key: cord-0688129-54mvr5ke
authors: Kasten, Meike; Chade, Annabel; Tanner, Caroline M.
title: Epidemiology of Parkinson's disease
date: 2007-09-06
journal: Handb Clin Neurol
DOI: 10.1016/s0072-9752(07)83006-5
sha: 87888574eed904f7328cf95266c4c09939333c2a
doc_id: 688129
cord_uid: 54mvr5ke

This chapter discusses the epidemiology of Parkinson's disease (PD). Classically, PD refers to progressive parkinsonism caused by loss of pigmented aminergic brainstem neurons without an identifiable cause, while parkinsonism refers simply to the syndrome of bradykinesia, resting tremor, rigidity and postural reflex impairment. Over nearly two centuries, Parkinson's clinical description has provided the framework for clinical investigations, including epidemiologic ones. Descriptions of PD were limited to selected clinical settings until the middle of the 20th century. Since then, epidemiologic approaches have been used not only to investigate the population distribution of PD, but also as a way to glean clues as to the cause of this “idiopathic” disorder. Because PD is relatively infrequent, a large base population must be surveyed to identify sufficient numbers of cases for a study. In some instances, PD cases can be identified through health service rosters within defined geographic areas or in enumerated populations. In others, cases of PD are sought independently of the health care system, such as through door-to-door surveys. While the latter approach is theoretically least likely to exclude cases, the time and cost involved are also greatest using this approach.

6.1. Introduction 6.1.1. Ove rview Parkinson's d isease (PD) was first described a s 'paralysis agitans' b y J ames Pa rkinson in 1817 ( Parkinson, 1817) . Class ically, PD refers to p rogressive parkinso nism due to loss of pigmented aminer gic brainstem neurons witho ut an identifiabl e cause , while 'parkinsoni sm' refers simpl y to the syndrome of bradykine sia, resting tremo r, rigidity and post ural ref lex imp airment. Over near ly two centuries, Parkinson 's clinical descr iption has provided the frame work for clini cal investigat ions, includi ng epid emiologi c on es. More recently , inve stigations of a few famili es with genetic parkinso nism have reve aled a wide range of clini cal and path ologica l featur es in persons sharing a single dise ase-caus ing mutat ion, cal ling into questio n the assumptio ns underlying the stric t syndromi c classificat ion employe d by mos t stud ies to date. Whet her a similar hete rogeneity appl ies to the com mon 'idiopathic' disorder is not know n. Although our curr ent clinicopat hologica l defini tion of PD may merit revisi on, further wor k is neede d to determ ine what an appro priate new definition should be, and the classical defini tions will be used in this disc ussion. Descript ions of PD were limit ed to selected clinical settings unti l the middle of the 20th cent ury, when several population-based epid emiologi c studies were publishe d ( Kurla nd, 1958; Gudmund sson, 1967 ) . Since then , epidem iologic approache s have been used not only to investigat e the popul ation distri bution of PD, but also as a way to glean clue s as to the cause of this 'idiopa thic' d isorder. Heredi ty, infection , toxican t exposu re and multifa ctorial gene-e nvironm ent intera ctions have been proposed. Altho ugh single genetic or environment al cause s have been identified, thes e explain only a small proportion of all cases (Marras and Tanner, 2002; Korell and Tanner, 2005) . This chapter will provide an overview of this work, beginning with descriptive studies, followed by studies investigating the determinants of PD. Because other chapters in this volume thoroughly address the genetics of PD, this topic will be considered briefly here.

Epidemiologic investigations of PD must overcome practical challenges (Table 6 .1). PD is relatively uncommon, and even studies of large populations will find relatively few cases. Therefore, the potential error in any single study may be significant. In analytic studies, this can be particularly problematic if the causes of disease differ across populations. Moreover, to the extent that the cause of PD is multifactorial, large populations will be necessary to test hypotheses involving multiple determinants.

Identification of the cases of PD within a community is typically not a trivial effort. Population-based registries of PD are not common, and voluntary registries cannot be assumed to be representative. Because PD is relatively infrequent, a fairly large base population must be surveyed to identify sufficient numbers of cases for a study. In some instances, PD cases can be identified through health service rosters within defined geographic areas or in enumerated populations. In others, cases of PD are sought independently of the health care system, such as through door-to-door surveys. While the latter approach is theoretically least likely to exclude cases, the time and cost involved are also greatest using this approach.

Population surveys of PD are further complicated because there is no diagnostic test for PD. Clinical features remain the only way to diagnose PD during life. Clinical diagnostic accuracy can vary with the experience of the practitioner. Essential tremor, for example, may be confused with PD in up to 40% of diagnoses in some settings (Mutch et al., 1986) . Conversely, actual cases of PD may be missed, particularly in older age groups, where slowness and tremor may be discounted as 'normal' or misdiagnosed as one of several other common disorders affecting this age group (for example, arthritis, stroke, dementia). A further difficulty is presented by persons with both parkinsonism and dementia, who may be classified as either primary disorder in different epidemiologic surveys. The common use of neuroleptics in institutionalized elderly, especially those with cognitive impairment, can further confound diagnosis in this age group.

Postmortem validation of clinical diagnosis, although ideal, is rarely available in a population-based setting. First, because survival with PD typically involves many years or even decades, very long follow-up is necessary. In addition, clinical diagnostic criteria do not perfectly predict 'classic' postmortem features of PD. Error rates of more than 20% were seen in one clinicopathological series by Hughes et al. (1993) . The same authors later suggested that the use of standard clinical criteria (e.g. the UK PD brain bank criteria) improved accuracy of a clinical diagnosis in 100 patients (Hughes et al., 2001) in which 90 were shown to have idiopathic PD at postmortem and 10 had other parkinsonian syndromes. In a report published the following year (n ¼ 143), Hughes et al. (2002) estimated that the positive predictive value of the clinical diagnosis for the whole group was 85.3%, with 122 cases correctly clinically diagnosed, 98.6% (72 out of 73) for idiopathic PD, and 71.4% (50 out of 70) for other parkinsonian syndromes. However, since autopsy is most likely performed when the clinical diagnosis is not certain, misclassification may be overestimated in published series . Nonetheless, in the few settings where postmortem validation of PD is possible, valuable insights can result (Ross et al., 2004) .

The uncertainty of clinical diagnosis can be an important consideration in the design and critical analysis of epidemiologic studies of PD. Inclusion of those without disease and exclusion of those with disease can produce under-or overestimates of the distribution of PD. In either case-control studies or family studies, including case subjects who do not actually have PD can obscure a causative association or even result in associations with factors determining a different disorder. In families, the mode of inheritance of a genetic defect can also be misinterpreted.

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are imaging techniques that detect and display the distribution of radiolabeled tracers within the body. Patients with PD show reduced tracer accumulation in the striatum contralateral to the affected limbs using markers of the presynaptic dopaminergic system in the very early stages of the disease (Marek et al., 1996; Wenning et al., 1998; Benamer et al., 2003) . Others have suggested that ultrasound may be a useful way of identifying nigral injury in PD (Berg et al., 2002) . Although these approaches are promising, their abilities to distinguish normal from abnormal and to distinguish PD from other forms of parkinsonism have not yet been developed to the extent that any of these techniques can be used outside the research setting. In epidemiologic research, broad application of these techniques remains difficult, as they are not widely available. However, combining these tools with other, more easily characterized, potential biomarkers, such as olfactory testing, may be useful in prospective studies to identify those 'at risk' for developing parkinsonism, to identify those persons appropriate for interventions to protect against PD and to provide better methods for case definition in studies of genetic and environmental risk factors, where incorrect classification of cases and controls could significantly alter results (Siderowf et al., 2005; Stiasny-Kolster et al., 2005) .

Investigations of new cases of PD present additional uncertainties, because the definition of a new case is particularly problematic. Onset of the motor features of PD is insidious. It is commonly held that at least 50% of substantia nigra pars compacta cells are damaged before the symptoms of PD prompt (Bernheimer et al., 1973) . It has long been observed in autopsy series that the pathologic changes of PD can be identified in the brains of persons who were not diagnosed during life; these 'incidental Lewy body' cases increase with increasing age of the population surveyed, and may represent clinically unrecognized PD (Gibb and Lees, 1991) . More recently, improved neuropathological methods led to the proposal that neuropathologic injury in PD begins in lower brainstem and olfactory nuclei, and progresses through predictable stages over time, involving the substantia nigra and producing classical parkinsonism only relatively late, at stage 4 (Braak et al., 2003a (Braak et al., , 2004 . Lewy neurite pathology can also be seen in autonomic ganglia outside the central nervous system, leading to the further hypothesis that PD may begin outside the central nervous system, well before the classic signs of parkinsonism develop (Braak et al., 2003b) . If this is correct, the true onset of the disease process may begin long before the neurological syndrome is diagnosed. This research hypothesis merits further investigation. To be effective, studies of risk or protective factors, as well as investigations of preventive therapies, may need to target time periods decades before the onset of disease.

Incidence, the number of new cases of a disorder diagnosed during a specific time interval within a defined population, provides the most complete description of the number of cases of disease, as this measurement is least affected by factors influencing survival. This is particularly important for a slowly progressive disorder such as PD. However, as discussed above, because the time of onset of PD is not easily determined, incidence can vary depending on the definition of disease, as well as by factors such as method of ascertainment and access to health care. Studies using more intensive ascertainment methods, such as inperson screening, may find higher rates (de Lau et al., 2004) . Crude estimates of incidence can also vary due to the age and gender distribution of the population studied, and crude rates must be compared with this in mind. For example, reported incidence of PD varies fourfold, from 4.5 to 19 per 100 000 population per year when the entire age spectrum of the population is considered (Rosati et al., 1980; Harada et al., 1983; Ashok et al., 1986; Granieri et al., 1991; Mayeux et al., 1995; Sutcliffe and Meara, 1995; Fall et al., 1996; Kusumi et al., 1996; Bower et al., 1999; Kuopio et al., 1999; MacDonald et al., 2000; Twelves et al., 2003; Van Den Eeden et al., 2003) . However, when studies using similar methods are compared, and rates are adjusted to a reference population, this range is markedly reduced (11.0-13.9/100 000 population per year; Van Den Eeden et al., 2003) .

Age is a key determinant of PD incidence. In all populations studied, PD is very rare before age 50 (Kurland, 1958; Brewis et al., 1966; Rosati et al., 1980; Ashok et al., 1986; Granieri et al., 1991; Wang et al., 1991; Tanner et al., 1992; Harada et al., 1983; Mayeux et al., 1995; Morens et al., 1996a; Marras and Tanner, 2002; Van Den Eeden et al., 2003; Korell and Tanner, 2005) . PD incidence increases steadily in the sixth through the eighth decades in most populations, but a decrease in late life is seen in some studies. Whether this apparent decline in PD incidence is the result of methodologic challenges, such as the greater difficulty identifying and diagnosing PD in the very old , rather than an actual decline in disease frequency, is not certain. If the decline is real, a biological 'window of vulnerability' for PD may exist. Investigation of the determinants of this could provide important insights into the causes of PD. PD incidence is also higher in men than in women in most populations studied, although gender-specific differences show more variability worldwide than do differences associated with increasing age. In a large study in northern California, PD incidence in men was 91% higher than for women (19/100 000 for men versus 9.9/100 000 for women, age-adjusted; Van Den Eeden et al., 2003) .

Whether PD incidence varies by racial or ethnic group has been addressed in only a few studies. In a northern California population, estimated PD incidence, adjusted for age and gender to a comparison population, was highest in Hispanics (16.6/100 000), then non-Hispanic whites (13.2/100 000), then Asians (11.3/100 000) and lowest in blacks (10.2/100 000; Van Den Eeden et al., 2003) . When rates in other incidence studies were adjusted to the same comparison population, PD incidence in northern Manhattan was higher in blacks (18/100 000) than in whites (12.9/100 000) or 'other' (11.8/100 000), and PD incidence in men of Japanese and Okinawan descent in Honolulu was 13.1/100 000 (Mayeux et al., 1995; Morens et al., 1996a) . Whether these variations within and across populations reflect real differences, or simply poor precision, resulting from small numbers of PD cases, will only be answered by additional race-and ethnicity-specific studies.

Has PD incidence changed over time? Periodic fluctuation in incidence could result from any episodic exposure, such as an infectious process. A steady increase over the past several decades could implicate exposures increasingly present, such as those due to industrialization or lifestyle practices. Conversely, if PD incidence has remained stable over time, recent environmental factors are unlikely to be important causes of PD. Only two reports have addressed this possibility, with differing results. Reviews of the Mayo Clinic database from Olmsted County, Minnesota, found no change in age-specific PD incidence between 1935 and 1990 (Rajput et al., 1984; Rocca et al., 2001) . One limitation to this work is the small population size. Only 154 PD cases were incident in 15 years, resulting in poor precision of these estimates. In contrast, in southwestern Finland, based on a larger number of cases, estimated incidence of PD was increased in men, particularly those aged 60 and older, in 1992 as compared to 1971 (Kuopio et al., 1999) . Although it is possible that these differences may reflect temporal changes in environmental exposures in Finland, but not in Minnesota, this cannot be determined from the published studies.

Because PD is relatively uncommon and associated with a long survival, estimates of prevalence are more easily obtained than estimates of incidence. PD prevalence is most commonly estimated through national or local reporting systems. In locations where health care is universally available, such methods provide a good estimate of correctly diagnosed cases, but exclude persons who have not sought medical care. Misclassification is dependent on the methods used to define cases, with those diagnosed by experts being likely the best estimates of PD in the population. Estimates of prevalence based on populations identified by other methods (such as participants in a hospital clinic) do not accurately reflect the general population of an area, since cultural, economic or other factors may influence case selection.

Ideally, both incidence and prevalence are determined by screening all members of entire populations defined by specific geographic or political boundaries. Door-to-door surveys of all households in an area, followed up by examination of individuals suspected of having parkinsonism based on the screen, is the generally the best measure of true prevalence. If cooperation is good, a door-to-door survey is the most likely means of identifying all cases of PD in a community. Typical community-based and door-to-door prevalence studies utilize health professionals or, more often, trained survey assistants who screen the population using a set of questions designed to identify all individuals who may have the disease (Anca et al., 2002) , even those who have not received medical attention (Tanner et al., 1990; Mutch et al., 1991; Duarte et al., 1995; Giroud-Benitez et al., 2000) . After the initial screening process, individuals suspected of having the disease are asked to have a careful evaluation performed by a neurologist and possibly ancillary diagnostic tests.

The estimated PD prevalence derived from medical care reporting systems in North America and Europe find rates between 100 and 200 cases/100 000 population, although rates in developing countries are reported to be as little as one-tenth of these rates (Kurland, 1958; Brewis et al., 1966; Jenkins, 1966; Marttila and Rinne, 1967; Kessler, 1972a, b; Rosati et al., 1980; Nishitani et al., 1981; Harada et al., 1983; Sutcliffe et al., 1985; Ashok et al., 1986; Chalmanov, 1986; Mutch et al., 1986; Shi, 1987; Okada et al., 1990; Granieri et al., 1991; Wang et al., 1991; Caradoc-Davies et al., 1992; Mayeux et al., 1992 Mayeux et al., , 1995 Tanner et al., 1992; Morens et al., 1996a; Hobson et al., 2005) . Table 6 .2 shows examples of crude estimated prevalence from door-todoor studies (Li et al., 1985; Schoenberg et al., 1985 Schoenberg et al., , 1988 Bharucha et al., 1988; Acosta et al., 1989; Morgante et al., 1992; Wang et al., 1994) . Recently, (Li et al,. 1985) > 50 years 44.0 Igbo-ora, Nigeria (Schoenberg et al., 1988) > 39 years 58.6 Kin-Hu, Kinmen, Taiwan, ROC (Wang et al., 1994) > 50 years 170.0 Sicily, Italy (Morgante et al., 1992) > 12 years 257.2 Vejer de la Frontera, Cadiz, Spain (Acosta et al., 1989) All ages 270.0 Copiah County, Mississippi, USA > 39 years 347.0 Parsi community, Bombay, India (Bharucha et al., 1988) All ages 328.3 Bankstown, Sydney, Australia (Chan et al., 2005) 55 years 780.0

Note: Studies listed should not be compared directly as the age and gender distributions of the underlying populations differ.

M. KASTEN ET AL.

estimates as high as 780/100 000 have been reported in Sydney, Australia (Chan et al., 2005) . Comparison of prevalence studies worldwide suggests that PD may be more common in the developed world. Because there are many methodological differences among studies, as well as differences in culture and health care among countries, this observation must be viewed with caution. Importantly, crude prevalence rates cannot be compared directly, since different age groups were surveyed, and the age distribution in the underlying populations differ. Longevity increases the number of PD cases one can expect in a population. While age adjustment reduces differences across populations, the range of estimated PD prevalence remains broad. Comparisons of prevalence for PD from different populations can also reflect the relationship between prevalence and methodology used. For example, apparent age-specific prevalence differences among studies may actually be quite similar when data are re-evaluated according to the same diagnostic criteria (Anderson et al., 1998) .

In one study, PD prevalence has been estimated at two time points. In southwestern Finland, PD prevalence appears to be increasing in men and in rural areas in 1992 as compared to 1971 (Kuopio et al., 1999) . Because ascertainment methods were similar at both time points, this may reflect a true difference in prevalence in this region, possibly the result of changes in exposure to risk factors. Lending more credence to this is the observation that similar changes in incidence were observed, making it less likely that the prevalence changes are due to improved survival of persons with PD in 1992.

Although PD is rare before age 40, after age 50 the prevalence rises almost exponentially (Kurland, 1958; Brewis et al., 1966; Jenkins, 1966; Marttila and Rinne, 1967; Kessler, 1972a, b; Rosati et al., 1980; Harada et al., 1983; Li et al., 1985; Schoenberg et al., 1985 Schoenberg et al., , 1988 Sutcliffe et al., 1985; Ashok et al., 1986; Mutch et al., 1986; Shi, 1987; Acosta et al., 1989; Mayeux et al., 1992 Mayeux et al., , 1995 Morgante et al., 1992; Tanner et al., 1992; Wang et al., 1994; Morens et al., 1996a) . By the eighth decade, estimated prevalence in European and North American populations is between 1000 and 3000 cases per 100 000 population. Although differences in the age distributions in these populations, diagnostic criteria, ascertainment methods, access to health care or disease survival rates may explain much of this variation, international variation in PD frequency is seen even after adjusting for many of these inconsistencies (Zhang and Roman, 1993) . Risk factors, which may vary geogra-phically, include both genetic differences in disease susceptibility and exposure to causative and protective environmental factors. Although PD is intimately related to aging, it has been well documented that its underlying process is distinct from natural aging (McGeer et al., 1988; Fearnley and Lees, 1991; Gibb and Lees, 1991 ). An age-determined process, such as an acquired defect in cellular metabolism, or a process requiring a long period of time to manifest -as might result from prolonged toxicant exposure or the cumulative effects of many individual injuries to nerve cells -might cause a similar pattern. It is also possible that both age-related vulnerability and time-dependent processes explain the late-life preponderance of PD.

Men are diagnosed with PD about twice as often as women, irrespective of geographic location or race (Tanner and Goldman, 1996; Baldereschi et al., 2000) . This pattern is seen in both prevalence and incidence studies. In a meta-analysis of seven incidence studies, men were found to have a 1.5-times greater relative risk for PD than women (Wooten et al., 2004) .

This increased risk in men may reflect biological differences between men and women, such as the effects of sex hormones or X-chromosome-linked susceptibility genes. Alternatively, culturally determined differences in male and female behavior, with associated differences in exposure to risk factors, could explain the pattern. The latter hypothesis is supported by a large Finnish study showing a dramatic increase in the male-to-female relative risk from 0.9 in 1971 to 1.9 in 1992 (Kuopio et al., 1999) . Others have suggested that hormonal differences between men and women explain these differences, although the relationship does not appear to be a simple one (see also section 6.3.7). Further epidemiologic studies, along with experimental laboratory studies, will be necessary to determine whether men are at greater risk for PD.

Although there are a surprising number of observations in the literature suggesting whites are at increased risk for PD, it has been thought that lower rates in non-whites might be related to socioeconomic or cultural differences, leading to ascertainment bias (Kessler, 1972a, b; Tanner and Goldman, 1996) . Nevertheless, two multiracial population-based studies estimating the incidence of PD in upper West-Side Manhattan (Mayeux et al., 1995) and in Northern California (Van Den Eeden et al., 2003) suggest racial differences in PD incidence. In the Manhattan study, African-American women had lower rates, but African-American men had higher rates than whites (Mayeux et al., 1995) . The Northern California study, a much larger evaluation of PD incidence, showed a lower frequency of PD in both men and women of African or Asian descent than in non-Hispanic whites (Van Den Eeden et al., 2003) . Results remain equivocal in both studies, however, as even in this large study the numbers of non-whites were low and between-group confidence intervals for race-specific PD incidence overlapped.

If there are true differences in PD risk among groups defined by race or ethnicity, this may reflect differences in biologic susceptibility. For example, mutations in the LRRK2 gene account for about 2% of parkinsonism in northern European populations, but 15-20% in persons of Ashkenazi Jewish and North African origin (LeSage et al., 2005; Ozelius et al., 2006) . Others have suggested that dermal melanin may protect against PD by trapping potential neurotoxins before they reach the brain (Mars and Larsson, 1999) . Because dermal melanin is regularly sloughed with keratinized skin, persons with more dermal melanin may be protected from the passage of toxicant compounds into the central nervous system. Alternatively, differences in non-genetic risk factors may explain differences among populations. For example, PD prevalence is high in the Inuit population of Greenland (Wermuth et al., 2004) . This population is at risk for dietary and other exposures to persistent organic pollutants (Dewailly et al., 1999) , agents suggested to be risk factors for PD.

Studying mortality of PD based on information from death certificates is problematic because PD is a chronic disorder that is not the direct cause of death; thus, the frequency of the disease can be underestimated from such evaluations. Compared to persons of the same age and gender, mortality is increased approximately twofold among individuals with PD (Di Rocco et al., 1996; Morens et al., 1996a; Louis et al., 1997; Morgante et al., 2000) . An observed north-south gradient of decreasing PD mortality (Lilienfeld et al., 1990) , although possibly reflecting true differences in regional mortality, could also be an artifact of differential access to medical care or death certificate completion inconsistencies among physicians (Pressley et al., 2005) .

Mortality in a clinical trial population may be affected by the influence of the health benefit obtained from participating in the study. After a 13-year followup, results from the DATATOP cohort study show that the mortality rate was similar to that of the general population and that PD did not affect survival differ-ently across gender or age groups in a selected group of otherwise healthy clinical trial participants (Marras et al., 2005a) . In other clinical trial populations, mortality has been higher than expected, however (Hely et al., 1999; Lees et al., 2001; Fall et al., 2003) . Among participants in the DATATOP study, severity, rate of worsening of parkinsonism and response to levodopa are related to survival (Marras et al., 2005b) , suggesting that differences in these factors among studies may also account for the observed differences in PD-related mortality among these studies.

6.3. Risk factors for Parkinson's disease 6.3.1. Introduction to epidemiologic clues

The demographic studies reviewed in the previous section may provide clues to the causes of PD (Table 6 .3). Demographic differences in the frequency of PD, particularly differences in PD incidence, may be the result of ascertainment bias. Alternatively, differences in risk factors for PD among different demographic groups may explain these patterns. Some of these possibilities have been discussed above. Disease clusters, representing more than the expected number of new cases of PD at a certain time and/or in a certain place, are anot her type of patter n that may suggest a shar ed cause of disease a nd provide clues to the underlying etiology of all c ases. A n example is the cluster of parkinsonism in narcotics addicts caused b y 1 -methyl-4-phenyl-1,2,3,6tetrahyd ropyridine (MPTP) exposure (Langston et al., 1983) (Fig. 6 .1). MPT P in du ces pa rkin so nis m tha t is similar to P D, with key symptoms that improve with levodopa tre atment and a simila r side-ef fect prof ile. Diffe rence s inc lude the more ra pid onse t of symptoms in MPTP-induced parkinsonism than in PD, a nd possibly so me diffe ren ce s in ne uro pa tholog ic f eatu res as well.

Although MPTP injection is c learly not a cause of most PD, investigation o f this c lus ter pr ovide d an impor tant animal model. Investigation of the me chanis m of M PTP toxici ty led to the hypothesis that toxicants may cause PD, and has focused interest on compounds with structural or functional similarities ( Fig. 6 .2). Othe r proposed clusters, such as the syndrome o f motor neur on disease-parkinsonism-dementia in certain areas of the Western Pacific (Spe nce r, 19 87 ) o r s everal cluster s in Canada (Kumar e t a l., 2 004) h ave yet to reveal specific etiologic f actors. Familial clusters are generally interpreted to indicate a genetic cause for disease, but certain patterns within f am i li es, s uc h a s t em po ra l c lu st er ing o f d is ea se , m ay be more suggestive of shared environmental risks. A number of case-control studies have found increased PD risk if a first-degree relative has PD (Se mc hu k et al., 1993; Morano et al., 1994; Payami et al., 1994; Bonifati et al., 1995; DeMichele et al., 1996; Marder et al., 1996) . Because persons with disease may be more aware of disease in relatives, these studies in part may reflect reporting bias. Elbaz et al. (2003a) showed evidence for family information bias whereby cases with PD are more likely to report a relative with PD than are control subjects, increasing the risk estimate by 133%. Studies in twins do not support a genetic cause for typical age at PD onset, although genetic factors appear to be increased in those with younger age at onset (Duvoisin et al., 1981; Marsden, 1987; Marttila et al., 1988; Vieregge et al., 1992; Tanner and Goldman, 1994; Wirdefeldt et al., 2004) .

Many proposed risks for PD will be reviewed here.

Genetic defects responsible for parkinsonism have been identified in some families (Bonifati et al., 1995; Polymeropoulos et al., 1996 Polymeropoulos et al., , 1997 Hattori et al., 1998; Kitada et al., 1998; Paisan-Ruiz et al., 2004; Zimprich et al., 2004) . In many of these cases, the clinical features resemble typical PD. mutations is less clear (Bonifati et al., 2005) . The LRRK2 G2019S mutation is the most common pathogenic mutation linked to parkinsonism, accounting for 1-2% of cases, including cases of not only younger but also older age at disease onset (Kay et al., 2006) . Other candidate PD loci have been proposed, including putative disease-causing mutations in the ubiquitin carboxy-terminal hydrolase L1 (UCHL1) (Leroy et al., 1998) and in a nuclear receptor of subfamily 4 (NR4A2 or NURRI) (Le et al., 2003) . These candidates do not map to known PD linkage regions, but polymorphisms in both genes have been associated with PD in some case-control studies (as reviewed by Bertram and Tanzi, 2005) . The GSK3B polymorphism has been reported to alter transcription and splicing and interact with tau haplotypes to modify PD risk (Kwok et al., 2005) . From an epidemiologic perspective, the monogenic causes of PD appear to constitute a proportion of cases worldwide. However, investigation of the protein products of these genes can further our understanding of the process of nerve cell death in parkinsonism. Investigation of these forms has emphasized the role of key proteins (like a-synuclein) and molecular pathways leading to neurodegeneration. Intriguingly, mitochondrial mechanisms, oxidative stress and protein clearance appear to be pathogenic in animal models derived both from toxicant and genetic forms of parkinsonism (Dawson and Dawson, 2003; DiMonte, 2003) .

Risk factor investigation in PD is challenging, as the time of life most important to investigate is not known.

It is likely that years, and possibly even decades, pass between the time of risk factor exposure and the clinical onset of parkinsonism. Case-control studies are an efficient way to study proposed disease risk factors, particularly in relatively uncommon disorders, such as PD. Potential limitations to this design include biased recall, the lack of validation of exposure and, in prevalent studies, survivor bias. Prospective cohort studies, assessing risk factors in advance of disease, avoid many of the biases of case-control studies, but risk factor investigation is limited to those selected for study and diagnostic accuracy may be less certain.

Numerous studies worldwide have identified rural living, farming, gardening and drinking well water as risk factors for PD (Semchuk et al., 1991; Butterfield et al., 1993; Hubble et al., 1993a; Morano et al., 1994; Ferraz et al., 1996; Gorell et al., 1998; Marder et al., 1998; Zorzon et al., 2002; Korell and Tanner, 2005) , but the results are somewhat inconsistent because of differences in the way the studies assessed the effects of rural living. Overall, risk of PD appears to be increased in rural dwellers -especially in the USA. Meta-analysis results (Priyadarshi et al., 2000) also support that risk factors include farm living and use of well water and pesticides. Although the specific associations are varied, the consistency of the general finding is remarkable.

Pesticide exposure is associated with an increased risk of PD in many reports. A meta-analysis of 19 published studies found a combined odds ratio (OR) of 1.94 (95% (Priyadarshi et al., 2000) . However, the category of pesticides is very broad, and includes chemicals with many different mechanisms of action. Only a few studies have identified specific compounds or compound classes, including herbicides, insecticides, alkylated phosphates, organochlorines, wood preservatives, dieldrin and paraquat (Firestone et al., 2005; Korell and Tanner, 2005) . Most of thes e stud ies have been limited by very broad measur es of exposu re. In many stud ies, the proportion of expose d pers ons was low , little was kn own about specifi c exposu res and validatio n of exposure was not possibl e.

Gene-environment interaction may also be important, and those with impaired pesticide metabolism may be most vulnerable. A recent report (Elbaz et al., 2004) indicates an increased risk of PD with pesticide exposure in normal metabolizers, and about twofold increase in risk with pesticide exposure for CYP2D6 poor metabolizers, and no effect of the metabolizing status on risk for PD without pesticide exposure.

Iron has been shown to cause a higher susceptibility to oxidative stress in two ways. By depleting stores of glutathione, iron may have a role in the progression of parkinsonism associated with exposure to other chemicals that are metabolized to free radicals and/or contribute to the adverse effects of oxidative stress (Kaur et al., 2003) . Also, since iron has a strong catalytic p o we r t o g en er at e h ig hly r ea ct iv e h yd ro xy l r ad ic al s from iron (II) and hydrogen peroxide, increased levels of iron in the brain can increase oxidative stress (Fenton reaction). Excessive iron accumulation in the brain is also a potential risk for neuronal damage, which may be promoted by other triggering factors (Lan and Jiang, 1997) . A combined high dietary intake of iron and manganese may increase the risk of developing PD (Po we rs et al., 2003) . Dietary intake of manganese alone does not seem to have toxic effects, except among individuals with liver failure (Hauser et al., 1994) . Although dietary intake is the main source of non-occupational exposure to manganese, occupational exposure seems to be a more influential PD risk factor. Case-control studies suggest that occupational exposure to metals (Gorell et al., 2004; Racette et al., 2005 ) may be at increased risk of PD, although cohort studies have not replicated this (Fryzek et al., 2005; Fored et al., 2006) .

PCBs are among the group of compounds classified as persistent environmental pollutants. In the USA, industrial use was common until 1977. Today, PCBs continue to cycle in the environment. Common sources of human exposure are fish and marine mammals, meat and dairy products. In laboratory studies, PCBs have been shown to reduce dopamine levels in the brain areas affected in PD (Seegal et al., 1986; Chu et al., 1996) . The association between PCBs and PD has been studied in a blinded comparison of postmortem determinations of caudate PCB concentrations in PD patients and contr ols ( Corrigan et al., 1998) . PD brains had significantly higher levels of PCB congener 153, and several other congeners tended to be higher in PD caudate. Also increased in PD brains were the organochlorine pesticide dieldrin and the dichloro-diphenyl-trichloroethane (DDT) metabolite 1,1-dichloro-2,2-bis(4-chlorophenyl)ethene (DDE). In a previ ous inve stigation , fron tal cortex of PD patients and controls did not show difference s in PCB or organ ochlorine levels. This regional specificity lends indirect support to an association between PCBs and PD.

Given the increasing evidence that environmental factors play a role in PD, there has been an increasing effort to identify occupational risk factors, but to date few have been identified. A higher frequency of PD has been reported among teachers and health care workers (Tsui et al., 1999) . These findings were replicated in a casecontrol study in twin pairs discordant for PD , and in very large occupational mortality studies in the USA (Schulte et al., 1996) and the UK (Coggon et al., 1995) . It has been suggested that an infectious etiology could explain the increased risk in these occupational groups. Alternatively, these associations could be related to some other unrecognized occupation-associated risk factor, to premorbid personality characteristics predisposing to certain occupations (Menza, 2000) or to issues of study design, such as ascertainment bias or confounding by age or other factors. A higher frequency of PD has also been reported in carpenters and cleaners (Fall et al., 1999) and in workers chronically exposed to metals (Gorell et al., 2004) . Welding has been proposed as a risk factor (Racette et al., 2005) , but this finding is controversial (Fryzek et al., 2005) , with recent results from a nationwide linkage study indicating no support for an association between welding and PD, or any other specific basal ganglia and movement disorders (Fored et al., 2006) . Overall, results from the available studies are inconclusive, reported findings need confirmation and not all occupations have been evaluated. Differences within even one type of occupation make occupation groups heterogeneous and comparisons difficult.

Querying occupation in such a way that it triggers exposure-specific questions as described by Stewart and Stewart (1994) may be more useful, but the potential misclassification of specific exposures will be appreciable and tend to bias effect measures toward the nulloccupational exposures in community-based studies are rare, which compounds the problem (Tielemans et al., 1999) . Ideally, in addition to asking about occupation and exposure, there should be a quantitative measure in exposure-response analyses -for most chronic diseases the exposure measure of choice is the level of exposure multiplied by the duration of exposure. The use of a single variable for primary lifetime occupation is problematic. Undoubtedly, most people work at a number of different jobs throughout their lives, and important associations may be missed or misclassified. A lifelong, job task-specific occupational history has the potential to provide more complete information, and direct interviews may improve historical accuracy. Studies within specific at-risk groups such as occupational cohorts can be important in clarifying whether there is a relationship between occupation and PD.

Diet is a very difficult exposure to measure both because of its complexity and the fact that most individuals have qualitatively relatively similar diets (Willett, 1990) . Despite these challenges, several dietary factors have been associated with PD.

Excess intake of dairy products has been associated with increased risk of PD in two large prospective cohorts (Chen et al., 2002b; Park et al., 2005) . In a study of health professionals, whether the effect was due to calcium or milk could not be determined. Moreover, the risk was most marked in men, and not clearly observed in women. In the second study, PD incidence was more than twice as high in men drinking more than 16 ounces (approximately 450 grams) daily in midlife, compared to those who consumed no milk. This effect was independent of calcium. No women were included in this cohort. The reason for this association is unclear. One explanation is that milk may be a vehicle for potential neurotoxicants such as organochlorine pesticides or tetrahydroisoquinolines.

Other studies suggested different dietary risk factors for PD. PD risk was mildly raised in association with high dietary iron intake, but the risk markedly increased with high intake of both iron and manganese (Powers et al., 2003) . Another study (Scheider et al., 1997) indicated increased risk with high vitamin C, carotenoids and sweet food, including fruit intake, but the number of cases studied was small (n ¼ 57). Among those with PD, homocysteinemia has been indicated as a potentially reversible risk factor for depression or cognitive decline (O'Suilleabhain et al., 2004) .

Studies of dietary antioxidant intake have been largely inconclusive. It is biologically plausible that dietary antioxidants may protect against nigral damage, analogous to their potential role in preventing heart disease and stroke (Rimm et al., 1993; Knekt et al., 1994 Knekt et al., , 1996 Gale et al., 1995) . One prospective cohort study of 41 836 women indicated a significant protective effect seen for both vitamin C and manganese consumption; however, vitamin A intake was associated with an increased risk of PD (Cerhan et al., 1994) . A sibpair study (Maher et al., 2002) reported a 3.2-year older mean age at onset for affected siblings who reported taking multivitamins. Protective effects were proposed for B vitamins and folate, because of their shared pathways with homocysteine and ability to lessen oxidative stress (Duan et al., 2002) . Comparison of two large prospective cohorts (Chen et al., 2004a) with 415 cases indicated PD risks did not differ in relation to dietary intakes of B vitamins and folate (relative risk 1.0 (95% CI 0.7-1.5) comparing the lowest to the highest intake quintile in men and 1.3 (95% CI 0.8-2.3) in women).

Dietary insufficiency has also been proposed as a risk factor for the development of PD, although evidence for this is indirect. In a 20-30-year follow-up of a cohort of ex-Far-East prisoners of war, who experienced severe dietary insufficiency between 1942 and 1945 (Gibberd and Simmonds, 1980) , 24 PD cases were identified out of 4684 subjects, producing a crude prevalence rate of 512 per 100 000. This is particularly high considering the relatively young age of the cohort and the observation that 15 cases (63%) had disease onset under the age of 50 years. Emotional and physical stress has also been implicated in increased frequencies of PD in another study of prisoners of war (Page and Tanner, 2000) , although a relationship to dietary insufficiency could not be determined.

Certain exotic dietary exposures have been proposed to cause atypical forms of parkinsonism, including ingestion of indigenous species from Guam (Spencer, 1987; Murch et al., 2004) , or the British West Indies (Champy et al., 2005) , although these reports are controversial.

Conversely, oxidative stress may be increased by lipid consumption and higher caloric intake, and eating foods high in animal fat has been associated with increased risk of PD in several studies (Korell and Tanner, 2005) . The link between measures of body composition and obesity and risk of PD is unclear.

M. KASTEN ET AL.

A large stud y in Japan ese-Amer ican men in Hawai i obser ved highe r preva lence of PD with higher triceps skin fold thickne ss, subscapul ar skinfold thi ckness and body mas s index (Abbo tt et al., 2002 ) . A similar analysis in the Nurses ' Hea lth and the Hea lth Profe ssion als' study did not fin d an assoc iation betwee n body mass index and risk of PD but, amo ng never smo kers, both waist circum ference and waist-hi p ratio show ed significa ntly posi tive associa tions with PD risk as compare d to smo kers ( Chen et al., 2004b ) .

Animal models have also been used to study the role of ph ysic al activity in PD. R esu lts of stu dies of fo rced limb use in 6-hydroxydopamine-injected rats (Cohen et al., 20 03 ) su gge st tha t prein jury force d limb use can pr even t the behavioral and neurochemical deficits. In treadmill tests of MPTP-injec te d r ats (Tillerson e t al., 2 003 ), exercise followin g th e nig rostriatal damag e ame lio rated related motor symptoms and neurochemical deficits. Physi cal activit y in epidem iological studies include s cohor t resu lts by Chen et al. (2005a) that show either that higher leve ls of physi cal activi ty may lower the risk o f PD in men , or that men p redisposed to PD tend to avoid strenuou s activit y in their early adul t year s. A sign ificantly lower leve l of physical act ivity was pres ent before diag nosis (men, 12 year s pri or; women, 2-4 years prior), and there was a sustai ned decrease in physical activity after d iagnosis. Case-control stud ies, howe ver, have show n inconsi stent results. In one Chinese hospi tal-based study inve stigat ing risk factors for classi c-onset versus youngonset PD, the durati on of exer cise was substant ially longe r in the yo ung-onset group than in control s or in the classic-o nset PD g roup ( Tsai et al., 2002 ) . In anot her small stud y assessi ng the lifeti me physi cal activit y via sport s/leisure act ivity and partic ipation usin g visu al analog scales, there was no difference in lifeti me physical act ivity betwee n case s and control s; howe ver, ther e was a greater decl ine in act ivity after age 50 years in those with PD ( Fertl et al., 1993 ) . In a nested case -contro l stud y of male Harvard stud ents, mode rate phy sical activit y was assoc iated with a lower risk of PD, but this associa tion was not seen at highe r levels of ph ysical activit y ( Sasco et al., 1992 ) .

6.3.5. Infla mmation, infe ction, head traum a, non -steroidal anti-in flammator y drugs (NS AIDs)

Sever al li nes of evidence suppor t the idea that inf lammati on is invol ved in the pathogene sis of PD ( Hirsch et al., 2003 ) . Postmor tem analyses showed gliosis and cluste ring of micro glial cells around nerve cells in 3 subject s who had present ed with MPTP -induced parkinso nism 3-16 years earlier (La ngston et al., 1999 ) . In cell cultur e exper iments injecti on of lipopolysacchari des (LPS), whi ch activa te gli a, killed dopaminergic neuro ns in mixed neuro n-glia but not in pure neuro n cultur es ( Bronst ein et al., 1995 ) . In an animal model, a sing le intran igral injecti on of LPS damaged dopamin ergic but no t serotone rgic or GABAergi c neuro ns (Herre ra et al., 2 000; Gao et al., 2002 ) . Applicat ion of dexameth asone before LPS injection preve nted the loss of catechol aminergi c content, tyrosi ne hyd roxylase activit y and immu nostaining, and the micro glia-mac rophage activa tion seen previous ly ( Castano et al., 2002 ) .

Hum an studies reve aled elev ated cytokine levels , which induce glia act ivation, in the brain and cerebros pinal fluid of PD patient s com pared to cont rols ( Nag atsu et al., 2000) . Additionally, increased expression of tumor necrosis factor-a, interleukin-b and interferon-g was observed in the substantia nigra of PD patients (Boka et al., 1994; Hunot et al., 1999) . In recent epidemiologic studies, intake of NSAIDs was inversely associated with PD risk ; more detailed analysis indicated that the association was significant for ibuprofen but not other NSAIDs (Chen et al., 2005b) . Higher levels of uric acid, a potent antioxidant, during midlife were associated with a 40% reduced risk of PD in one prospective cohort (Davis et al., 1996) . This observation was recently replicated in a nested case-control study in the health professional prospective cohort study (Weisskopf et al., 2006, unpublished; see Ascher io et al., 2006 for abstract) . Howeve r, uric acid levels can be increased by several agents inversely associated with PD, including alcohol, caffeine and aspirin, as well as by levodopa. Further studies are needed to determine whether this is a primary or secondary association.

The observation that encephalitis lethargica often resulted in parkinsonism during the influenza pandemic of the early 1900s suggested a possible infectious etiology for PD. Since that time, however, clinical and neuropathological criteria have clearly differentiated postencephalitic parkinsonism from typical idiopathic PD. Although subsequent studies have been unable to identify an infectious agent in PD (Marttila et al., 1977; Wang et al., 1993) , a number of studies have continued to suggest that infection may play a role in idiopathic PD. As described previously, increased PD frequency in health care workers and teachers has been linked to infection (Schulte et al., EPIDEMIOLOGY OF PARKINSON'S DISEASE 139 1996 ) . One stud y obser ved ele vated coron avirus antibody levels in the cerebros pinal fluid of PD patients, suppor ting a po ssible link of PD with coron avirus infect ions (Fazzi ni et al., 1992 ) , a common cause of resp iratory infect ions. Another stud y noticed reduced risk for PD associa ted with most viral childhoo d infect ions, especia lly mea sles (Sasco and Pa ffenbarger, 1985 ) ; both studies await replic ation. The soil path ogen Noca rdia asteroides causes a levo doparesp onsive move ment diso rder and nigral degene ration in mice (Kobb ata and Beaman, 1991 ), but a serologic case -control study did not support its role in human PD ( Hubble et al., 199 5) .

Previo us head tra uma has been assoc iated with PD in n umerous case -contro l studies ( Bharuc ha et al., 1986; Tanner et al., 1987; Ster n, 1991; Semchuk et al., 1993; Van Den Eeden et al., 2000; Bower et al., 2003 ) . Head inju ry can trigge r an inflammat ory casc ade, or conce ivably disrupt the blood -brain barrier, increasing risk of exposu re to toxican ts or inf ectious agents. In a sibp air study ( Maher et al., 2002 ) and a study of twin pairs concordant for PD ( Goldman et al., 2006 ) , the sibling with younger -onset PD was more likely to have sustained a head injury. In twins discorda nt for PD, a previous head injury wi th amnesi a or loss of consc iousn ess was assoc iated with a near ly four fold increased risk of PD. Signi ficant head injury is rare, howe ver, and there may be a latency up to 30 year s betwee n inju ry and PD diagnosi s, minimi zing the chanc e that d isease-re lated disab ility cause d the injury (Fact or and Weiner, 1991; Seidler et al., 1996; Taylo r et al., 1999 ) . Sever ity of head injury is likely to be important and there may be a do se effect ; there is no associa tion with PD and mild head injury witho ut loss of conscious ness. Neverthel ess, medical reco rd validat ion sugges ts that this is a real associa tion, not expl ained by recall bias .

Inflam matory mechanism s appea r to cont ribute to neuro degene ration in PD, and animal stud ies sugges t that NSA IDs have neuro protectiv e propert ies ( McGeer and McG eer, 2004 ) by reduc ing general inflammat ion. Studies of Alzheimer's disease have shown that the regular use of NSAIDs may reduce the risk of Alzheimer's in humans (Breitner and Zandi, 2001, in t' Veld et al., 2001; McGeer and McGeer, 2004) . The similarities in the pathogenetic background of PD and Alzheimer's disease and animal data suggesting that anti-inflammatory drugs may protect against PD (Ferger et al., 1999) h av e e nc ou ra ge d i nv es ti ga tio n o f the association between NSAID use and PD risk in humans. An inverse association of NSAID use with risk of PD has been observed in two prospective studies for non-aspirin NSAIDs, as well as for aspirin (Abbott et al., 2003; Chen et al., 2003) . Interestingly, in a cross-sectional study of 1258 PD cases and 6638 controls from the General Practice Research Database, this inverse association was again observed for men, but not women, in whom non-aspirin NSAID use was associated with a higher risk of PD (Hernan et al., 2006) . Whether this reflects a characteristic of the study population or method, or a true gender difference in risk, will require studies in other populations.

Although there are a numb er of health ris ks associated with smoking tobacco and drinkin g alc ohol, cigarett e, coffee and alcohol intakes are all inverse ly assoc iated with risk for developi ng PD, sugges ting they may be neuroprot ective agent s.

Not smo king cigarett es is the most consist ently observed risk factor for PD. An inve rse associa tion between cigarett e smoking and PD has been obser ved in stud ies spanning more than 30 years, involvi ng diverse pop ulations and including several large prospective investigati ons ( Doll et al., 1 994; Grandinet ti et al., 1994; Benedetti et al., 2000; Willems-Giesbergen et al., 2000 ) . A meta-analysis ( Hernan et al., 2002a ) indicated a 40% reduced risk of PD in smokers. Three basic categor ies of smo king were evaluat ed: ever smoking , past smo king and current smo king behavior . Long duration (highest pack/ year) corr elated with dose, and smoking more than 5 years prior to PD onset was not protective; recent smoking appeared more protective. Other research suggests cigarette smoking, on average, appears to lower the risk of developing PD by about half (Sugita et al., 2001) . This inverse association has been reported in nearly every population studied over more than 30 years (Quik, 2004) , and a recent study in a population characterized by a high prevalence of occupational pesticide exposure confirms an inverse correlation between cigarette smoking and PD in this potentially 'high-risk' group as well (Galanaud et al., 2005) . One report suggests the inverse association of smoking and PD is only present in those with a specific monoamine oxidase-B allele (Checkoway et al., 1998) , although this was not replicated (Hernan et al., 2002b) , and other single observations suggest other interactions of genes and smoking (Tan e t al., 2002) .

Non-sm oking behavi or in people fated to develop PD may be the resu lt of a lower rewar d of smo king due to low dopam inergic tone, a genetic ally conferred decr eased prope nsity to smoke or a prem orbid pers onality ( Menza, 2 000 ) . Indeed, the pers onalitie s of those who have gone on to develop PD have been described as shy, caut ious, inflexibl e, punct ual and depressive (Hubbl e et al., 1993b) ; such pers ons may be less likely to smoke or drink. In cont rast, indire ct evid ence against this theo ry d erives from a study in twin pairs discorda nt for PD . The twins witho ut PD had smoked mor e than their brot hers. Despite a high corr elation for smoking in monozygot ic twin pairs, this differ ence was mor e marked in the mono zygotic pairs, know n to be remar kably similar in personality . Sim ilar resu lts have been reporte d in othe r studies of twins (Bha rucha et al., 1986 ) and siblings ( Scott et al., 2005 ) disc ordant for PD.

If there is a biologic effect of smoking, whether this is due to nicotine or a combustion product is not known. Indirect evidence supporting a role for nicotine is provided by the observation that PD was less commonly reported among users of smokeless tobacco in a large prospective cohort (O'Reilly et al., 2005) . Animal studies suggest that nicotine may protect against experimental parkinsonism (Janson and Moller, 1993; Prasad et al., 1994) (Table 6 .5). N i co ti ne h a s b ee n f ou nd t o protect against transection-induced and MPTP-induced dopaminergic neuronal cell loss in rodent substantia nigra (Janson and Moller, 1993; Prasad et al., 1994) . In addition, nicotine has antioxidant properties (Fe rg er et al., 1998) , and increases striatal trophic factors (Maggio et al., 1997) . Alternatively, smoking may afford indirect protection by inducing peripheral detoxifying enzymes, or by reducing bioactivation of protoxins. This latter hypothesis is supported by the observation that cigarette smoking reduces monoamine oxidase-B activity in humans (Fowler et al., 1996) .

Ass uming smo king is neuro protectiv e, one might expect it to dela y the onset of PD and improve the course of the disease in people already affect ed. Neither hypot hesis has yet been p roven. Two studies compared clini cal featur es and did not find difference s between smokers and non-s mokers ( Alves et al., 2004; Papapetr opoulos et al., 2005 ) . Altho ugh a study b y Kuopio et al. (1999) reporte d the mea n age at onset in ever-smoki ng men was significantl y highe r than in never-smoki ng men, resu lts of four othe r stud ies assessing age at onset of PD in relation to smo king status (Haa ck et al., 1981; Rajput et al., 1987 ; More ns et al., 1996b; Lev y et al., 2002 , De Re uck et al., 2005 reve aled the sam e or a younger age of PD o nset in smokers . Interestingl y, however , in several prospective cohor t studies, surviv al of those persons with PD who cont inue to smo ke cigarett es appea rs to be simi lar to, or even somew hat better than, survival of nonsmokers wi th PD ( Grandinet ti et al., 199 4; Elbaz et al., 2003b; Che n et al., 2 006 ) , in contras t to the typically incr eased morta lity obser ved in cigarett e smokers. This tantal izing prelimi nary inf ormation suggests that som e aspec t of smoking may not only modify disease risk, but also improv e survi val once PD is manifest .

An inverse associa tion of both coffee and caffei ne consumpt ion and PD has been reporte d in case-con trol and cohor t stud ies ( Fall et al., 1999; Benedett i et al,. 2000; Ross et al,. 2000; Asc herio et al., 2001; Paganini-Hill, 2001 ) . For exampl e, a longit udinal stud y and two case -control studies of inciden t PD case s provide provoc ative evid ence that coffee drinkin g may be inversely associated with PD risk. A longitudinal study of Japanese-American men indicated greater use of coffee was inversely associated with PD risk in a dose-dependent fashion (Ross et al., 2000) . A very provocative finding in the same cohort was that greater use of coffee was inversely associated with incidental Lewy bodies at postmortem (Ross et al., 1999) . A similar dose-dependent inverse association between coffee drinking and PD was observed in two prospective studies (Benedetti et al., 2000; Willems-Giesbergen et al., 2000) , and retrospectively an incident case-control study in Northern California . In each case, the inverse association between PD and coffee drinking continued to be observed in multivariate analyses adjusting for cigarette smoking, alcohol use and other potential confounders. Similar associations had previously been reported in a few case-control studies of prevalent cases, but these results were inconsistent, and a dose-response gradient was not describ ed Goldman, 1996, Checkoway and . The effect of coffee appears to differ between men and women, with a direct dose-r espons e associati on in men (higher consum ption assoc iated with lower risk) but a U-shaped pattern in women, although fewer women have been studied . It h as been sugges ted a pote ntial interaction b etween hormone exposu re, primarily estroge n, and caff eine consum ption may mediate PD. In participa nts of the Cancer Preve ntion Study II, caffei ne intake was associa ted with a significantly lower morta lity of PD in men bu t not in women ( Ascher io et al., 2004) . In women, the assoc iation depended o n estroge n use, with a relat ive risk for PD of 0.47 (95% CI 0.27-0.8) in caffeine consumer s not usin g hormones and of 1.31 (95% CI 0.75-2.3) in hormone u sers. Caffeine may be neuro protective through its antagoni st act ion on the adenos ine A 2 A-recepto r (Chen et al., 2002a) , which in labo ratory stud ies, modulates dopamin ergic neurotransmission (Popo li et al., 1991; Neh lig et al., 1992 ) and prot ects against striatal dopam ine loss cause d by MPTP ( Richa rdson et al., 1997; Kan da et al., 1998 ) . A 2 A-rec eptor antagoni sts are rece iving increasing attenti on as pote ntial treatmen ts, in particu lar for on/of f fluctu ations and dyskinesia in combinatio n with levodopa therapy ( Xu et al., 2005 ) , b ut also as a possible mono therapy in early-stage PD becau se of posi tive results from animal stud ies and a sma ll clini cal trial ( Hauser et al., 2 003; Jenne r, 2003 ) .

Alcohol use has been found by som e to be inverse ly assoc iated wi th PD even after cont rolling for po ssible confo unding by smo king ( Hellenbr and et al., 1996; Fall et al., 1999; Paganini -Hill, 2001 ) . A biologic expl anation for this obser vation has not been artic ulated. One stud y found that fewer case s with PD had a diagnosi s of alc oholism than cont rols (Benedett i et al., 2000 ) . The variabi lity across studies is great and, overall, the curr ent evid ence for an assoc iation betwee n alcohol intake and risk of PD is weak. In the Nurses' Hea lth and the Health Profe ssional s' cohor ts, no associati on between inciden ce of PD and overa ll alcohol consum ption was obser ved ; however , an inverse associa tion of beer (but not wine or liquor) consum ption was seen. Comparison o f alc oholics and non-a lcoholics in a large database found com parable PD inciden ce in both groups (Hern an et al., 2004 ) . Int erestingl y, in a stratified analysis for men and women separat ely, male alcoho lics had a significantly lower incidence of PD whereas female alcoholics had a twofold increased incidence. Low consumption of alcohol in PD has common ly been attribut ed to the reserve d personal ity that has been obser ved prior to PD manifestation (Menza, 2000) .

As noted above, men appear to be at greater risk of developing PD than are women. This could reflect an intrinsic difference in risk, such as might be due to an X-chromosome-linked genetic characteristic or a sex hormone-related factor. Alternatively, genderdetermined differences in risk factor exposure may be the cause or a combination of biologic predisposition and differences in risk factors might explain this pattern. Benedetti et al. (2001) used a population-based case-control method to determine whether reproductive factors may influence PD risk in women. Hysterectomy with or without an oophorectomy and early menopause were associated with increased risk of PD (OR ¼ 3.36 and 2.18, respectively) and estrogen use after menopause was inversely associated with PD risk (OR ¼ 0.47), although the latter two differences were not statistically significant. Several subsequent casecontrol studies have similarly suggested that factors associated with estrogen deficiency such as hysterectomy and early menopause may increase PD risk Ragones e et al., 2004 ) . Recently , Popat et al. (2005) found that the association of postmenopausal hormone use with PD risk depended on the type of menopause. Among women with history of a hysterectomy with or without an oophorectomy, estrogen use alone was associated with a 2.6-fold increased risk and the risk of PD increased with increasing duration of estrogen use. In contrast, among women with natural menopause, no increased risk of PD was observed with hormone use.

Gender may also determine the effects of risk or protective factors associated with PD. Women appear to have different risk profiles to at least some of the exposures linked to PD in men, as discussed in previous sections. Although the explanation for these differences is not known, investigation of the combined effects of risk factors may explain some of these differences. For example, in two prospective cohort studies, PD risk was influenced by the combined effects of caffeine consumption and supplemental estrogen use. Women using supplemental estrogens with low caffeine consumption were at a lower risk of PD, but this effect was attenuated or reversed in women who had a high caffeine consumption and were at higher risk of PD (Ascherio et al., 2003 (Ascherio et al., , 2004 sufficient size to allow the separate assessment of risk factors in women will be important to clarify the question of gender and PD risk.

Research in the area of gene-environment interactions is complicated in that multiple genes and various environmental factors may combine to determine the level of risk for PD in any one individual. As described previously, several environmental factors, including pesticide and chemical exposure, have been consistently shown to modify the risk for PD in epidemiologic studies. If PD results from a combination of genetic and environmental factors, then an interaction of genetic factors with certain exposures could result in a high level of disease risk. For example, increased risk from an environmental toxin could be influenced by the genetically determined level of activity of metabolizing enzymes. Few gene-environment interactions have been investigated. One case-control study suggests that smoking history modifies the effect of family history on the risk for PD, such that the odds ratio is highest in those with a history of smoking and a family history of PD (OR 10.0; Elbaz et al., 2000) . This is a surprising finding given the increasing body of evidence that smoking is negatively associated with the occurrence of PD.

Other interactions have also been reported, including possible interactions between monoamine oxidase-B gene polymorphisms and smoking behavior. A reduced risk of PD with increasing number of pack-years of smoking was found in the presence of the G allele, whereas PD risk decreased with increasing pack-years smoked in the presence of the A allele (Checkoway et al., 1998) . Interactions between xenobiotic metabolizing enzyme genotype and pesticide exposure in the risk of PD have also been studied (Menegon et al., 1998; Taylor et al., 2000) . The association between pesticide exposure and PD may be modified by glutathione transferase P1 polymorphisms (Menegon et al., 1998) . In a study of 96 patients and 95 controls, no overall difference in the distribution of glutathione S-transferase (GST) P1 genotypes was found between cases and controls. In those with pesticide exposure, however, the GST P1 AA genotype was associated with the lowest risk for PD. Confirmation of each of these observations in additional populations may provide important clues to disease etiology.

Polymorphisms of many genes have been found to be associated with an increase or decrease in risk for PD in at least one or more studies. Unknown gene-gene or gene-environment interactions may produce misleading results if cases and controls are not appropriately matched, perhaps explaining some of the conflicting data seen in these studies. Whether the inconsistent results obtained to date are due to study design issues or to limited generalizability of the findings to different patient groups is not known.

6.5. The future of Parkinson's disease epidemiology An emerging direction of epidemiologic research in PD also deserves mention. Recent work involves investigation of those 'at risk' for PD, before disease is manifest. A variety of disorders may precede formal diagnosis of PD, including olfactory dysfunction, rapid-eye movement sleep behavior disorders, QT or rate-corrected QT (QTc) interval prolongation on the electrocardiogram, adiposity and constipation. In vivo imaging of the dopamine transporter with ( 99m Tc) TRODAT-1 (TRODAT) and olfactory testing have both been proposed as potential biomarkers in PD, and impaired smell recognition correlated with lower TRODAT uptake (Siderowf et al., 2005) . Rapid-eye movement sleep behavior disorder is strongly predictive of PD, and RBD patients have been shown to have impaired olfactory function compared to controls (Stiasny-Kolster et al., 2005) . In addition to olfactory dysfunction and rapid-eye movement sleep behavior disorders, a number of patients with PD and multiple system atrophy, have QT or QTc interval prolongation on the electrocardiogram. In one prospective cohort, these findings were highly predictive of PD incidence (LR White, personal communication). Although these QT or QTc interval abnormalities are likely related to autonomic dysfunction, the pathophysiology remains unknown (Deguchi et al., 2002) . Other characteristics in midlife associated with increased PD risk include increased triceps skinfold thickness (Abbott et al., 2002) and constipation. Men with less than one bowel movement per day at midlife had a 4.1-fold excess incidence of PD when compared with men with more frequent bowel movements (Abbott et al., 2001) . Taken together, these observations suggest that PD may begin decades before nervous system symptoms are observed. PD may be first a disorder of the peripheral autonomic nervous system. If an environmental trigger is involved, the gastrointestinal tract or the olfactory epithelium may be portals of entry. This hypothesis is indirectly supported by neuropathologic findings, suggesting that nigral pathology is a relatively late event in the pathogenesis of PD (Braak et al., 2004) . Further studies to identify those at risk will be essential in determining the causes of PD, and methods for its prevention.

In the next half-century, the average age of individuals in both developed and developing countries is expected to show a progressive increase. In the USA alone, this phenomenon of population aging is predicted to result in a three-to fourfold increase in PD frequency, or several million persons with the disease. The impact of PD can also be expected to affect disease-associated health expenditures, lost income and personal suffering. As described in this chapter, despite intensive research efforts during the past several decades, the cause (or causes) of typical PD remains unknown. Likely, PD will be understood to be multifactorial, and both genetic and environmental determinants will be important. For example, estimated lifetime penetrance in parkinsonism caused by LRRK2 in the Ashkenazi Jewish population is only about 30% (Ozelius et al., 2006) . Both genetic and environmental factors may determine expression of this monogenic form of parkinsonism. Typical PD may similarly be due to many different combinations of genetic or environmental determinants. The investigation of possible gene-environment interaction in PD is just beginning. In the next decade, investigations involving careful characterization of genetic and environmental factors will be essential to defining the causes of PD.

Frequency of bowel movements and the future risk of Parkinson's disease

Midlife adiposity and the future risk of Parkinson's disease

Environmental, life-style, and physical precursors of clinical Parkinson's disease: recent findings from the Honolulu-Asia Aging Study

Prevalence of Parkinson's disease and essential tremor in a village in southern Spain

Cigarette smoking in Parkinson's disease: influence on disease progression

Cross-sectional study of the prevalence of Parkinson's Disease in the Kibbutz Movement in Israel

Case ascertainment uncertainties in prevalence surveys of Parkinson's Disease

Prospective study of caffeine consumption and risk of Parkinson's disease in men and women

Caffeine, postmenopausal estrogen, and risk of Parkinson's disease

Coffee consumption, gender, and Parkinson's disease mortality in the cancer prevention study II cohort: the modifying effects of estrogen

Uricemia and risk of Parkison's disease

Parkinson's disease and parkinsonism in a longitudinal study: two-fold higher incidence in men

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Smoking, alcohol, and coffee consumption preceding Parkinson's disease: a case-control study

Hysterectomy, menopause, and estrogen use preceding Parkinson's disease: an exploratory case-control study

Echogenicity of the substantia nigra: association with increased iron content and marker for susceptibility to nigrostriatal injury

Brain dopamine and the syndromes of Parkinson and Huntington: clinical, morphological and neurochemical correlations

The genetic epidemiology of neurodegenerative disease

A case-control study of twin pairs discordant for Parkinson's disease: a search for environmental risk factors

Prevalence of Parkinson's disease in the Parsi community of Bombay

Immunocytochemical analysis of tumor necrosis factor and its receptors in Parkinson's disease

Familial Parkinson's disease: a clinical genetic analysis

Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism

Italian Parkinson Genetics Network. Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes

Incidence and distribution of parkinsonism in Olmsted County

Influence of strict, intermediate, and broad diagnostic criteria on the age and sex-specific incidence of Parkinson's disease

Head trauma preceding PD: a case-control study

Idiopathic Parkinson's disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen

Staging of brain pathology related to sporadic Parkinson's disease

Stages in the development of Parkinson's disease-related pathology

Do nonsteroidal antiinflammatory drugs reduce the risk of Alzheimer's disease?

Neurological disease in an English city

Gliadependent neurotoxicity and neuroprotection in mesencephalic cultures

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Is the prevalence of Parkinson's disease in New Zealand really changing?

The degenerative effect of a single intranigral injection of LPS on the dopaminergic system is prevented by dexamethasone, and not mimicked by rh-TNF-alpha, IL-1beta and IFNgamma

Antioxidant intake and risk of Parkinson's disease (PD) in older women

Epidemiological studies of parkinsonism in Sofia

Quantification of acetogenins in Annona muricata linked to atypical parkinsonism in Guadeloupe

Prevalence of Parkinson's disease in Sydney

A genetic polymorphism of MAO-B modifies the association of cigarette smoking and Parkinson's disease

Epidemiologic approaches to the study of Parkinson's Disease etiology

8-(3-Chlorostyryl) caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism

Diet and Parkinson's disease: a potential role of dairy products in men

Nonsteroidal anti-inflammatory drugs and the risk of Parkinson disease

Folate intake and risk of Parkinson's disease

Obesity and the risk of Parkinson's disease

Physical activity and the risk of Parkinson disease

Nonsteroidal antiinflammatory drug use and the risk for Parkinson's disease

Survival of Parkinson's disease patients in a large prospective cohort of male health professionals

Toxicity of 2,2 0 ,4,4 0 ,5,5 0 -hexachlorobiphenyl in rats: effects following a 90-day oral exposure

Occupational Health Decennial Supplement. Her Majesty's Stationery Office

Neuroprotective effects of prior limb use in 6-hydroxydopamine-treated rats: possible role of GDNF

Diorthosubstituted polychlorinated biphenyls in caudate nucleus in Parkinson's disease

Postmenopausal estrogen use affects risk for Parkinson disease

Observations on serum uric acid levels and the risk of idiopathic Parkinson's disease

Molecular pathways of neurodegeneration in Parkisnon's disease

Abnormalities of rate-corrected QT intervals in Parkinson's disease-a comparison with multiple system atrophy and progressive supranuclear palsy

Environmental and genetic risk factors in Parkinson's disease: a casecontrol study in Southern Italy

Comparison of age of onset and development of motor complications between smokers and non-smokers in Parkinson's disease

Concentration of organochlorines in human brain, liver, and adipose tissue autopsy samples from Greenland

The environment and parkinson's disease: is the nigrostriatal system preferentially targeted by neurotoxins?

Parkinson's disease: progression and mortality in the L-DOPA era

Mortality in relation to smoking: 40 years' observations on male British doctors

Dietary folate deficiency and elevated homocysteine levels endanger dopaminergic neurons in models of Parkinson's disease

Screening Parkinson's disease: a validated questionnaire of high specificity and sensitivity

Twin study of Parkinson disease

Parkinson's disease, smoking, and family history. EUROPARKINSON Study Group

Validity of family history data on PD: evidence for a family information bias

Survival study of Parkinson disease in Olmsted County

CYP2D6 polymorphism, pesticide exposure, and Parkinson's disease

Prior history of head trauma in Parkinson's disease

Agestandardized incidence and prevalence of Parkinson's disease in a Swedish community

Nutritional and occupational factors influencing the risk of Parkinson's disease: a case-control study in southeastern Sweden

Survival time, mortality and cause of death in elderly patients with Parkinson's disease: a 9-year follow-up

Cerebrospinal fluid antibodies to coronavirus in patients with Parkinson's disease

Ageing and Parkinson's disease: substantia nigra regional selectivity

Effects of nicotine on hydroxyl free radical formation in vitro and on MPTPinduced neurotoxicity in vivo

Salicylate protects against MPTP-induced motor impairments in the dopaminergic neurotransmission at the striatal and nigral level in mice

Rural or urban living and Parkinson's disease

Physical activity and sports in patients suffering from Parkinson's disease in comparison with healthy seniors

Pesticides and risk of Parkinson disease: a population-based case-control study

Parkinson's disease and other basal ganglia or movement disorders in a large nationwide cohort of Swedish welders

Inhibition of monoamine oxidase B in the brains of smokers

A cohort study of Parkinson's disease and other neurodegenerative disorders in Danish welders

Cigarette smoking and Parkinson's disease: a case-control study in a population characterized by a high prevalence of pesticide exposure

Vitamin C and risk of death from stroke and coronary heart disease in cohort of elderly people

Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons: relevance to Parkinson's disease

Anatomy, pigmentation, ventral and dorsal subpopulations of the substantia nigra, and differential cell death in Parkinson's disease

Neurological disease in ex-Far-East prisoners of war

Prevalence of Parkinson disease in an urban area of the Ciudad de La Habana province, Cuba. Door-todoor population study

Parkinson's disease in Ferrara, Italy

Head injury and Parkinson's disease risk in twins

The risk of Parkinson's disease with exposure to pesticides, farming, well water, and rural living

Multiple risk factors for Parkinson's disease

Prospective study of cigarette smoking and the risk of developing idiopathic Parkinson's disease

A clinical survey of parkinsonism in Iceland

Nicotine exposure and Parkinson disease

Epidemiology of Parkinson's disease in a Japanese city

Molecular genetic analysis of a novel parkin gene in Japanese families with autosomal recessive juvenile parkinsonism: evidence for variable homozygous deletions in the parkin gene in affected individuals

Manganese intoxication and chronic liver failure

Randomized trial of the adenosine A(2A) receptor antagonist istradefylline in advanced PD

Diet and Parkinson's disease. II: a possible role for the past intake of specific nutrients. Results from a self-administered food-frequency questionnaire in a case-control study

The Sidney Multicentre Study of Parkinson's disease: progression and mortality at 10 years

A meta-analysis of coffee drinking, cigarette smoking, and the risk of Parkinson's disease

MAOB intron 13 and COMT codon 158 polymorphisms, cigarette smoking, and the risk of PD

Alcohol consumption and the incidence of Parkinson's disease

A prospective study of alcoholism and the risk of Parkinson's disease

Nonsteroidal anti-inflammatory drugs and the incidence of Parkinson disease

The single intranigral injection of LPS as a new model for studying the selective effects of inflammatory reactions on dopaminergic system

The role of glial reaction and inflammation in Parkinson's disease

Cross-sectional survey of Parkinson's disease and parkinsonism in a rural area of the United Kingdom

Risk factors for Parkinson's disease

Personality and depression in Parkinson's disease

Nocardia species as an etiologic agent in Parkinson's disease: serological testing in a case-control study

A clinicopathologic study of 100 cases of Parkinson's disease

Improved accuracy of clinical diagnosis of Lewy body Parkinson's disease

The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service

FcepsilonRII/ CD23 is expressed in Parkinson's disease and induces, in vitro, production of nitric oxide and tumor necrosis factor-alpha in glial cells

Chronic nicotine treatment counteracts nigral cell loss induced by a partial mesodiencephalic hemitransection: an analysis of the total number and mean volume of neurons and glia in substantia nigra of the male rat

Epidemiology of parkinsonism in Victoria

A2A antagonists as novel non-dopaminergic therapy for motor dysfunction in PD

Adenosine A2A receptors modify motor function in MPTP-treated common marmosets

Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease

Parkinson's disease and LRRK2: frequency of a common mutation in U.S. movement disorder clinics

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Flavonoid intake and coronary mortality in Finland: a cohort study

Clustering of Parkinson disease: shared cause or coincidence?

Changing epidemiology of Parkinson's disease in southwestern Finland

Epidemiology of Parkinson's disease in Yonago City, Japan: comparison with a study carried out 12 years ago

Epidemiology. Incidence, geographic distribution and genetic considerations

GSK3B polymorphisms alter transcription and splicing in Parkinson's disease

Excessive iron accumulation in the brain: a possible potential risk of neurodegeneration in Parkinson's disease

Chronic parkinsonism in humans due to a product of meperidineanalog synthesis

Evidence of active nerve cell degeneration in the substantia nigra of humans years after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exposure

Mutations in NR4A2 associated with familial Parkinson's disease

Ten-year follow-up of three different initial treatments in de-novo PD: a randomized trial

The ubiquitin pathway in Parkinson's disease

French Parkinson's Disease Genetics Study Group G2019S LRRK2 mutation in French and North African families with Parkinson's disease

Do risk factors for Alzheimer's disease predict dementia in Parkinson's disease? An exploratory study

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Parkinsonism death rates by race, sex and geography: a 1980s update

Mortality from Parkinson's disease

The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK

Striatal increase of neurotrophic factors as a mechanism of nicotine protection in experimental parkinsonism

Epidemiologic study of 203 sibling pairs with Parkinson's disease: the GenePD study

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Risk of Parkinson's disease among first-degree relatives: a communitybased study

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[123I] beta-CIT/SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson's disease

Movement Disorders, Neurologic Principles and Practice

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Survival in Parkinson disease: thirteen-year follow-up of the DATATOP cohort

Twins and Parkinson's disease

Epidemiology of Parkinson's disease in Finland

Viral antibodies in the sera from patients with Parkinson's disease

Parkinson's disease in a nationwide twin cohort

Pheomelanin as a binding site for drugs and chemicals

A population-based investigation of Parkinson's disease with and without dementia: relationships to age and gender

The frequency of idiopathic Parkinson's disease by age, ethnic group, and sex in northern Manhattan

Inflammation and the degenerative diseases of aging

Rate of cell death in parkinsonism indicates active neuropathological process

Parkinson's disease, pesticides, and glutathione transferase polymorphisms

The personality associated with Parkinson's disease

Risk-factors for Parkinson's disease: case-control study in the province of Caceres, Spain

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Evidence against the operation of selective mortality in explaining the association between cigarette smoking and reduced occurrence of idiopathic Parkinson disease

Prevalence of Parkinson's disease and other parkinsonisms: a door-to-door survey in three Sicilian municipalities

Parkinson disease survival: a population-based study

A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam

Parkinson's disease in a Scottish city

A screening and alerting questionnaire for parkinsonism

Cytokines in Parkinson's disease

Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects

Association of alcohol and tobacco consumption with Parkinson's disease: a population-based study

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Prevalence of Parkinson's disease in Izumo City

Smokeless tobacco use and the risk of Parkinson's disease mortality

Elevated plasma homocysteine level in patients with Parkinson disease: motor, affective, and cognitive associations

LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews

Risk factors for parkinson's disease: the leisure world cohort study

Parkinson's disease and motor-neuron disease in former prisoners-of-war

Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease

Does cigarette smoking provide clinically significant neuroprotection among patients diagnosed with Parkinson's disease?

Consumption of milk and calcium in midlife and the future risk of Parkinson disease

An Essay on the Shaking Palsy. Sherwood

Increased risk of Parkinson's disease in parents and siblings of patients

Mapping of a gene for Parkinson's disease to chromosome 4q21-q23

Mutation in tha alpha-synuclein gene identified in families with Parkinson's disease

Effect of reproductive factors and postmenopausal hormone use on the risk of Parkinson disease

Akinesia due to catecholamine depletion in mice is prevented by caffeine. Further evidence for an involvement of adenosinergic system in the control of motility

Parkinson's disease risks associated with dietary iron, manganese, and other nutrient intakes

Chronic nicotine intake decelerates aging of nigrostriatal dopaminergic neurons

Disparities in the recording of Parkinson's disease on death certificates

A metaanalysis of Parkinson's disease and exposure to pesticides

Smoking, nicotine and Parkinson's disease

Prevalence of parkinsonism and relationship to exposure in a large sample of Alabama welders

Risk of Parkinson disease in women: effect of reproductive characteristics

Epidemiology of parkinsonism: incidence, classification and mortality

A case-control study of smoking habits, dementia, and other illnesses in idiopathic Parkinson's disease

Adenosine A2A receptor antagonists as new agents for the treatment of Parkinson's disease

Vitamin E consumption and the risk of coronary heart disease in men

Time trends in the incidence of parkinsonisms in Olmsted County

The risk of Parkinson's disease in Mediterranean people

Lack of association to midlife smoking or coffee consumption with presence of lewy bodies in the locus ceruleus or substantia nigra at autopsy

Association of coffee and caffeine intake with the risk of Parkinson disease

Parkinsonian signs and substantia nigra neuron density in decendents elders without PD

Measles infection and Parkinson's disease

The role of physical exercise in the occurrence of Parkinson's disease

Dietary antioxidants and other dietary factors in the etiology of Parkinson's disease

Prevalence of Parkinson's disease in the biracial population of Copiah County

Comparison of the prevalence of Parkinson's disease in black populations in the rural US and in rural Nigeria: door-to-door community studies

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Family-based case-control study of cigarette smoking and Parkinson disease

Polychlorinated biphenyls produce regional alterations of dopamine metabolism in rat brain

Possible environmental, occupational, and other etiologic factors for Parkinson's disease: a case-control study in Germany

Parkinson's disease and exposure to rural environmental factors: a population based case-control study

Parkinson's disease: a test of the multifactorial etiologic hypothesis

Study on the prevalence of Parkinson's disease in Hongkou District

SPECT imaging correlates with odor identification in early Parkinson disease

Guam ALS/Parkinsonism-Dementia: a long-latency neurotoxic disorder caused by "slow toxin(s)" in food? Can

Head trauma as a risk factor for Parkinson's disease

Occupational case-control studies: I. Collecting information on work histories and work-related exposures

Combination of 'idiopathic' REM sleep behaviour disorder and olfactory dysfunction as possible indicator for alpha

cleinopathy demonstrated by dopamine transporter FP-CIT-SPECT

Meta-analysis for epidemiologic studies on the relationship between smoking and Parkinson's disease

Parkinson's disease epidemiology in the Northampton District, England, 1992

Parkinson's disease in the district of the Northampton Health Authority, United Kingdom

Mitochondrial complex I polymorphism and cigarette smoking in Parkinson's disease

Epidemiology of movement disorders

Epidemiology of Parkinson's disease

Environmental factors in the etiology of Parkinson's disease

A brief screening questionnaire for parkinsonism

Parkinson's disease incidence in

Smoking and Parkinson's disease in twins

Occupation and Risk of Parkinson's Disease (PD): a preliminary investigation of standard occupational codes (SOC) in twins discordant for disease

Environmental, medical, and family history risk factors for Parkinson's disease: a New England-based case control study

Paraoxonase polymorphisms, pesticide exposure and Parkinson's disease in a Caucasian population

Assessment of occupational exposures in a general population: comparison of different methods

Exercise induces behavioral recovery and attenuates neurochemical deficits in rodent models of Parkinson's disease

Environmental risk factors of young onset Parkinson's disease: a case-control study

Occupational risk factors in Parkinson's disease

Systematic review of incidence studies of Parkinson's disease

The risk of Parkinson's disease associated with head injury and depression: a population-based case-control study

Incidence of Parkinson's disease: variation by age, gender, and race/ethnicity

Parkinson's disease in twins

Parkinson's disease in Kin-Hu, Kinmen: a community survey by neurologists

A casecontrol study on the environmental risk factors of Parkinson's disease in Tianjin

and the Collaborative Group of Neuroepidemiology of the PLA. The incidence and prevalence of Parkinson's disease in the People's Republic of China. Chung-Hua Liu Hsing Ping Hsueh Tsa Chih

123-I]-beta-CIT and [123-I]-IBZM-SPECT scanning in levodopanaive Parkinson's disease

Clinical characteristics of Parkinson's disease among Inuit in Greenland and inhabitants of the Faroe Islands and Als (Denmark)

Smoking, alcohol, and coffee consumption and the risk of Parkinson's disease: results from the Rotterdam Study

Overview of nutritional epidemiology

No evidence for heritability of Parkinson disease in Swedish twins

Are men at greater risk for Parkinson's disease than women?

Therapeutic potential of adenosine A(2A) receptor antagonists in Parkinson's disease

Worldwide occurrence of Parkinson's disease: an updated review

Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology

Familial and environmental risk factors in Parkinson's disease: a casecontrol study in north-east Italy

Drs Chade and Kasten are Michael J. Fox Foundation Fellows at The Parkinson's Institute. Thank you to Jennifer Wright for editorial assistance.