Biomarkers for parkinsonian disorders in CNS-originating extracellular vesicles

摘要 许多帕金森氏症病例，尤其是非典型帕金森病，都被误诊了。 误诊不仅会给患者、他们的家人和照顾者带来很大的压力和焦虑，而且 这是开发有效治疗这些疾病的主要障碍。最近，我们展示了 从血清或血浆中免疫沉淀的细胞外小泡(EVS)中的α-突触核蛋白浓度 少突胶质细胞和神经元标记物，特别是α-突触核蛋白浓度之间的比率 两种类型的EVS，是区分帕金森病和多系统的敏感生物标志物 萎缩。这种液体活组织检查方法只需要微创抽血，可能导致较大的 在开发这些疾病的诊断测试方面的进展。在这里，我们建议在最近的这些基础上 通过构建生物标记物小组，包括几个额外的候选标记，并应用该小组的发现 到另外两种非典型帕金森综合征--进行性核上性麻痹和皮质-基底综合征。 这项研究的血清样本将从几个国家生物库获得，并在当地收集， 前瞻性地，在专家诊所。研究设计强调在前两年进行生物标记物分析 诊断，以及在前驱综合征中，在最需要的时候测试生物标记物小组的效用。 该项目的另一个目标是开发确认电动汽车细胞来源的方法，这是一个紧迫的任务 田野上未得到满足的需求。该项目的成功将促进对生物标记物的研究 使用微创液体活组织检查的中枢神经系统疾病，在不久的将来可以转化为临床使用。

Summary Many cases of Parkinson’s disease, and even more so atypical parkinsonian disorders, are misdiagnosed. Misdiagnosis not only causes high stress and anxiety to patients, their families, and their caregivers, but also is a major impediment to development of effective therapy for these diseases. Recently, we have demonstrated that the α-synuclein concentration in extracellular vesicles (EVs) immunoprecipitated from serum or plasma using oligodendroglial and neuronal markers, and in particular the ratio between the α-synuclein concentrations in the two types of EVs, is a sensitive biomarker for distinguishing between Parkinson’s disease and multiple system atrophy. This liquid biopsy approach requires only a minimally invasive blood draw and could lead to a major advancement in developing diagnostic tests for these diseases. Here, we propose to build upon these recent findings by constructing a biomarker panel, including several additional candidate markers, and apply the panel to two additional atypical parkinsonian syndromes—progressive supranuclear palsy and corticobasal syndrome. Serum samples for the study will be obtained from several national biorepositories as well as collected locally, prospectively, in expert clinics. The study design emphasizes biomarker analysis within the first two years of diagnosis, and in prodromal synucleinopathy, to test the utility of the biomarker panel when it is most needed. An additional goal of the project is to develop methodology for validating the cellular origin of the EVs, an urgent unmet need in the field. Success of the project will lead both to an advancement of research on biomarkers for CNS diseases using a minimally invasive liquid biopsy that can be translated into clinical use in the near future.