In this community-based, biracial cohort, we found that higher plasma urate concentration was associated with lower occurrence of Parkinson's disease. This association was evident among men and Caucasians but was also suggested for women and African Americans. All study participants were 45–64 years of age at study visit 1 and have been followed for nearly 20 years. Because study participants were all younger than 65 years of age at baseline and we excluded possible prevalent cases from the primary analysis, most cases of Parkinson's disease in this analysis were likely incident. Further excluding cases identified during the early years of follow-up did not change the results. Finally, Parkinson's disease status was not related to change in urate levels from visit 1 to visit 2, suggesting that reverse causality is less likely to explain the observed urate–Parkinson's disease relation.
Results of this study are in line with those from previous cohorts of mostly male participants, where an association between higher urate level and lower Parkinson's disease risk was consistently reported (5
). Only the Rotterdam study included female participants, and the authors reported no difference by sex but did not provide any details (7
). Recent analyses of 2 clinical trials among Parkinson's disease patients that were initially designed to investigate other potential neuroprotective agents showed that higher levels of serum or cerebrospinal fluid urate were associated with slower Parkinson's disease progression in men (13
); for women, however, the association was not as evident. A sex difference was also observed in the analysis of the General Practice Research Database, in which gout or the use of gout medication was associated with a lower Parkinson's disease risk for men but not for women (15
). Although these results are informative, they could not be directly extrapolated to urate and Parkinson's disease development. It is well known that by the time of Parkinson's disease diagnosis, a majority of the dopaminergic neurons have already died. In the case of gout, only a small portion of individuals with high plasma urate concentrations develop gout, and gout risk is much lower for women (16
); therefore, a null association regarding gout and Parkinson's disease might not necessarily mean that urate is not related to Parkinson's disease in women. The current analysis, albeit limited by sample size, suggests that the finding on plasma urate and risk of developing Parkinson's disease may be generalizable to women and African Americans.
Prospective data on biomarkers and Parkinson's disease risk are rare (5
) because such research requires following tens of thousands of biospecimen donors for a long period. This is particularly true for women, who have a lower incidence of Parkinson's disease than men do. Compared with previous studies, the current study included more female Parkinson's disease cases and, also for the first known time, included African Americans. In addition, unlike previous studies, this study measured plasma urate for every eligible cohort participant twice 3 years apart. Although repeated measures over a longer period of time are desirable, the current analysis showed that Parkinson's disease status was not related to change in plasma urate level. Finally, although the possibility of residual confounding cannot be excluded, known risk factors for Parkinson's disease were adjusted throughout the analyses.
The consistency of a urate–Parkinson's disease relation across all available studies suggests that this association is unlikely due to chance. Even though none of the studies could exclude the possibility that the association was caused by unknown common genetic or environmental factors that underlie both urate and Parkinson's disease, the hypothesis that urate protects against Parkinson's disease development and progression should be carefully evaluated. Unlike other mammals, humans and apes have high levels of plasma urate as a result of mutations of uricase occurring millions of years ago (4
). The fact that plasma urate increases with age may be advantageous to human aging because urate is a potent scavenger of iron and free radicals, particularly against peroxynitrite, which kills dopaminergic neurons via oxidative stress (4
). While epidemiologic data have been consistently supportive of a potential benefit of urate on Parkinson's disease, to our knowledge this issue has received little attention in experimental research. An earlier study found that urate protected dopaminergic neurons from the toxicity of iron and rotenone in mice (20
); however, this study was not designed to evaluate the role of urate in animal parkinsonism. An alternative explanation for the current epidemiologic findings is that one or more urate precursors such as adenosine or inosine, rather than urate itself, modulate dopaminergic neuron survival. Each of these possibilities should be evaluated in future investigations, and, if urate or its precursors are etiologically linked to Parkinson's disease, the potential mechanisms should be elucidated.
The major limitations of this study include the lack of a systematic strategy to identify and validate Parkinson's disease diagnosis and the lack of information on date of diagnosis and onset. In the current study, Parkinson's disease cases were identified from multiple sources at various time points. Inevitably, some cases were not identified and some noncases were misclassified as cases. On the other hand, studies on Parkinson's disease based on self-report or medication data have made valuable contributions to the literature (21
). To evaluate the potential effects of self-reported Parkinson's disease in this particular study, we assessed the relation between Parkinson's disease and smoking or caffeine intake, 2 factors known to be related to lower Parkinson's disease risk. As expected, results obtained were similar to those reported in previous investigations in which systematic approaches to identifying Parkinson's disease were applied (25
). Although these findings indirectly support the validity of our study, a systematic strategy to identify and validate Parkinson's disease diagnoses is preferred. Because of the lack of information on date of diagnosis, we were unable to clearly differentiate incident from prevalent cases, nor to calculate Parkinson's disease incidence in the cohort. For the same reason, we used logistic regression but not proportional hazards modeling and therefore were not able to control for selective survival in the analysis. Finally, the small number of female and African-American cases limited the power of statistical analyses; further large studies are needed to confirm these preliminary findings.