The DIAGNOSE-CTE Research Project

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 Lumber 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 Lumber 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 Lumber 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 sever njury
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 kn won 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 kn won to cause QT Prolongation

- If they are unable to consent to study procedures