Abnormal α-synuclein aggregation is a key pathological feature of a group of neurodegenerative diseases known as synucleinopathies, which include Parkinson’s disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA). The pathogenic β-sheet seed conformation of α-synuclein is found in various tissues, suggesting potential as a biomarker, but few studies have been able to reliably detect these seeds in serum samples. In this study, we developed a modified assay system, called immunoprecipitation-based real-time quaking-induced conversion (IP/RT-QuIC), which enables the detection of pathogenic α-synuclein seeds in the serum of individuals with synucleinopathies. In our internal first and second cohorts, IP/RT-QuIC showed high diagnostic performance for differentiating PD versus controls (area under the curve (AUC): 0.96 (95% confidence interval (CI) 0.95–0.99)/AUC: 0.93 (95% CI 0.84–1.00)) and MSA versus controls (AUC: 0.64 (95% CI 0.49–0.79)/AUC: 0.73 (95% CI 0.49–0.98)). IP/RT-QuIC also showed high diagnostic performance in differentiating individuals with PD (AUC: 0.86 (95% CI 0.74–0.99)) and MSA (AUC: 0.80 (95% CI 0.65–0.97)) from controls in a blinded external cohort. Notably, amplified seeds maintained disease-specific properties, allowing the differentiation of samples from individuals with PD versus MSA. In summary, here we present a novel platform that may allow the detection of individuals with synucleinopathies using serum samples.

异常的 α-突触核蛋白聚集是一组称为突触核蛋白病的神经退行性疾病的关键病理特征，其中包括帕金森病 (PD)、路易体痴呆和多系统萎缩 (MSA)。α-突触核蛋白的致病性 β-片层种子构象存在于各种组织中，表明其作为生物标志物的潜力，但很少有研究能够可靠地检测血清样本中的这些种子。在这项研究中，我们开发了一种改进的检测系统，称为基于免疫沉淀的实时震动诱导转换 (IP/RT-QuIC)，该系统能够检测突触核蛋白病个体血清中的致病性 α-突触核蛋白种子。在我们的内部第一和第二队列中，IP/RT-QuIC 在区分 PD 与对照方面表现出较高的诊断性能（曲线下面积 (AUC)：0.96（95% 置信区间 (CI) 0.95–0.99）/AUC：0.93 (95 % CI 0.84–1.00)) 和 MSA 与对照相比 (AUC: 0.64 (95% CI 0.49–0.79)/AUC: 0.73 (95% CI 0.49–0.98))。IP/RT-QuIC 在区分 PD（AUC：0.86（95% CI 0.74–0.99））和 MSA（AUC：0.80（95% CI 0.65–0.97））个体与盲法外部队列中的对照个体方面也表现出较高的诊断性能。值得注意的是，扩增的种子保持了疾病特异性，从而可以区分 PD 个体和 MSA 个体的样本。总之，我们在这里提出了一个新的平台，可以使用血清样本检测患有突触核蛋白病的个体。