Diagnostic Accuracy of Biomarkers in CNS-originating Extracellular Vesicles for Parkinsonian Disorders: A meta-analysis

Abstract

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), 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 REM behavior disorder (RBD) to PD, MSA or DLB remains difficult to predict. Extracellular vesicles (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. However, replication and independent validation remain challenges in this field. We conducted a PRISMA-guided systematic review and meta-analysis, covering 15 studies with a total of 1,455 patients with PD, 206 MSA, 21 DLB, 172 PSP, 152 CBS, 189 RBD and 1,045 healthy controls (HCs), employing either hierarchical bivariate models or univariate models based on study size. Diagnostic accuracy was moderate for differentiating patients with PD from HCs, but revealed high heterogeneity and significant publication bias, suggesting an inflation of the perceived diagnostic effectiveness. The bias observed indicates that studies 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. Despite initial reports, our analyses suggest that using CNS-originating EV biomarkers may not reliably differentiate patients with MSA from HCs or patients with RBD from HCs, due to their lesser accuracy and substantial variability among the studies, further complicated by potential publication bias. Our findings underscore the moderate yet unreliable diagnostic accuracy of putative CNS-originating EV biomarkers in differentiating Parkinsonian disorders, highlighting the presence of substantial heterogeneity and significant publication bias. These observations reinforce the need for larger, more standardized, and unbiased studies to validate and enhance the utility of EV biomarkers in the differential diagnosis of these conditions.