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Abstract
Mild traumatic brain injuries (mTBI) are common injuries across civilian and military populations. Although most individuals recover after mTBI, some individuals continue to show long-term symptoms as well as increased risk for neurodegenerative and neuropsychiatric disorders. Currently, diagnosing TBI severity relies primarily on self-report and subjective symptoms, with limited tools for diagnosis or prognosis. Brain-derived exosomes, a form of extracellular vesicle, may offer a solution for interpreting injury states by aiding in diagnosis as well as outcome prediction with relatively low patient burden. Exosomes, which are released into circulation, contain both protein and RNA cargo that can be isolated and quantified, providing a molecular window into molecular status of the exosome source. Here we examined the current literature studying the utility of exosomes, in particular neuronal- and astrocyte-derived exosomes, to identify protein and miRNA biomarkers of injury severity, trajectory, and functional outcome. Current evidence supports the potential for these emerging new tools to capture an accessible molecular window into the brain as it responds to a traumatic injury, however a number of limitations must be addressed in future studies. Most current studies are relatively small and cross sectional; prospective, longitudinal studies across injury severity, and populations are needed to track exosome cargo changes after injury. Standardized exosome isolation as well as advancement in identifying/isolating exosomes from CNS-specific tissue sources will improve mechanistic understanding of cargo changes as well as reliability of findings. Exosomes are also just beginning to be used in model systems to understand functional effects of TBI-associated cargo such as toxicity. Finally linking exosome cargo changes to objective markers of neuronal pathology and cognitive changes will be critical in validating these tools to provide insights into injury and recovery states after TBI.
Highlights
Traumatic brain injury (TBI) is the leading cause of death and disability in the United States and in the developing world [1]
Tau is released into the cerebral spinal fluid (CSF) and blood following axonal injury [60], with tau and phosphorylated forms of tau (p-tau) detected in plasma after severe TBI as well as in some cases chronically [61,62,63]
Studies reporting significant elevations of Aβ42 included participants with mean ages ranging from 19 to 30 years at time of collection [25, 38, 40]. This difference in age could account for their failure to detect elevated Aβ42 levels in Veterans with chronic Mild traumatic brain injuries (mTBI), as NDE levels of Aβ42 could fluctuate with age, with Aβ42 rising with age [70]. These findings demonstrate the potential for exosome total tau, p-tau, and Aβ42 levels to be used as biological markers for TBI it will depend on tissue source of exosomes and potentially age range
Summary
Traumatic brain injury (TBI) is the leading cause of death and disability in the United States and in the developing world [1]. Because of the resources and expertise required, timing between injury, and CSF/imaging collection can impeded proper identification of mTBI patients who are underinsured or living in underserved, rural areas, making it harder to track chronic symptoms [20] These limitations have fueled research into alternative biomarkers derived from accessible biofluids. This review was conducted using the following search terms in pubmed, “((exosome) OR extracellular vesicles OR exosomal) AND (biomarker) AND ((tbi) OR (traumatic brain injury)).”. This yielded 68 results across all years (earliest found dated back to 2014). The references of selected articles were further searched by hand to obtain additional citations
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