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OBJECTIVE LRRK2 mutations, the most common genetic cause of Parkinson disease (PD), display incomplete penetrance, indicating the importance of other genetic and environmental influences on disease pathogenesis in LRRK2 mutation carriers. The present study investigates whether urate, an antioxidant, Nrf2 activator, and inverse risk factor for idiopathic PD, is one such candidate biomarker of PD risk modulation in pathogenic LRRK2 mutation carriers. METHODS Banked plasma samples or urate levels were obtained for 3 cohorts of age- and sex-matched subjects with and without a known LRRK2 mutation in PD and unaffected controls to conduct a pilot study of 192 subjects from the LRRK2 Cohort Consortium (LCC) and 2 validation studies of 380 additional subjects from the LCC and 922 subjects from the Parkinson's Progression Markers Initiative. Urate levels were compared by multiple regression between subjects with and without a PD diagnosis conditional on LRRK2 status, controlling for age and sex. RESULTS Nonmanifesting LRRK2 mutation carriers had significantly higher levels of urate than those who developed PD in each of the 3 independent cohorts. A meta-analysis demonstrated an adjusted mean difference of 0.62 mg/dL (p

Objective: To prospectively investigate potential signs of pre-clinical multiple sclerosis (MS) activity and when they are present prior to first symptom using data from a historical cohort. Methods: We linked the cognitive performance of all Norwegian men born in 1950-95 that underwent conscription examination at ages 18-19 to the Norwegian MS registry to identify those later developing MS, and randomly selected controls frequency-matched on year of birth from the Norwegian Conscript Service database. In this nested case-control study cognitive test-scores were available for 924/19530 male cases/controls. We estimated mean score differences among cases and controls (Student's t-test) and the risk of developing MS comparing lower to higher scores (Cox regression) in strata of years to clinical onset. Results: Men developing first clinical MS symptoms up to 2 years after the examination scored significantly lower than controls (Δ=0.80, p=0.0095), corresponding to a 6 intelligence quotient (IQ)-points difference. Those scoring lowest, i.e. over 1 standard deviation below the controls' mean, had an increased MS risk during the two following years (relative risk=2.81, 95% confidence interval: 1.52-5.20). While results were similar for relapsing-remitting MS cases (RRMS), those developing primary-progressive MS (PPMS) scored 4.6-6.9 IQ-points significantly lower than controls up to 20 years prior to first progressive symptoms. Interpretation: RRMS may start years prior to clinical presentation and disease processes in PPMS could start decades prior to first apparent progressive symptoms. Cognitive problems could be present in both MS forms before apparent symptoms. Apart from potential implications for clinical practice and research, these findings challenge our thinking about the disease. This article is protected by copyright. All rights reserved.

Objective Higher serum urate concentrations predict more favorable prognosis in individuals with Parkinson disease (PD). The purpose of this study was to test the causality of this association using a Mendelian randomization approach. Methods The study was conducted among participants in DATATOP and PRECEPT, 2 randomized trials among patients with early PD. The 808 patients with available DNA were genotyped for 3 SLC2A9 single nucleotide polymorphisms (SNPs) that identify an allele associated with lower urate concentrations, and for selected SNPs in other genes encoding urate transporters that have modest or no effect on serum urate levels. An SLC2A9 score was created based on the total number of minor alleles at the 3 SLC2A9 loci. Primary outcome was disability requiring dopaminergic treatment. Results Serum urate concentrations were 0.69mg/dl lower among individuals with ≥4 SLC2A9 minor alleles as compared to those with ≤2 (p = 0.0002). The hazard ratio (HR) for progression to disability requiring dopaminergic treatment increased with increasing SLC2A9 score (HR = 1.16, 95% confidence interval [CI] = 1.00–1.35, p = 0.056). In a comparative analysis, the HR was 1.27 (95% CI = 1.00–1.61, p = 0.0497) for a 0.5mg/dl genetically conferred decrease in serum urate, and 1.05 (95% CI = 1.01–1.10, p = 0.0133) for a 0.5mg/dl decrease in measured serum urate. No associations were found between polymorphisms in other genes associated with urate that do not affect serum urate and PD progression. Interpretation This Mendelian randomization analysis adds to the evidence of a causal protective effect of high urate levels. Ann Neurol 2014;76:862–868

Objective Prior research has suggested the possible role of oxidative stress in the pathogenesis of amyotrophic lateral sclerosis (ALS). Prospective data examining dietary antioxidants such carotenoids and vitamin C are limited. Methods Risk of ALS associated with carotenoid and vitamin C intake was investigated in 5 prospective cohorts: the National Institutes of Health–Association of American Retired Persons Diet and Health Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort, the Health Professionals Follow-up Study (HPFS), and the Nurses Health Study (NHS). ALS deaths were documented using the National Death Index, and confirmed nonfatal ALS cases were included from HPFS and NHS. A total of 1,153 ALS deaths occurred among 1,100,910 participants (562,942 men; 537,968 women). Participants were categorized into cohort-specific quintiles of intake for dietary variables. We applied Cox proportional hazards regression to calculate cohort-specific risk ratios (RRs), and pooled results using random-effects methods. Results A greater total major carotenoids intake was associated with a reduced risk of ALS (pooled, multivariate-adjusted RR for the highest to the lowest quintile = 0.75, 95% confidence interval [CI] = 0.61–0.91, p for trend = 0.004). Individually, higher dietary intakes of β-carotene and lutein were inversely associated with ALS risk. The pooled multivariate RRs comparing the highest to the lowest quintile for β-carotene and lutein were 0.85 (95% CI = 0.64–1.13, p for trend = 0.03) and 0.79 (95% CI = 0.64–0.96, p for trend = 0.01), respectively. Lycopene, β-cryptoxanthin, and vitamin C were not associated with reduced risk of ALS. Interpretation Consumption of foods high in carotenoids may help prevent or delay onset of ALS. ANN NEUROL 2013;73:236–245

To prospectively investigate potential signs of preclinical multiple sclerosis (MS) activity and when they are present prior to first symptom using data from a historical cohort.We linked the cognitive performance of all Norwegian men born 1950-1995 who underwent conscription examination at age 18 to 19 years to the Norwegian MS registry to identify those later developing MS, and randomly selected controls frequency-matched on year of birth from the Norwegian Conscript Service database. In this nested case-control study, cognitive test scores were available for 924 male cases and 19,530 male controls. We estimated mean score differences among cases and controls (Student t test) and the risk of developing MS comparing lower to higher scores (Cox regression) in strata of years to clinical onset.Men developing first clinical MS symptoms up to 2 years after the examination scored significantly lower than controls (Δ = 0.80, p = 0.0095), corresponding to a 6 intelligence quotient (IQ)-point difference. Those scoring lowest, that is,1 standard deviation below the controls' mean, had an increased MS risk during the 2 following years (relative risk = 2.81, 95% confidence interval = 1.52-5.20). Whereas results were similar for relapsing-remitting MS cases (RRMS), those developing primary-progressive MS (PPMS) scored a significant 4.6 to 6.9 IQ points lower than controls up to 20 years prior to first progressive symptoms.RRMS may start years prior to clinical presentation, and disease processes in PPMS could start decades prior to first apparent progressive symptoms. Cognitive problems could be present in both MS forms before apparent symptoms. Apart from potential implications for clinical practice and research, these findings challenge our thinking about the disease. Ann Neurol 2016;80:616-624.

As discussed in Part I of this review, the geographic distribution of multiple sclerosis (MS) and the change in risk among migrants provide compelling evidence for the existence of strong environmental determinants of MS, where "environmental" is broadly defined to include differences in diet and other behaviors. As we did for infections, we focus here primarily on those factors that may contribute to explain the geographic variations in MS prevalence and the change in risk among migrants. Among these, sunlight exposure emerges as being the most likely candidate. Because the effects of sun exposure may be mediated by vitamin D, we also examine the evidence linking vitamin D intake or status to MS risk. Furthermore, we review the evidence on cigarette smoking, which cannot explain the geographic variations in MS risk, but may contribute to the recently reported increases in the female/male ratio in MS incidence. Other proposed risk factors for MS are mentioned only briefly; although we recognize that some of these might be genuine, evidence is usually sparse and unpersuasive.

Although genetic susceptibility explains the clustering of multiple sclerosis (MS) cases within families and the sharp decline in risk with increasing genetic distance, it cannot fully explain the geographic variations in MS frequency and the changes in risk that occur with migration. Epidemiological data provide some support for the "hygiene hypothesis," but with the additional proviso for a key role of Epstein-Barr virus (EBV) in determining MS risk. We show that whereas EBV stands out as the only infectious agent that can explain many of the key features of MS epidemiology, by itself the link between EBV and MS cannot explain the decline in risk among migrants from high to low MS prevalence areas. This decline implies that either EBV strains in low-risk areas have less propensity to cause MS, or that other infectious or noninfectious factors modify the host response to EBV or otherwise contribute to determine MS risk. The role of infectious factors is discussed here; in a companion article, we will examine the possible role of noninfectious factors and provide evidence that high levels of vitamin D may have a protective role, particularly during adolescence. The primary purpose of these reviews is to identify clues to the causes of MS and to evaluate the possibility of primary prevention.

We investigated whether nonsteroidal antiinflammatory drug use was associated with a lower risk for Parkinson's disease (PD) in a large cohort of US men and women. PD risk was lower among ibuprofen users than nonusers. Compared with nonusers, the relative risks were 0.73 for users of fewer than 2 tablets/week, 0.72 for 2 to 6.9 tablets/week, and 0.62 for 1 or more tablets/day (p trend = 0.03). No association was found between the use of aspirin, other nonsteroidal antiinflammatory drugs, or acetaminophen and PD risk. The results suggest that ibuprofen use may delay or prevent the onset of PD.

We prospectively examined fruit and vegetable intake in relation to cognitive function and decline among aging women. Participants were followed from in 1976 with biennial questionnaires, and food frequency questionnaires were administered in 1984, 1986, and every 4 years thereafter. From 1995 to 2001, we administered, by telephone, six cognitive tests measuring general cognition, verbal memory, category fluency, and working memory. We repeated assessments two years later for 13,388 women (>90% follow-up). We averaged dietary intakes from 1984 through the first cognitive assessment, and used linear regression to obtain multivariable-adjusted mean differences in performance and decline in performance across intake levels. Fruits were not associated with cognition or cognitive decline. However, total vegetable intake was significantly associated with less decline. Specifically, on a global score combining all tests, women in the highest quintile of cruciferous vegetables declined slower (by 0.04 unit; 95% confidence interval, 0.003, 0.07; p trend = 0.1) compared with the lowest quintile. Women consuming the most green leafy vegetables also experienced slower decline than women consuming the least amount (by 0.05 unit; 95% confidence interval, 0.02, 0.09; p trend < 0.001). These mean differences were equivalent to those observed for women about 1 to 2 years apart in age.

Oxidative stress may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS). We therefore examined prospectively whether individuals who regularly use supplements of the antioxidant vitamins E and C have a lower risk of ALS than nonusers. The study population comprised 957,740 individuals 30 years of age or older participating in the American Cancer Society's Cancer Prevention Study II. Information on vitamin use was collected at time of recruitment in 1982; participants then were followed up for ALS deaths from 1989 through 1998 via linkage with the National Death Index. During the follow-up, we documented 525 deaths from ALS. Regular use of vitamin E supplements was associated with a lower risk of dying of ALS. The age- and smoking-adjusted relative risk was 0.99 (95% confidence interval [CI], 0.69-1.41) among occasional users, 0.59 (95% CI, 0.36-0.96) in regular users for less than 10 years, and 0.38 (95% CI, 0.16-0.92) in regular users for 10 years or more as compared with nonusers of vitamin E (p for trend = 0.004). In contrast, no significant associations were found for use of vitamin C or multivitamins. These results suggest that vitamin E supplementation could have a role in ALS prevention.

Cigarette smoking and caffeine consumption are associated with a decreased incidence of Parkinson's disease (PD). This inverse association may result from neuroprotective effects of cigarette smoke and caffeine, or from a disinclination of future PD patients to engage in habituating behaviors. We investigated the association between consumption of alcoholic beverages, another potentially habituating behavior, and risk of PD in two large prospective cohorts Nurses' Health Study, and Health Professionals' Follow-up Study. We detected 415 new cases of PD during follow-up. Compared with nondrinkers at baseline, the relative rate (95% confidence interval) was 1.0 (0.8-1.3) for drinkers of less than 5 gm/day, 1.0 (0.8-1.4) for 5 to less than 15 gm/day, 1.1 (0.8-1.6) for 15 to less than 30 gm/day, and 0.7 (0.5-1.2) for 30 gm/day or more (p for trend = 0.45). Consumption of wine or liquor was not associated with the incidence of PD. Compared with those who consumed beer less than once per month, the relative rate (95% confidence interval) was 0.7 (0.5-0.9) for one to three drinks of beer per month, and 0.7 (0.5, 0.9) for one or more drinks of beer per week. The risk of PD was similar in individuals who usually consume moderate amounts of alcohol and in abstainers.

We prospectively examined the changes of body weight among 468 individuals with Parkinson's disease (PD) before and after the diagnosis. The average weight of PD patients was stable until shortly before the diagnosis (p for trend = 0.2) and then declined (p for trend < 0.0001). Interestingly, PD patients tended to increase their energy intakes as their weights decreased (p for trend < 0.002). In conclusion, weight loss in PD patients appears to be a continuous process that starts several years before the diagnosis and is not caused by reduced energy intake.

Diet may play a causative role in Parkinson's disease (PD), but potential associations between diet and PD risk rarely have been assessed in prospective studies. We investigated associations between food intakes and PD risk in two large prospective cohorts in which 210 incident PD cases in men and 184 in women were documented. A positive association was found between dairy intake and PD risk in men (relative risk [RR] comparing extreme categories, 1.8; p trend = 0.004), but not in women (RR, 1.1; p trend = 0.9). No other food groups were associated with PD risk in either men or women. Further analyses among men showed significant positive associations with PD risk for intakes of several dairy foods as well as dairy calcium (RR, 1.5; p trend = 0.02), dairy vitamin D (RR, 1.6; p trend = 0.004), dairy protein (RR, 1.6; p trend = 0.01), and lactose (RR, 1.8; p trend = 0.002), but not dairy fat (RR, 1.1; p trend = 0.4). Intakes of calcium, vitamin D, and protein from other dietary or supplemental sources were not related to PD risk in men. Our results suggest that higher intake of dairy products may increase the risk of PD in men; however, this finding needs further evaluation, and the underlying active components need to be identified.

Higher serum urate concentrations predict more favorable prognosis in individuals with Parkinson disease (PD). The purpose of this study was to test the causality of this association using a Mendelian randomization approach.The study was conducted among participants in DATATOP and PRECEPT, 2 randomized trials among patients with early PD. The 808 patients with available DNA were genotyped for 3 SLC2A9 single nucleotide polymorphisms (SNPs) that identify an allele associated with lower urate concentrations, and for selected SNPs in other genes encoding urate transporters that have modest or no effect on serum urate levels. An SLC2A9 score was created based on the total number of minor alleles at the 3 SLC2A9 loci. Primary outcome was disability requiring dopaminergic treatment.Serum urate concentrations were 0.69mg/dl lower among individuals with ≥4 SLC2A9 minor alleles as compared to those with ≤2 (p = 0.0002). The hazard ratio (HR) for progression to disability requiring dopaminergic treatment increased with increasing SLC2A9 score (HR = 1.16, 95% confidence interval [CI] = 1.00-1.35, p = 0.056). In a comparative analysis, the HR was 1.27 (95% CI = 1.00-1.61, p = 0.0497) for a 0.5mg/dl genetically conferred decrease in serum urate, and 1.05 (95% CI = 1.01-1.10, p = 0.0133) for a 0.5mg/dl decrease in measured serum urate. No associations were found between polymorphisms in other genes associated with urate that do not affect serum urate and PD progression.This Mendelian randomization analysis adds to the evidence of a causal protective effect of high urate levels.

An inverse association between cigarette smoking and idiopathic Parkinson's disease has been reported in several retrospective studies, but prospective evidence is available only for men. We assessed the association between the incidence of Parkinson's disease and smoking in two large prospective cohort studies comprising men and women. New cases of Parkinson's disease were identified in the Nurses' Health Study for 1976-1996, and in the Health Professionals Follow-up Study for 1986-1996. Smoking history was assessed at baseline and updated on subsequent biennial questionnaires. In women, the age-adjusted rate ratios (95% confidence intervals) for Parkinson's disease relative to never-smokers were 0.7 (0.5, 1.0) for past smokers, and 0.4 (0.2, 0.7) for current smokers. In men, the age-adjusted rate ratios for Parkinson's disease relative to never-smokers were 0.5 (0.4, 0.7) for past smokers, and 0.3 (0.1, 0.8) for current smokers. In both cohorts, the strength of the association decreased with time since quitting (among past smokers), increased with number of cigarettes per day (among current smokers), and increased with pack-years of smoking. These prospective findings confirm that an inverse association between smoking and the incidence of Parkinson's disease exists in both men and women.

Results of case-control studies and of a prospective investigation in men suggest that consumption of coffee could protect against the risk of Parkinson's disease, but the active constituent is not clear. To address the hypothesis that caffeine is protective against Parkinson's disease, we examined the relationship of coffee and caffeine consumption to the risk of this disease among participants in two ongoing cohorts, the Health Professionals' Follow-Up Study (HPFS) and the Nurses' Health Study (NHS). The study population comprised 47,351 men and 88,565 women who were free of Parkinson's disease, stroke, or cancer at baseline. A comprehensive life style and dietary questionnaire was completed by the participants at baseline and updated every two to four years. During the follow-up (10 years in men, 16 years in women), we documented a total of 288 incident cases of Parkinson's disease. Among men, after adjustment for age and smoking, the relative risk of Parkinson's disease was 0.42 (95% CI: 0.23-0.78; p for trend < 0.001) for men in the top one-fifth of caffeine intake compared to those in the bottom one-fifth. An inverse association was also observed with consumption of coffee (p for trend = 0.004), caffeine from noncoffee sources (p for trend < 0.001), and tea (p for trend = 0.02) but not decaffeinated coffee. Among women, the relationship between caffeine or coffee intake and risk of Parkinson's disease was U-shaped, with the lowest risk observed at moderate intakes (1-3 cups of coffee/day, or the third quintile of caffeine consumption). These results support a possible protective effect of moderate doses of caffeine on risk of Parkinson's disease.

To determine whether multiple sclerosis (MS) risk increases following primary infection with the Epstein-Barr virus (EBV), we conducted a nested case-control study including 305 individuals who developed MS and 610 matched controls selected among the >8 million active-duty military personnel whose serum has been stored in the Department of Defense Serum Repository. Time of EBV infection was determined by measuring antibody titers in serial serum samples collected before MS onset among cases, and on matched dates among controls. Ten (3.3%) cases and 32 (5.2%) controls were initially EBV negative. All of the 10 EBV-negative cases became EBV positive before MS onset; in contrast, only 35.7% (n = 10) of the 28 controls with follow-up samples seroconverted (exact p value = 0.0008). We conclude that MS risk is extremely low among individuals not infected with EBV, but it increases sharply in the same individuals following EBV infection.

As discussed in Part I of this review, the geographic distribution of multiple sclerosis (MS) and the change in risk among migrants provide compelling evidence for the existence of strong environmental determinants of MS, where "environmental" is broadly defined to include differences in diet and other behaviors. As we did for infections, we focus here primarily on those factors that may contribute to explain the geographic variations in MS prevalence and the change in risk among migrants. Among these, sunlight exposure emerges as being the most likely candidate. Because the effects of sun exposure may be mediated by vitamin D, we also examine the evidence linking vitamin D intake or status to MS risk. Furthermore, we review the evidence on cigarette smoking, which cannot explain the geographic variations in MS risk, but may contribute to the recently reported increases in the female/male ratio in MS incidence. Other proposed risk factors for MS are mentioned only briefly; although we recognize that some of these might be genuine, evidence is usually sparse and unpersuasive.

Objective: Chronic, low-dose exposure to pesticides is suspected to increase the risk for Parkinson’s disease (PD), but data are inconclusive. Methods: We prospectively examined whether individuals exposed to pesticides have higher risk for PD than those not exposed. The study population comprised participants in the Cancer Prevention Study II Nutrition Cohort, a longitudinal investigation of US men and women initiated in 1992 by the American Cancer Society. Follow-up surveys were conducted in 1997, 1999, and 2001. The 143,325 individuals who returned the 2001 survey and did not have a diagnosis or symptoms of PD at baseline (1992) were included in the analyses. Results: Exposure to pesticides was reported by 7,864 participants (5.7%), including 1,956 farmers, ranchers, or fishermen. Individuals exposed to pesticides had a 70% higher incidence of PD than those not exposed (adjusted relative risk, 1.7; 95% confidence interval, 1.2–2.3; p 0.002). The relative risk for pesticide exposure was similar in farmers and nonfarmers. No relation was found between risk for PD and exposure to asbestos, chemical/acids/solvents, coal or stone dust, or eight other occupational exposures. Interpretation: These data support the hypothesis that exposure to pesticides may increase risk for PD. Future studies should seek to identify the specific chemicals responsible for this association. Ann Neurol 2006;60:197–203

Objective To characterize the association between infectious mononucleosis (IM), a frequent clinical manifestation of primary Epstein–Barr virus infection after childhood, and the risk for multiple sclerosis (MS). Methods We conducted a systematic review and meta-analysis of case–control and cohort studies of IM and MS. Results The combined relative risk of MS after IM from 14 studies was 2.3 (95% confidence interval, 1.7–3.0; p < 10−8). Potential sources of heterogeneity (ie, study design, MS definition, and latitude) barely influenced our results. Interpretation We conclude that Epstein–Barr virus infection manifesting as IM in adolescents and young adults is a risk factor for MS. Ann Neurol 2006; 59:499–503

Cigarette smoking and caffeine consumption are associated with a decreased incidence of Parkinson's disease (PD). This inverse association may result from neuroprotective effects of cigarette smoke and caffeine, or from a disinclination of future PD patients to engage in habituating behaviors. We investigated the association between consumption of alcoholic beverages, another potentially habituating behavior, and risk of PD in two large prospective cohorts Nurses' Health Study, and Health Professionals' Follow-up Study. We detected 415 new cases of PD during follow-up. Compared with nondrinkers at baseline, the relative rate (95% confidence interval) was 1.0 (0.8-1.3) for drinkers of less than 5 gm/day, 1.0 (0.8-1.4) for 5 to less than 15 gm/day, 1.1 (0.8-1.6) for 15 to less than 30 gm/day, and 0.7 (0.5-1.2) for 30 gm/day or more (p for trend = 0.45). Consumption of wine or liquor was not associated with the incidence of PD. Compared with those who consumed beer less than once per month, the relative rate (95% confidence interval) was 0.7 (0.5-0.9) for one to three drinks of beer per month, and 0.7 (0.5, 0.9) for one or more drinks of beer per week. The risk of PD was similar in individuals who usually consume moderate amounts of alcohol and in abstainers.

We prospectively examined the changes of body weight among 468 individuals with Parkinson's disease (PD) before and after the diagnosis. The average weight of PD patients was stable until shortly before the diagnosis (p for trend = 0.2) and then declined (p for trend0.0001). Interestingly, PD patients tended to increase their energy intakes as their weights decreased (p for trend0.002). In conclusion, weight loss in PD patients appears to be a continuous process that starts several years before the diagnosis and is not caused by reduced energy intake.

Diet may play a causative role in Parkinson's disease (PD), but potential associations between diet and PD risk rarely have been assessed in prospective studies. We investigated associations between food intakes and PD risk in two large prospective cohorts in which 210 incident PD cases in men and 184 in women were documented. A positive association was found between dairy intake and PD risk in men (relative risk [RR] comparing extreme categories, 1.8; p trend = 0.004), but not in women (RR, 1.1; p trend = 0.9). No other food groups were associated with PD risk in either men or women. Further analyses among men showed significant positive associations with PD risk for intakes of several dairy foods as well as dairy calcium (RR, 1.5; p trend = 0.02), dairy vitamin D (RR, 1.6; p trend = 0.004), dairy protein (RR, 1.6; p trend = 0.01), and lactose (RR, 1.8; p trend = 0.002), but not dairy fat (RR, 1.1; p trend = 0.4). Intakes of calcium, vitamin D, and protein from other dietary or supplemental sources were not related to PD risk in men. Our results suggest that higher intake of dairy products may increase the risk of PD in men; however, this finding needs further evaluation, and the underlying active components need to be identified.

An inverse association between cigarette smoking and idiopathic Parkinson's disease has been reported in several retrospective studies, but prospective evidence is available only for men. We assessed the association between the incidence of Parkinson's disease and smoking in two large prospective cohort studies comprising men and women. New cases of Parkinson's disease were identified in the Nurses' Health Study for 1976-1996, and in the Health Professionals Follow-up Study for 1986-1996. Smoking history was assessed at baseline and updated on subsequent biennial questionnaires. In women, the age-adjusted rate ratios (95% confidence intervals) for Parkinson's disease relative to never-smokers were 0.7 (0.5, 1.0) for past smokers, and 0.4 (0.2, 0.7) for current smokers. In men, the age-adjusted rate ratios for Parkinson's disease relative to never-smokers were 0.5 (0.4, 0.7) for past smokers, and 0.3 (0.1, 0.8) for current smokers. In both cohorts, the strength of the association decreased with time since quitting (among past smokers), increased with number of cigarettes per day (among current smokers), and increased with pack-years of smoking. These prospective findings confirm that an inverse association between smoking and the incidence of Parkinson's disease exists in both men and women.

Results of case-control studies and of a prospective investigation in men suggest that consumption of coffee could protect against the risk of Parkinson's disease, but the active constituent is not clear. To address the hypothesis that caffeine is protective against Parkinson's disease, we examined the relationship of coffee and caffeine consumption to the risk of this disease among participants in two ongoing cohorts, the Health Professionals' Follow-Up Study (HPFS) and the Nurses' Health Study (NHS). The study population comprised 47,351 men and 88,565 women who were free of Parkinson's disease, stroke, or cancer at baseline. A comprehensive life style and dietary questionnaire was completed by the participants at baseline and updated every two to four years. During the follow-up (10 years in men, 16 years in women), we documented a total of 288 incident cases of Parkinson's disease. Among men, after adjustment for age and smoking, the relative risk of Parkinson's disease was 0.42 (95% CI: 0.23-0.78; p for trend0.001) for men in the top one-fifth of caffeine intake compared to those in the bottom one-fifth. An inverse association was also observed with consumption of coffee (p for trend = 0.004), caffeine from noncoffee sources (p for trend0.001), and tea (p for trend = 0.02) but not decaffeinated coffee. Among women, the relationship between caffeine or coffee intake and risk of Parkinson's disease was U-shaped, with the lowest risk observed at moderate intakes (1-3 cups of coffee/day, or the third quintile of caffeine consumption). These results support a possible protective effect of moderate doses of caffeine on risk of Parkinson's disease.