Can diagnostic biomarkers for parkinsonian syndromes be measured in postmortem blood samples?

总结 许多帕金森病（PD）病例，甚至更多的非典型帕金森病，被误诊。 误诊不仅会给患者、家属和护理人员带来高度的压力和焦虑，而且也是一个重大的 阻碍了对这些疾病的有效治疗。最近，我们证明了α- 使用免疫沉淀法从血清或血浆中免疫沉淀的细胞外囊泡（EV）中的突触核蛋白浓度 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EV，为区分帕金森病和多发性硬化症提供了敏感的生物标志物。 系统萎缩（MSA）。这种液体活检方法只需要微创抽血， 在开发这些疾病的诊断测试方面取得了重大进展。然而，群体的定义 是基于临床诊断，这是容易出错的，造成一个鸡和蛋的问题。为了解决这个 问题，在这里，我们提出了一个试点研究测试生物标志物的血清样本收集死后， 病理证实诊断。由于特定的原因，这种策略对总α-突触核蛋白不起作用， 假设不适用于当前提案中的生物标志物。我们还将测试 每种新的生物标志物作为诊断生物标志物组的一部分，用于区分PD、MSA和两种额外的生物标志物。 进行性核上性麻痹和皮质基底神经综合征 和对照样品。初步研究的主要目标是确定是否经过病理学验证 尸检样本可用于CNS源性EV中的生物标志物测量，以用于帕金森病 综合征第二个目标是测试每种生物标志物对诊断组的贡献。该研究 可能导致未来开发微创生物标志物， 帕金森病的诊断。

Summary Many cases of Parkinson’s disease (PD), and even more so atypical parkinsonian disorders, are misdiagnosed. Misdiagnosis not only causes high stress and anxiety to patients, families, and caregivers, but also is a major impediment to developing 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, provided a sensitive biomarker for distinguishing between Parkinson’s disease and multiple system atrophy (MSA). 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. However, the definition of the groups was based on clinical diagnosis, which is error-prone, creating a chicken-and-egg problem. To address this issue, here we propose a pilot study testing biomarkers in serum samples collected postmortem for which the diagnosis was validated pathologically. This strategy could not work for total α-synuclein for specific reasons that are hypothesized not to be applicable to the biomarkers in the current proposal. We will also test the utility of each of the new biomarkers as part of diagnostic biomarker panel for distinguishing PD, MSA, and two additional atypical parkinsonian syndromes—progressive supranuclear palsy and corticobasal syndrome—from each other and from control samples. The main goal of the pilot study is to determine whether pathologically validated postmortem samples can be used for biomarker measurement in CNS-originating EVs for parkinsonian syndromes. A secondary goal is to test the contribution of each biomarker to the diagnostic panel. The study has the potential to lead to future development of minimally invasive biomarkers allowing early and accurate diagnosis of parkinsonian disorders.