Development of a Sensitive Diagnostic Assay for Parkinson Disease Quantifying α-Synuclein–Containing Extracellular Vesicles
Authors: Chen Tian
Catherine Pan
Kayla Borden
Zhen Hong
Tarek Khrisat
Elaine R Peskind
Matt Bercow
Jan Aasly
Tessandra Stewart
Lifu Sheng
David Soltys
Cyrus P Zabetian
Thomas J Montine
Jing Zhang
Patrick Aro
Min Shi
Joseph F Quinn
Journal: Neurology (2021)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: α-synuclein; extracellular vesicles; CSF; Parkinson disease; nanoscale flow cytometry
Affiliations: From the Departments of Pathology (Z.H., T.S., P.A., D.S., M.B., L.S., K.B., T.K., C.P., M.S., J.Z.), Neurology (C.P.Z.), and Psychiatry and Behavioral Sciences (E.R.P.), University of Washington School of Medicine, Seattle; Department of Neurology (Z.H.), West China Medical School, Sichuan University, Chengdu; Department of Pathology (C.T., J.Z.), Central Laboratory (J.Z.), The First Affiliated Hospital and School of Medicine, and National Health and Disease Human Brain Tissue Resource Center (J.Z.), Zhejiang University, Hangzhou; Geriatric Research, Education, and Clinical Center (C.P.Z.) and Mental Illness Research, Education, and Clinical Centre (E.R.P.), Veterans Affairs Puget Sound Health Care System, Seattle, WA; Parkinson's Disease Research, Education, and Clinical Care Center (J.F.Q.), Portland VA Medical Center; Department of Neurology (J.F.Q.), Oregon Health and Science University, Portland; Department of Pathology (T.J.M.), Stanford University School of Medicine, Palo Alto, CA; and Department of Neurology (J.A.), St. Olav's Hospital, Trondheim, Norway., From the Departments of Pathology (Z.H., T.S., P.A., D.S., M.B., L.S., K.B., T.K., C.P., M.S., J.Z.), Neurology (C.P.Z.), and Psychiatry and Behavioral Sciences (E.R.P.), University of Washington School of Medicine, Seattle; Department of Neurology (Z.H.), West China Medical School, Sichuan University, Chengdu; Department of Pathology (C.T., J.Z.), Central Laboratory (J.Z.), The First Affiliated Hospital and School of Medicine, and National Health and Disease Human Brain Tissue Resource Center (J.Z.), Zhejiang University, Hangzhou; Geriatric Research, Education, and Clinical Center (C.P.Z.) and Mental Illness Research, Education, and Clinical Centre (E.R.P.), Veterans Affairs Puget Sound Health Care System, Seattle, WA; Parkinson's Disease Research, Education, and Clinical Care Center (J.F.Q.), Portland VA Medical Center; Department of Neurology (J.F.Q.), Oregon Health and Science University, Portland; Department of Pathology (T.J.M.), Stanford University School of Medicine, Palo Alto, CA; and Department of Neurology (J.A.), St. Olav's Hospital, Trondheim, Norway.  .

Abstract:  Objective: To develop a reliable and fast assay to quantify the α-synuclein (α-syn)-containing extracellular vesicles (EVs) in CSF and to assess their diagnostic potential for Parkinson disease (PD). Methods: A cross-sectional, multicenter study was designed, including 170 patients with PD and 131 healthy controls (HCs) with a similar distribution of age and sex recruited from existing center studies at the University of Washington and Oregon Health and Science University. CSF EVs carrying α-syn or aggregated α-syn were quantified using antibodies against total or aggregated α-syn, respectively, and highly specific, sensitive, and rapid assays based on the novel Apogee nanoscale flow cytometry technology. Results: No significant differences in the number and size distribution of total EVs between patients with PD and HCs in CSF were observed. When examining the total α-syn-positive and aggregated α-syn-positive EV subpopulations, the proportions of both among all detected CSF EVs were significantly lower in patients with PD compared to HCs (p &lt; 0.0001). While each EV subpopulation showed better diagnostic sensitivity and specificity than total CSF α-syn measured directly with an immunoassay, a combination of the 2 EV subpopulations demonstrated a diagnostic accuracy that attained clinical relevance (area under curve 0.819, sensitivity 80%, specificity 71%). Conclusion: Using newly established, sensitive nanoscale flow cytometry assays, we have demonstrated that total α-syn-positive and aggregated α-syn-positive EVs in CSF may serve as a helpful tool in PD diagnosis. Classification of evidence: This study provides Class III evidence that total and aggregated α-syn-positive EVs in CSF identify patients with PD. 

Retracted: No

PubPeer comments:
 The disease under investigation in this paper is universally referred to in the English language as  Parkinson s disease , not  Parkinson disease , as rendered even in the title and abstract. This is not nitpicking. Numerous co-authors of this paper are based in the United States, and at least one is a member of a  Parkinson s disease center. Did the co-authors have access to the manuscript, and what were their actual contributions? Who reviewed the manuscript without noticing that the name of the disease was off, and what does this mean for the level of review by a journal called  Neurology ? ,