Synucleinopathies – Novel Targets in Early Diagnosis, Pathophysiology, and Therapeutic Approach

项目概要/摘要 帕金森氏病（PD）、路易体痴呆（DLB）和多系统萎缩（MSA）包括帕金森氏病（PD）、路易体痴呆（DLB）和多系统萎缩。 一组神经退行性疾病，共享异常聚集的病理生理机制， α-突触核蛋白（αSyn）。在已建立的突触核蛋白病中进行疾病修饰的有希望的尝试， 失败了，提出了一个重要的问题，即临床上明显的，确定的疾病患者过于先进 使疾病缓解疗法有效。因此，战略已经发展到允许更早地 疾病检测和确认，这是在我们目前的赠款期间追求的重点是纯 自主神经功能衰竭（PAF）。PAF最近被确定为突触核蛋白病之一， 以孤立性自主神经功能衰竭为特征，无运动或认知缺陷，代表运动前阶段 有高风险转化为MSA、PD或DLB。本赠款期的主要目标是确定和 验证PAF转化为运动性突触核蛋白病的脊髓液（CSF）和MRI生物标志物。我们有 通过在已建立的CSF和MRI标记物中识别高度预测机制， 突触核蛋白病，当应用于运动前阶段时，可以预测转换和转换表型。 REM睡眠行为障碍（RBD）是一种与突触核蛋白病密切相关的疾病， 在运动或认知症状出现前数年表现为孤立性RBD（iRBD）。的相关性和 iRBD作为前驱期突触核蛋白病的意义已经得到了很好的认识，但迄今为止还没有可靠的证据。 转化的预测因子、转化的表型或转化为已确立的突触核蛋白病的时间。 我们已经扩展了用于预测iRBD患者PAF表型转化的生物标志物，并确定了 离散CSF特征类似于PAF和明显运动和认知突触核蛋白病中观察到的特征，因此， 我们现在能够测试这些标志物在前驱期的生物标志物潜力。 在本次更新中，我们将研究按基线CSF生物标志物分层的睡眠研究证实的iRBD患者 表型（MSA-、PD/DLB或正常型）与健康对照受试者一起进行沿着，并进行系列临床评价 结合自主神经、CSF和MRI生物标志物研究。我们将提高达成的可行性 通过丰富北方参与者的招募，为每种生物标志物表型制定招募目标 美国前驱体突触核蛋白病协会确定为达到我们的 招聘目标。第二，我们会继续跟进在资助期内入组的阵发性房颤病人 尚未发生表型转化的人来巩固已开发的生物标志物的预测价值。 这项更新提案的结果应该会导致建立运动前和运动后的生物标志物， 突触核蛋白病的前驱期，这可能转化为疾病修饰治疗试验， 更好的机会，证明疗效，这可能最终甚至允许诊断选定的 临床前阶段的神经退行性疾病。

PROJECT SUMMARY/ABSTRACT Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) comprise a group of neurodegenerative diseases that share the pathophysiological mechanism of abnormal aggregation of alpha-synuclein (αSyn). Promising attempts at disease modification in established synucleinopathies have failed, raising the important issue that patients who have clinically overt, established disease are too advanced for disease-modifying therapies to be efficacious. Therefore, strategies have evolved to allow for earlier disease detection and confirmation which was pursued in our current grant period with focus on pure autonomic failure (PAF). PAF has more recently been established as one of the synucleinopathies, and is characterized by isolated autonomic failure without motor or cognitive deficits, representing a pre-motor stage with high risk of conversion to MSA, PD, or DLB. The main goal of the current grant period was to identify and validate spinal fluid (CSF) and MRI biomarkers of conversion of PAF to motor synucleinopathies. We have accomplished that goal by identifying highly predictive mechanism-based CSF and MRI markers in established synucleinopathies, that when applied to the pre-motor stage can predict conversion and conversion phenotype. REM sleep behavior disorder (RBD) is a condition with close association with synucleinopathies and frequently presents as isolated RBD (iRBD) years before motor or cognitive symptoms develop. The relevance and implications of iRBD as prodromal synucleinopathy has been well recognized, but to date there are no reliable predictors of conversion, phenotype of conversion, or timing of conversion to an established synucleinopathy. We have expanded the biomarkers developed to predict PAF phenoconversion to iRBD patients and identified discrete CSF profiles akin to those seen in PAF and in manifest motor and cognitive synucleinopathies, so that we are now in a position to test the biomarker potential of these markers at the prodromal stage. In this renewal, we shall study sleep-study confirmed iRBD patients stratified by baseline CSF biomarker phenotype (MSA-, PD/DLB, or normal type) along with healthy control subjects with serial clinical evaluations combined with autonomic, CSF, and MRI biomarker studies. We will enhance the feasibility of reaching recruitment goals for each biomarker phenotype by enriching recruitment with participants in the North American Prodromal Synucleinopathy Consortium identified as biomarker phenotype required to reach our recruitment goals. Secondly, we will continue to follow PAF patients enrolled during the current grant period who have not yet phenoconverted to solidify the predictive value of developed biomarkers. The findings from this renewal proposal should result in establishing biomarkers for the pre-motor and prodromal stages of syncucleinopathies, which may translate to disease-modifying therapy trials standing a better chance at demonstrating efficacy, and which may eventually even allow for diagnosing selected neurodegenerative diseases at the preclinical stage.