Extracellular vesicles as a liquid biopsy for amyotrophic lateral sclerosis: a systematic review and meta-analysis.

Authors

Magdalena M Bolsinger, Nandhana Vivek, Javraj Singh, Ashrit Challa, Amanda Zhu, Trent Rothell, Samuel Wang, Timothy Zhang, Shirley Zhu, Nathan Robbins, Leony Fenwick, Grant Ruttenberg, Aleksander Bogoniewski, Hash Brown Taha

Published in

Journal of translational medicine. Jul 15, 2026. Epub Jul 15, 2026.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome diagnosed clinically using standardized criteria, with neuropathological confirmation of motor neuron loss and TDP-43 aggregates in postmortem brain tissue. Extracellular vesicles (EVs) have emerged as potential minimally invasive biomarkers for ALS, but studies vary widely in methodology and reproducibility. We conducted a systematic review and meta-analysis to evaluate the diagnostic potential of EV-associated proteins and RNAs in ALS. Following PRISMA guidelines, we searched PubMed and EMBASE from inception to May 21st, 2026. Forty-one studies met inclusion criteria. Where published summary statistics were available, these were used directly; where they were not, data were reconstructed from figures or obtained from authors and re-analyzed to derive standardized effect sizes and exploratory diagnostic accuracy estimates. Random-effects models were used for continuous outcomes, and diagnostic accuracy was assessed using hierarchical summary ROC and bivariate random-effects models. Publication bias was evaluated using Begg, Egger, and funnel plots. EV-associated TDP-43 was the most frequently studied protein. Meta-analysis of five studies showed a moderate but non-significant increase in EVs from ALS vs. controls (SMD = 1.30) with high heterogeneity (I = 97.8%). Sixteen studies assessing EV-RNA biomarkers showed minimal overlap and limited independent replication. Diagnostic accuracy meta-analysis across 11 studies yielded moderate performance (AUC = 0.839). No publication bias was found across both meta-analyses. EV biomarkers for ALS show biological promise but are limited by methodological variability and insufficient replication. This work highlights the need for standardized protocols, transparent data sharing, and independent validation.

PMID:
42458453
Bibliographic data and abstract were imported from PubMed on 16 Jul 2026.

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