Evaluation of α-Synuclein in CNS-originating Extracellular Vesicles for Parkinsonian Disorders: A Systematic Review and Meta-analysis.

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Abstract Parkinsonian disorders, including Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS), present shared early motor symptoms but have distinct cellular and regional pathophysiology, making accurate premortem diagnosis challenging. Extracellular vesicles (EVs) provide a unique central nervous system (CNS) insight, as they contain cell-state-specific biomolecules and can cross the blood-brain barrier to the peripheral circulation. Measuring biomarkers in blood CNS-originating EVs, specifically neuronal and oligodendroglial EVs (nEVs and oEVs), has become a promising avenue for minimally invasive diagnostics. This meta-analysis aimed to evaluate the potential of blood-isolated nEVs and oEVs α-synuclein (α-syn) proteoforms in parkinsonian disorders. Thirteen studies were included, with a total of 1,565 PD, 206 MSA, 21 DLB, 172 PSP, 152 CBS patients, and 967 healthy controls (HCs). An inverse-variance random-effects model was used to quantify effect size (SMD), while QUADAS-2 assessed the risk of bias. Begg’s rank correlation and Egger’s regression tests evaluated publication bias. The findings suggest that a combination of nEVs and oEVs α-syn concentrations are higher in patients with PD compared to HCs (SMD = 0.21; p = 0.021). Interestingly, nEVs α-syn was lower in patients with PSP and CBS when compared to PD patients (SMD = -1.04; p = 0.0017) or HCs (SMD = -0.41, p 

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