Development of a Sensitive Diagnostic Assay for Parkinson Disease Quantifying α-Synuclein-Containing Extracellular Vesicles

Zhen Hong, Chen Tian, Tessandra Stewart, Patrick Aro, David Soltys, Matt Bercow, Lifu Sheng, Kayla Borden, Tarek Khrisat, Catherine Pan, Cyrus P. Zabetian, Elaine R. Peskind, Joseph F. Quinn, Thomas J. Montine, Jan Aasly, Min Shi, Jing Zhang

Research output: Contribution to journalArticlepeer-review

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 < 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.

Original languageEnglish (US)
Pages (from-to)e2332-e2345
JournalNeurology
Volume96
Issue number18
DOIs
StatePublished - May 4 2021

ASJC Scopus subject areas

  • Clinical Neurology

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