?DESCRIPTION (provided by applicant): The goal of this project is to examine the clinical presentation and biomarkers that accompany chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with exposure to repetitive head impacts. A history of repetitive head impacts is a necessary factor in the development of CTE, though it is not a sufficient cause of the disease. The specific head impact exposures, other modifying risk factors (e.g., genetics), and incidence and prevalence of CTE remain unknown. To be able to address these critical issues, as well as to begin clinical trials, it is necessary to develop methods of detecting and diagnosing CTE during life and distinguish it from other clinically similar presentations. This proposed investigation is a continuation of the Diagnosing and Evaluating Traumatic Encephalopathy with Clinical Tests (DETECT) project. Our study population will include 110 former NFL players (high exposure to head impacts; HE) and 30 former elite non- contact sport athletes (low exposure to head impacts; LE). The HE group includes symptomatic and asymptomatic subjects; the LE group includes only asymptomatic subjects. All subjects will undergo a two-day evaluation, including clinical examinations (neurological, motor, cognitive, mood and behavioral evaluations), blood draw (for genetic sequencing and genotyping of APOE, MAPT, and MAO-A), EEG, lumbar puncture (CSF tau, p-tau, and Abeta42; monoamine metabolites), and neuroimaging (including volumetrics, cortical thickness, diffusion tensor imaging, free water imaging, and magnetic resonance spectroscopy). Specific tests were chosen to maximize the ability to share and compare data through datasets such as the Federal Interagency Traumatic Brain Injury Research (FITBIR) informatics system and the National Alzheimer's Coordinating Center. For the 80 subjects (60 HE and 20 LE) who previously participated in the initial DETECT study, this evaluation will serve as a 3-yr follow-up. The remaining former HE and LE subjects will return for a 3-yr follow-up evaluation within this study cycle. We will also examine 20 individuals with mild cognitive impairment (MCI) due to Alzheimer's disease and 20 individuals with Alzheimer's disease dementia (AD). AD and MCI subjects will have no contact sport or TBI history and will only receive a single evaluation for ths study; their data are only for cross-sectional comparison purposes. This project will utilize a multi-modal approach evaluating the relationship between head impact exposure and later-life clinical and biomarker outcomes, taking into account potential modifying variables. Additionally, expanding the cohort to include individuals with AD and MCI as well as older and asymptomatic HE and LE subjects will provide a more comprehensive picture of the repercussions of repetitive head impacts, and the factors that differentiate CTE from other disease processes. Furthermore, longitudinal evaluation will allow for important examination of the progression of clinical course and biomarker outcomes. Given the millions of Americans who participate in contact sports at all levels of play this study has the potential to have a tremendous impact on public health.