Developing Biomarkers of Mild Traumatic Brain Injury: Promise and Progress of CNS-Derived Exosomes

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.

An Overview on the Use of miRNAs as Possible Forensic Biomarkers for the Diagnosis of Traumatic Brain Injury

“…Among EVs, exosomes are of particular interest due to the ability of their miRNA cargo to modulate the gene expression pattern in recipient cells and induce systemic inflammation [ 21 , 22 , 23 ]. Such a role is highlighted in the work of Long et al [ 24 ], who carried out an experimental study in which TBI brain extracts were used to stimulate the production of exosomes in primary cultured astrocytes; once detected by immunofluorescence, exosomes were separated from astrocytes and added to primary cultured microglia.…”

The evolving role of extracellular vesicles (exosomes) as biomarkers in traumatic brain injury: Clinical perspectives and therapeutic implications

“…The quantification of EVs as a biomarker has been investigated in studies using serum and plasma-derived EVs without sample enrichment for specific EV subtypes (Younas et al, 2022 ). The majority of attempts to establish EV-derived biomarkers of TBI have centered on leveraging the presence of traditionally investigated blood-derived proteins inside EVs for diagnosis and evaluating neurological impairments predicting the outcome (Winston et al, 2019 ; Vaughn et al, 2021 ).…”

“…As a result, there is an unmet clinical need for accurate biomarkers that can identify all TBIs, including mTBI, and predict the likelihood of developing long-term sequelae, including post-concussive syndrome chronic traumatic encephalopathy (Ghaith et al, 2022 ; Mavroudis et al, 2022 ). Recent research has revealed that circulating exosomes enriched for CNS-specific tissue sources may be a method to develop practical biomarkers for TBI, particularly mild TBI, to circumvent these difficulties (Goetzl et al, 2019 , 2020 ; Winston et al, 2019 ; Vaughn et al, 2021 ).…”

“…Multiple investigations, similar to those showing an increase in tau protein, have revealed that Aβ42 is upregulated and increased in isolated exosomes in every clinical classification of TBI (mild, moderate, severe, and repetitive). Moreover, Aβ42 has been found to be increased in both neuronal and astrocyte-enriched exosomal samples of TBI patients and remained in circulation from days to years after the initial injury (Edwards and Soto, 2017 ; Gill et al, 2018b ; Goetzl et al, 2019 , 2020 ; Winston et al, 2019 ; Vaughn et al, 2021 ).…”

Mesenchymal stromal cell treatment attenuates repetitive mild traumatic brain injury-induced persistent cognitive deficits via suppressing ferroptosis

“…A traumatic cerebral concussion can induce mild traumatic brain injury (mTBI), accounting for 75% of all reported cases of head injury, and mTBI can cause various debilitating symptoms, including headaches, irritability, fatigue, attention deficits, sleep disturbances, depression, and anxiety [ 1 , 2 ]. However, the incidence of mTBI is grossly underestimated since most individuals completely recover within the first days to weeks after injury, preventing them from seeking medical treatment [ 3 ]. People with sustained single mTBI have an increased risk of developing repetitive mTBI (rmTBI) [ 4 ].…”