Project Summary/Abstract (1 page) Exposure to mild traumatic brain injury (mTBI) and repetitive head impacts (RHI) during sport participation has been associated with adverse long-term consequences (e.g., cognitive decline). Research investigating these associations has been limited to cross-sectional studies at single points of the lifespan without consideration of factors that can influence these associations. Greater mTBI/RHI history is associated with cerebral blood flow (CBF) and white matter (WM) abnormalities, even within younger athletes. CBF and WM abnormalities are two indicators of pathological aging and longitudinal decline in the general population. Age and cardiovascular risk factors across the lifespan can influence these abnormalities. The scientific objective of this proposal is to determine the influence of mTBI/RHI on MRI metrics of pathological aging and neurobehavioral function across the lifespan. Our central hypothesis is that mTBI/RHI will be associated with neurobehavioral function and CBF/WM abnormalities, and that the strength of this association is independently influenced by increasing age and the presence of cardiovascular risk factors. The rationale for this project is that determining the influence of mTBI/RHI on MRI metrics of pathological aging and neurobehavioral function across the lifespan, as well as factors that influence this relationship, will provide insight into the process underlying cumulative head injury and neurological decline later in life. Our hypothesis will be tested with two specific and one exploratory aims: 1) Determine the associations between mTBI/RHI and neurobehavioral function across the lifespan and the influence of comorbid cardiovascular risk factors; 2) Determine the associations between mTBI/RHI and MRI metrics of pathological aging across the lifespan and the influence of comorbid cardiovascular risk factors; Exploratory) Examine if MRI metrics of pathological aging mediate the association between cumulative mTBI/RHI and neurobehavioral function across the lifespan. To establish an independent research program that identifies the mechanisms by which mTBI/RHI can result in long-term neurological disease burden, the training objective of this proposal is to receive expert training/mentorship in a) the analysis and interpretation of neuroimaging data, b) the cumulative effects of aging and cardiovascular risk factors on long-term brain health and function, and c) the molecular mechanisms and progression of neuropathology as a consequence of mTBI/RHI. We will employ an innovative lifespan approach by leveraging data from four large-scale, prospective, multi-center studies of athletes across several decades of life. Harmonization of several mentor- directed, large-scale multisite datasets of athletes will allow a hybrid prospective, cross-sectional design. We will utilize advanced analytical approaches to examine the potential influence of aging and comorbid cardiovascular risk factors ...