Parkinsonian disorders, including Parkinson\'s disease (PD), multiple system atrophy (MSA), dementia with Lewy body (DLB), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP) are often misdiagnosed due to overlapping symptoms and the absence of precise biomarkers. Furthermore, there are no current methods to ascertain the progression and conversion of prodromal conditions such as REM behaviour disorder (RBD). Extracellular vesicles (EVs), containing a mixture of biomolecules, have emerged as potential sources for parkinsonian diagnostics. However, inconsistencies in previous studies have left their diagnostic potential unclear. We conducted a meta-analysis, following PRISMA guidelines, to assess the diagnostic accuracy of general EVs isolated from various bodily fluids, including cerebrospinal fluid (CSF), plasma, serum, urine or saliva, in differentiating patients with parkinsonian disorders from healthy controls (HCs). The meta-analysis included 21 studies encompassing 1285 patients with PD, 24 with MSA, 105 with DLB, 99 with PSP, 101 with RBD and 783 HCs. Further analyses were conducted only for patients with PD versus HCs, given the limited number for other comparisons. Using bivariate and hierarchal receiver operating characteristics (HSROC) models, the meta-analysis revealed moderate diagnostic accuracy in distinguishing patients with PD from HCs, with substantial heterogeneity and publication bias. The trim-and-fill method revealed at least two missing studies with null or low diagnostic accuracy. CSF-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, labour- and cost-intensive to isolate. In conclusion, while holding promise, utilizing biomarkers in general EVs for PD diagnosis remains unfeasible due to existing challenges. The focus should shift toward harmonizing the field through standardization, collaboration, and rigorous validation. Current efforts by the International Society For Extracellular Vesicles (ISEV) aim to enhance the accuracy and reproducibility of EV-related research through rigor and standardization, aiming to bridge the gap between theory and practical clinical application.

UNASSIGNED: Real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA) have been developed to detect minute amounts of amyloidogenic proteins via amplification techniques and have been used to detect misfolded α-synuclein (αSyn) aggregates in the cerebrospinal fluid (CSF) and other source materials of patients with Parkinson\'s Disease and other synucleinopathies.
UNASSIGNED: The aim of this systematic review and meta-analysis was to evaluate the diagnostic accuracy of αSyn seed amplification assays (αSyn-SAAs), including RT-QuIC and PMCA, using CSF as source material to differentiate synucleinopathies from controls.
UNASSIGNED: The electronic MEDLINE database PubMed was searched for relevant articles published until June 30, 2022. Study quality assessment was performed using the QUADAS-2 toolbox. A random effects bivariate model was exploited for data synthesis.
UNASSIGNED: Our systematic review identified 27 eligible studies according to the predefined inclusion criteria, of which 22 were included in the final analysis. Overall, 1855 patients with synucleinopathies and 1378 non-synucleinopathies as control subjects were included in the meta-analysis. The pooled sensitivity and specificity to differentiate synucleinopathies from controls with αSyn-SAA were 0.88 (95% CI, 0.82-0.93) and 0.95 (95% CI, 0.92-0.97), respectively. Evaluating the diagnostic performance of RT-QuIC in a subgroup analysis for the detection of patients with multiple system atrophy the pooled sensitivity decreased to 0.30 (95% CI, 0.11-0.59).
UNASSIGNED: While our study clearly demonstrated a high diagnostic performance of RT-QuIC and PMCA for differentiating synucleinopathies with Lewy bodies from controls, results for the diagnosis of multiple system atrophy were less robust.