Abstract
Mild traumatic brain injury (mTBI) disproportionately affects military service members and is very difficult to diagnose. To-date, there is currently no blood-based, diagnostic biomarker for mTBI cases with persistent post concussive symptoms. To examine the potential of neuronally-derived (NDE) and astrocytic-derived (ADE) exosome cargo proteins as biomarkers of chronic mTBI in younger adults, we examined plasma exosomes from a prospective longitudinal study of combat-related risk and resilience, marine resiliency study II (MRSII). After return from a combat-deployment participants were interviewed to assess TBI exposure while on deployment. Plasma exosomes from military service members with mTBI (mean age, 21.7 years, n = 19, avg. days since injury 151), and age-matched, controls (deployed service members who did not endorse a deployment-related TBI or a pre-deployment history of TBI; mean age, 21.95 years, n = 20) were precipitated and enriched against a neuronal adhesion protein, L1-CAM, and an astrocyte marker, glutamine aspartate transporter (GLAST) using magnetic beads to immunocapture the proteins and subsequently selected by fluorescent activated cell sorting (FACS). Extracted protein cargo from NDE and ADE preparations were quantified for protein levels implicated in TBI neuropathology by standard ELISAs and on the ultra-sensitive single molecule assay (Simoa) platform. Plasma NDE and ADE levels of Aβ42 were significantly higher while plasma NDE and ADE levels of the postsynaptic protein, neurogranin (NRGN) were significantly lower in participants endorsing mTBI exposure compared to controls with no TBI history. Plasma NDE and ADE levels of Aβ40, total tau, and neurofilament light (NFL), P-T181-tau, P-S396-tau were either undetectable or not significantly different between the two groups. In an effort to understand the pathogenetic potential of NDE and ADE cargo proteins, neuron-like cultures were treated with NDE and ADE preparations from TBI and non-TBI groups. Lastly, we determined that plasma NDE but not ADE cargo proteins from mTBI samples were found to be toxic to neuron-like recipient cells in vitro. These data support the presence of markers of neurodegeneration in NDEs of mTBI and suggest that these NDEs can be used as tools to identify pathogenic mechanisms of TBI.
Highlights
Traumatic brain injury (TBI) is a global public health concern
Mouse anti-human CD171 (L1CAM) or glutamine aspartate transporter (GLAST) (ACSA-1) biotinylated antibody was coupled to magnetic streptavidin beads followed by the binding of plasma exosomes isolated from matched young, healthy military service members with no history of TBI and service members endorsing > 1 combat-related mild TBI (mTBI) events within the past 4–6 months
We report, for the first time, that plasma NDE and Astrocyte-Derived Exosomes (ADEs) levels of Aβ42 and NRGN can differentiate military service members with mTBI from those with no TBI with moderate sensitivity and accuracy
Summary
Epidemiological data suggests approximately 10 million people worldwide will sustain a TBI each year (Hyder et al, 2007). This is likely a gross underestimation as many mTBI cases go unreported, especially amongst sports athletes and military service members (Langlois et al, 2006). 75% of all TBI cases are mild TBI (mTBI) or concussions (Holm et al, 2005; Langlois et al, 2006). 5–20% of mTBI cases experience chronic, post concussive symptoms long after the injury (Ponsford et al, 2011; Karr et al, 2014; Eme, 2017). The underestimation of reported head injury cases and the chronic sequelae of TBI signifies the need for better diagnostic tools and therapeutic interventions for head injury patients
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