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

描述(由首席研究人员提供)：尿酸盐是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，可能对帕金森病(PD)的发展提供天然防御。在以前的研究中，发现血尿酸盐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测量评估，最近诊断为帕金森病的患者的血尿酸水平较高，预测疾病进展的有利(较慢)速度。这些研究表明，尿酸盐可能是导致帕金森病及其进展的神经退行性变的强有力的预测因子，而且由于尿酸盐及其代谢途径特别容易受到药物和饮食操作的影响，具有潜在的治疗意义。然而，这种联系是否反映了尿酸盐或其代谢前体的神经保护作用，或者是否由一个仍未确定的共同因素/混杂因素解释，仍有待确定。此外，尽管在男性中血尿酸与帕金森病风险和进展之间存在强烈的负相关，但在女性中的结果是不确定的，因为以前的研究中很少包括女性。拟议调查的主要目的是系统和深入地分析血尿酸盐及其决定因素，包括尿酸途径中的遗传变异，如何影响男性和女性的PD UriskU和UProgressionU。调查将包括两个主要部分。一项是嵌套式病例对照研究，包括1,492例帕金森病发病病例(685名女性)和3,316名配对对照，以检查：1)血尿酸盐水平是否独立于帕金森病的已知或疑似危险因素以及尿酸血症的遗传和非遗传决定因素预测帕金森病的风险，以及2)参与尿酸盐代谢的基因突变是否与血尿酸盐水平和帕金森病风险相关。第二项是对两个先前在早期帕金森病患者中进行的大型随机试验的参与者进行的队列分析。我们将检查：1)先前报道的血清尿酸与帕金森病进展之间的强烈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尿酸盐或脑脊液水平，或帕金森病的进展。流行病学(疾病风险)和临床(疾病进展)结果的结合是这一应用的一个新方面，这是由于帕金森病流行病学家和临床研究人员之间的密切合作。公共卫生相关性我们建议研究血液尿酸(尿酸)水平和影响尿酸形成或尿酸排泄的基因突变是否可以预测帕金森氏症患者患帕金森氏症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，血尿酸盐具有保护作用。由于现有药物可以改变血尿酸盐水平，因此这项拟议的项目可能会带来预防和治疗帕金森氏症的新方法。

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.