Role of Inflammation in Traumatic Brain Injury-Associated Risk for Neuropsychiatric Disorders: State of the Evidence and Where Do We Go From Here.

In the past decade, there has been an increasing awareness that traumatic brain injury (TBI) and concussion substantially increase the risk for developing psychiatric disorders. Even mild TBI increases the risk for depression and anxiety disorders such as posttraumatic stress disorder by two- to threefold, predisposing patients to further functional impairment. This strong epidemiological link supports examination of potential mechanisms driving neuropsychiatric symptom development after TBI. One potential mechanism for increased neuropsychiatric symptoms after TBI is via inflammatory processes, as central nervous system inflammation can last years after initial injury. There is emerging preliminary evidence that TBI patients with posttraumatic stress disorder or depression exhibit increased central and peripheral inflammatory markers compared with TBI patients without these comorbidities. Growing evidence has demonstrated that immune signaling in animals plays an integral role in depressive- and anxiety-like behaviors after severe stress or brain injury. In this review, we will 1) discuss current evidence for chronic inflammation after TBI in the development of neuropsychiatric symptoms, 2) highlight potential microglial activation and cytokine signaling contributions, and 3) discuss potential promise and pitfalls for immune-targeted interventions and biomarker strategies to identify and treat TBI patients with immune-related neuropsychiatric symptoms.

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

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.