Abstract Mild traumatic brain injury (mTBI) is a major cause of mortality and morbidity especially among service- members and veterans. mTBI is linked to long-term development of dementia conditions such as Alzheimer's disease and related disorders, but the exact pathophysiologic mechanisms remain poorly-defined. Vascular disease and cardiovascular risk factors are strongly linked with dementia. We propose to test the hypothesis that long-term mTBI-induced cognitive dysfunction is due to, at least in part, persistent cerebrovascular dysfunction. We will also test the hypothesis that early onset mTBI and later development of hypertension will have synergistic effects on cerebrovascular and cognitive dysfunction compared to hypertension or mTBI alone. In Aim 1, we will measure the temporal changes (subacute and chronic) in cerebrovascular and cognitive function in a rat model of mTBI while establishing the mechanistic role of cerebrovascular dysfunction in mTBI-induce cognitive impairment. Following midline fluid percussion injury or sham surgery in Sprague-Dawley rats, we will measure subacute (8 weeks) and chronic (12 months) cerebrovascular function (in-vivo by brain contrast MRI and ex-vivo by measuring cerebral artery vasoreactivity) and cognitive function and establish their relationship. We will also determine if early (starting at 2 weeks post-injury) or late (starting at 10 months post-injury) aerobic exercise training will improve cerebrovascular function leading to improvement in cognitive function. We will identify molecular mechanisms by which cerebrovascular function modulates cognitive function in mTBI by investigating the role of endothelial function in the regulation of brain-derived neurotrophic factor. In Aim 2, we will probe the interaction between early onset mTBI and later development of hypertension in chronic cerebrovascular and cognitive dysfunction. Here we will use rats genetically prone to develop hypertension (spontaneously hypertensive rats) to determine the effects of early onset mTBI in modulating chronic cerebrovascular and cognitive function. We will also have an exploratory aim to look at effects of mTBI in Sprague-Dawley and hypertensive rats on cardiac structure and function and coronary artery function. The proposal could provide critical and novel insights on the mechanisms underlying vascular dysfunction in TBI and their role in the development of cognitive dysfunction.

Project Narrative Traumatic brain injury (TBI) is associated with later development of impaired cognitive function and dementia. The mechanisms underlying this relationship remain largely unknown. TBI causes early and late impairment of cerebrovascular function, much in the same way that dementia disorders such as Alzheimer’s disease and vascular dementia were associated with early development of impaired vascular function. Our overall goal is to test the hypotheses that long-term mild TBI (mTBI)-induced cognitive dysfunction is due, at least in part, to persistent cerebrovascular dysfunction and that early onset mTBI will contribute to worse cerebrovascular and cognitive function with concomitant hypertension. We will use a validated model of diffuse mTBI in rats using fluid percussion injury. We will measure cognitive function using novel object recognition tasks. We will measure cerebrovascular function in living animals using magnetic resonance imaging and by measuring reactivity of blood vessels isolated from the brain. We will determine the relationship between cerebrovascular function and cognitive function and evaluate whether aerobic exercise training will attenuate the effects of mTBI. In rats genetically predisposed to develop hypertension, we will also compare cerebrovascular and cognitive function with mTBI versus those without. The proposal is significant in filling in our knowledge gaps about how mTBI causes impaired cognitive function as well as understanding the underlying causes on how TBI induces impaired cerebrovascular function. If successful, the study will uncover important new treatment pathways that could be used to prevent impaired cognitive and cerebrovascular function following TBI.