Blast exposure is a common experience of Operation Iraqi Freedom/Operation Enduring Freedom/ Operation New Dawn (OIF/OEF/OND) Veterans. There is growing concern that repetitive blast exposure may be a risk factor for neurological disorders, including chronic traumatic encephalopathy (CTE). The pathogenic processes that link early-occurring, often transient brain injuries, to subsequent chronic behavioral and cognitive impairments are not well understood. The pathology underlying these impairments is poorly understood. A number of important knowledge gaps currently impede progress toward elucidating the patho- physiology of repetitive blast-related mTBI that include, limited insight into the translational significance of the pathology produced in blast-induced animal TBI models with reference to neuroimaging findings in Veterans with blast-related mTBI. Moreover, the very limited neuropathological information from such Veterans significantly limits our understanding of blast-related mTBI. Adding to the complexity of this issue numerous research groups have reported multiple forms of blast- induced pathology in a number of animal blast TBI models including: aberrant tau expression, reactive astrocytosis, microgliosis, axonal injury, myelin damage, and blood-brain barrier (BBB) disruption. Much attention has been placed on tau because of its close association with sports-related CTE. Whether repetitive blast-related mTBI follows that same pathogenic pathway to CTE, which is defined chiefly by specific tau deposits, remains an open question. However, recent findings call attention to prominent glial pathology in Veterans with blast-related mTBI, raising the possibility that this form of neurotrauma may represent a distinct class; or possibly a distinct pathogenic process leading to chronic mTBI (which also may involve tau pathology). In repetitive blast exposed mice we have found microglial and astroglial pathology that, especially in subcortical regions of the brain, is quite similar to the white matter-associated glial pathology recently reported in Veterans with blast-related mTBI. We also have evidence that discrete microdomains of early-occurring BBB disintegrity are closely associated with aberrant microglial responses that include myelin phagocytosis, astrogliosis, and neuron loss. These data have prompted us test four closely related hypotheses: Specific Aim 1: will test the hypothesis that in blast exposed mice, specific brain regions are vulnerable to early-occurring blood-brain barrier (BBB) disruption; and that these disruptions may trigger later persistent pathology associated with myelin disruption, as well as axonal and neuronal injury. Specific Aim 2: will test the hypothesis that in mice, white matter pathology involving glial-mediated myelin phagocytosis and axonal injury will be closely associated with reduced fractional anisotropy. Specific Aim 3: will test the hypothesis that specific brain regions with myelin, axonal injury, and BBB disrupt- tion in mice will correspond to DTl neuroimaging findings in similar brain regions in Veterans with blast- related mTBI. Specific Aim 4: will test the hypothesis that neuropathology findings in brains from Veterans with blast-related mTBI will be found in the same anatomical regions as those identified by neuroimaging in living Veterans and will correspond with the pathology in blast-exposed mice. Successful completion of these aims will: (i) facilitate progress toward understanding the pathogenic cascades leading to chronic behavioral and cognitive impairments in Veterans with blast-related mTBI; and (ii) refine the translational relevance of animal blast TBI models needed to improve their usefulness as tools to speed the search for strategies to treat and prevent chronic blast-related neurodegeneration.

Blast-related mTBI is common among Veterans of the Iraq and Afghanistan wars, due in part to the frequent use of powerful improvised explosive devices (IEDs) by insurgents. TBI is a well-established risk factor for developing, Parkinson's disease, Alzheimer's disease-related dementia; and repetitive mTBI is an important risk factor for chronic traumatic encephalopathy. Thus, there is growing concern that blast-exposed Veterans face significant risk of developing cognitive dysfunction and dementia. There is great need to: (i) develop and refine animal models of repetitive blast-induced TBI that are highly translationally relevant to Veterans with blast-related mTBI; (ii). Elucidate the disease processes that underlie abnormal neuroimaging findings in such Veterans; and (iii) make more progress toward understanding the neuropathology occurring in Veterans with blast-related mTBI. The studies outlined in this proposal will address these important issues.