afra, had placed her
body in a tomb, he ordered all four to be enclosed in one grave with
the corpse and burnt alive.
It is, of course, quite impossible to compute the number of the
victims, but it was unquestionably very large. We do not, perhaps,
hear of as many bishops and priests being put to death as might
have been expected, but if the extreme rigour of the law had been
enforced the Empire would have been turned into a shambles. The
fact is, as we have said, that very much depended upon the personal
character of the Governors and the local magistrates. In some
places altars were put up in the law courts and no one was allowed
either to bring or defend a suit without offering sacrifice. In other
towns they were erected in the market squares and by the side of
the public fountains, so that one could neither buy nor sell, nor even
draw water, without being challenged to do homage to the gods.
Some Governors, such as Datianus in Spain, Theotecnus in Galatia,
Urbanus of Palestine, and Hierocles of Bithynia and Egypt, were
noted for the ferocity with which they carried out the edicts; others—
and, when the evidence is carefully examined, the humane judges
seem to have formed the majority—presided with reluctance at these
lamentable trials. Many exhausted every means in their power to
convert the prisoners back to the old religion, partly from motives of
humanity, and partly, no doubt, because their success in this respect
gained them the notice and favour of their superiors.
We hear of magistrates who ordered the attendants of the court to
place by force a few grains of incense in the hands of the prisoner
and make him sprinkle it upon the altar, or to thrust into his mouth a
portion of the sacrificial meat. The victim would protest against his
involuntary defilement, but the magistrate would declare that the
offering had been made. Often, the judge sought to bribe the
accused into apostasy. “If you obey the Governor,” St. Victor of
Galatia was told, “you shall have the title of ‘Friend of Cæsar’ and a
post in the palace.” Theotecnus promised Theodotus of Ancyra “the
favour of the Emperors, the highest municipal dignities, and the
priesthood of Apollo.” The bribe was great, but it was withstood. The
steadfast confessor gloried in replying to every fresh taunt, entreaty,
or bribe, “I am a Christian.” It was to him the only, as well as the
highest argument.
Sometimes the kindest-hearted judges were driven to
exasperation by their total inability to make the slightest impression
upon the Christians. “Do abandon your foolish boasting,” said
Maximus, the Governor of Cilicia, to Andronicus, “and listen to me as
you would listen to your father. Those who have played the madman
before you have gained nothing by it. Pay honour to our Princes and
our fathers and submit yourself to the gods.” “You do well,” came the
reply, “to call them your fathers, for you are the sons of Satan, the
sons of the Devil, whose works you perform.” A few more remarks
passed between judge and prisoner and then Maximus lost his
temper. “I will make you die by inches,” he exclaimed. “I despise,”
retorted Andronicus, “your threats and your menaces.” While an old
man of sixty-five was being led to the torture, a friendly centurion
said to him, “Have pity on yourself and sacrifice.” “Get thee from me,
minister of Satan,” was the reply. The main feeling uppermost in the
mind of the confessor was one of exultation that he had been found
worthy to suffer. Such a spirit could neither be bent nor broken.
Of active disloyalty to the Emperor there is absolutely no trace.
Many Christian soldiers boasted of their long and honourable service
in the army; civilians were willing to pay unto Cæsar the things that
were Cæsar’s. But Christ was their King. “There is but one God,”
cried Alphæus and Zachæus at Cæsarea, “and only one King and
Lord, who is Jesus Christ.” To the pagan judge this was not merely
blasphemy against the gods, but treason against the Emperor.
Sometimes, but not often, the martyr’s feelings got the better of him
and he cursed the Emperor. “May you be punished,” cried the
dauntless Andronicus to Maximus, when the officers of the court had
thrust between his lips the bread and meat of sacrifice, “may you be
punished, bloody tyrant, you and they who have given you the power
to defile me with your impious sacrifices. One day you will know what
you have done to the servants of God.” “Accursed scoundrel,” said
the judge, “dare you curse the Emperors who have given the world
such long and profound peace?” “I have cursed them and I will curse
them,” replied Andronicus, “these public scourges, these drinkers of
blood, who have turned the world upside down. May the immortal
hand of God tolerate them no longer and punish their cruel
amusements, that they may learn and know the evil they have done
to God’s servants.” No doubt, most Christians agreed with the
sentiments expressed by Andronicus, but they rarely gave
expression to them. “I have obeyed the Emperors all the years of my
life,” said Bishop Philippus of Heraclea, “and, when their commands
are just, I hasten to obey. For the Holy Scripture has ordered me to
render to God what is due to God and to Cæsar what is due to
Cæsar. I have kept this commandment without flaw down to the
present time, and it only remains for me to give preference to the
things of heaven over the attractions of this world. Remember what I
have already said several times, that I am a Christian and that I
refuse to sacrifice to your gods.” Nothing could be more dignified or
explicit. It is the Emperor-God and his fellow deities of Olympus, not
the Emperor, to whom the Christian refuses homage. During a trial at
Catania in Sicily the judge, Calvisianus, said to a Christian,
“Unhappy man, adore the gods, render homage to Mars, Apollo, and
Æsculapius.” The answer came without a second’s hesitation: “I
adore the Father, Son, and Holy Ghost—the Holy Trinity—beyond
whom there is no God. Perish the gods who have not made heaven
and earth and all that they contain. I am a Christian.” From first to
last, in Spain as in Africa, in Italy as in Sicily, this is the alpha and the
omega of the Christian position, “Christianus sum.”
To what extent was the martyrdom self-inflicted? How far did the
Christians pile with their own hands the faggots round the stakes to
which they were tied? It is significant that some churches found it
necessary to condemn the extraordinary exaltation of spirit which
drove men and women to force themselves upon the notice of the
authorities and led them to regard flight from danger as culpable
weakness. They not only did not encourage but strictly forbade the
overthrowing of pagan statues or altars by zealous Christians
anxious to testify to their faith. They did not wish, that is to say, to
provoke certain reprisals. Yet, in spite of all their efforts, martyrdom
was constantly courted by rash and excitable natures in the frenzy of
religious fanaticism, like that which impelled Theodorus of Amasia in
Pontus to set fire to a temple of Cybele in the middle of the city and
then boast openly of the deed. Often, however, such martyrs were
mere children. Such was Eulalia of Merida, a girl of twelve, whose
parents, suspecting her intention, had taken her into the country to
be out of harm’s way. She escaped their vigilance, returned to the
city, and, standing before the tribunal of the judge, proclaimed
herself a Christian.
 ”Mane superba tribunal adit,
Fascibus adstat et in mediis.“

The judge, instead of bidding the officials remove the child, began
to argue with her, and the argument ended in Eulalia spitting in his
face and overturning the statue which had been brought for her to
worship. Then came torture and the stake, a martyred saint, and in
later centuries a stately church, flower festivals, and a charming
poem from the Christian poet, Prudentius. But even his graceful
verses do not reconcile us to the pitiful futility of such child-
martyrdom as that of Eulalia of Merida or Agnes of Rome.
Or take, again, the pathetic inscription found at Testur, in Northern
Africa;
“Sanctæ Tres;
Maxima,
Donatilla
Et Secunda,
Bona Puella.”
These were three martyrs of Thuburbo. Two of them, Maxima and
Donatilla, had been denounced to the judge by another woman.
Secunda, a child of twelve, saw her friends from a window in her
father’s house, as they were being dragged off to prison. “Do not
abandon me, my sisters,” she cried. They tried to wave her back.
She insisted. They warned her of the cruel fate which was certain to
await her; Secunda declared her confidence in Him who comforts
and consoles the little ones. In the end they let her accompany them.
All three were sentenced to be torn by the wild beasts of the
amphitheatre, but when they stood up to face that cruel death, a wild
bear came and lay at their feet. The judge, Anulinus, then ordered
them to be decapitated. Such is the story that lies behind those
simple and touching words, “Secunda, Bona Puella.”
Nor were young men backward in their zeal for the martyr’s crown.
Eusebius tells us of a band of eight Christian youths at Cæsarea,
who confronted the Governor, Urbanus, in a body shouting, “We are
Christians,” and of another youth named Aphianus, who, while
reading the Scriptures, heard the voice of the heralds summoning
the people to sacrifice. He at once made his way to the Governor’s
house, and, just as Urbanus was in the act of offering libation,
Aphianus caught his arm and upbraided him for his idolatry. He
simply flung his life away.
In this connection may be mentioned the five martyred statuary
workers belonging to a Pannonian marble quarry. They had been
converted by the exhortations of Bishop Cyril, of Antioch, who had
been condemned to labour in their quarry, and, once having become
Christians, their calling gave them great searching of heart. Did not
the Scriptures forbid them to make idols or graven images of false
gods? When, therefore, they refused to undertake a statue of
Æsculapius, they were challenged as Christians, and sentenced to
death. Yet they had not thought it wrong to carve figures of Victory
and Cupid, and they seem to have executed without scruple a
marble group showing the sun in a chariot, doubtless satisfying
themselves that these were merely decorative pieces, which did not
necessarily involve the idea of worship. But they preferred to die
rather than make a god for a temple, even though that god were the
gentle Æsculapius, the Healer.
We might dwell at much greater length upon this absorbing subject
of the persecution of Diocletian, and draw upon the Passions of the
Saints for further examples of the marvellous fortitude with which so
many of the Christians endured the most fiendish tortures for the
sake of their faith. “I only ask one favour,” said the intrepid Asterius:
“it is that you will not leave unlacerated a single part of my body.” In
the presence of such splendid fidelity and such unswerving faith,
which made even the weakest strong and able to endure, one sees
why the eventual triumph of the Church was certain and assured.
One can also understand why the memory and the relics of the
martyrs were preserved with such passionate devotion; why their
graves were considered holy and credited with powers of healing;
and why, too, the names of their persecutors were remembered with
such furious hatred. It may be too much to expect the early
chroniclers of the Church to be fair to those who framed and those
who put into execution the edicts of persecution, but we, at least,
after so many centuries, and after so many persecutions framed and
directed by the Churches themselves, must try to look at the
question from both sides and take note of the absolute refusal of the
Christian Church to consent to the slightest compromise in its
attitude of hostility to the religious system which it had already
dangerously undermined.
It is not easy from a study of the Passions of the Saints to draw
any sweeping generalisations as to what the public at large thought
of the torture and execution of Christians. We get a glimpse, indeed,
of the ferocity of the populace at Rome when Maximian went thither
to celebrate the Ludi Cereales in 304. The “Passion of St. Savinus”
shews an excited crowd gathered in the Circus Maximus, roaring for
blood and repeating twelve times over the savage cry, “Away with
the Christians and our happiness is complete. By the head of
Augustus let not a Christian survive.”[15] Then, when they caught
sight of Hermogenianus, the city præfect, they called ten times over
to the Emperor, “May you conquer, Augustus! Ask the præfect what it
is we are shouting.” Such a scene was natural enough in the Circus
of Rome; was it typical of the Empire? Doubtless in all the great
cities, such as Alexandria, Antioch, Ephesus, Carthage, the “baser
sort” would be quite ready to shout, “Away with the Christians.” But it
is to be remembered that we find no trace anywhere in this
persecution of a massacre on the scale of that of St. Bartholomew or
the Sicilian Vespers. On the contrary, we see that though the prisons
were full, the relations of the Christians were usually allowed to visit
them, take them food, and listen to their exhortations. Pamphilus of
Cæsarea, who was in jail for two years, not only received his friends
during that period, but was able to go on making copies of the
Scriptures!
We rarely hear of the courts being packed with anti-Christian
crowds, or of the judges being incited by popular clamour to pass the
death sentence. The reports of the trials shew us silent, orderly
courts, with the judges anxious not so much to condemn to death as
to make a convert. If Diocletian had wanted blood he could have had
it in rivers, not in streams. But he did not. He wished to eradicate
what he believed to be an impious, mischievous, and, from the point
of view of the State’s security, a dangerous superstition. There was
no talk of persecuting for the sake of saving the souls of heretics;
that lamentable theory was reserved for a later day. Diocletian
persecuted for what he considered to be the good of the State. He
lived to witness the full extent of his failure, and to realise the
appalling crime which he had committed against humanity, amid the
general overthrow of the political system which he had so laboriously
set up.
 CHAPTER III
THE ABDICATION OF DIOCLETIAN AND THE
SUCCESSION
OF CONSTANTINE

On the 1st of May, in the year 305, Diocletian, by an act of

unexampled abnegation, resigned the purple and retired into private
life. The renunciation was publicly performed, not in Rome, for Rome
had ceased to be the centre of the political world, but on a broad
plain in Bithynia, three miles from Nicomedia, which long had been
the Emperor’s favourite residence. In the centre of the plain rose a
little hill, upon which stood a column surmounted by a statue of
Jupiter. There, years before, Diocletian had with his own hands
invested Galerius with the symbols of power; there he was now to
perform the last act of a ruler by nominating those whom he thought
most fit to succeed him. A large platform had been constructed; the
soldiers of the legions had been ordered to assemble in soldier’s
meeting and listen to their chief’s farewell. Diocletian took leave of
them in few words. He was old, he said, and infirm. He craved for
rest after a life of toil. The Empire needed stronger and more
youthful hands than his. His work was done. It was time for him to
go.
The two Augusti were laying down their powers simultaneously, for
Maximian was performing a similar act of renunciation at Milan. The
two Cæsars, Constantius and Galerius, would thus automatically
move up into the empty places and become Augusti in their stead. It
had been necessary, therefore, to select two new Cæsars, and these
Diocletian was about to present to the loyalty of the legions. We are
told that the secret had been well kept, and that the soldiers waited
with suppressed excitement until Diocletian suddenly announced
that his choice had fallen upon Severus, one of his trusted generals,
and upon Maximin Daza, a nephew of Galerius. Severus had already
been sent to Milan to be invested by Maximian; Maximin was present
on the tribunal and was then and there robed in the purple. The
ceremony over, Diocletian—a private citizen once more, though he
still retained the title of Augustus—drove back to Nicomedia and at
once set out for Salona, on the Adriatic, where he had built a
sumptuous palace for his retirement.
 CONSTANTINE THE GREAT.
FROM GROSVENOR’S “CONSTANTINOPLE.”

The scene which we have depicted is described most fully and

most graphically by a historian whose testimony, unfortunately, is
entirely suspect in matters of detail. The author of The Deaths of the
Persecutors—it is very doubtful whether Lactantius, to whom the
work has long been attributed, really wrote it, but for the sake of
convenience of reference we may credit him with it—is at once the
most untrustworthy and the most vigorous and attractive writer of the
period. His object throughout is to blacken the characters of the
Emperors who persecuted the Christian Church, and he does not
scruple to distort their actions, pervert their motives, and even invent,
with well calculated malice, stories to their discredit. Lactantius
knows, or pretends to know, all that takes place even in the most
secret recesses of the palace; he recounts all that passes at the
most confidential conferences; and with consummate artistry he
throws in circumstantial details and touches of local colour which
give an appearance of truth, but are really the most convincing
proofs of falsehood. Lactantius represents the abdication of
Diocletian as the act of an old man, shattered in health, and even in
mind, by a distressing malady sent by Heaven as the just
punishment of his crimes. He depicts him cowering in tears before
the impatient insolence of Galerius, now peremptorily clamouring for
the succession with threats of civil war. They discuss who shall be
the new Cæsars. “Whom shall we appoint?” asks Diocletian.
“Severus,” says Galerius. “What?” says the other, “that drunken sot
of a dancer who turns night into day and day into night?” “He is
worthy,” replies Galerius, “for he has proved a faithful general, and I
have sent him to Maximian to be invested.” “Well, well,” says the old
man, “who is the second choice?” “He is here,” says Galerius,
indicating his nephew, a young semi-barbarian named Maximin
Daza. “Why, who is this you offer me?” “He is my kinsman,” is the
reply. Then said Diocletian, with a groan, “These are not fit men to
whom to entrust the care of the State.” “I have proved them,” said
Galerius. “Well, you must look to it,” rejoins Diocletian, “you who are
about to assume the reins of the Empire. I have toiled enough. While
I ruled, I took care that the State stood safe. If any harm now befalls,
the fault is not mine.”[16]
Such is a characteristic specimen of Lactantius’s history, and so,
when he comes to describe the ceremony of abdication, he makes
Galerius draw Maximin Daza to the front of the group of imperial
officials by whom Diocletian is surrounded, and represents the
soldiers as staring in surprise at their new Cæsar, as at one whom
they had never seen before. Yet a favourite nephew of Galerius can
scarcely have been a stranger to the troops of Nicomedia. Galerius
not only—according to Lactantius—drew forward Maximin Daza, but
at the same time rudely thrust back into the throng the son of
Constantius, the senior of the two new Augusti. This was young
Constantine, the future Emperor, who for some years past had been
living at the Court of Diocletian.
But it was no broken down Emperor in his dotage, passing,
according to the spasms of his malady, from sanity to insanity, who
resigned the throne on the plain of Nicomedia. Diocletian was but
fifty-nine years of age. He had just recovered, it is true, from a very
severe illness, which, even on the testimony of Lactantius, had
caused “grief in the palace, sadness and tears among his guards,
and anxious suspense throughout the whole State.”[17] But his brain
was never clearer than when he took final leave of his troops. His
abdication was the culminating point of his policy. He had planned it
twenty years before. He had kept it before his eyes throughout a
long and busy reign. It was the completion of, the finishing touch to
his great political system. It would have been perfectly easy for
Diocletian to forswear himself. Probably very few of his
contemporaries believed that he would fulfil his promise to abdicate
after twenty years of reign. Kings talk of the allurements of
retirement, but they usually cling to power as tenaciously as to life.
The first Augustus had delighted to mystify his Ministers of State by
speaking of restoring the Republic. He died an Emperor. Diocletian,
alone of the Roman Emperors, laid down the sceptre when he was
at the height of his glory. It was a hazardous experiment, but he was
faithful to his principles. He thought it best for the world that its
master should not grow old and feeble on the throne.
 Constantine, of whom we have just caught a glimpse at the
abdication of Diocletian, was born either in 273 or 274. The
uncertainty attaching to the year of his birth attaches even more to
its place. No one now believes that he was born in Britain—a
pleasing fiction which was invented by English monks, who delighted
to represent his mother Helena as the daughter of a British King,
though they were quite at a loss where to locate his kingdom. The
only foundation for this was a passage in one of the Panegyrists,
who said that Constantine had bestowed lustre upon Britain “illic
oriundo.” But the words are now taken as referring to his accession
and not to his birth. He was certainly proclaimed Emperor in Britain,
and might thus be said to have “sprung thence.” Constantine’s birth-
place seems to have been either Naissus, a city in Upper Moesia, or
Drepanum, a city near Nicomedia. The balance of evidence, though
none of it is very trustworthy, inclines to the former.
His father was Constantius Chlorus, afterwards Cæsar and
Augustus, but at the time of Constantine’s birth merely a promising
officer in the Roman army. Constantius belonged to one of the
leading families of Moesia and his mother was a niece of the capable
and soldierly Claudius, the conqueror of the Goths. Claudius had
only been dead four years when Constantine was born, and we may
suppose that it was his influence which had set Constantius in the
way of rapid promotion. He had formed one of those secondary
marriages which were recognised by Roman law, when the wife was
not of the same social standing as the husband. Helena is said to
have been the daughter of an innkeeper of Drepanum, and
Constantine’s enemies lost no opportunity of dwelling upon the
obscurity of his ancestry upon his mother’s side. But that he was
born in wedlock is beyond question. Had the relationship between
Constantius and Helena been an irregular one, there would have
been no need for Maximian to insist on a divorce when he ratified
Constantius’s elevation to the purple by giving him the hand of his
daughter, Theodora.
Of Constantine’s early years we know nothing, though we may
suppose that they were spent in the eastern half of the Empire.
Constantius served with the eastern legions in the campaigns which
preceded the accession of Diocletian in 284, and it is as a young
officer in the entourage of that Emperor that Constantine makes his
earliest appearance in history. Eusebius tells us[18] that he first saw
the future champion of Christianity in the train of Diocletian during
one of the latter’s visits to Palestine. He recalls his vivid
remembrance of the young Prince standing at the Emperor’s right
hand and attracting the gaze of all beholders by the beauty of his
person and the imposing air which betokened his consciousness of
having been born to rule. Eusebius adds that while Constantine’s
physical strength extorted the respectful admiration of his younger
associates, his remarkable qualities of prudence and wisdom
aroused the jealousy and excited the apprehensions of his chiefs.
However, the recollections of the Bishop of Cæsarea, with half a
century of interval, are somewhat suspect, and we need see no
more than a high-spirited, handsome, and keen-witted Prince in
Eusebius’s “paragon of bodily strength, physical beauty, and mental
distinction.” As for Diocletian’s jealous fears, they are best refuted by
the fact that Constantine was promoted to be a tribune of the first
rank and saw considerable military service. The foolish stories that
his superiors set him to fight a gigantic Sarmatian in single combat,
and dared him to contend against ferocious wild beasts, in the hope
that his pride and courage might be his undoing, may be dismissed
as childish. If Diocletian had feared Constantine, Constantine would
never have survived his residence in the palace.
It is certainly remarkable that we should know so little, not only of
the youth but of the early manhood of Constantine, who was at least
in his thirty-first year when Diocletian retired into private life. Why
had he spent all those years in the East instead of sharing with his
father the dangers and glories of his Gallic and British campaigns?
The answer is doubtless to be found in the fact that it was no part of
Diocletian’s system for the son to succeed the father. Constantius’s
loyalty was never in doubt, but Constantine, if Zosimus[19] can be
trusted, had already given evidence of consuming ambition to rule.
However that may be, it is obvious that his position became much
more hazardous when Galerius succeeded Diocletian as supreme
ruler in the palace of Nicomedia. One can understand Galerius
wondering whether the capable young Prince, who slept under his
roof, was destined to cross his path, and the anxiety of Constantius,
conscious of declining strength, that his long-absent son should join
him. Constantine himself might well be uneasy, and scheme to quit a
place where he could not hope to satisfy his natural ambitions. We
need not doubt, therefore, that Constantius repeatedly sent
messages to Galerius asking that his son might come to him, or that
the son was eager to comply.
Lactantius,[20] who does his best to make history romantic and
exciting, describes the eventual escape of Constantine in one of his
most graphic chapters. He shows us Galerius in his palace
reluctantly signing an order which authorised Constantine to travel
post across the Continent of Europe. He only consented to do so, we
are told, because he could find no pretext for further delay, and he
gave the order to Constantine late in the afternoon, on the
understanding that he should see him again in the morning to
receive his final instructions. Yet all the time, says Lactantius,
Galerius was scheming to find some excuse for keeping him in
Nicomedia, or contemplated sending a message to Severus, asking
him to delay Constantine when he reached the border of northern
Italy. Galerius then took dinner, retired for the night, and slept so well
and deliberately that he did not wake until the following midday (Cum
consulto ad medium diem usque dormisset). He then sent for
Constantine to come to his apartment. But Constantine was already
gone, scouring the roads as fast as the post horses could carry him,
and so anxious to increase the distance between himself and
Galerius that he caused the tired beasts to be hamstrung at every
stage. He had waited for Galerius to retire and had then slipped
away, lest the Emperor should change his mind. Galerius was
furious when he found that he had been outwitted. He ordered
pursuit. His servants came back to tell him that the fugitive had
swept the stables clear of horses. And then Galerius could scarce
restrain his tears (Vix lacrimas tenebat).
It is a story which does infinite credit to Lactanius’s feeling for
strong melodramatic situation. No picturesque detail is omitted—the
setting sun, the tyrant plotting vengeance over dinner, his resolve to
sleep long, his baffled triumph, the escaping hero, and the butchery
of the horses. Yet we question if there is more than a shred of truth
in the whole story. Galerius would not have given Constantine the
sealed order overnight had he intended to take it back the next
morning. A word to the officer of the watch in the palace and to the
officer on duty at the city gate would have prevented Constantine
from quitting Nicomedia. The imperial post service must have been
very much underhorsed if the Emperor’s servants could not find
mounts for the effective pursuit of a single fugitive. Galerius may
very well have been unwilling for Constantine to go, and Constantine
doubtless covered the early stages of his long journey at express
speed, in order to minimise the chance of recall, but the lurid details
of Lactantius are probably simply the outcome of his own lively
imagination.
Constantine seems to have found his father at the port of
Gessoriacum (Boulogne), just waiting for a favourable wind to carry
him across the Channel into Britain. Constantius was ill, and
welcomed with great joy the son whom he had not seen for many
years. We do not know what time elapsed before Constantius died at
York,—apparently it was after the conclusion of a campaign in
Scotland,—but before he died he commended to Constantine the
welfare of his young half-brothers and half-sisters, the eldest of
whom was no more than thirteen years of age, and he also evidently
commended Constantine himself to the loyalty of his legions. The
Emperor, we are informed both by Lactantius and by the author of
the Seventh Panegyric, died with a mind at rest because he was
sure of his heir and successor—Jupiter himself, says the pagan
orator,[21] stretched out his right hand and welcomed him among the
gods. Clearly, the ground had been well prepared, for no sooner was
the breath out of Constantius’s body than the troops saluted
Constantine with the title of Augustus. Aurelius Victor adds the
interesting detail that he had no stouter supporter than Erocus, a
Germanic King, who was serving as an auxiliary in the Roman army.
Constantine was nothing loth, though, as usual in such
circumstances, he may have feigned a reluctance which he did not
feel. His panegyrist, indeed, represents him as putting spurs to his
horse to enable him to shake off the robe which the soldiers sought
to throw over his shoulders, and suggests that it had been
Constantine’s intention to write “to the senior Princes” and consult
their wishes as to the choice of a successor. Had he done so, he
knew very well that Galerius would have sent over to Britain some
trusted lieutenant of his own to take command and Constantine
would have received peremptory orders to return. Instead of that,
Constantine assumed the insignia of an Emperor, and wrote to
Galerius announcing his elevation. Galerius, it is said, hesitated long
as to the course he should adopt. That the news angered him we
may be sure. Apart from all personal considerations, this choice of
an Emperor by an army on active service was a return to the bad old
days of military rule, from which Diocletian had rescued the Empire,
and was a clear warning that the new system had not been
established on a permanent basis. The only alternative, however,
before Galerius was acceptance or war. For the latter he was hardly
prepared, and moreover, there was no reply to the argument that
Constantius had been senior Augustus, and, therefore, had been
fully entitled to have his word in the appointment of a successor.
Galerius gave way. He accepted the laurelled bust which
Constantine had sent to him and, instead of throwing it into the fire
with the officer who had brought it—which, according to Lactantius,
had been his first impulse,--he sent the messenger back with a
purple robe to his master as a sign that he frankly admitted his
claims to partnership in the Empire.
But while he acknowledged Constantine as Cæsar, he refused him
the full title of Augustus, which he bestowed upon the Cæsar
Severus. This has been represented as an act of petty spite. In
reality, it was simply the automatic working of the system of
Diocletian. The latest winner of imperial dignity naturally took the
fourth place. Constantine accepted the check without demur. He had
not spent so many years by the side of Diocletian and Galerius
without discovering that if it came to war, it was the master of the
best army who was sure to be the winner and survivor, whether his
title were Cæsar or Augustus. Thus, in July, 306, Constantine
commenced his eventful reign as the Cæsar of the West, overlord of
Gaul, Spain, and Britain, and commander of the Army of the Rhine,
and, for the next six years, down to his invasion of Italy in 312, he
spent most of his time in the Gallic provinces, where he gained the
reputation of being a capable soldier and a generous Prince.