DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) affects more than 1.7 million each year, with most cases being mild (mTBI) including more than 300,000 service members returning from Iraq and Afghanistan. Moreover, 15-30% of mTBI subjects have symptoms that do not resolve 3 months post-injury and which can lead to permanent disability. In view of these facts, early detection of brain injury is critical to identifying those who are most at risk for poor outcome. Unfortunately mTBI is difficult to diagnose because conventional CT/MRI is not sensitive and clinical diagnosis is non-specific. Recent technical developments, however, have enabled measurements such as diffusion tensor imaging (DTI), susceptibility weighted imaging (SWI), and magnetic resonance spectroscopy (MRS). We have advanced these methods further with patient specific profiles, free-water correction, and spectral edited MRS. Combining these novel tools will make possible a "virtual biopsy" of mTBI to characterize, indirectly, different tissue components (i.e., neurons, axons, neurotransmitters, glial cells, myelin), as well as different aspects of TBI pathology (acute micro-hemorrhage, edema, inflammation, gliosis, and degeneration). This multi-modal approach will enable the development of biomarkers of injury, and with a longitudinal design, to chart brain changes following injury, including the evolution of neurocognitive recovery and persistent post-concussive symptoms (PPCS). In this proposal, 48 acute mTBI patients and 30 matched orthopedic controls will be recruited and will undergo imaging and clinical/cognitive evaluation at 1 week, 3 and 6 months post-injury at the Translational Research Center for TBI and Stress Disorders (TRACTS), VA Boston Healthcare System. In addition, 96 mTBI Veterans (1/2 blast/1/2 no blast, with/without PPCS), and 48 Veteran controls will be selected from previously acquired data using an identical imaging protocol on the same hardware and matched to the acute sample on age, gender, and socio-economic status. Our strategy is to combine multi-modal imaging to provide prognosis of mTBI outcome, based on neuroimaging markers at the acute stage. Our aims are: 1) to detect brain abnormalities associated with PPCS using advanced patient-specific multimodal imaging profiles of injury; 2) to chart the longitudinal course of mTBI from injury to recovery or PPCS; and 3) to identify multimodal imaging predictors of recovery versus PPCS. Using longitudinal data, we will make predictions about recovery versus PPCS based on a priori hypotheses and an empirically derived algorithm. These predictors will be generalized to the VA population, where common and unique patterns of injury will be identified, making imaging predictors a valuable tool in theater, and a first ste in determining treatment interventions. Based on preliminary results and prior studies, we that expect PPCS in VA and acute mTBI will show altered imaging markers associated with gliosis, and with axonal degeneration and chronic neuroinflammation, although the location and severity of abnormalities will be different. We also expect acute mTBI patients will differ from controls, early in the course of injury, and as a group will evince axonal injury, small vasculature hemorrhage, increased myelin injury, vasogenic edema, and increased inflammation, assessed using diffusion indices, and decreased N-acetyl aspartate (NAA; MRS neuronal marker), and increased glutamate (Glu; MRS marker of excitotoxicity). We predict that brain injury will begin to normalize in subjects who recover, suggesting a staging of brain recovery. For those who do not recover at 6 months, we expect to see greater evidence of gliosis, axonal degeneration and inflammation, on diffusion indices, also reflected in choline, Glu, and glutathione changes on MRS indices. A combination of inflammatory processes, extensive axonal damage and gliosis multimodal imaging markers at 1 week, will predict poor recovery and clinical PPCS at 6 months, while evidence of white matter regeneration at early stages will be among the strongest predictors of good recovery.

PUBLIC HEALTH RELEVANCE: Mild traumatic brain injury (mTBI) affects both service members and civilians, but is difficult to detect using conventional MRI/CT. Identifying neuroimaging biomarkers to detect (diagnosis) and to predict outcome (prognosis) of persistent post-concussive symptoms (PPCS) is an urgent need since it could lead to early intervention strategies prior to the entrenchment of severe symptoms, thus potentially averting disability and enhancing functional outcome. This proposal will develop objective radiological markers for the diagnosis of mTBI using advanced multimodal neuroimaging techniques and a brain atlas will be used to characterize individual profiles of injury (personalized medicine) in both civilian and Veteran populations. The atlas will also be used in a longitudinal study of acute mTBI (scans at 1 week, 3 and 6 months post-injury) to predict recovery versus PPCS. Comparisons will be made to Veterans with blast/no blast injuries (with good and poor outcome) and controls. Such a study is critical to understanding the neurological and cognitive/clinical sequelae of mTBI.