Background & AimsParkinsonian disorders, such as Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS), share early motor symptoms but have distinct pathophysiology. As a result, accurate premortem diagnosis is challenging for neurologists, hindering efforts for disease‐modifying therapeutic discovery. 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. This meta‐analysis evaluated blood‐isolated neuronal and oligodendroglial EVs (nEVs and oEVs) α‐synuclein levels in Parkinsonian disorders.MethodsFollowing PRISMA guidelines, the meta‐analysis included 13 studies. An inverse‐variance random‐effects model quantified effect size (SMD), QUADAS‐2 assessed risk of bias and publication bias was evaluated. Demographic and clinical variables were collected for meta‐regression.ResultsThe meta‐analysis included 1,565 patients with PD, 206 with MSA, 21 with DLB, 172 with PSP, 152 with CBS and 967 healthy controls (HCs). Findings suggest that combined concentrations of nEVs and oEVs α‐syn is higher in patients with PD compared to HCs (SMD = 0.21, p = 0.021), while nEVs α‐syn is lower in patients with PSP and CBS compared to patients with PD (SMD = ‐1.04, p = 0.0017) or HCs (SMD = ‐0.41, p < 0.001). Additionally, α‐syn in nEVs and/or oEVs did not significantly differ in patients with PD vs. MSA, contradicting the literature. Meta‐regressions show that demographic and clinical factors were not significant predictors of nEVs or oEVs α‐syn concentrations.ConclusionThe results highlight the need for standardized procedures and independent validations in biomarker studies and the development of improved biomarkers for distinguishing Parkinsonian disorders.

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 < 0.001). Contrary to existing literature, α-syn levels in oEVs did not effectively differ among PD, MSA, or HCs. Meta-regressions revealed that demographic and clinical factors were not significant predictors of nEVs or oEVs α-syn concentrations. These findings emphasize the need for adopting more rigorous, standardized procedures and independent validations across all laboratories studying biomarkers in CNS-originating EVs. Furthermore, there is a pressing need for improved biomarkers to better distinguish between parkinsonian disorders.

No abstract

No abstract

No abstract