Assessment of brain‐derived extracellular vesicle enrichment for blood biomarker analysis in age‐related neurodegenerative diseases: An international overview

Abstract

AbstractINTRODUCTIONBrain‐derived extracellular vesicles (BEVs) in blood allows for minimally‐invasive investigations of central nervous system (CNS) ‐specific markers of age‐related neurodegenerative diseases (NDDs). Polymer‐based EV‐ and immunoprecipitation (IP)‐based BEV‐enrichment protocols from blood have gained popularity. We systematically investigated protocol consistency across studies, and determined CNS‐specificity of proteins associated with these protocols.METHODSNDD articles investigating BEVs in blood using polymer‐based and/or IP‐based BEV enrichment protocols were systematically identified, and protocols compared. Proteins used for BEV‐enrichment and/or post‐enrichment were assessed for CNS‐ and brain‐cell‐type‐specificity, extracellular domains (ECD+), and presence in EV‐databases.RESULTSA total of 82.1% of studies used polymer‐based (ExoQuick) EV‐enrichment, and 92.3% used L1CAM for IP‐based BEV‐enrichment. Centrifugation times differed across studies. A total of 26.8% of 82 proteins systematically identified were CNS‐specific: 50% ECD+, 77.3% were listed in EV‐databases.CONCLUSIONSWe identified protocol steps requiring standardization, and recommend additional CNS‐specific proteins that can be used for BEV‐enrichment or as BEV‐biomarkers.Highlights Across NDDs, we identified protocols commonly used for EV/BEV enrichment from blood. We identified protocol steps showing variability that require harmonization. We assessed CNS‐specificity of proteins used for BEV‐enrichment or found in BEV cargo. CNS‐specific EV proteins with ECD+ or without were identified. We recommend evaluation of blood‐BEV enrichment using these additional ECD+ proteins.