Evaluation of α-synuclein in CNS-originating extracellular vesicles for Parkinsonian disorders: A systematic review and meta-analysis

Abstract

Background & aims: Parkinsonian 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.

Methods: Following 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.

Results: The 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.

Conclusion: The results highlight the need for standardized procedures and independent validations in biomarker studies and the development of improved biomarkers for distinguishing Parkinsonian disorders.

Keywords: Diagnosis; L1CAM; Parkinson's disease; extracellular vesicles; α-Synuclein.

FIGURE 1

PRISMA flow diagram for study inclusion or exclusion strategy.

FIGURE 2

Meta‐analysis for neuronal EVs (nEVs) α‐synuclein in Parkinsonian disorders vs. healthy controls (HC). A positive or negative SMD indicates higher or lower nEVs α‐synuclein concentrations in a Parkinsonian disorder versus HCs, respectively. CBS, corticobasal syndrome; CI, confidence intervals; DLB, dementia with Lewy body; MSA, multiple system atrophy; PD, Parkinson's disease; PSP, progressive supranuclear palsy; SMD, standardized mean difference.

FIGURE 3

Meta‐analysis for the combination of neuronal and oligodendroglial EVs (nEVs and oEVs) α‐synuclein in (A) PD, MSA and DLB versus HCs, (B) PD versus HCs and (C) MSA versus HCs. A positive or negative SMD indicates higher or lower α‐synuclein, respectively. CI, confidence intervals; DLB, dementia with Lewy body; HC, healthy controls; MSA, multiple system atrophy; PD, Parkinson's disease; SMD, standardized mean difference.

FIGURE 4

Meta‐analysis for neuronal EVs (nEVs) α‐synuclein in CBS and PSP versus HCs. A negative SMD indicates lower nEVs α‐synuclein concentrations in CBS and PSP versus HCs. CBS, corticobasal syndrome; CI, confidence intervals; HC, healthy controls; PSP, progressive supranuclear palsy; SMD, standardized mean difference.

FIGURE 5

Meta‐analysis for neuronal EVs (nEVs) α‐synuclein in PD and DLB vs. MSA. A positive or negative SMD indicates higher or lower nEVs α‐synuclein concentrations in PD or DLB versus MSA, respectively. CI, confidence intervals; DLB, dementia with Lewy body; MSA, multiple system atrophy; PD, Parkinson's disease; SMD, standardized mean difference.

FIGURE 6

Meta‐analysis for neuronal EVs (nEVs) α‐synuclein in (A) PD, MSA and DLB vs PSP and (B) PD, MSA and DLB versus CBS. A positive or negative SMD indicates higher or lower concentrations of α‐synuclein, respectively. CBS, corticobasal syndrome; CI, confidence intervals; DLB, dementia with Lewy body; MSA, multiple system atrophy; PD, Parkinson's disease; PSP, progressive supranuclear palsy; SMD, standardized mean difference.

FIGURE 7

Meta‐analysis for oligodendroglial EVs (oEVs) α‐synuclein in (A) PD and HC versus MSA, (B) PD versus MSA and (C) HC versus MSA. A positive or negative SMD indicates higher or lower concentrations of α‐synuclein, respectively. CI, confidence intervals; DLB, dementia with Lewy body; HC, healthy controls; MSA, multiple system atrophy; PD, Parkinson's disease; SMD, standardized mean difference.

FIGURE 8

Meta‐analysis for neuronal and oligodendroglial EVs (oEVs) α‐synuclein in MSA and HC versus PD. A positive and negative SMD indicates higher or lower concentrations of α‐synuclein, respectively. CI, confidence intervals; DLB, dementia with Lewy body; HC, healthy controls; MSA, multiple system atrophy; PD, Parkinson's disease; SMD, standardized mean difference.