Obesity and the Risk of Parkinson’s Disease

Honglei Chen1 , Shumin M. Zhang2,3, Michael A. Schwarzschild4, Miguel A. Hernán2, Walter C. Willett1,2,5 and Alberto Ascherio1,2,5

1 Department of Nutrition, Harvard School of Public Health, Boston, MA.
2 Department of Epidemiology, Harvard School of Public Health, Boston, MA.
3 Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA.
4 Department of Neurology, Massachusetts General Hospital, Boston, MA.
5 Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA.

Received for publication June 3, 2003; accepted for publication September 2, 2003.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Dopamine is involved in the regulation of food intake, and obese persons have decreased dopamine D2 receptor availability in the striatum. Furthermore, midlife triceps skinfold thickness has been found to be positively associated with the risk of Parkinson’s disease (PD) among Japanese-American men in Hawaii. The authors prospectively investigated whether obesity was associated with PD risk in two large cohorts of US men and women. They documented 249 cases of PD in men (1986–2000) and 202 cases in women (1976–1998). Neither baseline body mass index (weight (kg)/height (m)2) nor early adult body mass index was associated with PD risk. The multivariate relative risk for a baseline body mass index of >=30 versus <23 was 0.8 (95% confidence interval (CI): 0.6, 1.2; p for trend = 0.3). Overall, waist circumference and waist-to-hip ratio were not related to PD risk. However, among never smokers, both variables showed significantly positive associations with PD risk. The relative risks for comparisons of extreme quintiles were 1.9 (95% CI: 1.0, 3.4; p for trend = 0.03) for waist circumference and 2.0 (95% CI: 1.1, 3.6; p for trend = 0.03) for waist-to-hip ratio. The results do not support a role of overall obesity in PD pathogenesis; however, central obesity may be associated with higher PD risk among never smokers, and this finding merits further investigation.

body composition; body mass index; obesity; Parkinson disease; prospective studies

Abbreviations: Abbreviations: BMI, body mass index; CI, confidence interval; HPFS, Health Professionals Follow-up Study; NHS, Nurses’ Health Study; RR, relative risk.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Neurotransmitters, including dopamine, play important roles in the regulation of food intake (13). Obese persons have lower dopamine D2 receptor availability in the striatum (4), and patients with Parkinson’s disease have neurodegeneration and reduced dopamine activity in the hypothalamus (5, 6). In a prospective epidemiologic study that examined the potential association between obesity and the risk of Parkinson’s disease among Japanese-American men in Hawaii, Abbott et al. (7) reported that greater midlife triceps skinfold thickness was associated with higher future risk of Parkinson’s disease, independent of body mass index (BMI) and other potentially confounding factors. Here we report findings on the association between obesity and Parkinson’s disease risk in both men and women, using data from two large prospective cohort studies: the Health Professionals Follow-up Study (HPFS) and the Nurses’ Health Study (NHS).


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
The HPFS cohort was established in 1986, when 51,529 male health professionals (dentists, optometrists, pharmacists, osteopaths, podiatrists, and veterinarians) aged 40–75 years responded to a mailed questionnaire regarding dietary habits, disease history, and lifestyle (8). The NHS was initiated in 1976 when 121,700 registered nurses aged 30–55 years provided detailed information on their medical history and lifestyle (9). In both cohorts, follow-up questionnaires are mailed to participants every 2 years to obtain updated information on potential risk factors for chronic diseases and to ascertain whether any major medical events have occurred. A specific question on lifetime Parkinson’s disease occurrence was first asked in 1988 for men and in 1994 for women, and a question on Parkinson’s disease diagnosis within the previous 2 years was posed in the subsequent surveys. Participants were asked to report their height and current weight in 1986 (men) or 1976 (women), and body weight was updated every 2 years thereafter. The present investigation was restricted to men and women who provided baseline information on body weight and height, did not report symptoms of Parkinson’s disease at baseline, and had not received a diagnosis of stroke or cancer (other than nonmelanoma skin cancer) before they answered the baseline questionnaire. We followed the eligible 47,700 men and 117,062 women from baseline to the date of occurrence of the first symptoms of Parkinson’s disease, the date of death or stroke, or the end of follow-up (January 31, 2000, for men and May 31, 1998, for women), whichever occurred first. These studies were approved by the human subjects research committees at the Harvard School of Public Health and Brigham and Women’s Hospital.

Parkinson’s disease case ascertainment
Ascertainment of Parkinson’s disease cases in these cohorts has been previously described (10). Briefly, after obtaining permission from participants who reported a new diagnosis of Parkinson’s disease, we asked the treating neurologist (or internist if the neurologist did not respond) to complete a questionnaire to confirm the diagnosis and the certainty of the diagnosis, or to send a copy of the medical record. A case was confirmed if a diagnosis of Parkinson’s disease was considered definite or probable by the treating neurologist or internist, or if the medical record included either a final diagnosis of Parkinson’s disease made by a neurologist or evidence at neurologic examination of at least two of the three cardinal signs (rest tremor, rigidity, bradykinesia) in the absence of features suggesting other diagnoses. The review of medical records was conducted by the investigators, blind to exposure status. Overall, the diagnosis was confirmed by the treating neurologist in 82.3 percent of the cases, by review of the medical records in 3.1 percent of the cases, and by the treating internist without further support in the remaining 14.6 percent of the cases.

Measurements of body weight and waist and hip circumferences
At baseline, participants in both cohorts were asked to report their height (in inches; 1 inch = 2.54 cm) and current body weight (in pounds; 1 pound = 0.45 kg), the latter of which was then updated biennially during follow-up. The HPFS 1986 questionnaire also elicited information on weight at age 21 years. In 1987, HPFS participants were asked in a supplementary questionnaire to measure their waist and hip circumferences (inches) with a paper tape and were given detailed measuring directions. In the NHS, weight at age 18 years was elicited in the 1980 questionnaire, and waist and hip circumferences were asked about in 1986. BMI was calculated as weight in kilograms divided by height squared in meters. Waist-to-hip ratio, calculated as waist circumference divided by hip circumference, was used as an indicator of central obesity along with waist circumference. Adult weight change was defined as baseline body weight minus weight at age 21 years in men or body weight in 1980 minus weight at age 18 years in women.

The validity of the self-reported weight data was high (the Pearson correlation coefficient was 0.98 in both cohorts), as evaluated among 123 HPFS and 140 NHS participants who were weighed twice 6–9 months apart by trained technicians (11). The Pearson correlation coefficients for the correlation between self-reported and technician-measured waist circumference and waist-to-hip ratio were 0.98 and 0.77, respectively, in men and 0.91 and 0.75, respectively, in women (11).

Statistical analyses
To minimize the potential effects of extreme values on regression analyses and to allow for nonlinear associations, we categorized all anthropometric variables before conducting the analyses and used the median value in each category to create a continuous variable for linear trend tests. Multivariate relative risks were calculated using Cox proportional hazards models, with adjustment for age, smoking, caffeine intake, and alcohol consumption. However, for the BMI analyses in women, only age- and smoking-adjusted relative risks are reported. Information on alcohol consumption and caffeine intake was not collected at baseline (1976) in women, and further adjustment for these two variables as derived from the first dietary assessment in 1980 did not change the risk estimates. We weighted log relative risks from the two cohorts by the inverse of their variances to obtain a pooled relative risk. We calculated 95 percent confidence intervals for all relative risks, and all p values were two-tailed ({alpha} = 0.05).

Since Parkinson’s disease patients may begin to lose weight several years prior to diagnosis (12), we used the anthropometric variables measured at baseline in primary analyses. To further exclude the possibility that weight loss early in the course of the disease might bias our results, we repeated the analyses after excluding the first 3 or 4 years of follow-up. In secondary analyses, we related each biennially updated BMI to the incidence of Parkinson’s disease in the following 2 years of follow-up.

Previous analyses of the HPFS cohort showed that BMI peaked at the age of 60–65 years and then declined, whereas waist circumference and waist-to-hip ratio increased across all age groups (13). For this reason, as well as to make our data more comparable with those of the Hawaiian study (7), in which all participants were younger than 68 years (mean age = 54 years; range, 45–68 years), we further conducted the analyses in men according to age at baseline (<65 years vs. >=65 years). No age-subgroup analyses were performed in women, because the women were all younger than 55 years at recruitment. Finally, we conducted separate analyses in never smokers and ever smokers because smoking was related to both body weight and Parkinson’s disease risk.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
We documented a total of 249 Parkinson’s disease cases in men and 202 cases in women during follow-up. The average age at which the first symptom of Parkinson’s disease was noticed was 69.5 years (standard deviation, 8.5) in men and 63.1 years (standard deviation, 6.7) in women. The 5-year age-group-specific incidence rates (per 100,000 person-years) in men were 3 (age 40–44 years), 9 (age 45–49 years), 8 (age 50–54 years), 19 (age 55–59 years), 40 (age 60–64 years), 63 (age 65–69 years), 82 (age 70–74 years), 132 (age 75–79 years), and 173 (age 80–84 years), respectively. In women, the incidence rates for each 5-year age group from ages 40 to 74 years (per 100,000 person-years) were 1, 3, 3, 11, 18, 27, and 34, respectively. No significant associations were observed between baseline BMI and Parkinson’s disease risk (table 1). Using a BMI less than 23 as the reference group, the pooled relative risk associated with a BMI of 30 or more was 0.8 (95 percent confidence interval (CI): 0.6, 1.2; p for trend = 0.3). Results were barely changed in the 4-year-lagged analyses (corresponding relative risk (RR) = 0.8, 95 percent CI: 0.5, 1.2; p for trend = 0.2). However, when the most recent (updated) BMI was used instead of baseline BMI, an inverse association between BMI and Parkinson’s disease risk was observed. The pooled relative risk for a comparison between the two extreme BMI categories was 0.5 (95 percent CI: 0.3, 0.9; p for trend = 0.03).


View this table:
[in this window]
[in a new window]
 
TABLE 1. Relative risk* of Parkinson’s disease according to baseline body mass index, early adult body mass index, and weight change since early adulthood, Health Professionals Follow-up Study and Nurses’ Health Study
 
BMI in early adulthood (age 21 years in men and age 18 years in women) was not associated with later risk of Parkinson’s disease; the relative risk was 1.0 in both men and women when we compared participants whose BMI was 27 or more with those whose BMI was less than 20. A nonsignificantly higher risk (RR = 1.5, 95 percent CI: 0.9, 2.3) was found among men with weight gains of 45 or more pounds from early adulthood to baseline as compared with men who gained less than 5 pounds; however, this comparison in women showed a nonsignificantly lower risk (RR = 0.7, 95 percent CI: 0.4, 1.2). In neither men nor women was the linear trend test associated with weight gain statistically significant.

Neither waist circumference nor waist-to-hip ratio was associated with risk of Parkinson’s disease in men (table 2), and the results remained the same after further adjustment for BMI. Women in the lowest quintile of waist circumference (<28.0 inches) had the lowest risk of Parkinson’s disease, and women in the second (28.0–29.9 inches) and fourth (32.0–34.9 inches) quintiles had marginally significant increases in Parkinson’s disease risk (RR = 2.1 (95 percent CI: 1.0, 4.6) and RR = 2.1 (95 percent CI: 1.0, 4.5), respectively) (table 2). After controlling for BMI, the relative risks associated with increasing categories of waist circumference among women were 1.0 (referent), 2.4, 2.1, 2.7, and 2.9 (95 percent CI: 1.1, 7.9), and the p value for the trend test was marginally significant (p for trend = 0.09).


View this table:
[in this window]
[in a new window]
 
TABLE 2. Relative risk* of Parkinson’s disease according to waist circumference and waist-to-hip ratio, Health Professionals Follow-up Study and Nurses’ Health Study
 
No significant interactions were found between baseline anthropometric measurements and age in men, although among younger men a slightly higher risk was found when comparing the extreme categories of BMI (RR = 1.3, 95 percent CI: 0.6, 2.7) (table 3), while a slightly lower risk was found among older men (RR = 0.7, 95 percent CI: 0.3, 1.8). The results for waist circumference and waist-to-hip ratio were also comparable between younger men and older men.


View this table:
[in this window]
[in a new window]
 
TABLE 3. Relative risk* of Parkinson’s disease in comparisons of the highest categories of anthropometric variables with the lowest categories among men aged <65 years and >=65 years, Health Professionals Follow-up Study
 
The subgroup analyses of BMI by smoking status showed no difference between never smokers and ever smokers (table 4). However, a significant effect of interaction between waist circumference and smoking status on Parkinson’s disease risk was found in pooled analyses (p = 0.04), and the interaction between waist-to-hip ratio and smoking status was marginally significant (p = 0.09). Among never smokers, greater waist circumference or waist-to-hip ratio was associated with higher Parkinson’s disease risk in both men and women. In comparison with the lowest quintile, the pooled relative risks for quintiles 2–5 of waist circumference were 1.6, 1.6, 2.5, and 1.9 (p for trend = 0.03). The corresponding relative risks for waist-to-hip ratio were 1.3, 2.4, 1.8, and 2.0 (p for trend = 0.03), respectively. The results were similar after further adjustment for BMI: The pooled relative risks for quintiles 2–5 were 1.6, 1.5, 2.4, and 2.0, respectively, for waist circumference (p for trend = 0.06) and 1.3, 2.2, 1.7, and 1.9, respectively, for waist-to-hip ratio (p for trend = 0.06). Neither waist circumference nor waist-to-hip ratio was associated with risk of Parkinson’s disease in ever smokers (p values for trend were 0.3 and 0.7, respectively, in the pooled analyses). After further adjustment for BMI, the relative risks associated with higher waist circumference quintiles increased among female smokers (RRs for quintiles 2–5: 2.1, 1.1, 2.0, and 2.8; p for trend = 0.2), but BMI adjustment made no difference in the risk estimates for waist-to-hip ratio among female smokers or for either variable in male smokers.


View this table:
[in this window]
[in a new window]
 
TABLE 4. Relative risk{dagger} of Parkinson’s disease according to categories of anthropometric variables and smoking status, Health Professionals Follow-up Study and Nurses’ Health Study{ddagger}
 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
In participants from these large prospective cohort studies, we did not find significant associations between BMI, waist circumference, or waist-to-hip ratio and risk of Parkinson’s disease for either men or women. However, greater waist circumference and waist-to-hip ratio were related to higher risk of Parkinson’s disease among never smokers.

Both the HPFS and the NHS are prospectively designed studies with long follow-up periods, allowing us to rule out the effect of preclinical weight change via lag-time analyses. The self-reported anthropometric information in both cohorts has been validated previously (11) and has been successfully used to investigate associations between obesity and the risks of major chronic diseases, including cardiovascular disease, type II diabetes mellitus, and cancer (1318).

To our knowledge, only one prospective epidemiologic study has examined the relation between obesity and risk of Parkinson’s disease. A total of 137 Parkinson’s disease cases were identified among 7,990 Japanese-American men in Honolulu, Hawaii, with 30 years of follow-up (7). In that population, a strong positive association was found between triceps skinfold thickness and Parkinson’s disease risk. Compared with the lowest quartile of triceps skinfold thickness, the multivariate relative risk for the highest quartile was 2.8 (95 percent CI: 1.4, 5.6; p for trend < 0.001). Higher Parkinson’s disease incidence was also found when higher quartiles of BMI or subscapular skinfold thickness were compared with the lowest quartile; however, in both cases, the test for linear trend was not statistically significant (p for trend = 0.1). We did not have measures of peripheral obesity in our study, and thus we were unable to determine the relative importance of peripheral obesity in the etiology of Parkinson’s disease.

We did not find any significant associations between BMI and Parkinson’s disease risk, even after restricting our analysis to men younger than 65 years of age, a population with an age composition comparable to that of the men in the Hawaiian study (7). In women, higher BMI was associated with nonsignificantly lower risk of Parkinson’s disease. A statistically significant inverse association was found between the biennially updated BMI and risk of Parkinson’s disease. Previous investigations have suggested that Parkinson’s disease patients tend to lose weight (19, 20), and we further found that these weight losses are likely to begin 2–4 years prior to diagnosis (12). Thus, the inverse association between updated BMI and Parkinson’s disease risk is likely to reflect the preclinical weight loss. Therefore, our results do not support an important role for overall obesity in determining susceptibility to Parkinson’s disease.

Obesity is a well-known risk factor for coronary heart disease and type II diabetes. Previous investigations have suggested that abdominal obesity, as measured by waist circumference or waist-to-hip ratio, increases the risk of these diseases independently of overall obesity (1315). Our current investigation suggests that abdominal obesity may increase Parkinson’s disease risk among nonsmokers. The highest quintile of waist circumference or waist-to-hip ratio was associated with an approximately twofold increased risk over the lowest quintile, with a statistically significant trend. Although we could not exclude the possibility that these findings were due to chance or residual confounding, positive associations were present in both men and women and were controlled for known Parkinson’s disease risk factors. The fact that we did not find such a positive association among ever smokers may be explained by the strong inverse association between smoking and Parkinson’s disease (2123). In animal models of Parkinson’s disease, cigarette smoke and nicotine could attenuate the neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2426). Therefore, it may be hypothesized that, among smokers, the adverse effect on Parkinson’s disease associated with abdominal fat may somehow be neutralized by the protective effect of cigarette smoking.

Reasons as to why abdominal fatness is associated with risk of Parkinson’s disease are unknown. Similar rates of concordance of Parkinson’s disease between homozygotic and heterozygotic twins strongly suggest an environmental component in sporadic Parkinson’s disease etiology (27). Pesticides or herbicides such as rotenone and paraquat cause dopaminergic neuron death and/or induce parkinsonism in animal models (28, 29), and the use of pesticides and residence in rural areas have been linked to increased Parkinson’s disease risk in epidemiologic investigations (30). Adipose tissue may serve as a reservoir for lipid-soluble environmental neural toxicants, and visceral fat is more metabolically active and thus probably more ready for chronic neurotoxin release.

A recent clinical observation showed that extremely obese persons had a significantly lower availability of dopamine D2 receptor in the striatum than nonobese controls (4). A proposed explanation is that obesity down-regulates dopamine D2 receptor to compensate for the increased dopamine concentration associated with eating (1, 2, 4). Alternatively, one can speculate that lower dopamine D2 receptor availability may lead to overeating and obesity (31). In either case, the lower dopamine D2 receptor availability may predispose obese persons to later higher Parkinson’s disease risk. As Abbott et al. (7) speculated, there might be a compensatory increase in dopamine turnover among obese persons, which may induce oxidative stress and dopaminergic neuron death. Finally, obesity may be associated with low-grade chronic and systematic inflammation that may in turn increase the risk of Parkinson’s disease (32).

Interpretation of our results should consider the potential limitations of this study. We relied on the judgment of the patients’ treating physicians (in most cases, their neurologist) for the Parkinson’s disease diagnosis. Since these cases were not pathologically confirmed, we cannot exclude the possibility that a few of them were misdiagnosed. In earlier studies, approximately 24 percent of the clinically diagnosed Parkinson’s disease cases could not be confirmed upon pathologic examination (33, 34); however, diagnostic accuracy has improved to 90 percent or higher in most recent clinicopathologic studies (35, 36). Furthermore, the incidence rates of our study are comparable to those reported by other investigators (3740), and we have previously reported in these cohorts the well-recognized inverse associations between cigarette smoking (21) and caffeine consumption (10, 41) and Parkinson’s disease risk. This provides, albeit indirectly, evidence against substantial diagnostic misclassification in our cohorts. Some misclassification of exposure variables is inevitably present in observational studies. According to our validation study (11), random measurement error was higher for waist-to-hip ratio, and therefore the relative risk corresponding to this exposure may have been underestimated. Participants in our cohorts were well-educated health professionals who had average BMIs of 25.5 (men) and 23.8 (women) at baseline; few of them had a BMI greater than 35 (1.4 percent in men and 2.2 percent in women). Therefore, our results may not be applicable to persons who are extremely obese.

In summary, the results of our study suggest that overall obesity does not increase the risk of Parkinson’s disease. Among nonsmokers, abdominal obesity may be a risk factor for Parkinson’s disease, and this association warrants further investigation.


    ACKNOWLEDGMENTS
 
This study was supported by research grants NS35624 and CA87969 from the National Institutes of Health and by a gift from the Kinetics Foundation (Los Altos, California).

The authors are indebted to Drs. Frank E. Speizer and Graham A. Colditz, the Principal Investigators of the Nurses’ Health Study. They also thank Al Wing, Karen Corsano, Laura Sampson, Gary Chase, Barbara Egan, Mira Kaufman, Betsy Frost-Hawes, Stacey DeCaro, and Mitzi Wolff for their technical help.


    NOTES
 
Correspondence to Dr. Honglei Chen, Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115 (e-mail: hchen{at}hsph.harvard.edu). Back


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Martel P, Fantino M. Mesolimbic dopaminergic system activity as a function of food reward: a microdialysis study. Pharmacol Biochem Behav 1996;53:221–6.[CrossRef][ISI][Medline]
  2. Meguid MM, Fetissov SO, Varma M, et al. Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition 2000;16:843–57.[CrossRef][ISI][Medline]
  3. Schwartz MW, Woods SC, Porte D Jr, et al. Central nervous system control of food intake. Nature 2000;404:661–71.[ISI][Medline]
  4. Wang GJ, Volkow ND, Logan J, et al. Brain dopamine and obesity. Lancet 2001;357:354–7.[CrossRef][ISI][Medline]
  5. Shannak K, Rajput A, Rozdilsky B, et al. Noradrenaline, dopamine and serotonin levels and metabolism in the human hypothalamus: observations in Parkinson’s disease and normal subjects. Brain Res 1994;639:33–41.[CrossRef][ISI][Medline]
  6. Langston JW, Forno LS. The hypothalamus in Parkinson disease. Ann Neurol 1978;3:129–33.[ISI][Medline]
  7. Abbott RD, Ross GW, White LR, et al. Midlife adiposity and the future risk of Parkinson’s disease. Neurology 2002;59:1051–7.[Abstract/Free Full Text]
  8. Rimm EB, Giovannucci EL, Stampfer MJ, et al. Reproducibility and validity of an expanded self-administered semiquantitative food frequency questionnaire among male health professionals. Am J Epidemiol 1992;135:1114–26.[Abstract]
  9. Colditz GA, Manson JE, Hankinson SE. The Nurses’ Health Study: 20-year contribution to the understanding of health among women. J Womens Health 1997;6:49–62.[ISI][Medline]
  10. Ascherio A, Zhang SM, Hernán MA, et al. Prospective study of caffeine consumption and risk of Parkinson’s disease in men and women. Ann Neurol 2001;50:56–63.[CrossRef][ISI][Medline]
  11. Rimm EB, Stampfer MJ, Colditz GA, et al. Validity of self-reported waist and hip circumferences in men and women. Epidemiology 1990;1:466–73.[Medline]
  12. Chen H, Zhang SM, Hernán MA, et al. Weight loss in Parkinson’s disease. Ann Neurol 2003;53:676–9.[CrossRef][ISI][Medline]
  13. Rimm EB, Stampfer MJ, Giovannucci E, et al. Body size and fat distribution as predictors of coronary heart disease among middle-aged and older US men. Am J Epidemiol 1995;141:1117–27.[Abstract]
  14. Rexrode KM, Carey VJ, Hennekens CH, et al. Abdominal adiposity and coronary heart disease in women. JAMA 1998;280:1843–8.[Abstract/Free Full Text]
  15. Carey VJ, Walters EE, Colditz GA, et al. Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women: The Nurses’ Health Study. Am J Epidemiol 1997;145:614–19.[Abstract]
  16. Chan JM, Rimm EB, Colditz GA, et al. Obesity, fat distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care 1994;17:961–9.[Abstract]
  17. Huang Z, Willett WC, Colditz GA, et al. Waist circumference, waist:hip ratio, and risk of breast cancer in the Nurses’ Health Study. Am J Epidemiol 1999;150:1316–24.[Abstract]
  18. Michaud DS, Giovannucci E, Willett WC, et al. Physical activity, obesity, height, and the risk of pancreatic cancer. JAMA 2001;286:921–9.[Abstract/Free Full Text]
  19. Beyer PL, Palarino MY, Michalek D, et al. Weight change and body composition in patients with Parkinson’s disease. J Am Diet Assoc 1995;95:979–83.[CrossRef][ISI][Medline]
  20. Abbott RA, Cox M, Markus H, et al. Diet, body size and micronutrient status in Parkinson’s disease. Eur J Clin Nutr 1992;46:879–84.[ISI][Medline]
  21. Hernán MA, Zhang SM, Rueda-deCastro AM, et al. Cigarette smoking and the incidence of Parkinson’s disease in two prospective studies. Ann Neurol 2001;50:780–6.[CrossRef][ISI][Medline]
  22. Tanner CM, Goldman SM, Aston DA, et al. Smoking and Parkinson’s disease in twins. Neurology 2002;58:581–8.[Abstract/Free Full Text]
  23. Checkoway H, Nelson LM. Epidemiologic approaches to the study of Parkinson’s disease etiology. Epidemiology 1999;10:327–36.[ISI][Medline]
  24. Carr LA, Basham JK, York BK, et al. Inhibition of uptake of 1-methyl-4-phenylpyridinium ion and dopamine in striatal synaptosomes by tobacco smoke components. Eur J Pharmacol 1992;215:285–7.[CrossRef][ISI][Medline]
  25. Carr LA, Rowell PP. Attenuation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity by tobacco smoke. Neuropharmacology 1990;29:311–14.[CrossRef][ISI][Medline]
  26. Quik M, Di Monte DA. Nicotine administration reduces striatal MPP+ levels in mice. Brain Res 2001;917:219–24.[CrossRef][ISI][Medline]
  27. Tanner CM, Ottman R, Goldman SM, et al. Parkinson disease in twins: an etiologic study. JAMA 1999;281:341–6.[Abstract/Free Full Text]
  28. Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci 2000;3:1301–6.[CrossRef][ISI][Medline]
  29. McCormack AL, Thiruchelvam M, Manning-Bog AB, et al. Environmental risk factors and Parkinson’s disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 2002;10:119–27.[CrossRef][ISI][Medline]
  30. Priyadarshi A, Khuder SA, Schaub EA, et al. Environmental risk factors and Parkinson’s disease: a metaanalysis. Environ Res 2001;86:122–7.[CrossRef][ISI][Medline]
  31. Wang GJ, Volkow ND, Fowler JS. The role of dopamine in motivation for food in humans: implications for obesity. Expert Opin Ther Targets 2002;6:601–9.[Medline]
  32. Das UN. Is obesity an inflammatory condition? Nutrition 2001;17:953–66.[CrossRef][ISI][Medline]
  33. Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinsonism—a prospective study. Can J Neurol Sci 1991;18:275–8.[ISI][Medline]
  34. Hughes AJ, Daniel SE, Kilford L, et al. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 1992;55:181–4.[Abstract]
  35. Hughes AJ, Daniel SE, Lees AJ. Improved accuracy of clinical diagnosis of Lewy body Parkinson’s disease. Neurology 2001;57:1497–9.[Abstract/Free Full Text]
  36. Hughes AJ, Daniel SE, Ben-Shlomo Y, et al. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 2002;125:861–70.[Abstract/Free Full Text]
  37. Bower JH, Maraganore DM, McDonnell SK, et al. Incidence and distribution of parkinsonism in Olmsted County, Minnesota, 1976–1990. Neurology 1999;52:1214–20.[Abstract/Free Full Text]
  38. Mayeux R, Marder K, Cote LJ, et al. The frequency of idiopathic Parkinson’s disease by age, ethnic group, and sex in northern Manhattan, 1988–1993. Am J Epidemiol 1995;142:820–7.[Abstract]
  39. Morens DM, Davis JW, Grandinetti A, et al. Epidemiologic observations on Parkinson’s disease: incidence and mortality in a prospective study of middle-aged men. Neurology 1996;46:1044–50.[Abstract]
  40. Van Den Eeden SK, Tanner CM, Bernstein AL, et al. Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 2003;157:1015–22.[Abstract/Free Full Text]
  41. Ascherio A, Chen H, Schwarzschild MA, et al. Caffeine, postmenopausal estrogen, and risk of Parkinson’s disease. Neurology 2003;60:790–5.[Abstract/Free Full Text]