Mild traumatic brain injury (mTBI) caused by blast effects of explosive devices is the “signature injury” of Servicemembers deployed to combat operations in Iraq and Afghanistan. Resultant persistent postconcussive symptoms (PCS), such as impairment of memory and concentration, irritability, mood instability, sleep disturbances, and migraine headaches frequently have disabling personal, professional and domestic consequences. In addition to these immediate consequences, repetitive mTBI may initiate processes leading to neurodegeneration and dementia. This competitive renewal application proposes to continue longitudinally a currently funded VA RR&D Merit Review: B77421, "Mild TBI and Biomarkers of Neurodegeneration". In the current funding period, we have made substantial progress in 1) identifying objective structural and functional neuroimaging biomarkers that characterize the clinical phenotype of blast-induced mTBI, 2) identifying objective impairment and longitudinal decline in cognitive function in mTBI Veterans using our refined neuropsychological assessment battery, and 3) identifying in cerebrospinal fluid (CSF) and plasma a group mTBI-specific inter-related neuroinflammatory chemoattractant, vascular disturbance, and neurodegeneration biomarkers. We have integrated neuroimaging, cognitive, and biomarker findings into a consistent model of regional cerebellar- thalamic-frontoparietal cortical and brainstem dysfunction in repetitive blast mTBI. Goals of this continuation proposal are to determine whether cognitive performance is associated with neuroimaging and/or CSF and plasma biomarkers of mTBI and/or genetic risk factors for neurodegenerative dementia, and to determine whether neuroimaging and CSF and plasma biomarker abnormalities are transient, static, or progressive. We also propose 1) a new plasma biomarker goal: central nervous system (CNS)-derived plasma exosomal cargo proteins, 2) new clinical assessments of sleep: in-theater sleep history and sleep/activity monitoring via Actigraphy, and 3) an additional advanced neuroimaging analyses: diffusion tensor imaging Automating-Fiber- Tract Quantification. Specific Aim 1: To continue characterizing longitudinally the clinical (neurocognitive, neurologic, behavioral) and structural/functional neuroimaging characteristics of disrupted cerebellar-thalamic-frontoparietal cortical and brainstem function in OIF/OEF/OND Veterans with repetitive blast trauma mTBI. Specific Aim 2: To determine if OEF/OIF/OND Veterans with repetitive mTBI exhibit CSF and plasma neurovascular, neuroinflammatory, and neurodegeneration biomarker changes associated with the onset and progression of neurodegenerative dementing disorders. Specific Aim 3: To determine the effects of genetic risk factors for neurodegeneration (apolipoprotein E [APOE] polymorphisms and microtubule associated protein tau [MAPT] subhaplotypes) on clinical characteristics and neuroimaging and biofluid biomarkers in OEF/OIF/OND Veterans w...