Chronic Traumatic Encephalopathy (CTE) is a progressive neurodegenerative disease that occurs as a consequence of repetitive mild traumatic brain injury (mTBI). CTE causes personality and behavioral changes, executive dysfunction and memory loss and is characterized by the accumulation of phosphorylated tau protein in the brain. The ongoing wars in Iraq and Afghanistan have resulted in a large cohort of OEF/OIF veterans with mTBI from blast exposure who may be at increased risk for CTE. Presently, CTE can only be diagnosed at autopsy and there are no known clinical biomarkers. The development of biomarkers to diagnose this disorder in living individuals would be a major scientific and clinical advance. We hypothesize that multiple combat blast-induced mTBIs cause altered tau metabolism indicative of preclinical CTE. We expect that increased tau biomarkers will be detected in cerebrospinal fluid (CSF) and in brain using advanced brain imaging techniques in veterans with a history of multiple blast mTBIs. In addition, recent data from our Translational Research Center for TBI and Stress Disorders (TRACTS) show that veteran with significant blast exposure exhibit greater rates and more severe post-traumatic stress disorder (PTSD) than veterans not exposed to blast neurotrauma. This suggests that the same individuals at risk for PTSD may also be at high risk for CTE. This project will draw its sample from the TRACTS cohort, which presently consists of 200 OEF/OIF veterans and will increase to ~400 during the proposed study period. History of blast exposure and TBI are documented via a semi-structured interview using the Boston Assessment of TBI: Lifetime (BAT-L). PTSD and other psychiatric illnesses are diagnosed using DSM-IV criteria. The proposed study will investigate the correlative relationship between mTBI metrics (number, severity, distance from blast) and neurocognitive measures of attention and executive function, phosphorylated tau pathology, axonal fiber tract damage, and structural brain changes. We will recruit two groups of 30 participants (total sample size of 60) from the TRACTS cohort that differ maximally in their history of combat TBI: (1) two or more blast mTBIs with associated cognitive symptoms (i.e., acute change in mental status, post-traumatic amnesia or loss of consciousness immediately after the blast) (mTBI); and (2) a matched control group without history of blast exposure or impact head injury (CON). All participants will have served in either OEF or OIF and have a diagnosis of PTSD based on DSM-IV criteria. We will measure tau biomarkers (phosphorylated tau (ptau), total tau, exosome ptau, oligomeric tau) in cerebrospinal fluid (CSF) by plate-based ELISA and conduct advanced brain imaging techniques using simultaneous PET/MRI. We will determine whether there is an association between CSF tau biomarkers, regional (dorsolateral frontal and orbital frontal) PET index metrics, mTBI metrics (number, severity, distance from blast), and neurocognitive measures of attention and executive function, Blast associated mTBI, PTSD and CTE represent significant scientific challenges in terms of determining their biological origins, their differential diagnosis and respective treatments. If not addressed immediately, the VA will be faced with daunting costs and responsibilities associated with caring for these debilitating neurological and psychiatric disorders. The development of reliable biomarkers to detect CTE will enable the diagnosis and monitoring of this condition during life and assessing the efficacy of potential therapies as they are developed. ! PUBLIC HEALTH RELEVANCE: Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease that occurs as a consequence of mild traumatic brain injury (mTBI). CTE causes personality and behavioral changes, executive dysfunction and memory loss and is characterized by the accumulation of tau protein in the brain. OEF/OIF veterans with a history of mTBI from blast exposure may be at increased risk for CTE. We will measure tau in cerebrospinal fluid (CSF) and conduct advanced brain imaging techniques in blast-injured OEF/OIF veterans in order to develop biomarkers for CTE, as currently none exist. If research geared at determining biomarkers and treatments for blast associated mTBI and CTE is not addressed immediately, the VA will be faced with daunting costs and responsibilities associated with caring for these debilitating neurological and psychiatric disorders. !