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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.
Glossary
- α-syn=
- α-synuclein;
- AUC=
- area under the curve;
- CI=
- confidence interval;
- CV=
- coefficient of variation;
- DLB=
- dementia with Lewy bodies;
- EV=
- extracellular vesicle;
- H&Y=
- Hoehn & Yahr;
- HC=
- healthy control;
- IgG=
- immunoglobulin G;
- LEDD=
- levodopa equivalent daily dose;
- MD=
- difference in means;
- MoCA=
- Montreal Cognitive Assessment;
- NTA=
- Nanoparticle Tracking Analysis;
- PBS=
- phosphate-buffered saline;
- PD=
- Parkinson disease;
- PFA=
- paraformaldehyde;
- PMCA=
- protein-misfolding cyclic amplification;
- ROC=
- receiver operating characteristic;
- RT-QuIC=
- real-time quaking-induced conversion;
- UPDRS=
- Unified Parkinson’s Disease Rating Scale;
- UW=
- University of Washington;
- VA=
- Veterans Affairs
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
↵* These authors contributed equally to this work.
Class of Evidence: NPub.org/coe
- Received November 6, 2019.
- Accepted in final form February 5, 2021.
- © 2021 American Academy of Neurology
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