Current Environment:


The purpose of this 5-year prospective research study is to characterize the association between concussions, sub-concussive exposure, and long-term neurologic health outcomes in former NFL players. To achieve the study aims, the investigators will conduct detailed research visits that include clinical outcome assessments, blood-based biomarkers, advanced magnetic resonance imaging (MRI), positron emission tomography (PET) using investigational tracers and genetic testing. Ultimately, the goal of this study is to translate the findings from this study into clinical, interventional studies for at risk former NFL players.


Concussion, Brain

Recruitment Status

Enrolling by invitation

Detailed Description

There is growing concern that repetitive concussions, or even exposure to sub-concussive blows during collision sports, may be associated with chronic neurologic problems, including CTE. Despite the lay media attributing devastating clinical problems to CTE, no studies conclusively demonstrate a connection between the pathological findings and clinical effects. Experts at the 5th International Conference on Concussion concluded that "a cause-and-effect relationship has not yet been demonstrated between CTE and SRCs [sport-related concussions]" and "the notion that repeated concussion or sub-concussive impacts cause CTE remains unknown." As there are no treatments or prevention strategies available for CTE, some former players who attribute their problems to CTE develop depression, despair, and suicidality. There is a pressing need to understand the risk, incidence, character, progression, and treatment of the neurologic health problems of former NFL players. The investigators propose an in-depth study assessing the association between concussion, sub-concussive exposure, cerebral tau, and clinical outcomes; assessing former NFL players for autoantibodies to cis-tau; assessing carbon monoxide (CO), memantine, environmental enrichment (EE), and cis P-tau antibodies for preventing and treating neurologic sequela of rmTBI. The most promising treatment(s) from preclinical studies will ultimately be translated into clinical trials for individuals identified during the clinical study who are at risk for long-term neurologic health problems. The study will be carried out at 2 sites, The University of North Carolina at Chapel Hill and The Medical College of Wisconsin both at the oversight of the main grant awardee, Boston Children's Hospital. In order to prospectively and longitudinally track progression of neurologic health and assess associations with concussion and sub-concussive exposure the investigators plan to execute multiple study phases: (1) Former National Football League (NFL) Players will complete the General Health Survey (GHS)(part of a previous research study); (2) Stratification based on age and the GHS; (3) Phone Screening with Brief Test of Adult Cognition by Telephone (BTACT); (4) Re-stratification based on BTACT scores; (5) In-Person Neurobiopsychosocial Research Evaluation 1; (6) Annual Follow-Up Health Surveys; and (7) In-Person Neurobiopsychosocial Research Evaluation 2. Based on the stratification above, 250 subjects will be enrolled for In-Person Research Evaluation 1. This cohort will include 100 high cognitive functioning former NFL players, 100 low cognitive functioning former NFL players, and a group of 50 demographically matched healthy controls. Informants of the former NFL subjects, that are selected for In-Person Research Evaluation 1, will also be asked to complete a series of informant-based questionnaires (n=200). Subjects enrolled in the In-Person Research Evaluation 1 will complete an assessment of neurobiopsychosocial function, to include a detailed neuropsychological assessment, patient-reported outcomes, and symptom validity measures. Assessment of neurobiopsychosocial function will also include proteomic and genomic studies, multi-modal magnetic resonance imaging (MRI) and position emission tomography (PET) molecular imaging studies of tau, amyloid and inflammation. Annual follow-up surveys of health status and life function (selected repeat measures from the GHS) will be sent/administered annually for 5 years. Based upon the annual follow-up survey of health status and life function, a subset of former NFL players and all controls will return for second a research assessment of neurobiopsychosocial function that mirrors the in-person research evaluation.

Eligibility Criteria

Inclusion Criteria for Former NFL Player Group:

At least 1 year of participation in National Football League (NFL groups)
Retired from professional football
Ages between 50-70

Inclusion Criteria for Healthy Controls:

No prior exposure to football, collision sports, or prior concussions
They will be matched to former NFL players by age and estimated premorbid intellectual functioning.
Ages between 50-70

Exclusion Criteria:

Any contraindications to MRI, PET, or biological study procedures
History of Moderate or Severe TBI
Current primary Axis I diagnosis of Psychotic Disorder
History or clinical suspicion of other conditions (e.g., epilepsy, stroke, dementia) known to cause cognitive dysfunction
Diagnosis /associated treatment that would preclude participation in full study protocol (e.g., terminal cancer)


Intervention Type

Intervention Name


[11C] PiB


[18F] PBR111


[18F] Flortaucipir


Phase 1



Min Age

50 Years

Max Age

70 Years

Download Date

June 12, 2024

Principal Investigator


Primary Contact Information

For more information on this trial, visit


For more information and to contact the study team:

NFL LONG Prospective Study NCT04263337