α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson’s disease from multiple system atrophy,Acta Neuropathologica

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α-Synuclein in blood exosomes immunoprecipitated using neuronal and oligodendroglial markers distinguishes Parkinson’s disease from multiple system atrophy
Acta Neuropathologica ( IF 9.3 ) Pub Date : 2021-05-15 , DOI: 10.1007/s00401-021-02324-0
Suman Dutta ₁ , Simon Hornung _{1,

2} , Adira Kruayatidee ₁ , Katherine N Maina ₁ , Irish Del Rosario ₃ , Kimberly C Paul ₃ , Darice Y Wong ₁ , Aline Duarte Folle ₃ , Daniela Markovic ₄ , Jose-Alberto Palma ₅ , Geidy E Serrano ₆ , Charles H Adler ₇ , Susan L Perlman ₁ , Wayne W Poon ₈ , Un Jung Kang ₅ , Roy N Alcalay ₉ , Miriam Sklerov ₁₀ , Karen H Gylys _{11,

12} , Horacio Kaufmann ₅ , Brent L Fogel _{1,

12,

13} , Jeff M Bronstein _{1,

12} , Beate Ritz _{3,

12} , Gal Bitan _{1,

12,

14}

Affiliation

Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
Division of Peptide Biochemistry, Technical University of Munich, 85354, Freising, Germany.
Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, CA, 90095, USA.
Department of Medicine, Division of General Internal Medicine and Health Services Research, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
Department of Neurology, Dysautonomia Center, The Marlene and Paolo Fresco Institute for Parkinson's and Movement Disorders, New York University School of Medicine, New York, NY, 10016, USA.
Banner Sun Health Research Institute, Sun City, AZ, 85351, USA.
Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale, AZ, 85259, USA.
Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, 92697, USA.
Department of Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, 10032, USA.
Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
School of Nursing, University of California, Los Angeles, CA, 90095, USA.
Brain Research Institute, University of California, Los Angeles, CA, 90095, USA.
Clinical Neurogenomics Research Center, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.
Molecular Biology Institute, University of California, Los Angeles, CA, 90095, USA.

The diagnosis of Parkinson’s disease (PD) and atypical parkinsonian syndromes is difficult due to the lack of reliable, easily accessible biomarkers. Multiple system atrophy (MSA) is a synucleinopathy whose symptoms often overlap with PD. Exosomes isolated from blood by immunoprecipitation using CNS markers provide a window into the brain’s biochemistry and may assist in distinguishing between PD and MSA. Thus, we asked whether α-synuclein (α-syn) in such exosomes could distinguish among healthy individuals, patients with PD, and patients with MSA. We isolated exosomes from the serum or plasma of these three groups by immunoprecipitation using neuronal and oligodendroglial markers in two independent cohorts and measured α-syn in these exosomes using an electrochemiluminescence ELISA. In both cohorts, α-syn concentrations were significantly lower in the control group and significantly higher in the MSA group compared to the PD group. The ratio between α-syn concentrations in putative oligodendroglial exosomes compared to putative neuronal exosomes was a particularly sensitive biomarker for distinguishing between PD and MSA. Combining this ratio with the α-syn concentration itself and the total exosome concentration, a multinomial logistic model trained on the discovery cohort separated PD from MSA with an AUC = 0.902, corresponding to 89.8% sensitivity and 86.0% specificity when applied to the independent validation cohort. The data demonstrate that a minimally invasive blood test measuring α-syn in blood exosomes immunoprecipitated using CNS markers can distinguish between patients with PD and patients with MSA with high sensitivity and specificity. Future optimization and validation of the data by other groups would allow this strategy to become a viable diagnostic test for synucleinopathies.

中文翻译：

使用神经元和少突胶质细胞标记物免疫沉淀血液外泌体中的 α-突触核蛋白，以区分帕金森病和多系统萎缩

由于缺乏可靠、易于获取的生物标志物，帕金森病 (PD) 和非典型帕金森综合征的诊断很困难。多系统萎缩症 (MSA) 是一种突触核蛋白病，其症状通常与 PD 重叠。使用 CNS 标记物通过免疫沉淀从血液中分离出的外泌体提供了了解大脑生物化学的窗口，并可能有助于区分 PD 和 MSA。因此，我们询问此类外泌体中的 α-突触核蛋白 (α-syn) 是否可以区分健康个体、PD 患者和 MSA 患者。我们在两个独立队列中使用神经元和少突胶质细胞标记物通过免疫沉淀从这三组的血清或血浆中分离出外泌体，并使用电化学发光 ELISA 测量这些外泌体中的 α-syn。在这两个队列中，与 PD 组相比，对照组的 α-syn 浓度显着较低，MSA 组的 α-syn 浓度显着较高。假定的少突胶质细胞外泌体中的 α-syn 浓度与假定的神经元外泌体中的 α-syn 浓度之比是区分 PD 和 MSA 的特别敏感的生物标志物。将该比率与 α-syn 浓度本身和总外泌体浓度相结合，在发现队列上训练的多项逻辑模型将 PD 与 MSA 分开，AUC = 0.902，应用于独立验证时对应于 89.8% 的敏感性和 86.0% 的特异性队列。数据表明，使用 CNS 标记物免疫沉淀的血液外泌体中的 α-syn 微创血液检测可以以高灵敏度和特异性区分 PD 患者和 MSA 患者。其他小组对数据的未来优化和验证将使该策略成为突触核蛋白病的可行诊断测试。

更新日期：2021-05-15

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