This is a study to develop methods of diagnosing chronic traumatic encephalopathy (CTE) during life, as well as to examine possible risk factors for this neurodegenerative disease. One component of this study is the use of an investigational PET scan radio tracer to detect abnormal tau protein in the brain.

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease characterized by a distinct deposition of phosphorylated tau (p-tau) in neurons and astrocytes in a pattern that is unique from other tauopathies, including Alzheimer's disease (AD). Although the neuropathological features of CTE have become further clarified in recent years, the clinical presentation of CTE is still not well characterized. Diagnostic criteria have only recently been published and lack validation.

Neuroimaging and fluid biomarkers developed for the diagnosis of other neurodegenerative diseases have only been used in preliminary studies of individuals at high risk for CTE, namely athletes with histories of significant exposure to repetitive head impacts (RHI), such as former football players and boxers. There is thus an urgent need to develop accurate methods for detecting and diagnosing CTE during life so that effective interventions for prevention and treatment can be developed. Moreover, though a history of RHI is a necessary risk factor for CTE, it alone is not sufficient. There is a need to understand what specific aspects of RHI exposure places an individual at increased risk for CTE and to examine potential genetic polymorphisms that modify that risk.

To address these needs, the investigators are conducting a multidisciplinary, multicenter, longitudinal study of former NFL and varsity college football players (with and without symptoms), and a control group of asymptomatic same-age men without any history of RHI exposure, traumatic brain injury or military service. Subjects will be seen at 1 of 4 participating study sites in Boston; Las Vegas, ; New York; and Scottsdale/Phoenix . Subjects will undergo a baseline evaluation and a 3 year follow-up evaluation (currently former college players will not complete the follow-up evaluation). Each evaluation will be take place over a 3 day period and consist of the following procedures/tests: neurocognitive testing, determination of functional independence, neuropsychiatric examination (with measures of mood and behavior), neurological assessment (motor, headache, postural stability), neuroimaging (including structural, diffusion, functional, biochemical, and molecular imaging), lumbar punctures (for Cerebrospinal Fluid (CSF) biomarkers), blood draws (for blood biomarkers and DNA), and saliva samples (for biomarkers).

Inclusion Criteria:

Former NFL Players:

• English as primary language
• No MRI or Lumbar Puncture (LP) contraindications
• Have played ≥12 years of organized football (including =>3 in college and =>3 seasons in the NFL)
• Must have played one of following positions offensive lineman, defensive lineman, linebacker, tight end, wide receiver, running back, or defensive back.
• Agree to provide name and contact information of a study partner who will complete questionnaires regarding subject's mood, behavior, thinking and cognitive function should the subject enroll in the study.

Former Collegiate Football Players

• English as primary language
• No MRI or Lumbar Puncture (LP) contraindications
• Must have played =>6 years of organized football (with => 3 years at the college level, but no organized football or other contact sport following college.)
• Must have played one of following positions offensive lineman, defensive lineman, linebacker, tight end, wide receiver, running back, or defensive back.
• No military service
• Agree to provide name and contact information of a study partner who will complete questionnaires regarding subject's mood, behavior, thinking and cognitive function should the subject enroll in the study.

Control Group

• English as primary language
• No MRI or Lumbar Puncture (LP) contraindications
• No history of organized contact sports or known traumatic brain injury (TBI) and/or moderate/severe concussions
• No history of participation in any of the following organized sports at any level: football, hockey, rugby, soccer, lacrosse, wrestling, boxing, gymnastics, martial arts, and kickboxing.
• No military service.
• Must have BMI >=24
• Must have at least 2 years post-secondary education at a 4-year accredited college or university, or have an associate's degree if they did not attend a 4-year accredited college or university
• Must have never been diagnosed with, or treated for, any of the following: depression, manic-depressive or bipolar disorder, anxiety, or other psychiatric or mental health problems
• Agree to provide name and contact information of a study partner who will complete questionnaires regarding subject's mood, behavior, thinking and cognitive function should the subject enroll in the study.
• Must be asymptomatic when screened by telephone.

Former NFL and Varsity Collegiate Football Players Exclusion Criteria:

• If they do not meet inclusion criteria
• If they have a history of clinical stroke confirmed on neuroimaging
• If they have vision or hearing impairment significant enough to compromise neuropsychological testing
• If they have been hospitalized or treated in an emergency room following a severe injury to their head since they stopped playing football
• If they are unable to undergo MRI/PET Scan
• If they have a spinal fusion at L3-4 and/or L4-5
• If they are unable to travel to one of 4 study sites to participate
• If they are an insulin dependent diabetic
• If they cannot provide the name and contact information of an eligible study partner
• If they are taking blood thinners that would make LP unsafe
• If they have a type of abnormal heart rhythm called Torsades de pointes AKA TdP
• If they have an abnormal heart rhythm disorder called QT Prolongation or take certain medications known to cause QT Prolongation
• If they do not agree to all study tests and procedures
• If they are unable to consent to study procedures

Control Group Exclusion:

• If they do not meet inclusion criteria
• If they have vision or hearing impairment significant enough to compromise neuropsychological testing
• If they are unable to undergo MRI/PET Scan
• If they have a spinal fusion at L3-4 and/or L4-5
• If they are an insulin dependent diabetic
• If they are unable to travel to one of 4 study sites to participate
• If they cannot provide the name and contact information of an eligible study partner
• If they report any cognitive concerns or dementia during screening process
• If they have a type of abnormal heart rhythm called Torsades de pointes AKA TdP
• If they have an abnormal heart rhythm disorder called QT Prolongation or take certain medications known to cause QT Prolongation
• If they are unable to consent to study procedures

Former National Football League Players, Former Varsity Level College Football Players, Healthy Controls

De-identified data will be shared with FITBIR and other data sharing portals