The Etiopathogenesis of Parkinson Disease and Suggestions for Future Research.
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J Neuropathol Exp Neurol Vol. 66, No. 4
Copyright Ó 2007 by the American Association of Neuropathologists, Inc. April 2007
pp. 251Y257
REVIEW ARTICLE
The Etiopathogenesis of Parkinson Disease and Suggestions
for Future Research. Part I
Irene Litvan, MD, Glenda Halliday, PhD, Mark Hallett, MD, Christopher G. Goetz, MD,
Walter Rocca, MD, MPH, Charles Duyckaerts, MD, Yoav Ben-Shlomo, MBBS, FFPHM, PhD,
Dennis W. Dickson, MD, Anthony E. Lang, MD, Marie-Francoise Chesselet, MD, PhD,
William J. Langston, MD, Donato A. Di Monte, MD, Thomas Gasser, MD, PhD, Theo Hagg, MD, PhD,
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John Hardy, PhD, Peter Jenner, PhD, Eldad Melamed, MD, Richard H. Myers, PhD,
Davis Parker, Jr., MD, and Donald L. Price, MD
DEFINITION
INTRODUCTION
We are at a critical juncture in our knowledge of the etiology and Current Knowledge
pathogenesis of Parkinson disease (PD). It is clear that PD is not a The definition of idiopathic Parkinson disease (PD)
single entity simply resulting from a dopaminergic deficit; rather it remains controversial. Classically, it includes a characteristic
is most likely caused by a combination of genetic and environ- motor phenotype (1) and a distinctive neuropathology and
mental factors and, although there is extensive new information on substantial loss of dopaminergic neurons from the substantia
the etiology and pathogenesis of PD that may advance its treatment, nigra associated with the presence of >-synuclein-positive
new syntheses of this information are needed. The first part of this inclusions in the cell body (Lewy bodies) and processes
two-part, state-of-the-art review by leaders in Parkinson research (Lewy neurites) of specific neurons of the brainstem.
critically examines the field to identify where new knowledge and
Parkinson Syndrome Without Synucleinopathy
ideas might be helpful for treatment purposes. Topics reviewed in
Some genetically determined Parkinson syndromes
Part I include the definition of the disease, neuropathologic
resemble, sometimes closely, idiopathic PD, but differ from
contributions, and epidemiologic, environmental, and demographic
it neuropathologically, sometimes substantially. In partic-
issues.
ular, a number of juvenile-onset autosomal recessive cases
Key Words: Lewy bodies, Parkinson disease, Synucleinopathies of familial Parkinson syndrome do not have >-synuclein
lesions (2), contrasting with the autosomal dominant forms
of the disease which often have unusual types of lesions
(3Y5). The recently identified leucine-rich repeat kinase 2
(LRRK2, Park-8) mutations produce variable pathologic
From the University of Louisville School of Medicine (IL, TH), Louisville, phenotypes. Although the most common is Lewy body
Kentucky; the Prince of Wales Medical Research Institute (GH), disease, nigral degeneration with ubiquitin inclusions or, in a
Sydney, Australia; the National Institute of Neurological Disorders and few cases, even pathologic changes more typical of
Stroke (MH), National Institutes of Health, Baltimore, Maryland; Rush
Medical College (CGG), Rush University Medical Center, Chicago,
frontotemporal lobar degeneration or progressive supra-
Illinois; the Mayo Clinic College of Medicine (WR), Rochester, nuclear palsy have been described in patients with LRRK2
Minnesota; Hôpital de la Salpetrière (CD), Salpetrière, France; the mutations (6). Two recent reports insist on the high
University of Bristol (YB-S), Bristol, UK; the Mayo Clinic Jacksonville prevalence of Lewy bodies in the LRRK2 mutations (7) but
(DWD), Jacksonville, Florida; Toronto Western Hospital (AEL), also describe a family with tau pathology (8).
Toronto, Ontario, Canada; the University of California Los Angeles
(M-FC), Los Angeles, California; The Parkinson Institute (WJL, DAD),
Sunnyvale, California; the University of Tübingen (TG), Tübingen, Association With Other Neurodegenerative
Germany; the National Institute of Aging (JH), National Institutes of Conditions
Health, Bethesda, MD; King’s College (PJ), London, UK; the Rabin Neuropathology has revealed the considerable fre-
Medical CenterYBeilinson Campus Sackler School of Medicine (EM), quency with which idiopathic PD is associated with other
Petah, Tikva, Israel; Boston University School of Medicine (RHM),
Boston, Massachusetts; the University of Virginia Health System (DP), degenerative conditions, notably Alzheimer disease, particu-
Charlottesville, Virginia; and The Johns Hopkins School of Medicine larly in advanced age, even though the clinical consequences
(DLP), Baltimore, Maryland. of multiple pathologies remain poorly defined. Moreover, an
Send correspondence and reprint requests to: Irene Litvan, MD, Raymond association with genetic variants that increase tau tran-
Lee Lebby Professor of Parkinson Disease Research, Director, Move-
ment Disorder Program, University of Louisville School of Medicine,
scription occurs in all forms of Lewy body diseases (sporadic
Department of Neurology, A Building, Room 113, 500 South Preston and familial), providing additional support for the involve-
Street, Louisville, KY 40202; E-mail: i.litvan@louisville.edu ment of tau in the pathogenic process (9, 10). Unfortunately,
J Neuropathol Exp Neurol Volume 66, Number 4, April 2007 251
Copyright @ 2007 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited.Litvan et al J Neuropathol Exp Neurol Volume 66, Number 4, April 2007
the cellular mechanisms by which this or other potential Coexisting Pathologies in the AgedVHow Often
detrimental processes interact to produce the features of any Is Pure Disease Observed?
form of PD remain purely speculative. Large autopsy series of community samples show that
the majority of people harbor multiple cellular neuro-
Synucleinopathies Without Parkinson Disease pathologies as they age (20Y22). This finding suggests that
Other synucleinopathies (disorders with >-synuclein clinical parkinsonism in the elderly could arise from differ-
aggregates) include dementia with Lewy bodies (DLB), ing pathologies within the dopamine pathways. Alzheimer
multiple system atrophy in which >-synuclein constitutes disease can be responsible for such alterations that induce an
characteristic inclusions, predominantly in oligodendrocyte extrapyramidal syndrome (23, 24), which is important to
cell bodies (11), and neurodegeneration with brain iron remember when epidemiologic data of age-related preva-
accumulation in which >-synuclein accumulates in axonal lence are being discussed, as there is a much greater
spheroids (12). The recognition of such varied disorders likelihood of nonsynuclein-related pathologies contributing
associated with abnormal >-synuclein aggregation in multi- to clinical features with advancing age. The impact of
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ple cell types and cell compartments has broad implications overlapping pathologies in PD is poorly understood,
for the etiopathogenesis of this group of disorders, suggest- although the identification of cases with high burdens of
ing that the selective disruption of diverse intracellular >-synuclein accumulation but without clinical deficits (25)
events utilizing >-synuclein leads to distinctive anatomical suggests that the etiopathogenesis may be related to addi-
and cellular patterns of pathology. In particular, some tional, more toxic pathologies that are worthy of inves-
patients with DLB have patterns of >-synuclein deposition tigation. Whereas several clinicopathologic studies support
identical to those seen in idiopathic PD but have no the concept that increasing cortical Lewy body burden
parkinsonism (13, 14). Moreover, as olfactory dysfunction, contributes to clinical dementia in PD, additional patholo-
constipation, rapid eye movement sleep behavior disorder, gies and/or cell loss may also underlie substantive clinical
and depression may precede or present commonly in early deficits (14) and warrant further investigation.
PD, they are proposed to be prodromic signs of PD (15).
These symptoms correlate well with the deposition of
>-synuclein in Braak stages 1 (olfactory bulb and peripheral Synucleinopathy or Synucleinopathies?
and central medullary autonomic neurons) and 2 (locus Is there any clue that could assist in recognizing the
ceruleus and pontine tegmentum), which are proposed to >-synuclein phenotype? In other words, do all of the
precede the clinical symptoms of PD (stage 3 with >-synuclein synucleinopathies (i.e. Lewy body diseases, multiple system
deposition in the substantia nigra) (16). atrophy, or neurodegeneration with brain iron accumulation)
have something in common? >-Synuclein aggregations
concentrate in different cell types in various patterns in
Research Challenges
different diseases with diverse pathogenesis. What clinical
Should the definition of PD rely on clinical (the features, if any, do these disorders have in common?
extrapyramidal syndrome), pathologic (the >-synuclein Without a biologic marker, how good are we at identifying
deposition), or genetic data? When the full spectrum of this broader group of patients in a clinical setting?
clinical PD is present, there is a high probability of finding a
devastating loss of dopamine neurons (17) with >-synuclein
accumulation. Moreover, the loss of nigral neurons is Future Developments
correlated with the severity of akinesia and rigidity (18). There is an urgent need for clarification of the
However, the accumulation of >-synuclein may be absent in nomenclature. Inasmuch as the aim of the nosologic
patients with genetically determined clinical PD. Mild classification is to orient research and suggest therapy, it
parkinsonian symptoms in the elderly may also relate to appears that similarity in the topography of the lesions does
the loss of dopamine neurons in the absence of >-synuclein not imply similarity in the full spectrum of disease patho-
deposition (19). In most if not all of these >-synuclein- genesis. We think it advisable to carefully distinguish the
negative cases, clinical PD is determined by lesions of the various Parkinsonian syndromes by their pathologic and
nigrostriatal pathway. Should we then use the term BPD[ for genetic characteristics, including those syndromes with and
any type of pathology as soon as it induces an alteration of without Lewy bodies. On the other hand, lesions of the
the nigrostriatal pathway sufficient to cause the PD clinical nigrostriatal pathway, responsible for clinical parkinsonism,
phenotype? Should we reserve it for cases in which clinical do not necessarily imply >-synuclein dysfunction and could
PD and nigrostriatal degeneration are associated with an be related to alterations in other intracellular pathways that
alteration of >-synuclein metabolism responsible for Lewy also justify research. For these reasons, we would favor the
bodies and Lewy neurites formation? Or, should we reserve Bsplitter[ approach that combines clinical and pathologic
it for the widespread disorder that in addition to the phenotypes with the study of genotype, rather than lumping
nigrostriatal system affects serotoninergic, noradrenergic, all cases under the common name of idiopathic PD. We
and cholinergic brainstem nuclei and the olfactory, periph- would restrict the term Bidiopathic PD[ to cases with clinical
eral sympathetic, and myenteric nervous system? (16). The parkinsonism associated with Lewy body pathology for
latter will include now better-recognized nonmotor PD which we are not sure of the genetic etiology (i.e. no known
symptoms (i.e. anosmia, constipation, rapid eye movement or suspected genetic abnormality). This would require that
sleep disorder, and depression). the Bidiopathic[ form of the disease be pathologically
252 Ó 2007 American Association of Neuropathologists, Inc.
Copyright @ 2007 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited.J Neuropathol Exp Neurol Volume 66, Number 4, April 2007 Etiopathogenesis of Parkinson Disease
confirmed with genetic screening to ensure similar cellular sleep behavior disorder, constipation, or other subtle fea-
etiology. We therefore propose that the clinical use of the tures that may be reflective of this pathology (34). There
terms possible and probable clinical PD be more routinely may nevertheless be a significant preclinical period in
adopted and genetic testing be performed when possible and which a threshold of pathology needs to be reached (both
warranted. cell loss and >-synuclein accumulation) before onset of any
symptoms (16).
Analysis of the similarities and differences between
NEUROPATHOLOGIC CONTRIBUTIONS cases with Lewy body pathology has led to the proposal of
progressive disease stages in which the intracellular deposi-
Current Knowledge
tion of >-synuclein affects medullary sites before more
Neuropathologic studies have been essential in defin- rostral brain regions, with the last stages associated with
ing and characterizing the Lewy body inclusions of involvement of cortical association neurons (16). This
idiopathic PD. More than 30 proteins have been identified scheme of progression raises difficulties: the proposal
within these inclusions (26) with the core filament composed
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suggests that autonomic centers in the medulla are initially
of >-synuclein (27). These studies provide crucial informa- affected, yet marked autonomic symptoms are not an early
tion for the laboratory modeling of PD. Lewy bodies and prominent disease feature in idiopathic PD or associated
Lewy neurites are either asymptomatic or found in patho- with the degree of cell loss (35), and predominant autonomic
logic conditions, grouped under the heading BLewy body symptoms and cell loss in relevant medullary sites rather
disease[ that include idiopathic PD, PD with dementia, and suggest a diagnosis of multiple system atrophy (36). Thus, it
DLB (28). From a neuropathologic point of view, the is possible that the pathologic deposition of >-synuclein does
distribution of Lewy pathology follows three schematic not produce profound cellular deficits, except in association
profiles: brainstem, transitional (equal to limbic Lewy body with additional pathologies and/or cell loss, a finding
disease), and diffuse (equal to neocortical Lewy body consistent with recent clinicopathologic studies of these
disease) (29), with additional widespread occurrence in medullary regions (36). In the late stages, cortical deposition
olfactory and central and peripheral autonomic neurons in of >-synuclein correlates with progressive cognitive decline
most cases (16, 30). In Alzheimer disease, Lewy body (31, 37), although in DLB the dementia is an early not a late
pathology can be limited to the amygdala, which does not fit dominating clinical feature.
into any of these categories. The brainstem type is generally
associated with clinical PD, whereas the transitional and Correlations Between Lewy Bodies, Clinical
diffuse types are generally linked to dementia, either PD
Features, and NeurodegenerationVWhat Do
with dementia (a long history of PD followed by dementia)
Lewy Bodies Do?
or DLB (dementia early in the course), usually associated
Because of the considerable dopamine cell loss
with varying degrees of concurrent Alzheimer-type pathol-
observed in PD, it has always been assumed that Lewy
ogy (14). In prospectively studied patients with PD with
bodies cause cell loss. However, to determine whether Lewy
dementia in particular, cortical Lewy bodies appear to be the
body cell loss is a consistent feature in all brain regions
main substrate driving the progression of cognitive impair-
would require the analysis of longitudinally followed
ment (31). However, as discussed above, in synucleinopa-
patients who do not exhibit the common overlapping
thies without PD, the diffuse type of Lewy body disease can
pathologies of the aged. There has also been considerable
occur without significant evidence of parkinsonism or debate over the role of >-synuclein aggregation in contrib-
dementia (25) and other pathologies associated with demen-
uting to cortical dementia, but the bulk of studies support
tia in PD (14). The effects of widespread Lewy body
a strong association between the presence of this cellular
pathology in central and peripheral autonomic regions pathology and clinical dementia. The initial controversy was
require further clarification (32, 33).
largely due to overlapping pathologies in the majority of
cases analyzed and the difficulty in attributing clinical
Research Challenges deficits to any single pathology. The current debate is
Progression of Lewy Pathology whether >-synuclein deposition in Lewy bodies is detri-
Analysis of the cellular events occurring in PD can mental or protective (38), a concept also difficult to
only be done at cross-section with comparison between determine in cases with limited clinical history and multiple
cases at different disease stages identifying any cellular pathologies. The few studies of prospectively collected,
dynamics, assuming the disease tempo and processes are autopsy-confirmed pure DLB with neocortical Lewy bodies
relatively homogeneous. There is a substantial body of evi- have shown limited gross tissue atrophy (39) and restricted
dence showing that, in most autopsy cases with clinical cell loss (40). >-Synuclein aggregates do not accumulate
PD, pathology is not restricted to the substantia nigra but extracellularly and disappear when the neuron dies, in
reaches widespread areas within the brain, spinal cord, and contrast to what occurs in Alzheimer disease in which
peripheral nervous system. On the other hand, recent the accumulation of tau protein remains visible in the ex-
studies confirm that a proportion of the elderly population tracellular space (ghost tangles). The presence of numerous
have >-synuclein aggregates without substantive clinical >-synuclein depositions in cases with long disease durations
symptoms (25, 32, 33). These patients may, however, have (e.g. PD with dementia) suggests that the neurons harboring
relevant nonmotor symptoms such as rapid eye movement these inclusions may remain viable within the tissue for a
Ó 2007 American Association of Neuropathologists, Inc. 253
Copyright @ 2007 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited.Litvan et al J Neuropathol Exp Neurol Volume 66, Number 4, April 2007
long time, particularly if Lewy bodies are thought to start neuropathology in the medical community, the public,
accumulating intracellularly before onset of symptoms. patient associations, and in the administrative staff of the
hospitals.
Future Developments
EPIDEMIOLOGIC, ENVIRONMENTAL,
Progression of Lewy Pathology AND DEMOGRAPHIC ISSUES
Autopsy studies are necessary to determine whether
there are indeed predictable stages in the progression of Lewy Current Knowledge
pathology, and because these studies require a large number Although single gene defects (e.g. in the Parkin gene),
of patients, collaboration of multiple centers would be bene- single environmental toxins (e.g. 1-methyl-4-phenyl-1,2,3,6-
ficial. In the Braak scheme, Lewy pathology is four times tetrahydropyridine), or single infectious agents (e.g. ence-
more frequently in motorically asymptomatic (stages 1Y3) phalitis lethargica) have been associated with rare forms of
than associated with clinical motor syndromes (stages 4Y6); relatively pure parkinsonism, current pathogenic theories
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therefore, such studies have to be planned in the general concerning idiopathic PD focus on a combination of genetic
population without the bias of selecting cases. The duration of susceptibility and environmental risk factors (41, 42).
the stages may be extrapolated from their prevalence. With Putative environmental and demographic factors that may
respect to clinical motor PD, substantial dopamine cell loss predispose individuals to idiopathic PD include age, sex,
only occurs at stage 4 and greater, with severe dementia estrogen status, race or ethnicity, exposure to pesticides,
associated with stage 6. Cases without clinical PD but with head trauma, not smoking, not drinking alcohol, and not
dominant dementia also need to be analyzed to determine the drinking coffee. In addition, personality traits and behaviors,
likelihood of a Btop down[ versus a Bbottom up[ disease whether genetically or environmentally determined, may
process. play a role. Of all factors, age is the most highly linked to
PD: the incidence of PD increases steeply with age in both
Correlations Between Clinical Features, men and women (43, 44).
Neurodegeneration, Lewy Bodies, and Other The late 19th century observation by Gowers of a male
Coexisting Pathologies in the Aged predominance in PD has been confirmed through many
Large autopsy series are also necessary to elucidate observational studies (43, 44). Whether this difference
clinicopathologic correlations in prospectively studied relates to hormonal (e.g. estrogen vs testosterone), behav-
cohorts to identify symptoms linked with specific brain ioral (e.g. different occupations in men and women), or
regions (dorsal nucleus of the vagus nerve, ceruleus- genetic factors (e.g. genes on chromosome X vs Y) remains
subceruleus complex, amygdala, and the CA2Y3 sectors, to unknown. Epidemiologic investigations of estrogen in
name a few). Clear assessment of clinical stages that would women (45) show that women with PD are more likely to
fit with such increasing burdens of pathology should be have undergone hysterectomy (with and without unilateral
determined, in addition to the current emphasis on searching oophorectomy) or bilateral oophorectomy and had more
for any earlier clinical phenomena. early menopause than control subjects. However, normal
The second purpose of a large study is to determine cyclic changes in estrogen and progesterone in premeno-
whether the presence of >-synuclein pathology alone causes pausal women do not correlate with changes in the signs or
symptoms with or without cell loss. Control subjects, symptoms of parkinsonism (46). Several studies have
without symptoms, should also be studied to determine the suggested that Caucasians are affected more often than
frequency of the lesions in the general populationVa African Americans; however, this question remains unsettled
precaution that has rarely been taken in the past. Better (44, 47). An analysis of seven European populations
knowledge of the association between Alzheimer-type, revealed no substantial difference in the prevalence of PD
Lewy-type, and vascular lesions needs to be acquired. The across European countries (48, 49). Other reports of variable
frequency with which Alzheimer-type pathology causes or incidence rates in different cultures may at least partly relate
contributes to the cognitive deficit or to the extrapyramidal to the lack of uniform diagnostic criteria and differences in
syndrome has to be determined. selected diagnostic tools (50Y52).
In summary, >-synuclein pathology must be better Some studies have suggested that PD is more common
studied in human material in parallel with the experimental in highly industrialized countries than in agricultural
models to determine the normal expression of the molecule societies and more frequent in Europe and North America
in glia and neurons, the parts of the molecule involved in than in the Far East (53Y55). However, there remains
different types of inclusions, its relationship with ubiquitin surprising uncertainty as to whether PD prevalence rates
and the proteasome, and the reasons for the sensitivity of differ across the five continents or between developed and
dopamine (and other) neurons in this pathology. Many of the developing countries, as suggested by recent findings from
answers to the questions that have been raised here depend China (52, 56, 57). Several studies suggested that chronic
on series of autopsy cases involving not only patients but exposure to well water and living near or working with
also control subjects. The project of increasing the number industrial chemicals or pesticide and herbicide products
of systematic autopsies needs to be planned in general increase the risk for PD, especially in subjects with young
hospitals and in conjunction with movement disorder clinics. onset (53, 58, 59). In an urban United States multiethnic
Such an action implies better awareness of the role of community, rural living, area farming, and well water
254 Ó 2007 American Association of Neuropathologists, Inc.
Copyright @ 2007 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited.J Neuropathol Exp Neurol Volume 66, Number 4, April 2007 Etiopathogenesis of Parkinson Disease
drinking were associated with PD only in African Americans, Severe head trauma in mice is associated with age-
whereas in Hispanics, area farming was protective and drinking dependent enhanced immunoreactivity to synucleins, which
unfiltered water was a risk factor (60). In Denmark, a could be the pathogenetic basis of PD after trauma in
consistent pattern of high PD morbidity was found among humans (79); however, studies of synuclein immunoreactiv-
occupational groups employed in agriculture and horticul- ity patterns in patients with PD and a history of trauma have
ture (61). The concept that well water might accumulate not yet been performed. Head trauma has been posited as a
chemical products more readily than free flowing water has risk factor, although the scientific question has been blurred
indirectly supported an environmental hypothesis of PD. Of by medical and legal issues. Nevertheless, one population-
interest, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a based study in which trauma history was documented
selective dopaminergic cell toxin associated with parkinson- routinely in the medical records of a records-linkage system
ism, was industrially developed as a potential herbicide with showed a clear association between severe head trauma and
a structure resembling paraquat but was never produced an increased risk of PD in later life (80). Finally, based on
commercially. The herbicide rotenone, a potent inhibitor of the observations of postencephalitic parkinsonism as a
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mitochondrial complex I, is currently of particular research sequela of epidemic encephalitis, numerous viral and
interest (62, 63). Exposure to hydrocarbons has been linked bacterial exposures have been examined, but no consistent
to PD (64), and the issue of chronic manganese exposure as agent has been identified.
a risk factor for PD has also been debated (65Y67).
Similarly, exposure to maneb, a widely used fungicide, has Research Challenges
been associated with parkinsonism in humans, and both The multiple putative risk factors identified so far do
maneb and its major active element (manganese ethylene- not appear to share a common pathophysiologic mechanism.
bis-dithiocarbamate) cause selective nigrostriatal neurode- In addition, an exposure causing an increased risk of PD
generation in animal and in vitro models, partially attributed may not influence the natural history after PD starts and may
to proteasomal inhibition (68). not accelerate clinical decline with continued exposure. For
Almost all studies have confirmed a lower incidence of example, smoking is associated with reduced risk of PD, but
PD among subjects with a history of smoking (69). Within twin does not appear to influence disease progression after
pairs, the risk of developing PD was inversely associated diagnosis. Moreover, although associations between dopa-
with the dose of cigarette smoking as measured by pack and mine D2 receptor polymorphisms, MAO-B intron 13 poly-
years (70). However, the protective effect of smoking in morphisms, and COMT codon 158 polymorphisms have
twins was less marked when cases with PD were compared been observed with cigarette smoking; exactly how these
with control subjects (71). Once patients have developed PD, genetic variants relate to PD risk remains speculative.
however, there is no evidence that smokers have milder Future Developments
disability or slower progression than nonsmokers (72).
Because large-scale population studies are expensive
Coffee drinking has also been linked with reduced risk of
and time consuming, internationally agreed-upon diagnostic
PD; however, the evidence is less robust than for smoking
criteria, screening instruments, and examination protocols
(69, 73, 74). Interactions between caffeine intake and
for field studies need to be uniformly applied. Prioritization
exogenous estrogen have been implicated by a study that
of research on biochemical mechanisms underlying the two
showed a protective effect of caffeinated beverage intake in
most likely environmental risk or protection factors for PD,
postmenopausal women without estrogen supplementation,
smoking and pesticides, may lead to the development of new
but a higher risk in women who received hormones (75). A
neuroprotective agents. Similarly, studies of the two primary
pooled analysis of data from three prospective studies found
demographic features that predispose to PD, age and sex,
that alcohol drinking reduced PD risk, even after statistical
may lead to a clearer delineation of intrinsic subcellular
adjustment for smoking patterns (76). This effect was
events that occur in at-risk populations. In addition, focusing
primarily driven by beer drinking, as opposed to other
the search for environmental and demographic risk factors
consumption of types of alcohol.
on Benriched[ populations at presumed high genetic risk,
The Bparkinsonian personality[ has been a topic of
such as carriers of putative susceptibility genes (UCHL1,
interest for decades, and twin studies have suggested that the
NAT2, or MAO-B genes) as well as heterozygotes for the
siblings with the more introspective, conservative, and passive
autosomal recessive causes of PD (i.e. Parkin) may provide
personalities are at higher risk for PD than their twin pairs with
the most rapid insights into the mechanisms underlying these
assertive, extroverted features (77). In a cohort study,
influences (42).
personality traits of anxiety (odds ratio = 2.0) and negativity
(odds ratio = 1.7) measured decades before the onset of PD
were associated with an increased risk of PD (78). If a CONCLUSIONS
constellation of personality features can be identified that It is clear that PD is not a single entity; rather it is
typify persons at high risk for PD many years before the clinically, pathologically, and etiologically diverse.
onset of the disease, statistical techniques that model all Although the different entities have not been fully defined
confirmed risk factors may eventually allow a Bfingerprint[ or agreed upon, it is crucial in any clinical study to clearly
of PD risk (disease prediction). Alternatively, these features indicate which patient population is being studied. Whether
could represent very early features of the disease rather than idiopathic PD will survive as one of the entities of PD is
risk factors. unlikely. As with all disorders, the different phenotypes of
Ó 2007 American Association of Neuropathologists, Inc. 255
Copyright @ 2007 by the American Association of Neuropathologists, Inc. Unauthorized reproduction of this article is prohibited.Litvan et al J Neuropathol Exp Neurol Volume 66, Number 4, April 2007
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