Biomarkers in Blood-isolated CNS-originating EVs for Parkinsonian Disorders: A Systematic Review & 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 CNS-originating extracellular vesicles (EVs) can be used for the differential diagnosis of Parkinsonian disorders including Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy body (DLB), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS) or prodromal conditions such as REM behavior disorder (RBD).
Background:

Parkinsonian disorders exhibit overlapping early-stage symptoms, complicating definitive diagnosis despite heterogeneous cellular and regional pathophysiology. Additionally, the progression and eventual conversion of prodromal conditions such as RBD remains difficult to predict. EVs are small, membrane-enclosed structures released by cells, playing a vital role in communicating cell-state-specific messages. Due to their ability to cross the blood-brain-barrier into the peripheral circulation, the measurement of biomarkers in blood-isolated putative CNS-originating EVs has become a popular diagnostic approach for Parkinsonian disorders. However, replication and independent validation remain challenging.

Design/Methods:

We conducted a PRISMA-guided systematic review and diagnostic meta-analysis, covering 17 studies with a total of 1,604 patients with PD, 253 with MSA, 21 with DLB, 172 with PSP, 152 with CBS, 189 with RBD and 1,182 healthy controls (HCs). We employed either bivariate models or univariate models based on study size.

Results:

Diagnostic accuracy was moderate for differentiating patients with PD from HCs (partial AUC = 0.703), but revealed high heterogeneity and significant publication bias, suggesting an inflation of the perceived diagnostic effectiveness. The bias observed indicates that studies (estimated n=5 using the trim-and-fill method) with non-significant or lower effect sizes were less likely to be published. Although results for differentiating patients with PD from MSA or PSP and CBS appeared promising, their validity is limited due to the small number of involved studies coming from the same research group.

Conclusions:

Our findings underscore the moderate yet unreliable diagnostic accuracy of putative CNS-originating EV biomarkers in differentiating Parkinsonian disorders, highlighting substantial heterogeneity and significant publication bias.

10.1212/WNL.0000000000204643