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

项目摘要NINDS推荐的帕金森临床研究的最高优先事项是 定义“前驱帕金森病(PPD)的特征和自然病史，包括事件 这是临床表现为帕金森病的表型转换的基础，以及生物标记物或其他决定因素 前驱亚型，目的是提供足够的理论基础来启动概念验证预防 审判……“我们处于有利地位，可以通过利用25年的研究来解决这一优先事项 护士健康研究(NHS)和卫生专业人员跟踪研究(HPFS)中的PD，大型 这些女性和男性在中年生活中被招募，并前瞻性地跟踪了30多年。在……里面 2012年，我们对这些队列中的活跃参与者进行了可能的快速眼动睡眠行为障碍的筛查 (PRBD)和便秘，并选择了一个因这些特征而丰富的子队列进行进一步研究 (亲民党队列)。这一子队列包括20,455名个人，他们到目前为止已经完成了两项 嗅觉测试和两项关于产后抑郁的非运动性和早期运动特征的综合邮寄调查， 并一直受到积极关注，直到2018年。我们现在提议延长纵向随访 这一独特的队列及其来源人群，以监测先兆特征和进展 表型转化为临床表现的帕金森病(简称“表型转化”)，因此提供了重要的 对产后抑郁过程的洞察，填补现有知识与我们需要了解的知识之间的空白 用于实施预防试验。此外，作为拟议项目的一部分，我们将研究其影响 新冠肺炎治疗PPD及其进展并收集新的生物样本来评估皮脂 挥发组和代谢组，可能发挥重要作用的新的有前途的非侵入性生物标志物 在产后抑郁早期识别中的作用。研究的目的包括：i)获得深入的描述性 产后抑郁的特征及其异质性；ii)确定产后抑郁进展的危险因素和 表型转换；iii)评估SARS-Cov2/新冠肺炎对前驱PD特征和 表型转化；以及iv)评估皮脂挥发组和代谢组之间的关系 有前驱症状和明显的帕金森病(皮脂样本将从高 PPD、显性PD和配对对照的概率)。一种独特的、几乎不可复制的力量 这项拟议的研究是从中年起前瞻性收集的数据(男性年龄在40岁到65岁之间 招募，女性30至55岁)关于生活方式和病史，包括帕金森病的风险因素和几个 与PPD相关的功能。如果得到资助，这项拟议的研究将带来开创性的成果 发现并创建无价资源，为进一步深入研究提供大量机会 产后抑郁及其影响因素的研究。最重要的是，由 拟议的调查将是评估预防试验的可行性并为其设计提供信息的关键。

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.