The goal of this project is to examine the clinical presentation and biomarkers that accompany chronic traumatic encephalopathy (CTE;also known as dementia pugilistica), a preventable cause of dementia. Although concussive and/or subconcussive brain trauma appears to be a necessary factor in the development of CTE, it is not sufficient. The specific additional risk factors (e.g., genetics), and possible preventive strategies (e.g., concussion management, limiting overall subconcussive trauma) for this condition remain unknown. Moreover, although case studies have suggested that the pre-dementia clinical presentation includes cognitive deficits, depression, suicidal behavior, and problems with impulse control, there have been no systematic studies to support these observations. The research team has conducted neuropathological studies demonstrating that CTE is a tauopathy with a unique profile of neurodegeneration that is distinct from Alzheimer's and other neurodegenerative diseases of aging. To date, the only means of diagnosing CTE is post-mortem brain examination. In order to conduct prospective research into the epidemiology, early detection, risk factors, clinical course, and, ultimately, treatment and prevention of CTE, objective biomarkers for the disease must first be discovered. This project involves a cross-sectional examination of the biomarkers and clinical presentation of CTE. This initial study will focus on a sample of subjects who are at high risk of developing CTE: a randomly selected group of 150 retired NFL athletes, ages 40-69, all with high head trauma exposure (load) based on a combination of the total years played and positions played, incorporating helmet sensor data to determine the relative risk of various positions. We will also select a control group of same-age male athletes, with exclusion criteria based on a history of brain trauma or any participation in organized sports or military that may have caused exposure to even subconcussive brain trauma. In addition, APOE genotype will be examined as a potential moderating variable, based on our neuropathological findings and other data reported in the literature, both of which suggest that the APOE 54 allele may increase disease susceptibility. We will compare the high exposure group to the control group on several potential biomarkers, selected based on our previous neuropathological studies of CTE, our pilot neuroimaging data, and other findings by our team and in the literature regarding the long-term effects of repetitive brain trauma. We will then compare the groups on pertinent clinical variables, including neurologic, motor, neuropsychological, and psychiatric evaluations, and examine the relationship between the clinical variables and biomarkers in the high exposure group. Results of this initial investigation will help guide future longitudinal studies into the epidemiology, risk factors, and clinical presentation of CTE, and may provide additional knowledge relevant to the pathogenesis, detection, and eventual treatment of other neurodegenerative diseases such as AD. PUBLIC HEALTH RELEVANCE: Chronic Traumatic Encephalopathy (CTE) is a degenerative disease of the brain resulting from repetitive head injuries, such as those experienced by athletes involved in football and other contact sports. Given the millions of Americans who participate in these sports at all levels of play, including youth, high school, college, and professional, it is imperative to be able to detect, diagnose, and eventually treat this preventable, progressive brain disease. This study will be the first to address these issues and may, therefore, have a tremendous impact on public health.