Brief Summary

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.

Trial Health

On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment

250

participants targeted

Target at P75+ for phase_1

Timeline

27mo left

Started Mar 2020

Longer than P75 for phase_1

Geographic Reach

1 country

3 active sites

Status

active not recruiting

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

8.4 years study duration

Study Progress73%

Mar 2020Aug 2028

First Submitted

Initial submission to the registry

January 31, 2020

Completed

10 days until next milestone

First Posted

Study publicly available on registry

February 10, 2020

Completed

1 month until next milestone

Study Start

First participant enrolled

March 12, 2020

Completed

8.4 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

August 1, 2028

Expected

Same day until next milestone

Study Completion

Last participant's last visit for all outcomes

August 1, 2028

Last Updated

April 22, 2026

Status Verified

April 1, 2026

Enrollment Period

8.4 years

First QC Date

January 31, 2020

Last Update Submit

April 21, 2026

Conditions

Concussion, Brain

Keywords

ConcussionFormer NFL PlayersFootballNeurologicSub-concussive Exposure

Outcome Measures

Primary Outcomes (30)

PET Neuroimaging SUVR Over Time
Positron Emission Tomography (PET) Scan- Standard uptake value ratio (SUVR) of the following tracers: Tau tracer, \[18 F\]Flortaucipir; AV1415 Amyloid tracer, Pittsburgh compound-B (11C-PiB); Neuroinflammation tracer, \[18 F\] peripheral benzodiazepine receptor (PBR111)
Baseline, up to 3 Year Follow-up
MRI Neuroimaging Over Time
Advanced MRI Sequence Structural imaging (T1, T2, T2-FLAIR) Tissue/microstructural organization-Diffusion MRI Cerebral blood flow-Arterial Spin Labeling Susceptibility weighted imaging/quantitative susceptibility mapping Functional MRI- resting state functional MRI
Baseline, up to 3 Year Follow-up
Serum Biomarkers Over Time
Blood collection for analysis of serum markers of neurodegenerative disease and neurodegeneration
Baseline, up to 3 Year Follow-up
Mean Change in Headache Impact Test (HIT-6)
The HIT-6 is a screening measure that assesses the degree to which individual's experiences of headaches impacts their ability to perform daily functional roles. The six-items can be responded to in five ways, which include, never (6-points), rarely (8-points), sometimes (10-points), very often (11-points), and always (13-points).
Baseline, up to 3 Year Follow-up
Mean Change in MDS-UPDRS Score
The MDS-UPDRS evaluates motor and non-motor symptoms in persons with Parkinson's and consists of 4 parts with various questions and evaluations. Parts I and II (non-motor) each contain 13 questions/evaluations, Part III (motor) contains 33 and Part IV (motor) contains 6. Each question/evaluation score ranges from 0 (normal) to 4 (severe). Higher scores indicate a greater impact of Parkinson's disease symptoms (i.e., worse symptoms).
Baseline, up to 3 Year Follow-up
Mean Change in Postural Stability-Sensory Organization Test
The stability-sensory organization test is an index obtained by the NeuroCom Balance System. The minimum score is 0 and there is no specified maximum value. A lower score indicates better postural stability. Postural stability is measured utilizing a dynamic force plate to quantify the vertical forces exerted through the patient's feet to measure center of gravity position and postural control.
Baseline, up to 3 Year Follow-up
Mean Change in Structured Inventory of Malingered Symptomatology (SIMS)
A 75 true-or-false item measures that assesses malingering psychopathology and neuropsychological symptoms. The measure provides an overall score for probably malingering, as well as five subscales; including Psychosis, Low Intelligence, Neurologic Impairment, Affective Disorders, and Amnestic Disorders Endorsement of highly atypical symptoms and endorsement pattern profiles, this measure has demonstrated efficacy in differentiating malingerers from true clinical populations.
Baseline, up to 3 Year Follow-up
Mean Change in Medical Symptom Validity Test (MSVT)
The MSVT is measure typically used in the detection of suboptimal effort. The test consists of a process in which participants are asked to learn 10 word pairs and later recall the word pairs. The minimum score is 0% and the maximum value is 100%.
Baseline, up to 3 Year Follow-up
Mean Change in National Institute of Health (NIH) Toolbox
A computerized measure of cognitive functioning across several domains of cognition developed by the NIH. The Toolbox Cognition measure is comprised of several subtests assessing various domains of cognitive functioning. The minimum score is 0 and there is no maximum score.
Baseline, up to 3 Year Follow-up
Mean Change in Rey Auditory Verbal Learning Test (RAVLT)
The RAVLT is a measure of auditory verbal learning, which is commonly affected among individuals with memory and other related cognitive disorders. Subjects are asked the learn and immediately recall a 15-word list across 5 different trials. They are asked to do the same for second, intrusion list, and then they are asked to recall the first list immediately after. Following a 30 minute delay, participants are asked to spontaneously recall the word list. Immediately following the delay recall trial, recognition memory is tested in a yes/no format where subjects are asked to discriminate words from the original list from novel distractors. The minimum score is 0 and the maximum score is 15.
Baseline, up to 3 Year Follow-up
Mean Change in Dot Counting Test
The Dot Counting Test is a measure effort and validity of session results. Within the measure, subjects are essentially asked to count the number of dots on various stimuli pages. Each specific page has a maximum ranging from 7-28 and the minimum score is 0.
Baseline, up to 3 Year Follow-up
Mean Change in Delis Kaplan Executive Function System (DKEFS) Verbal Fluency, Trailmaking Test (TMT), and Color-Word Interference
The DKEFS is a measure that is associated with integrity and functioning of the frontal system of the brain, or executive functioning. Verbal fluency involves administration of 3 trials in which participants generate words based on letter prompts. The minimum score is 0 and there is no maximum. Two additional trials involving generation of word lists based on categories is also included. The DKEFS TMT is a test of speeded sequencing and set-shifting with sensitivity to sport-related concussion. There are 4 trials consisting of psychomotor speed, number sequencing, letter sequencing, and letter-number sequencing/shifting. The minimum is 0 and there is no maximum. DKEFS Color-Word consists of 4 trials in which participants are timed on (1) colors on the page, (2) read words on the page, (3) inhibit responses of words and state colors that items are printed in, and (4) set-shift in their ability to perform number 3 based on different principles. The minimum is 0 and there is no maximum.
Baseline, up to 3 Year Follow-up
Mean Change in Satisfaction with Life Scale (SWLS) Score
Satisfaction with Life Scale is a short 5-item instrument designed to measure global cognitive judgments of satisfaction with one's life. Questions are responded to on a 7-point Likert scale ranging from 1 (strongly disagree) to 7 (strongly agree). Total scores can be classified at extremely satisfied (31-35), satisfied (26-30), slightly satisfied (21-25), neutral (20), slightly dissatisfied (15-19), dissatisfied (10-14), and extremely dissatisfied (5-9).
Baseline, up to 3 Year Follow-up
Mean Change in Alcohol Use Disorders Identification Test (AUDIT) score
Alcohol Use Disorders Identification Test consists of three domains: Hazardous alcohol use (items 1-3), dependence symptoms (items 4-6), and harmful alcohol use (items 7-10). Participants respond to items on a scale between 0 to 4, and a total score can be calculated based on individual items.
Baseline, up to 3 Year Follow-up
Mean Change in PROMIS Cognitive Functioning Score
The PROMIS Cognitive Function is a self-reported measure that assesses patient-perceived cognitive deficits and the extent to which cognitive impairments interfere with daily functioning. The short-form consists of 4-itens that are scored on a 5-point Likert scale (5-never) to 1 (very often). Raw scores are converted into T-score for each participant. A T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10.
Baseline, up to 3 Year Follow-up
Mean Change in WAIS-IV Coding and Symbol Search
The Coding and Symbol Search subtests of the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) are two subtests that make up the Processing Speed Index of the WAIS-IV. Each subtest requires two minutes to complete and ultimately, reflect the participants ability to complete as many items correctly as possible within the time limit. The minimum score is 0 and the maximum is 60 for Symbol Search and 135 for Coding.
Baseline, up to 3 Year Follow-up
Mean Change in Neuro-Quality Of Life (QOL): Emotional and Behavioral Dyscontrol
This is an eight-item measure from the Neuro-QOL set of tools, which assesses various symptoms and behaviors associated with frontal lobe dysfunction, particularly as it relates to disinhibited actions or behaviors. Items are scored on a five-point Likert scale, ranging from 1 (never) to 5 (always). A T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10.
Baseline, up to 3 Year Follow-up
Mean Change in Frontal systems behavior scale (FrsBe)
The FrSBe is a 46-item self-report measure of various symptoms and behaviors commonly associated with executive dysfunction. On a 5-point Likert scale ranging from 1 to 5, participants endorse the degree to which they experience the symptom/behavior before and after the present illness/injury. A total frontal systems score can be calculated for before and after the injury/illness, as well as three subscales of frontal lobe symptoms or behaviors, including apathy, disinhibition, and executive dysfunction. Raw scores are converted into T-score for each participant. The T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10.
Baseline, up to 3 Year Follow-up
Mean Change in Everyday Cognition assessment (ECog)
This measure is intended to be used as a measure of behaviors typically associated with forgetfulness and other cognitive difficulties. This will aid in identifying neurological health difficulties (i.e., cognitive decline) among those individuals who have limited insight on self-report cognitive functioning measures. The ECog Assessment is comprised of 12-items that are rated on a 4-point Likert scale ranging from 1 (better or no change compared to 10 years earlier) to 4 (consistently much worse). Total scores from the measure are calculated by summing responses on all items and dividing by the number of questions answered.
Baseline, up to 3 Year Follow-up
Mean Change in Minnesota Multiphasic Personality Inventory (MMPI)-2-RF Cognitive Complaints Scale
The cognitive complaints scale is a subscale of the derived from the full MMPI-2-RF. As part of the full instrument, the Cognitive Complaints Scale has been used as an embedded measure of symptom validity. In order to avoid administering the full over 500 item instrument, only the 13-itmes from the Cognitive Complaints Scale are administered in isolation for the current study. Items are presented in a true-false format. This method of administration has been performed in a number of studies in the published literature. A T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10.
Baseline, up to 3 Year Follow-up
Mean Change in PROMIS_29 Score
A self-report 29-itme measure of overall functioning. Participants respond on a Likert scale ranging from 5 (without any difficulty) to 1 (unable to do). The measure generates an overall score of functioning, as well as subscales of physical function, anxiety, depression, fatigue, sleep disturbance, able to participate in social roles/activities, pain interference, and pain intensity. Raw scores are converted into T-score for each participant. The T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10.
Baseline, up to 3 Year Follow-up
Mean Change in Beck Depression Inventory (BDI-II) Score
A 21-item measure inquiring about common symptoms of depression. Each item is measured on a scale from 0-3, with higher numbers reflecting a higher-degree of symptomology over the last 2 weeks for that item. Raw scores can be classified into severity categories, including normal (0-13), mild (14-19), moderate (20-28), and severe (29-63).
Baseline, up to 3 Year Follow-up
Mean Change in Beck Anxiety Inventory (BAI-II)-Score
A 21-item measure of common physiological and worry-related symptoms associated with anxiety. Responses are recorded on a 4-point Likert scale ranging from 0 (not at all) to 3 (severely). Raw scores can be classified into severity categories, including minimal anxiety (0-7), mild anxiety (8-15), moderate (16-25), and severe (26-63).
Baseline, up to 3 Year Follow-up
Mean Change in Neuropsychiatric Inventory Questionnaire NPI-Q2 Score
A measure of common dementia-related behavioral symptoms among older adults. Within the measure 12 domains of these symptoms are recorded, including delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability, and aberrant motor activity night-time behavioral disturbances and appetite, and eating abnormalities. A screening question is asked about each sub-domain. If the responses to these questions indicate that the patient has problems with a particular sub-domain of behavior, the caregiver is only then asked all the questions about that domain, rating the frequency of the symptoms on a 4-point scale, their severity on a 3-point scale, and the distress the symptom causes them on a 5-point scale.
Baseline, up to 3 Year Follow-up
Mean Change in Social Readjustment Rating Scale (SRRS) Score
This 43-item measure quantifies stress associated with common life events (life changing unit), with a unique value associated with each event over a 12-month period. For example, death of a spouse garners a score of 100 and major holidays equals 11 points. The total number of points is summed and a higher score is representative of a greater degree of life-event related distress. A score of 150 life units or less suggests a 30% change of suffering from stress, 150-299 is associated with a 50% chance of suffering from stress, and over 300 life units suggests that the person has an 8% chance of developing a stress related illness.
Baseline, up to 3 Year Follow-up
Mean Change in Ego Resilience Scale (ER89) Score
This is a 14-item measure used to assess resilience in individuals following stressful events. Items are scored on a 4 point Likert Scale ranging from 1-Does not Apply at All, 2-Applies Slightly, 3-Applies Somewhat, and 4- Applies Very Strongly; and scores for each item are summed to obtain a total score. Higher scores indicate a more favorable outcome
Baseline, up to 3 Year Follow-up
Mean Change in Athlete Identity Questionnaire Score
This questionnaire has been adapted from the previously established "Athletic Identity Measurement Scale" for currently active athletes (not retired). Items are scored on a 7 point Likert Scale ranging from 1-Strongly Disagree to 7-Strongly Agree.
Baseline, up to 3 Year Follow-up
Mean Change in Childhood Development and Adversity Questions Score
This is a 33-item questionnaire that was developed from previous work to give insight into childhood experiences, socioeconomic stability, and other important environmental factors that may influence later-life socioeconomic factors, health, and well-being. The questionnaire contains items pertaining to Social and Community Context (1 item), Economic Stability (4 items), Education Access and Quality (1 item), Health Care Access and Quality (2 items), Neighborhood and Built Environment (3 items), and Adverse Childhood Experiences (Emotional Neglect \[6 items\], Financial Need \[2 items\], Parental Intimidation \[4 items\], Parental Violence \[2 items\], and Family Problems and Separation \[4 items\]).
Baseline, up to 3 Year Follow-up
Mean Change in International Physical Activity Questionnaire (IPAQ) Score
This is a 4-item questionnaire intended to obtain data on health-related physical activity. It was developed for both research studies and patient monitoring. Each of the 4 items asks about the number of days per week, and the duration of time in each day participating in different physical activities: vigorous; moderate; walking; and sitting. Answers to these questions will be used to compare to activity recommendations put forth by organizations such as the American College of Sports Medicine.
Baseline, up to 3 Year Follow-up
Mean Change in Rapid Eating Assessment for Participants (REAPS) Score
This is a 16-item questionnaire about the individuals' behaviors regarding food consumption. Participants respond to the first 13 items by selecting from the following options: "Usually/often"; "Sometimes"; "Rarely/Never"; or, when appropriate, a selection that the item does not apply to them. Responses from these first 13 items are then scored and summed into a diet quality score, where the total range of values falls between "13" (lowest quality diet) and "39" (highest quality diet). Items 14 and 15 request "Yes" or "No" responses: 14. "You or a member of your family usually shops and cooks rather than eating sit-down or take-out restaurant food?"; and 15. "Usually feel well enough to shop or cook." The 16th item is answered on a 5-point Likert scale from "1" (Very willing) to "5" (Not at all willing).
Baseline, up to 3 Year Follow-up

Study Arms (10)

Low Cognitive Functioning/Low Concussion History

OTHER

Former NFL players with low cognitive function and low concussion history will be included in this group.