α‐Synuclein in Blood CNS‐originating Extracellular Vesicles For Parkinsonian Disorders: Systematic Review and Meta‐analysis

Abstract

AbstractBackgroundParkinsonian 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 differing cellular and regional pathophysiology. Accurate premortem diagnosis remains challenging. Extracellular vesicles (EVs) contain cell‐state‐specific biomolecules and can cross the blood‐brain barrier to the peripheral circulation, providing a unique central nervous system (CNS) insight. Measuring biomarkers in blood CNS‐originating EVs have become a promising avenue for minimally invasive diagnostics. This study evaluated the potential the levels of blood‐isolated neuronal and oligodendroglial EVs (nEVs and oEVs) α‐synuclein (α‐syn) proteoforms in parkinsonian disorders.MethodWe searched PUBMED, EMBASE, google scholar and recent reviews of the literature to include studies that have measured mean ± SD of α‐syn in putative nEVs and oEVs in patients with PD and at least one other parkinsonian disorder or healthy controls (HCs). Thirteen studies were included in the final meta‐analysis and demographic and clinical variables were collected for meta‐regressions. We quantified the effect size (SMD) using an inverse‐variance random‐effects model. QUADAS‐2 was used to assess risk of bias. Begg’s rank correlation and Egger’s regression tests were used to assess publication bias.ResultThe studies included 1,565 patients with PD, 206 with MSA, 21 with DLB, 172 with PSP, 152 with CBS and 967 HCs. Findings suggest that a combination of nEVs and oEVs α‐syn concentrations are higher in patients with PD vs. HCs (k = 14, SMD = 0.21; 95% CI 0.01, 0.42 p = 0.021), while nEVs α‐syn is lower in patients with PSP and CBS vs. PD (k = 6, SMD = ‐1.04; p = 0.0017) or HCs (k = 4, SMD = ‐0.41, p < 0.001). Additionally, α‐syn levels in oEVs didn’t effectively differ among PD, MSA, or HCs, contradicting the literature. Meta‐regressions showed demographic/ clinical were not significant predictors of nEVs or oEVs α‐syn concentrations.ConclusionThese findings highlight the need for adopting more rigorous, standardized procedures and independent validations across all laboratories studying biomarkers in CNS‐originating EVs. Additionally, there is a pressing need for improved biomarkers to distinguish among parkinsonian disorders more effectively.