Biomarkers in Extracellular Vesicles from Bodily Fluids for Parkinsonian Disorders: A Systematic Review & Diagnostic Meta-analysis
Hash Brown Taha1, Aleksander Bogonwieski2
1Leonard Davis School of Gerontology, University of Southern California, 2Medical and Molecular Pharmacology, University of California Los Angeles
Objective:

To assess whether biomarkers in extracellular vesicles (EVs) isolated from bodily fluids can be used for the differential diagnosis of Parkinson’s disease from healthy controls (HCs) and/or other parkinsonian disorders including multiple system atrophy (MSA), dementia with Lewy body (DLB), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS) or REM behavior disorder (RBD). Also, to compare such diagnostic efficacy of biomarkers in EVs vs. CNS-originating EVs.

Background:

Parkinsonian disorders exhibit overlapping early-stage symptoms, complicating definitive diagnosis despite heterogeneous cellular and regional pathophysiology. EVs are small, membrane-enclosed structures released by cells, playing a vital role in communicating cell-state-specific messages. EVs are believed to contain a rich source of biomarkers. As such, they have become a popular diagnostic approach for Parkinsonian disorders. However, replication and independent validation remain challenges in the field.

Design/Methods:

We conducted a PRISMA-guided systematic review and diagnostic meta-analysis, including 21 studies encompassing 1,285 patients with PD, 24 with MSA, 105 with DLB, 99 with PSP, 101 with RBD, and 783 HCs, employing a hierarchical bivariate model. Analyses were conducted only for patients with PD vs. HCs, given the limited number for other comparisons.

Results:

The meta-analysis revealed moderate diagnostic accuracy in distinguishing PD from HCs, with substantial heterogeneity and publication bias detected. The trim-and-fill method revealed at least two missing studies with null or low diagnostic accuracy. Cerebrospinal fluid-EVs showed better overall diagnostic accuracy, while plasma-EVs had the lowest performance. General EVs demonstrated higher diagnostic accuracy compared to CNS-originating EVs, which are more time-consuming, labor- and cost-intensive to isolate.

Conclusions:
In conclusion, while holding promise, utilizing biomarkers in general EVs for PD diagnosis is superior to CNS-originating EVs. However, such approach remains unfeasible due to existing challenges including heterogeneity and publication bias. The focus should shift toward harmonizing the field through standardization, collaboration, and rigorous validation.
10.1212/WNL.0000000000204644