Urate, the end product of purine metabolism, at physiological concentrations is an effective antioxidant and may provide a natural defense against the development of Parkinson's disease (PD). In previous studies, healthy individuals with higher blood levels of urate were found to have a reduced risk of developing PD. Further, we found that higher blood urate levels in patients recently diagnosed with PD predict a favorable (slower) rate of disease progression, assessed by both clinical and neuroimaging measures. These studies suggest that urate may serve as a robust predictor of the neurodegeneration that leads to PD and its progression, and, because urate and its metabolic pathways are particularly amenable to pharmacological and dietary manipulations, have a potential therapeutic significance. It remains to be established, however, whether this association reflects a neuroprotective effect of urate or its metabolic precursors, or whether it is explained by a still unidentified common factor/confounder. Further, whereas a strong inverse association between blood urate and both PD risk and progression has been established in men, results in women are uncertain, because few women were included in previous studies. Primary purpose of the proposed investigation is to conduct a systematic and in depth analysis of how blood urate and its determinants, including genetic variations in the urate pathway, affect both PD UriskU and UprogressionU in men and women. The investigation will comprise two main components. One is a nested case-control study including 1,492 incident cases of PD (685 women) and 3,316 matched controls to examine: 1) whether blood levels of urate predict risk of PD independently from known or suspected risk factors for PD and from genetic and non-genetic determinants of uricemia, and 2) whether mutations in genes involved in urate metabolism are associated with blood levels of urate and PD risk. The second is a cohort analysis among participants in two previously conducted large randomized trial in patients with early PD. We will examine: 1) whether the previously reported strong inverse associations between serum urate and PD progression are independent of genetic mutations affecting urate metabolism, and 2) whether these genetic mutations predict blood or CSF levels of urate, or PD progression. The combination of an epidemiological (disease risk) and clinical (disease progression) outcome is a novel aspect of this application, which is made possible by a close collaboration between PD epidemiologists and clinical investigators.

Public Health Relevance

We propose to examine whether blood levels of urate (uric acid) and genetic mutations that affects the formation of urate or its excretion predict the risk of developing Parkinson's disease or the progression of symptoms among patients with Parkinson's disease. Parkinson's disease is a chronic progressive disease for which there is no cure. Preliminary results suggest that blood urate could exert a protective effect. Because blood levels of urate can be modified with existing drugs, the proposed project could lead to novel approaches to the prevention and treatment of Parkinson's disease.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
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Neurological, Aging and Musculoskeletal Epidemiology (NAME)
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Sutherland, Margaret L
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Harvard University
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Hughes, Katherine C; Gao, Xiang; O'Reilly, Eilis J et al. (2018) Genetic variants related to urate and risk of Parkinson's disease. Parkinsonism Relat Disord 53:4-9
Kim, Iris Y; O'Reilly, √Čilis J; Hughes, Katherine C et al. (2017) Differences in Parkinson's Disease Risk with Caffeine Intake and Postmenopausal Hormone Use. J Parkinsons Dis 7:677-684
Hagan, Kaitlin A; Munger, Kassandra L; Ascherio, Alberto et al. (2016) Epidemiology of Major Neurodegenerative Diseases in Women: Contribution of the Nurses' Health Study. Am J Public Health 106:1650-5
Hughes, Katherine C; Gao, Xiang; Kim, Iris Y et al. (2016) Intake of antioxidant vitamins and risk of Parkinson's disease. Mov Disord 31:1909-1914
Gao, Xiang; O'Reilly, √Čilis J; Schwarzschild, Michael A et al. (2016) Prospective study of plasma urate and risk of Parkinson disease in men and women. Neurology 86:520-6
Tsai, Alexander C; Lucas, Michel; Okereke, Olivia I et al. (2014) Suicide mortality in relation to dietary intake of n-3 and n-6 polyunsaturated fatty acids and fish: equivocal findings from 3 large US cohort studies. Am J Epidemiol 179:1458-66
Wong, Janice C; Li, Yanping; Schwarzschild, Michael A et al. (2014) Restless legs syndrome: an early clinical feature of Parkinson disease in men. Sleep 37:369-72
Lucas, Michel; O'Reilly, Eilis J; Pan, An et al. (2014) Coffee, caffeine, and risk of completed suicide: results from three prospective cohorts of American adults. World J Biol Psychiatry 15:377-86
Simon, Kelly Claire; Eberly, Shirley; Gao, Xiang et al. (2014) Mendelian randomization of serum urate and parkinson disease progression. Ann Neurol 76:862-8
Lucas, Michel; O'Reilly, Eilis J; Mirzaei, Fariba et al. (2013) Cigarette smoking and completed suicide: results from 3 prospective cohorts of American adults. J Affect Disord 151:1053-8

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