The Etiopathogenesis of Parkinson Disease and Suggestions for Future Research. Part I

By Litvan, Irene; Halliday, Glenda; Hallett, Mark; Goetz, Christopher G; Et al

INTRODUCTION

We are at a critical juncture in our knowledge of the etiology and pathogenesis of Parkinson disease (PD). It is clear that PD is not a single entity simply resulting from a dopaminergic deficit; rather it is most likely caused by a combination of genetic and environmental factors and, although there is extensive new information on the etiology and pathogenesis of PD that may advance its treatment, new syntheses of this information are needed. The first part of this two-part, state-of-the-art review by leaders in Parkinson research critically examines the field to identify where new knowledge and ideas might be helpful for treatment purposes. Topics reviewed in Part I include the definition of the disease, neuropathologic contributions, and epidemiologic, environmental, and demographic issues.

Key Words: Lewy bodies, Parkinson disease, Synucleinopathies

DEFINITION

Current Knowledge

The definition of idiopathic Parkinson disease (PD) remains controversial. Classically, it includes a characteristic motor phenotype (1) and a distinctive neuropathology and substantial loss of dopaminergic neurons from the substantia nigra associated with the presence of α-synuclein-positive inclusions in the cell body (Lewy bodies) and processes (Lewy neurites) of specific neurons of the brainstem.

Parkinson Syndrome Without Synucleinopathy

Some genetically determined Parkinson syndromes resemble, sometimes closely, idiopathic PD, but differ from it neuropathologically, sometimes substantially. In particular, a number of juvenile-onset autosomal recessive cases of familial Parkinson syndrome do not have α-synuclein lesions (2), contrasting with the autosomal dominant forms of the disease which often have unusual types of lesions (3-5). The recently identified leucine-rich repeat kinase 2 (LRRK2, Park-8) mutations produce variable pathologic phenotypes. Although the most common is Lewy body disease, nigral degeneration with ubiquitin inclusions or, in a few cases, even pathologic changes more typical of frontotemporal lobar degeneration or progressive supranuclear palsy have been described in patients with LRRK2 mutations (6). Two recent reports insist on the high prevalence of Lewy bodies in the LRRK2 mutations (7) but also describe a family with tau pathology (8).

Association With Other Neurodegenerative Conditions

Neuropathology has revealed the considerable frequency with which idiopathic PD is associated with other degenerative conditions, notably Alzheimer disease, particularly in advanced age, even though the clinical consequences of multiple pathologies remain poorly defined. Moreover, an association with genetic variants that increase tau transcription occurs in all forms of Lewy body diseases (sporadic and familial), providing additional support for the involvement of tau in the pathogenic process (9, 10). Unfortunately, the cellular mechanisms by which this or other potential detrimental processes interact to produce the features of any form of PD remain purely speculative.

Synucleinopathies Without Parkinson Disease

Other synucleinopathies (disorders with α-synuclein aggregates) include dementia with Lewy bodies (DLB), multiple system atrophy in which α-synuclein constitutes characteristic inclusions, predominantly in oligodendrocyte cell bodies (11), and neurodegeneration with brain iron accumulation in which α- synuclein accumulates in axonal spheroids (12). The recognition of such varied disorders associated with abnormal α-synuclein aggregation in multiple cell types and cell compartments has broad implications for the etiopathogenesis of this group of disorders, suggesting that the selective disruption of diverse intracellular events utilizing α-synuclein leads to distinctive anatomical and cellular patterns of pathology. In particular, some patients with DLB have patterns of α-synuclein deposition identical to those seen in idiopathic PD but have no parkinsonism (13, 14). Moreover, as olfactory dysfunction, constipation, rapid eye movement sleep behavior disorder, and depression may precede or present commonly in early PD, they are proposed to be prodromic signs of PD (15). These symptoms correlate well with the deposition of α- synuclein in Braak stages 1 (olfactory bulb and peripheral and central medullary autonomie neurons) and 2 (locus ceruleus and pontine tegmentum), which are proposed to precede the clinical symptoms of PD (stage 3 with α-synuclein deposition in the substantia nigra) (16).

Research Challenges

Should the definition of PD rely on clinical (the extrapyramidal syndrome), pathologic (the α-synuclein deposition), or genetic data? When the full spectrum of clinical PD is present, there is a high probability of finding a devastating loss of dopamine neurons (17) with α-synuclein accumulation. Moreover, the loss of nigral neurons is correlated with the severity of akinesia and rigidity (18). However, the accumulation of α-synuclein may be absent in patients with genetically determined clinical PD. Mild parkinsonian symptoms in the elderly may also relate to the loss of dopamine neurons in the absence of α-synuclein deposition (19). In most if not all of these α-synuclein-negative cases, clinical PD is determined by lesions of the nigrostriatal pathway. Should we then use the term “PD” for any type of pathology as soon as it induces an alteration of the nigrostriatal pathway sufficient to cause the PD clinical phenotype? Should we reserve it for cases in which clinical PD and nigrostriatal degeneration are associated with an alteration of α-synuclein metabolism responsible for Lewy bodies and Lewy neurites formation? Or, should we reserve it for the widespread disorder that in addition to the nigrostriatal system affects serotoninergic, noradrenergic, and cholinergic brainstem nuclei and the olfactory, peripheral sympathetic, and myenteric nervous system? (16). The latter will include now better- recognized nonmotor PD symptoms (i.e. anosmia, constipation, rapid eye movement sleep disorder, and depression).

Coexisting Pathologies in the Aged-How Often Is Pure Disease Observed?

Large autopsy series of community samples show that the majority of people harbor multiple cellular neuropathologies as they age (20- 22). This finding suggests that clinical parkinsonism in the elderly could arise from differing pathologies within the dopamine pathways. Alzheimer disease can be responsible for such alterations that induce an extrapyramidal syndrome (23, 24), which is important to remember when epidemiologic data of age-related prevalence are being discussed, as there is a much greater likelihood of nonsynuclein- related pathologies contributing to clinical features with advancing age. The impact of overlapping pathologies in PD is poorly understood, although the identification of cases with high burdens of α-synuclein accumulation but without clinical deficits (25) suggests that the etiopathogenesis may be related to additional, more toxic pathologies that are worthy of investigation. Whereas several clinicopathologic studies support the concept that increasing cortical Lewy body burden contributes to clinical dementia in PD, additional pathologies and/or cell loss may also underlie substantive clinical deficits (14) and warrant further investigation.

Synucleinopathy or Synucleinopathies?

Is there any clue that could assist in recognizing the α- synuclein phenotype? In other words, do all of the Synucleinopathies (i.e. Lewy body diseases, multiple system atrophy, or neurodegeneration with brain iron accumulation) have something in common? α-Synuclein aggregations concentrate in different cell types in various patterns in different diseases with diverse pathogenesis. What clinical features, if any, do these disorders have in common? Without a biologic marker, how good are we at identifying this broader group of patients in a clinical setting?

Future Developments

There is an urgent need for clarification of the nomenclature. Inasmuch as the aim of the nosologic classification is to orient research and suggest therapy, it appears that similarity in the topography of the lesions does not imply similarity in the full spectrum of disease pathogenesis. We think it advisable to carefully distinguish the various Parkinsonian syndromes by their pathologic and genetic characteristics, including those syndromes with and without Lewy bodies. On the other hand, lesions of the nigrostriatal pathway, responsible for clinical parkinsonism, do not necessarily imply α-synuclein dysfunction and could be related to alterations in other intracellular pathways that also justify research. For these reasons, we would favor the “splitter” approach that combines clinical and pathologic phenotypes with the study of genotype, rather than lumping all cases under the common name of idiopathic PD. We would restrict the term “idiopathic PD” to cases with clinical parkinsonism associated with Lewy body pathology for which we are not sure of the genetic etiology (i.e. no known or suspected genetic abnormality). This would require that the “idiopathic” form of the disease be pathologically confirmed with genetic screening to ensure similar cellular etiology. We ther\efore propose that the clinical use of the terms possible and probable clinical PD be more routinely adopted and genetic testing be performed when possible and warranted.

NEUROPATHOLOGIC CONTRIBUTIONS

Current Knowledge

Neuropathologic studies have been essential in defining and characterizing the Lewy body inclusions of idiopathic PD. More than 30 proteins have been identified within these inclusions (26) with the core filament composed of α-synuclein (27). These studies provide crucial information for the laboratory modeling of PD. Lewy bodies and Lewy neurites are either asymptomatic or found in pathologic conditions, grouped under the heading “Lewy body disease” that include idiopathic PD, PD with dementia, and DLB (28). From a neuropathologic point of view, the distribution of Lewy pathology follows three schematic profiles: brainstem, transitional (equal to limbic Lewy body disease), and diffuse (equal to neocortical Lewy body disease) (29), with additional widespread occurrence in olfactory and central and peripheral autonomic neurons in most cases (16, 30). In Alzheimer disease, Lewy body pathology can be limited to the amygdala, which does not fit into any of these categories. The brainstem type is generally associated with clinical PD, whereas the transitional and diffuse types are generally linked to dementia, either PD with dementia (a long history of PD followed by dementia) or DLB (dementia early in the course), usually associated with varying degrees of concurrent Alzheimer-type pathology (14). In prospectively studied patients with PD with dementia in particular, cortical Lewy bodies appear to be the main substrate driving the progression of cognitive impairment (31). However, as discussed above, in synucleinopathies without PD, the diffuse type of Lewy body disease can occur without significant evidence of parkinsonism or dementia (25) and other pathologies associated with dementia in PD (14). The effects of widespread Lewy body pathology in central and peripheral autonomic regions require further clarification (32, 33).

Research Challenges

Progression of Lewy Pathology

Analysis of the cellular events occurring in PD can only be done at cross-section with comparison between cases at different disease stages identifying any cellular dynamics, assuming the disease tempo and processes are relatively homogeneous. There is a substantial body of evidence showing that, in most autopsy cases with clinical PD, pathology is not restricted to the substantia nigra but reaches widespread areas within the brain, spinal cord, and peripheral nervous system. On the other hand, recent studies confirm that a proportion of the elderly population have α-synuclein aggregates without substantive clinical symptoms (25, 32, 33). These patients may, however, have relevant nonmotor symptoms such as rapid eye movement sleep behavior disorder, constipation, or other subtle features that may be reflective of this pathology (34). There may nevertheless be a significant preclinical period in which a threshold of pathology needs to be reached (both cell loss and α-synuclein accumulation) before onset of any symptoms (16).

Analysis of the similarities and differences between cases with Lewy body pathology has led to the proposal of progressive disease stages in which the intracellular deposition of α-synuclein affects medullary sites before more rostral brain regions, with the last stages associated with involvement of cortical association neurons (16). This scheme of progression raises difficulties: the proposal suggests that autonomic centers in the medulla are initially affected, yet marked autonomic symptoms are not an early prominent disease feature in idiopathic PD or associated with the degree of cell loss (35), and predominant autonomic symptoms and cell loss in relevant medullary sites rather suggest a diagnosis of multiple system atrophy (36). Thus, it is possible that the pathologic deposition of α-synuclein does not produce profound cellular deficits, except in association with additional pathologies and/or cell loss, a finding consistent with recent clinicopathologic studies of these medullary regions (36). In the late stages, cortical deposition of α-synuclein correlates with progressive cognitive decline (31, 37), although in DLB the dementia is an early not a late dominating clinical feature.

Correlations Between Lewy Bodies, Clinical Features, and Neurodegeneration-What Do Lewy Bodies Do?

Because of the considerable dopamine cell loss observed in PD, it has always been assumed that Lewy bodies cause cell loss. However, to determine whether Lewy body cell loss is a consistent feature in all brain regions would require the analysis of longitudinally followed patients who do not exhibit the common overlapping pathologies of the aged. There has also been considerable debate over the role of α-synuclein aggregation in contributing to cortical dementia, but the bulk of studies support a strong association between the presence of this cellular pathology and clinical dementia. The initial controversy was largely due to overlapping pathologies in the majority of cases analyzed and the difficulty in attributing clinical deficits to any single pathology. The current debate is whether α-synuclein deposition in Lewy bodies is detrimental or protective (38), a concept also difficult to determine in cases with limited clinical history and multiple pathologies. The few studies of prospectively collected, autopsy- confirmed pure DLB with neocortical Lewy bodies have shown limited gross tissue atrophy (39) and restricted cell loss (40). α- Synuclein aggregates do not accumulate extracellularly and disappear when the neuron dies, in contrast to what occurs in Alzheimer disease in which the accumulation of tau protein remains visible in the extracellular space (ghost tangles). The presence of numerous α-synuclein depositions in cases with long disease durations (e.g. PD with dementia) suggests that the neurons harboring these inclusions may remain viable within the tissue for a long time, particularly if Lewy bodies are thought to start accumulating intracellularly before onset of symptoms.

Future Developments

Progression of Lewy Pathology

Autopsy studies are necessary to determine whether there are indeed predictable stages in the progression of Lewy pathology, and because these studies require a large number of patients, collaboration of multiple centers would be beneficial. In the Braak scheme, Lewy pathology is four times more frequently in motorically asymptomatic (stages 1-3) than associated with clinical motor syndromes (stages 4-6); therefore, such studies have to be planned in the general population without the bias of selecting cases. The duration of the stages may be extrapolated from their prevalence. With respect to clinical motor PD, substantial dopamine cell loss only occurs at stage 4 and greater, with severe dementia associated with stage 6. Cases without clinical PD but with dominant dementia also need to be analyzed to determine the likelihood of a “top down” versus a “bottom up” disease process.

Correlations Between Clinical Features, Neurodegeneration, Lewy Bodies, and Other Coexisting Pathologies in the Aged

Large autopsy series are also necessary to elucidate clinicopathologic correlations in prospectively studied cohorts to identify symptoms linked with specific brain regions (dorsal nucleus of the vagus nerve, ceruleus-subceruleus complex, amygdala, and the CA2-3 sectors, to name a few). Clear assessment of clinical stages that would fit with such increasing burdens of pathology should be determined, in addition to the current emphasis on searching for any earlier clinical phenomena.

The second purpose of a large study is to determine whether the presence of α-synuclein pathology alone causes symptoms with or without cell loss. Control subjects, without symptoms, should also be studied to determine the frequency of the lesions in the general population-a precaution that has rarely been taken in the past. Better knowledge of the association between Alzheimer-type, Lewy- type, and vascular lesions needs to be acquired. The frequency with which Alzheimer-type pathology causes or contributes to the cognitive deficit or to the extrapyramidal syndrome has to be determined.

In summary, α-synuclein pathology must be better studied in human material in parallel with the experimental models to determine the normal expression of the molecule in glia and neurons, the parts of the molecule involved in different types of inclusions, its relationship with ubiquitin and the proteasome, and the reasons for the sensitivity of dopamine (and other) neurons in this pathology. Many of the answers to the questions that have been raised here depend on series of autopsy cases involving not only patients but also control subjects. The project of increasing the number of systematic autopsies needs to be planned in general hospitals and in conjunction with movement disorder clinics. Such an action implies better awareness of the role of neuropathology in the medical community, the public, patient associations, and in the administrative staff of the hospitals.

EPIDEMIOLOGIC, ENVIRONMENTAL, AND DEMOGRAPHIC ISSUES

Current Knowledge

Although single gene defects (e.g. in the Parkin gene), single environmental toxins (e.g. 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine), or single infectious agents (e.g. encephalitis lethargica) have been associated with rare forms of relatively pure parkinsonism, current pathogenic theories concerning idiopathic PD focus on a combination of genetic susceptibility and environmental risk factors (41, 42). Putative environmental and demographic factors that may predispose individuals to idiopathic PD include age, sex, estrogen status, race or ethnicity, exposure to pesticides, head trauma, not smoking, not drinki\ng alcohol, and not drinking coffee. In addition, personality traits and behaviors, whether genetically or environmentally determined, may play a role. Of all factors, age is the most highly linked to PD: the incidence of PD increases steeply with age in both men and women (43, 44).

The late 19th century observation by Gowers of a male predominance in PD has been confirmed through many observational studies (43, 44). Whether this difference relates to hormonal (e.g. estrogen vs testosterone), behavioral (e.g. different occupations in men and women), or genetic factors (e.g. genes on chromosome X vs Y) remains unknown. Epidemiologic investigations of estrogen in women (45) show that women with PD are more likely to have undergone hysterectomy (with and without unilateral oophorectomy) or bilateral oophorectomy and had more early menopause than control subjects. However, normal cyclic changes in estrogen and progesterone in premenopausal women do not correlate with changes in the signs or symptoms of parkinsonism (46). Several studies have suggested that Caucasians are affected more often than African Americans; however, this question remains unsettled (44, 47). An analysis of seven European populations revealed no substantial difference in the prevalence of PD across European countries (48, 49). Other reports of variable incidence rates in different cultures may at least partly relate to the lack of uniform diagnostic criteria and differences in selected diagnostic tools (50-52).

Some studies have suggested that PD is more common in highly industrialized countries than in agricultural societies and more frequent in Europe and North America than in the Far East (53-55). However, there remains surprising uncertainty as to whether PD prevalence rates differ across the five continents or between developed and developing countries, as suggested by recent findings from China (52, 56, 57). Several studies suggested that chronic exposure to well water and living near or working with industrial chemicals or pesticide and herbicide products increase the risk for PD, especially in subjects with young onset (53, 58, 59). In an urban United States multiethnic community, rural living, area farming, and well water drinking were associated with PD only in African Americans, whereas in Hispanics, area farming was protective and drinking unfiltered water was a risk factor (60). In Denmark, a consistent pattern of high PD morbidity was found among occupational groups employed in agriculture and horticulture (61). The concept that well water might accumulate chemical products more readily than free flowing water has indirectly supported an environmental hypothesis of PD. Of interest, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine, a selective dopaminergic cell toxin associated with parkinsonism, was industrially developed as a potential herbicide with a structure resembling paraquat but was never produced commercially. The herbicide rotenone, a potent inhibitor of mitochondrial complex I, is currently of particular research interest (62, 63). Exposure to hydrocarbons has been linked to PD (64), and the issue of chronic manganese exposure as a risk factor for PD has also been debated (65-67). Similarly, exposure to maneb, a widely used fungicide, has been associated with parkinsonism in humans, and both maneb and its major active element (manganese ethylene-bis-dithiocarbamate) cause selective nigrostriatal neurodegeneration in animal and in vitro models, partially attributed to proteasomal inhibition (68).

Almost all studies have confirmed a lower incidence of PD among subjects with a history of smoking (69). Within twin pairs, the risk of developing PD was inversely associated with the dose of cigarette smoking as measured by pack and years (70). However, the protective effect of smoking in twins was less marked when cases with PD were compared with control subjects (71). Once patients have developed PD, however, there is no evidence that smokers have milder disability or slower progression than nonsmokers (72). Coffee drinking has also been linked with reduced risk of PD; however, the evidence is less robust than for smoking (69, 73, 74). Interactions between caffeine intake and exogenous estrogen have been implicated by a study that showed a protective effect of caffeinated beverage intake in postmenopausal women without estrogen supplementation, but a higher risk in women who received hormones (75). A pooled analysis of data from three prospective studies found that alcohol drinking reduced PD risk, even after statistical adjustment for smoking patterns (76). This effect was primarily driven by beer drinking, as opposed to other consumption of types of alcohol.

The “parkinsonian personality” has been a topic of interest for decades, and twin studies have suggested that the siblings with the more introspective, conservative, and passive personalities are at higher risk for PD than their twin pairs with assertive, extroverted features (77). In a cohort study, 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 constellation of personality features can be identified that typify persons at high risk for PD many years before the onset of the disease, statistical techniques that model all confirmed risk factors may eventually allow a “fingerprint” of PD risk (disease prediction). Alternatively, these features could represent very early features of the disease rather than risk factors.

Severe head trauma in mice is associated with age-dependent enhanced immunoreactivity to synucleins, which could be the pathogenetic basis of PD after trauma in humans (79); however, studies of synuclein immunoreactivity patterns in patients with PD and a history of trauma have not yet been performed. Head trauma has been posited as a risk factor, although the scientific question has been blurred by medical and legal issues. Nevertheless, one population-based study in which trauma history was documented routinely in the medical records of a records-linkage system showed a clear association between severe head trauma and an increased risk of PD in later life (80). Finally, based on the observations of postencephalitic parkinsonism as a sequela of epidemic encephalitis, numerous viral and bacterial exposures have been examined, but no consistent agent has been identified.

Research Challenges

The multiple putative risk factors identified so far do not appear to share a common pathophysiologic mechanism. In addition, an exposure causing an increased risk of PD may not influence the natural history after PD starts and may not accelerate clinical decline with continued exposure. For example, smoking is associated with reduced risk of PD, but does not appear to influence disease progression after diagnosis. Moreover, although associations between dopamine D^sub 2^ receptor polymorphisms, MAO-B intron 13 polymorphisms, and COMT codon 158 polymorphisms have been observed with cigarette smoking; exactly how these genetic variants relate to PD risk remains speculative.

Future Developments

Because large-scale population studies are expensive and time consuming, internationally agreed-upon diagnostic criteria, screening instruments, and examination protocols for field studies need to be uniformly applied. Prioritization of research on biochemical mechanisms underlying the two most likely environmental risk or protection factors for PD, smoking and pesticides, may lead to the development of new neuroprotective agents. Similarly, studies of the two primary demographic features that predispose to PD, age and sex, may lead to a clearer delineation of intrinsic subcellular events that occur in at-risk populations. In addition, focusing the search for environmental and demographic risk factors on “enriched” populations at presumed high genetic risk, such as carriers of putative susceptibility genes (UCHL1, NAT2, or MAO-B genes) as well as heterozygotes for the autosomal recessive causes of PD (i.e. Parkin) may provide the most rapid insights into the mechanisms underlying these influences (42).

CONCLUSIONS

It is clear that PD is not a single entity; rather it is clinically, pathologically, and etiologically diverse. Although the different entities have not been fully defined or agreed upon, it is crucial in any clinical study to clearly indicate which patient population is being studied. Whether idiopathic PD will survive as one of the entities of PD is unlikely. As with all disorders, the different phenotypes of PD most likely arise from complex combinations of genetics and modifiers, with many of the latter coming from the environment. Recent understanding of the nonmotor aspects of PD and degeneration outside the substantia nigra has increased the challenge of this work but also identifies what needs to be investigated.

REFERENCES

1. Litvan I. Parkinsonian features: When are they Parkinson disease? JAMA 1998;280:1654-55

2. Hattori N. Autosomal recessive juvenile parkinsonism: A key to understanding nigral degeneration in sporadic Parkinson’s disease. Neuropathology 2000;20(Suppl):S85-S90

3. Gwinn-Hardy K, Mehta ND, Farrer M, et al. Distinctive neuropathology revealed by α-synuclein antibodies in hereditary parkinsonism and dementia linked to chromosome 4p. Acta Neuropathol (Berl) 2000:99: 663-72

4. Spira PJ, Sharpe DM, Halliday G, et al. Clinical and pathological features of a Parkinsonian syndrome in a family with an Ala53Thr α-synuclein mutation. Ann Neurol 2001;49:313-19

5. Duda JE. Concurrence of α-synuclein and tau brain pathology in the Contursi kindred. Acta Neuropathol (Berl) 2002;104:7-11

6. Zimprich A, Biskup S, Leitner P, et al. Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 2004;44:601-7

7. Ross OA, Toft M, Whittle AJ, et al. Lrrk2 an\d Lewy body disease. Ann Neurol 2006;59:388-93

8. Rajput A, Dickson DW, Robinson CA, et al. Parkinsonism, Lrrk2 G2019S, and tau neuropathology. Neurology 2006;67:1506-8

9. Healy DG, Abou-Sleiman PM, Lees AJ, et al. Tau gene and Parkinson’s disease: A case-control study and meta-analysis. J Neurol Neurosurg Psychiatry 2004;75:962-65

10. Kwok JB, Teber ET, Loy C, et al. Tau haplotypes regulate transcription and are associated with Parkinson’s disease. Ann Neurol 2004;55: 329-34

11. Burn DJ, Jaros E. Multiple system atrophy: Cellular and molecular pathology. Mol Pathol 2001;54:419-26

12. Galvin JE, Giasson B, Hurtig HI, et al. Neurodegeneration with brain iron accumulation, type 1 is characterized by α-, β-, and -γ-synuclein neuropathology. Am J Pathol 2000;157:361-68

13. Tsuboi Y, Dickson DW. Dementia with Lewy bodies and Parkinson’s disease with dementia: Are they different? Parkinsonism Relat Disord 2005;11(Suppl 1):S47-S51

14. Burn DJ. Cortical Lewy body disease and Parkinson’s disease dementia. Curr Opin Neurol 2006;19:572-79

15. Stiasny-Kolster K, Doerr Y, Moller JC, et al. Combination of ‘idiopathic’ REM sleep behaviour disorder and olfactory dysfunction as possible indicator for α-synucleinopathy demonstrated by dopamine transporter FP-CIT-SPECT. Brain 2005;128:126-37

16. Braak H, Del Tredici K, Rub U, et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol Aging 2003;24:197-211

17. Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: Substantia nigra regional selectivity. Brain 1991;114:2283-2301

18. Greffard S, Verny M, Bonnet AM, et al. Motor score of the unified Parkinson disease rating scale as a good predictor of Lewy body-associated neuronal loss in the substantia nigra. Arch Neurol 2006;63: 584-88

19. Ross GW, Petrovitch H, Abbott RD, et al. Parkinsonian signs and substantia nigra neuron density in decendents elders without PD. Ann Neurol 2004;56:532-39

20. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Lancet 2001;357:169-75

21. Fernando MS, Ince PG. Vascular pathologies and cognition in a population-based cohort of elderly people. J Neurol Sci 2004;226:13- 17

22. Knopman DS, Parisi JE, Salviati A, et al. Neuropathology of cognitively normal elderly. J Neuropathol Exp Neurol 2003;62:1087- 95

23. Burns JM, Galvin JE, Roe CM, et al. The pathology of the substantia nigra in Alzheimer disease with extrapyramidal signs. Neurology 2005; 64:1397-403

24. Schneider JA, Li JL, Li Y, et al. Substantia nigra tangles are related to gait impairment in older persons. Ann Neurol 2006;59:166-73

25. Parkkinen L, Kauppinen T, Pirttila T, et al. α- Synuclein pathology does not predict extrapyramidal symptoms or dementia. Ann Neurol 2005; 57:82-91

26. Zhang J, Goodlett DR. Proteomic approach to studying Parkinson’s disease. Mol Neurobiol 2004;29:271-88

27. Crowther RA, Daniel SE, Goedert M. Characterisation of isolated α-synuclein filaments from substantia nigra of Parkinson’s disease brain. Neurosci Lett 2000;292:128-30

28. Litvan I, MacIntyre A, Goetz CG, et al. Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease, and dementia with Lewy bodies: a clinicopathologic study. Arch Neurol 1998;55: 969-78

29. Kosaka K. Lewy body disease with and without dementia: A clinicopathological study of 35 cases. Clin Neuropathol 1988;7: 299- 305

30. Wakabayashi K, Takahashi H. Neuropathology of autonomic nervous system in Parkinson’s disease. Eur Neurol 1997;38:2-7

31. Aarsland D, Perry R, Brown A, et al. Neuropathology of dementia in Parkinson’s disease: A prospective, community-based study. Ann Neurol 2005;58:773-76

32. Bloch A, Probst A, Bissig H, et al. α-Synuclein pathology of the spinal and peripheral autonomic nervous system in neurologically unimpaired elderly subjects. Neuropathol Appl Neurobiol 2006;32:284-95

33. Klos KJ, Ahlskog JE, Josephs KA, et al. α-Synuclein pathology in the spinal cords of neurologically asymptomatic aged individuals. Neurology 2006;66:1100-102

34. Boeve BF, Silber MH, Ferman TJ, et al. Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord 2001;16:622-30

35. Benarroch EE, Schmeichel AM, Sandroni P, et al. Involvement of vagal autonomic nuclei in multiple system atrophy and Lewy body disease. Neurology 2006;66:378-83

36. Benarroch EE, Schmeichel AM, Low PA, et al. Involvement of medullary regions controlling sympathetic output in Lewy body disease. Brain 2005;128:338-44

37. Braak H, Rub U, Jansen Steur EN, et al. Cognitive status correlates with neuropathologic stage in Parkinson disease. Neurology 2005;64: 1404-10

38. Lee HG, Zhu X, Takeda A, et al. Emerging evidence for the neuroprotective role of α-synuclein. Exp Neurol 2006;200:1-7

39. Cordato NJ, Halliday GM, Harding AJ, et al. Regional brain atrophy in progressive supranuclear palsy and Lewy body disease. Ann Neurol 2000;47:718-28

40. Harding AJ, Broe GA, Halliday GM. Visual hallucinations in Lewy body disease relate to Lewy bodies in the temporal lobe. Brain 2002; 125:391-403

41. Tanner CM, Aston DA. Epidemiology of Parkinson’s disease and akinetic syndromes. Curr Opin Neurol 2000;13:427-30

42. Vila M, Przedborski S. Genetic clues to the pathogenesis of Parkinson’s disease. Nat Med 2004;10(Suppl):S58-S62

43. Bower JH, Maraganore DM, McDonnell SK, et al. Influence of strict, intermediate, and broad diagnostic criteria on the age- and sex-specific incidence of Parkinson’s disease. Mov Disord 2000;15:819-25

44. Van Den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of Parkinson’s disease: Variation by age, gender, and race/ ethnicity. Am J Epidemiol 2003;157:1015-22

45. Benedetti MD, Maraganore DM, Bower JH, et al. Hysterectomy, menopause, and estrogen use preceding Parkinson’s disease: An exploratory case-control study. Mov Disord 2001;16:830-37

46. Kompoliti K, Comella CL, Jaglin JA, et al. Menstrual-related changes in motoric function in women with Parkinson’s disease. Neurology 2000;55:1572-75

47. Schoenberg BS, Anderson DW, Haerer AF. Prevalence of Parkinson’s disease in the biracial population of Copiah County, Mississippi. Neurology 1985;35:841-45

48. de Rijk MC, Launer LJ, Berger K, et al. Prevalence of Parkinson’s disease in Europe: A collaborative study of population- based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 2000; 54:S21-S23

49. Rocca WA. Dementia, Parkinson’s disease, and stroke in Europe: A commentary. Neurology 2000;54:S38-S40

50. Schrag A, Ben-Shlomo Y, Quinn N. How valid is the clinical diagnosis of Parkinson’s disease in the community? J Neurol Neurosurg Psychiatry 2002;73:529-34

51. Twelves D, Perkins KS, Counsell C. Systematic review of incidence studies of Parkinson’s disease. Mov Disord 2003;18:19-31

52. Rocca WA. Prevalence of Parkinson’s disease in China. Lancet Neurol 2005;4:328-29

53. Tanner CM, Chen B, Wang W, et al. Environmental factors and Parkinson’s disease: A case-control study in China. Neurology 1989;39: 660-64

54. Rajput AH. Environmental causation of Parkinson’s disease. Arch Neurol 1993;50:651-52

55. Woo J, Lau E, Ziea E, et al. Prevalence of Parkinson’s disease in a Chinese population. Acta Neurol Scand 2004;109:228-31

56. Ben-Shlomo Y, Whitehead AS, Smith GD. Parkinson’s, Alzheimer’s, and motor neurone disease. BMJ 1996;312:724

57. Zhang ZX, Roman GC, Hong Z, et al. Parkinson’s disease in China: Prevalence in Beijing, Xian, and Shanghai. Lancet 2005;365:595-97

58. Baldereschi M, Di Carlo A, Vanni P, et al. Lifestyle-related risk factors for Parkinson’s disease: A population-based study. Acta Neurol Scand 2003;108:239-44

59. DiMonte D. The environment and Parkinson’s disease: Is the nigrostriatal system preferentially targeted by neurotoxins? Lancet Neurol 2003;2:531-38

60. Marder K, Logroscino G, Alfaro B, et al. Environmental risk factors for Parkinson’s disease in an urban multiethnic community. Neurology 1998;50:279-81

61. Tuchsen F, Jensen AA. Agricultural work and the risk of Parkinson’s disease in Denmark, 1981-1993. Scand J Work Environ Health 2000; 26:359-62

62. Greenamyre JT, Sherer TB, Betarbet R, et al. Complex I and Parkinson’s disease. IUBMB Life 2001;52:135-41

63. Lapointe N, St-Hilaire M, Martinoli MG, et al. Rotenone induces non-specific central nervous system and systemic toxicity. FASEB J 2004;18:717-19

64. Pezzoli G. Hydrocarbon exposure and Parkinson’s disease. Neurology 2000;55:667-73

65. Racette BA, McGee-Minnich L, Moerlein SM, et al. Welding- related parkinsonism: Clinical features, treatment, and pathophysiology. Neurology 2001;56:8-13

66. Levy BS, Nassetta WJ. Neurologic effects of manganese in humans: A review. Int J Occup Environ Health 2003;9:153-63

67. Jankovic J. Searching for a relationship between manganese and welding and Parkinson’s disease. Neurology 2005;64:2021-28

68. Zhou Y, Shie FS, Piccardo P, et al. Proteasomal inhibition induced by manganese ethylene-bis-dithiocarbamate: Relevance to Parkinson’s disease. Neuroscience 2004;128:281-91

69. Hernan MA, Takkouche B, Caamano-Isorna F, et al. A meta- analysis of coffee drinking, cigarette smoking, and the risk of Parkinson’s disease. Ann Neurol 2002;52:276-84

70. Tanner CM, Goldman SM, Aston DA, et al. Smoking and Parkinson’s disease in twins. Neurology 2002;58:581-88

71. Wirdefeldt K, Gatz M, Pawitan Y, et al. Risk and protective factors for Parkinson’s disease: A study in Swedish twins. Ann Neurol 2005;57: 27-33

72. Alves G, Kurz M, Lie SA, et al. Cigarette smoking in PD: Influence on disease progression. Mov Disord 2004;19:1087-92

73. Benedetti MD, Bower JH, Maraganore DM, et al. Smoking, alcohol, and coffee consumption preceding Parkinson’s disease: A case-control study. Neurology 2000;55:1350-58

74. Ragonese P, S\alemi G, Morgante L, et al. A case-control study on cigarette, alcohol, and coffee consumption preceding Parkinson’s disease. Neuroepidemiology 2003;22:297-304

75. Ascherio A, Chen H, Schwarzschild MA, et al. Caffeine, postmenopausal estrogen, and risk of Parkinson’s disease. Neurology 2003;60: 790-95

76. Hernan MA, Chen H, Schwarzschild MA, et al. Alcohol consumption and the incidence of Parkinson’s disease. Ann Neurol 2003;54:170-75

77. Menza MA, Forman NE, Goldstein HS, et al. Parkinson’s disease, personality, and dopamine. J Neuropsychiatry Clin Neurosci 1990;2: 282-87

78. Bower JH, Grossardt BR, Maraganore DM, et al. The Mayo Clinic Cohort Study of Personality and Aging: Results for Parkinson’s disease. Neurology 2005;64(Suppl 1):A282-A283

79. Urye K. Age-dependent synucleins pathology following traumatic brain injury in mice. Exp Neurol 2003;184:214-24

80. Bower JH, Maraganore DM, Peterson BJ, et al. Head trauma preceding PD: A case-control study. Neurology 2003;60:1610-15

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, John Hardy, PhD, Peter Jenner, PhD, Eldad Melamed, MD, Richard H. Myers, PhD, Davis Parker, Jr., MD, and Donald L. Price, MD

From the University of Louisville School of Medicine (IL, TH), Louisville, Kentucky; the Prince of Wales Medical Research Institute (GH), Sydney, Australia; the National Institute of Neurological Disorders and Stroke (MH), National Institutes of Health, Baltimore, Maryland; Rush Medical College (CGG), Rush University Medical Center, Chicago, Illinois; the Mayo Clinic College of Medicine (WR), Rochester, Minnesota; Hpital de la Salpetrire (CD), Salpetrire, France; the University of Bristol (YB-S), Bristol, UK; the Mayo Clinic Jacksonville (DWD), Jacksonville, Florida; Toronto Western Hospital (AEL), Toronto, Ontario, Canada; the University of California Los Angeles (M-FC), Los Angeles, California; The Parkinson Institute (WJL, DAD), Sunnyvale, California; the University of Tbingen (TG), Tbingen, Germany; the National Institute of Aging (JH), National Institutes of Health, Bethesda, MD; King’s College (PJ), London, UK; the Rabin Medical Center-Beilinson Campus Sackler School of Medicine (EM), Petah, Tikva, Israel; Boston University School of Medicine (RHM), Boston, Massachusetts; the University of Virginia Health System (DP), Charlottesville, Virginia; and The Johns Hopkins School of Medicine (DLP), Baltimore, Maryland.

Send correspondence and reprint requests to: Irene Litvan, MD, Raymond Lee Lebby Professor of Parkinson Disease Research, Director, Movement Disorder Program, University of Louisville School of Medicine, Department of Neurology, A Building, Room 113, 500 South Preston Street, Louisville, KY 40202; E-mail: i.litvan@louisville.edu

Copyright Lippincott Williams & Wilkins Apr 2007

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