Biomarkers and risk factors for prodromal Parkinson's disease and its progression

NINDS推荐的临床帕金森病研究的最高优先级是 定义“前驱帕金森病（PPD）的特征和自然史，包括事件 其是表型转化为临床表现PD的基础，以及生物标志物或其他决定因素， 前驱亚型，目的是为启动概念验证预防提供充分的依据 审判...”我们处于一个特殊的位置，通过利用25年的研究来解决这一优先事项， 护士健康研究（NHS）和卫生专业人员随访研究（HPFS）中的PD，大型 在中年时期招募了一批女性和男性，并前瞻性地跟踪了30多年。在 2012年，我们筛选了这些队列中可能存在REM睡眠行为障碍的活跃参与者， （pRBD）和便秘，并选择了一个富含这些特征的子队列进行进一步研究 (the ProPD队列）。该子队列包括20，455名迄今已完成两项 嗅觉测试和PPD的非运动和早期运动特征的两个全面的邮寄调查， 并一直积极跟进到2018年。我们现在建议延长纵向跟踪 这一独特的队列及其来源人群，以监测前驱症状的进展， 表型转化为临床表现的PD（简称“表型转化”），从而提供重要的 对PPD过程的见解，并填补现有知识与我们需要知道的知识之间的差距 进行预防试验。此外，作为拟议工程计划的一部分，我们会研究 新冠病毒对PPD及其进展的影响，并收集新的生物样本以评估皮脂 挥发组和代谢组，新的有前途的和非侵入性的生物标志物，可以发挥重要的 在PPD早期识别中的作用。该研究的目的包括：i）获得深入的描述 PPD及其异质性的表征; ii）鉴定PPD进展的风险因素， 表型转化; iii）评估SARS-Cov 2/covid-19对前驱PD特征的影响， 表型转化;和iv）评价皮脂挥发组和代谢组之间的关系 具有前驱期特征和明显PD的患者（皮脂样品将从具有高PD的个体收集）。 PPD、显性PD和匹配对照的概率）。一个独特的和几乎不可复制的力量 这项拟议的研究的数据是前瞻性地收集自中年以来的数据（男性年龄为40至65岁， 招募，女性30至55岁）的生活方式和病史，包括PD的风险因素和几个 与PPD相关的特征。如果得到资助，这项拟议中的研究将导致开创性的 发现和创造一个宝贵的资源，将提供许多机会，进一步深入 PPD及其决定因素的调查。最重要的是， 拟议的调查对于评估预防试验的可行性和为其设计提供信息至关重要。

PROJECT SUMMARY The highest priority recommended by NINDS for clinical Parkinson’s research is to define “the features and natural history of prodromal Parkinson disease (PPD), including the events that underlie phenoconversion to clinically manifest PD, and biomarkers or other determinants of prodromal subtypes with the goal of providing sufficient rationale to initiate proof-of-concept prevention trials....” We are in a privileged position to address this priority by leveraging 25 years of research on PD in the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), large cohorts of women and men recruited in mid-adult life and followed prospectively for over 30 years. In 2012, we screened the active participants in these cohorts for probable REM sleep behavior disorder (pRBD) and constipation, and selected a sub-cohort enriched for these features for further investigation (the ProPD cohort). This sub-cohort included 20,455 individuals who have so far completed two olfactory tests and two comprehensive mailed surveys of non-motor and early motor features of PPD, and have been actively followed until 2018. We are now proposing to extend the longitudinal follow-up of this unique cohort and its source population to monitor the progression of prodromal features and phenoconversion to clinically manifest PD (“phenoconversion”, for brevity), thus providing important insights on the course of PPD and fill the gap between current knowledge and what we need to know for implementing prevention trials. Further, as part of the proposed project, we will examine the impact of covid-19 on PPD and its progression and collect new biological samples to evaluate the sebum volatilome and metabolome, novel promising and non-invasive biomarkers that could play an important role in the early identification of PPD. The Aims of the study include: i) to obtain an in-depth descriptive characterization of PPD and its heterogeneity; ii) to identify risk factors for PPD progression and phenoconversion; iii) to assess the impact of SARS-Cov2/covid-19 on features of prodromal PD and phenoconversion; and iv) to evaluate the relationship between the sebum volatilome and metabolome with prodromal features and manifest PD (sebum samples will be collected from individuals with high probability of PPD, manifest PD, and matched controls). A unique and virtually irreproducible strength of the proposed study are the data prospectively collected since mid-adult life (men were 40 to 65 at recruitment, women 30 to 55) on lifestyle and medical history, including risk factors for PD and several features associated with PPD. If funded, the proposed study stands to lead to groundbreaking discoveries and create an invaluable resource that will offer numerous opportunities for further in-depth investigations on PPD and its determinants. Most importantly, the information generated by the proposed investigation will be pivotal to assess the feasibility of prevention trials and inform their design.