脑脊液中α-突触核蛋白原纤维：帕金森病的潜在生物标志物。

Alpha-Synuclein Protofibrils in Cerebrospinal Fluid: A Potential Biomarker for Parkinson's Disease.

机构信息

Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.

BioArctic AB, Stockholm, Sweden.

出版信息

J Parkinsons Dis. 2020;10(4):1429-1442. doi: 10.3233/JPD-202141.

DOI:10.3233/JPD-202141

PMID:33016895

Abstract

BACKGROUND

Currently, there is no established biomarker for Parkinson's disease (PD) and easily accessible biomarkers are crucial for developing disease-modifying treatments.

OBJECTIVE

To develop a novel method to quantify cerebrospinal fluid (CSF) levels of α-synuclein protofibrils (α-syn PF) and apply it to clinical cohorts of patients with PD and atypical parkinsonian disorders.

METHODS

A cohort composed of 49 patients with PD, 12 with corticobasal degeneration (CBD), 22 with progressive supranuclear palsy, and 33 controls, that visited the memory clinic but had no biomarker signs of Alzheimer's disease (AD, tau<350 pg/mL, amyloid-beta 42 (Aβ42)>530 pg/mL, and phosphorylated tau (p-tau)<60 pg/mL) was used in this study. The CSF samples were analyzed with the Single molecule array (Simoa) technology. Total α-synuclein (α-syn) levels were analyzed with a commercial ELISA-kit.

RESULTS

The assay is specific to α-syn PF, with no cross-reactivity to monomeric α-syn, or the β- and γ-synuclein variants. CSF α-syn PF levels were increased in PD compared with controls (62.1 and 40.4 pg/mL, respectively, p = 0.03), and CBD (62.1 and 34.2 pg/mL, respectively, p = 0.02). The accuracy of predicting PD using α-syn PF is significantly different from controls (area under the curve 0.68, p = 0.0097) with a sensitivity of 62.8% and specificity of 67.7%. Levels of total α-syn were significantly different between the PD and CBD groups (p = 0.04).

CONCLUSION

The developed method specifically quantifies α-syn PF in human CSF with increased concentrations in PD, but with an overlap with asymptomatic elderly controls.

摘要

背景

目前，尚无帕金森病（PD）的确立生物标志物，而易于获得的生物标志物对于开发疾病修饰疗法至关重要。

目的

开发一种新方法来定量检测脑脊液（CSF）中α-突触核蛋白原纤维（α-syn PF）的水平，并将其应用于 PD 及非典型帕金森病患者的临床队列中。

方法

本研究纳入了一个由 49 名 PD 患者、12 名皮质基底节变性（CBD）患者、22 名进行性核上性麻痹患者和 33 名对照者组成的队列，这些患者曾就诊于记忆诊所，但无阿尔茨海默病（AD）的生物标志物迹象（tau<350pg/mL，淀粉样蛋白-β 42（Aβ42）>530pg/mL，磷酸化 tau（p-tau）<60pg/mL）。使用单分子阵列（Simoa）技术分析 CSF 样本。使用商业 ELISA 试剂盒分析总α-突触核蛋白（α-syn）水平。

结果

该检测方法特异性识别α-syn PF，与单体 α-syn 或β-和γ-突触核蛋白变体无交叉反应。与对照组（分别为 62.1 和 40.4pg/mL，p=0.03）和 CBD 组（分别为 62.1 和 34.2pg/mL，p=0.02）相比，PD 患者的 CSF α-syn PF 水平升高。使用α-syn PF 预测 PD 的准确性与对照组明显不同（曲线下面积 0.68，p=0.0097），其灵敏度为 62.8%，特异性为 67.7%。PD 和 CBD 组之间总α-syn 水平存在显著差异（p=0.04）。