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

项目摘要/摘要 帕金森病(PD)、路易体痴呆(DLB)和多系统萎缩(MSA)包括 一组神经退行性疾病，具有共同的异常聚集的病理生理机制 α-突触核蛋白(αsyn)。在已确定的联核症中进行疾病修饰的有希望的尝试已经 失败，提出了一个重要的问题，即临床上有明确疾病的患者太晚期了 改变疾病的疗法才能有效。因此，战略已经演变为能够更早地 疾病检测和确认是在我们当前的赠款期间进行的，重点是纯 自主神经衰竭(PAF)。最近，PAF被确定为联核病之一，并被 以孤立的自主神经衰竭为特征，没有运动或认知障碍，代表运动前阶段 具有较高的转换为MSA、PD或DLB的风险。目前赠款期间的主要目标是确定和 验证脊髓液(CSF)和MRI生物标记物将PAF转化为运动性突触核病。我们有 通过确定基于机制的高度预测的脑脊液和磁共振标志物来实现这一目标 共核病，当应用于运动前阶段时，可以预测转换和转换表型。 快速眼动睡眠行为障碍(RBD)是一种与突触核病密切相关的疾病，经常 表现为孤立性RBD(IRBD)，在运动或认知症状出现前数年出现。关联性和 IRBD作为先兆综合征的意义已经被充分认识，但到目前为止还没有可靠的证据 转换的预测因子，转换的表型，或转换为已建立的并核病的时间。 我们已经扩展了用于预测PAF表型转化为iRBD患者的生物标记物，并确定了 离散的脑脊液图谱类似于PAF以及明显的运动和认知突触核病，因此 我们现在能够在前驱阶段测试这些标记物的生物标记物潜力。 在这次更新中，我们将研究睡眠研究证实的iRBD患者，按基线脑脊液生物标记物进行分层 表型(MSA-、PD/DLB型或正常型)和健康对照受试者进行一系列临床评估 结合自主神经、脑脊液和核磁共振生物标记物研究。我们将增强达成协议的可行性 通过丰富北方参与者的招聘来实现每种生物标志物表型的招聘目标 美国前驱综合征联盟被确认为需要达到我们的 招聘目标。其次，我们将继续关注在当前资助期内登记的PAF患者 那些尚未表型转换以巩固已开发生物标志物的预测价值的人。 这项更新提案的发现应该导致建立运动前和运动前的生物标志物 合体核病的前驱阶段，这可能转化为长期有效的疾病修改治疗试验 更好的机会证明有效性，甚至最终可能允许诊断选定的 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.