Urate as a Predictor of Parkinson's Disease Risk and Progression

描述（由首席研究员提供）：尿酸盐，嘌呤代谢的最终产物，在生理浓度下是一种有效的抗氧化剂，可能为帕金森病（PD）的发展提供天然防御。在之前的研究中，血液中尿酸水平较高的健康人患帕金森病的风险较低。此外，我们发现，通过临床和神经影像学评估，最近诊断为PD的患者血尿酸水平较高预示着有利的（较慢的）疾病进展率。这些研究表明，尿酸盐可以作为导致帕金森病及其进展的神经退行性变的可靠预测因子，而且，由于尿酸盐及其代谢途径特别容易受到药理学和饮食操纵的影响，因此具有潜在的治疗意义。然而，这种关联是否反映了尿酸盐或其代谢前体的神经保护作用，或者是否由尚未确定的共同因素/混杂因素解释，仍有待确定。此外，尽管在男性中血尿酸与PD风险和进展之间存在强烈的负相关，但在女性中的结果尚不确定，因为之前的研究中很少包括女性。该研究的主要目的是对血液尿酸及其决定因素（包括尿酸途径的遗传变异）如何影响男性和女性PD UriskU和UprogressionU进行系统和深入的分析。调查将包括两个主要部分。一项是一项套式病例对照研究，包括1492例PD病例（685名女性）和3316名匹配的对照，以检验：1)血尿酸水平是否独立于已知或疑似PD危险因素，以及尿酸血症的遗传和非遗传决定因素，预测PD的风险；2)参与尿酸代谢的基因突变是否与血尿酸水平和PD风险相关。第二项是对先前进行的两项早期PD患者大型随机试验的参与者进行的队列分析。我们将研究：1)先前报道的血清尿酸与PD进展之间的强负相关是否独立于影响尿酸代谢的基因突变，以及2)这些基因突变是否预测血液或脑脊液中尿酸水平或PD进展。流行病学（疾病风险）和临床（疾病进展）结果的结合是该应用的一个新方面，这是由PD流行病学家和临床研究者之间的密切合作实现的。我们建议研究血液中尿酸（尿酸）水平和影响尿酸形成或其排泄的基因突变是否能预测帕金森病患者患帕金森病的风险或症状的进展。帕金森氏症是一种慢性进行性疾病，目前尚无治愈方法。初步结果表明血尿酸可以起到保护作用。因为血液中的尿酸水平可以用现有的药物来改变，这个拟议的项目可能会带来预防和治疗帕金森病的新方法。

DESCRIPTION (provided by principal investigator): 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.