Title : Alpha-synuclein in blood CNS-originating extracellular vesicles for parkinsonian disorders: Systematic review and meta-analysis
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 differing cellular and regional pathophysiology. Accurate premortem diagnosis is challenging, highlighting the need for reliable biomarkers. Extracellular vesicles (EVs) contain cell-statespecific 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 of blood-isolated neuronal and oligodendroglial EVs (nEVs and oEVs) with α-synuclein (α-syn) proteoforms as discriminatory biomarkers for parkinsonian disorders. We conducted a comprehensive systematic review and meta-analysis following PRISMA 2020 guidelines. We 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 further collected for metaregressions. We calculated the standardized mean difference (SMD) based on Cohen’s d to quantify the effect size. QUADAS-2 was used to assess risk of bias. Begg’s rank correlation and Egger’s regression tests and Funnel plots were used to assess publication bias. The 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 variables including age, gender, disease stage, motor and cognitive impairment severity were not significant predictors of nEVs or oEVs α-syn concentrations. Heterogeneity was high in most analyses (>88.0%) but exclusion of influential studies using sensitivity analyses did not alter the results, suggesting robustness. These 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.
Audience Take Away
- The potential of blood-isolated neuronal and oligodendroglial extracellular vesicles (nEVs and oEVs) α-synuclein (α-syn) proteoforms as discriminatory biomarkers for Parkinsonian disorders
- The results of a comprehensive systematic review and meta-analysis of studies measuring α-sin in
putative nEVs and oEVs in patients with Parkinsonian disorders and healthy controls - The limitations of this technique in distinguishing Parkinsonian disorders effectively and the need for adopting more rigorous, standardized procedures
- The importance of independent validations across laboratories studying biomarkers in central nervous system (CNS)-originating extracellular vesicles
- The pressing need for improved biomarkers to differentiate among Parkinsonian disorders more effectively
