Emergence of Extracellular Vesicles as “Liquid Biopsy” for Neurological Disorders – Boom or Bust

Extracellular vesicles (EVs) have emerged as an attractive liquid biopsy approach in the diagnosis and prognosis of multiple diseases and disorders. The feasibility of enriching specific subpopulations of EVs from biofluids based on their unique surface markers has opened novel opportunities to gain molecular insight from various tissues and organs, including the brain. Over the past decade, EVs in bodily fluids have been extensively studied for biomarkers associated with various neurological disorders, such as Alzheimer’s disease, Parkinson’s disease, schizophrenia, bipolar disorder, major depressive disorders, substance use disorders, human immunodeficiency virus-associated neurocognitive disorder, and cancer/treatment-induced neurodegeneration. These studies have focused on the isolation and cargo characterization of either total EVs or brain cells, such as neuron-, astrocyte-, microglia-, oligodendrocyte-, pericyte-, and endothelial-derived EVs from biofluids to achieve early diagnosis and molecular characterization and to predict the treatment and intervention outcomes. The findings of these studies have demonstrated that EVs could serve as a repetitive and less invasive source of valuable molecular information for these neurological disorders, supplementing existing costly neuroimaging techniques and relatively invasive measures, like lumbar puncture. However, the initial excitement surrounding blood-based biomarkers for brain-related diseases has been tempered by challenges, such as lack of central nervous system specificity in EV markers, lengthy protocols, and the absence of standardized procedures for biological sample collection, EV isolation, and characterization. Nevertheless, with rapid advancements in the EV field, supported by improved isolation methods and sensitive assays for cargo characterization, brain cell-derived EVs continue to offer unparallel opportunities with significant translational implications for various neurological disorders.

Brain cell–derived extracellular vesicles (BDEs) in biofluids could serve as
liquid biopsy for various neurological disorders

EVs secreted by various brain cells find their way into peripheral circulation. Based upon their specific surface markers, various BDEs can be isolated by immunocapture method. BDEs are characterized for their biophysical properties, purity, and/or expression of specific biomarkers by multiple techniques, such as nanoparticle tracking analysis (NTA), nano-flow cytometry, and electron microscopy. Furthermore, the cargo of BDEs can be characterized by multiple techniques. For proteins, mass spectrometry, ELISA, arrays, and western blotting (WB) can be used. Nucleic acids can be analyzed through RNA sequencing (RNA-seq) and qPCR, and metabolites and lipids can be studied using targeted or untargeted mass spectrometry and Raman spectroscopy.

Kumar A, Nader MA, Deep G. (2024) Emergence of Extracellular Vesicles as “Liquid Biopsy” for Neurological Disorders: Boom or Bust. Pharmacol Rev 76(2):199-227. [article]

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