NFL LONG Prospective Study

Neurologic Function Across the Lifespan: A Prospective, LONGitudinal, and Translational Study for Former National Football League Players

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.

Study Overview

• Status: Enrolling by invitation
• Conditions: Concussion, Brain
• Intervention / Treatment: Drug: [11C] PiB; Drug: [18F] PBR111; Drug: [18F] Flortaucipir

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.

• Study Type: Interventional
• Enrollment (Anticipated): 250
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Waltham, Massachusetts, United States, 02453
      • Boston Children's Hospital
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina at Chapel Hill
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 50 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

10

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Low Cognitive Functioning/Low Concussion History; Former NFL players with low cognitive function and low concussion history will be included in this group.	Drug: [11C] PiB; Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: C11 PiB Amyloid; Drug: [18F] PBR111; Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 PBR-111; Drug: [18F] Flortaucipir; Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 T807 Tau
Other: High Cognitive Functioning/ High Concussion History; Former NFL players with high cognitive function and high concussion history will be included in this group.	Drug: [11C] PiB; Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: C11 PiB Amyloid; Drug: [18F] PBR111; Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 PBR-111; Drug: [18F] Flortaucipir; Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 T807 Tau
Other: Low Cognitive Functioning/High Concussion History; Former NFL players with low cognitive function and high concussion history will be included in this group.	Drug: [11C] PiB; Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: C11 PiB Amyloid; Drug: [18F] PBR111; Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 PBR-111; Drug: [18F] Flortaucipir; Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 T807 Tau
Other: High Cognitive Functioning/Low Concussion History; Former NFL players with high cognitive function and low concussion history will be included in this group.	Drug: [11C] PiB; Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: C11 PiB Amyloid; Drug: [18F] PBR111; Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 PBR-111; Drug: [18F] Flortaucipir; Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 T807 Tau
Other: Healthy Male Controls; Healthy male demographically matched controls will be included in this group.	Drug: [11C] PiB; Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: C11 PiB Amyloid; Drug: [18F] PBR111; Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 PBR-111; Drug: [18F] Flortaucipir; Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 T807 Tau
Other: Low Cognitive Functioning/Medium Concussion History; Former NFL players with low cognitive function and medium concussion history will be included in this group.	Drug: [11C] PiB; Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: C11 PiB Amyloid; Drug: [18F] PBR111; Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 PBR-111; Drug: [18F] Flortaucipir; Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 T807 Tau
Other: Medium Cognitive Functioning/Low Concussion History; Former NFL Players with medium cognitive functioning and low concussion history with be included in this group.	Drug: [11C] PiB; Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: C11 PiB Amyloid; Drug: [18F] PBR111; Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 PBR-111; Drug: [18F] Flortaucipir; Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 T807 Tau
Other: Medium Cognitive Functioning/Medium Concussion History; Former NFL Players with medium cognitive functioning and medium concussion history with be included in this group.	Drug: [11C] PiB; Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: C11 PiB Amyloid; Drug: [18F] PBR111; Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 PBR-111; Drug: [18F] Flortaucipir; Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 T807 Tau
Other: Medium Cognitive Functioning/High Concussion History; Former NFL Players with medium cognitive functioning and high concussion history with be included in this group.	Drug: [11C] PiB; Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: C11 PiB Amyloid; Drug: [18F] PBR111; Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 PBR-111; Drug: [18F] Flortaucipir; Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 T807 Tau
Other: High Cognitive Functioning/Medium Concussion History; Former NFL Players with high cognitive functioning and high concussion history with be included in this group.	Drug: [11C] PiB; Per study protocol static PET images will be acquired after IV infusion of CPiB to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: C11 PiB Amyloid; Drug: [18F] PBR111; Per study protocol static PET images will be acquired after IV infusion of F-PBR111 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 PBR-111; Drug: [18F] Flortaucipir; Per study protocol static PET images will be acquired after IV infusion of F-T807 to generate standard uptake values (SUVs). PET imaging is necessary in order to address the primary and secondary outcome measures as a component of neurological health (i.e., presence of proteinopathies empirically associated with neurodegenerative disease, cognitive decline, and neurological signs/symptoms). All groups will participate in this portion of the protocol.; Other Names: F18 T807 Tau

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Whole Brain standardized uptake values (SUV) of SC11 PiB (Amyloid): Baseline	Static PET images will be acquired after IV infusion of C-PIB PET. The study team will rigidly align the PET images of each subject to their corresponding T1-weighted MR images. Based on the subject specific ROI-labeled maps of the T1-weighted MR images, ROI-averaged PET SUV ratios will be extracted as features for group comparison and clinical outcome prediction. After injection of radiotracers, there is a dormant period for the patient of about 45-50 minutes, and the actual imaging is approximately 15-20 minutes. The C-11 tracer has a half-life of 20 minutes. All participants will undergo scans prior to expiration of the half-life.	Baseline
Whole Brain standardized uptake values (SUV) of SC11 PiB (Amyloid): 3-Year Follow-Up	Static PET images will be acquired after IV infusion of C-PIB PET. The study team will rigidly align the PET images of each subject to their corresponding T1-weighted MR images. Based on the subject specific ROI-labeled maps of the T1-weighted MR images, ROI-averaged PET SUV ratios will be extracted as features for group comparison and clinical outcome prediction. After injection of radiotracers, there is a dormant period for the patient of about 45-50 minutes, and the actual imaging is approximately 15-20 minutes. The C-11 tracer has a half-life of 20 minutes. All participants will undergo scans prior to expiration of the half-life.	3-Year Follow-Up
Change in Whole Brain standardized uptake values (SUV) of SC11 PiB (Amyloid) between time points	The difference in Whole Brain standardized uptake values of SC11 PiB (Amyloid) between time points will be calculated after the second visit.	Baseline, 3-Year Follow-Up
Whole Brain standardized uptake values (SUV) of F18 T807 (Tau): Baseline	Static PET images will be acquired after IV infusion of F18 T807 PET. The study team will rigidly align the PET images of each subject to their corresponding T1-weighted MR images. Based on the subject specific ROI-labeled maps of the T1-weighted MR images, ROI-averaged PET SUV ratios will be extracted as features for group comparison and clinical outcome prediction. After injection of radiotracers, there is a dormant period for the patient of about 45-50 minutes, and the actual imaging is approximately 15-20 minutes. The F18 tracer has a half-life of 120 minutes. All participants will undergo scans prior to expiration of the half-life.	Baseline
Whole Brain standardized uptake values (SUV) of F18 T807 (Tau): 3-Year Follow-Up	Static PET images will be acquired after IV infusion of F18 T807 PET. The study team will rigidly align the PET images of each subject to their corresponding T1-weighted MR images. Based on the subject specific ROI-labeled maps of the T1-weighted MR images, ROI-averaged PET SUV ratios will be extracted as features for group comparison and clinical outcome prediction. After injection of radiotracers, there is a dormant period for the patient of about 45-50 minutes, and the actual imaging is approximately 15-20 minutes. The F18 tracer has a half-life of 120 minutes. All participants will undergo scans prior to expiration of the half-life.	3-Year Follow-Up
Change in Whole Brain standardized uptake values (SUV) of F18 T807 (Tau) between time points	The difference in Whole Brain standardized uptake values of SC11 PiB (Amyloid) between time points will be calculated after the second visit.	Baseline, 3-Year Follow-Up
Whole Brain standardized uptake values (SUV) of F18 PBR-111 (Neuroinflammation): Baseline	Static PET images will be acquired after IV infusion of F18 PBR-111 PET. The study team will rigidly align the PET images of each subject to their corresponding T1-weighted MR images. Based on the subject specific ROI-labeled maps of the T1-weighted MR images, ROI-averaged PET SUV ratios will be extracted as features for group comparison and clinical outcome prediction. After injection of radiotracers, there is a dormant period for the patient of about 45-50 minutes, and the actual imaging is approximately 15-20 minutes. The F18 tracer has a half-life of 120 minutes. All participants will undergo scans prior to expiration of the half-life.	Baseline
Whole Brain standardized uptake values (SUV) of F18 PBR-111 (Neuroinflammation): 3-Year Follow-Up	Static PET images will be acquired after IV infusion of F18 PBR-111 PET. The study team will rigidly align the PET images of each subject to their corresponding T1-weighted MR images. Based on the subject specific ROI-labeled maps of the T1-weighted MR images, ROI-averaged PET SUV ratios will be extracted as features for group comparison and clinical outcome prediction. After injection of radiotracers, there is a dormant period for the patient of about 45-50 minutes, and the actual imaging is approximately 15-20 minutes. The F18 tracer has a half-life of 120 minutes. All participants will undergo scans prior to expiration of the half-life.	3-Year Follow-Up
Change in Whole Brain standardized uptake values (SUV) of F18 PBR-111 (Neuroinflammation) between time points	The difference in Whole Brain standardized uptake values of F18 PBR-111 (Neuroinflammation) between time points will be calculated after the second visit.	Baseline, 3-Year Follow-Up
Whole-Brain Cortical Thickness: Baseline	High resolution 3D T1-weighted spoiled gradient-recalled echo (SPGR) images will be obtained and employed for tissue segmentation and volumetric analysis using standardized processing pipelines (e.g., FreeSurfer). Thinner cortices would be considered a worse outcome. There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline
Whole-Brain Cortical Thickness: 3-Year Follow-Up	High resolution 3D T1-weighted spoiled gradient-recalled echo (SPGR) images will be obtained and employed for tissue segmentation and volumetric analysis using standardized processing pipelines (e.g., FreeSurfer). Thinner cortices would be considered a worse outcome. There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	3-Year Follow-Up
Change in Whole-Brain Cortical Thickness between Time Points	The difference in Whole-Brain Cortical Thickness between time points will be assessed. Greater change would be considered a worse outcome. There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline, 3-Year Follow-Up
Whole-Brain Cortical Volume: Baseline	High resolution 3D T1-weighted spoiled gradient-recalled echo (SPGR) images will be obtained and employed for tissue segmentation and volumetric analysis using standardized processing pipelines (e.g., FreeSurfer). Lower cortex volume would be considered a worse outcome. There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline
Whole-Brain Cortical Volume: 3-Year Follow-Up	High resolution 3D T1-weighted spoiled gradient-recalled echo (SPGR) images will be obtained and employed for tissue segmentation and volumetric analysis using standardized processing pipelines (e.g., FreeSurfer). Lower cortex volume would be considered a worse outcome. There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	3-Year Follow-Up
Change in Whole-Brain Cortical Volume between Time Points	The difference in Whole-Brain Cortical Volume between time points will be assessed. Greater difference in cortex volume would be considered a worse outcome. There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline, 3-Year Follow-Up
Whole-Brain Subcortical Volume: Baseline	High resolution 3D T1-weighted spoiled gradient-recalled echo (SPGR) images will be obtained and employed for tissue segmentation and volumetric analysis using standardized processing pipelines (e.g., FreeSurfer). Lower volume would be considered a worse outcome. There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline
Whole-Brain Subcortical Volume: 3-Year Follow-Up	High resolution 3D T1-weighted spoiled gradient-recalled echo (SPGR) images will be obtained and employed for tissue segmentation and volumetric analysis using standardized processing pipelines (e.g., FreeSurfer). Lower volume would be considered a worse outcome. There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	3-Year Follow-Up
Change in Whole-Brain Subcortical Volume between Time Points	The difference in Whole-Brain Subcortical Volume between time points will be assessed. Greater change in volume would be considered a worse outcome. There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline, 3-Year Follow-Up
Whole-Brain White Matter Lesion Volume: Baseline	3D T2-weighted fluid-attenuated inversion recovery (FLAIR) images will be obtained and employed for white matter lesion analysis using standardized processing pipelines (e.g., FreeSurfer). Lower cortex volume would be considered a better outcome. There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline
Whole-Brain White Matter Lesion Volume: 3-Year Follow-Up	3D T2-weighted fluid-attenuated inversion recovery (FLAIR) images will be obtained and employed for white matter lesion analysis using standardized processing pipelines (e.g., FreeSurfer). Lower cortex volume would be considered a better outcome. There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	3-Year Follow-Up
Change in Whole-Brain White Matter Lesion Volume between Time Points	The difference in Whole-Brain White Matter Lesion Volume between time points will be assessed. Lower change in cortex volume would be considered a better outcome. There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline, 3-Year Follow-Up
Tract-Based Diffusion (Fractional Anisotropy [FA]): Baseline	Diffusion tensor imaging (DTI) data will be analyzed using tract-based spatial static analyses in order to study between-group differences. Within the white-matter skeleton, non-parametric permutation-based statistics will be employed in TBSS (i.e., the randomise command) will be used for voxelwise statistical analysis. White-matter voxels will be deemed significant if p < 0.05 after being adjusted for multiple comparisons by controlling false discovery rate (FDR). Higher FA values are considered a normal response to acute traumatic brain injury, and so higher FA in this study will be considered a worse outcome (e.g., residual effects of prior injury or head impact exposure). There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline
Tract-Based Diffusion (Fractional Anisotropy [FA]): 3-Year Follow-Up	Diffusion tensor imaging (DTI) data will be analyzed using tract-based spatial static analyses in order to study between-group differences. Within the white-matter skeleton, non-parametric permutation-based statistics will be employed in TBSS (i.e., the randomise command) will be used for voxelwise statistical analysis. White-matter voxels will be deemed significant if p < 0.05 after being adjusted for multiple comparisons by controlling false discovery rate (FDR). Higher FA values are considered a normal response to acute traumatic brain injury, and so higher FA in this study will be considered a worse outcome (e.g., residual effects of prior injury or head impact exposure). There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	3-Year Follow-Up
Change in Tract-Based Diffusion (Fractional Anisotropy [FA]) between Time Points	The difference in Tract-Based Diffusion (Fractional Anisotropy [FA]) between time points will be assessed. Lower change in cortex volume would be considered a better outcome. Higher FA values are considered a normal response to acute traumatic brain injury, and so larger changes in FA in this study will be considered a worse outcome (e.g., residual effects of prior injury or head impact exposure). There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline, 3-Year Follow-Up
Tract-Based Diffusion (Mean Diffusivity [MD]): Baseline	Diffusion tensor imaging (DTI) data will be analyzed using tract-based spatial static analyses in order to study between-group differences. Within the white-matter skeleton, non-parametric permutation-based statistics will be employed in TBSS (i.e., the randomise command) will be used for voxelwise statistical analysis. White-matter voxels will be deemed significant if p < 0.05 after being adjusted for multiple comparisons by controlling false discovery rate (FDR). Higher MD values are considered a normal response to acute traumatic brain injury, and so higher MD in this study will be considered a worse outcome (e.g., residual effects of prior injury or head impact exposure). There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline
Tract-Based Diffusion (Mean Diffusivity [MD]): 3-Year Follow-Up	Diffusion tensor imaging (DTI) data will be analyzed using tract-based spatial static analyses in order to study between-group differences. Within the white-matter skeleton, non-parametric permutation-based statistics will be employed in TBSS (i.e., the randomise command) will be used for voxelwise statistical analysis. White-matter voxels will be deemed significant if p < 0.05 after being adjusted for multiple comparisons by controlling false discovery rate (FDR). Higher MD values are considered a normal response to acute traumatic brain injury, and so higher MD in this study will be considered a worse outcome (e.g., residual effects of prior injury or head impact exposure). There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	3-Year Follow-Up
Change in Tract-Based Diffusion (Mean Diffusivity [MD]) between Time Points	The difference in Tract-Based Diffusion (Mean Diffusivity [MD]) between time points will be assessed. Lower change in cortex volume would be considered a better outcome. Higher MD values are considered a normal response to acute traumatic brain injury, and so larger changes in MD in this study will be considered a worse outcome (e.g., residual effects of prior injury or head impact exposure). There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline, 3-Year Follow-Up
Tract-Based Diffusion (Axial Diffusivity [AD]): Baseline	Diffusion tensor imaging (DTI) data will be analyzed using tract-based spatial static analyses in order to study between-group differences. Within the white-matter skeleton, non-parametric permutation-based statistics will be employed in TBSS (i.e., the randomise command) will be used for voxelwise statistical analysis. White-matter voxels will be deemed significant if p < 0.05 after being adjusted for multiple comparisons by controlling false discovery rate (FDR). Lower AD values are considered a normal response to acute traumatic brain injury, and so lower AD in this study will be considered a worse outcome (e.g., residual effects of prior injury or head impact exposure). There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline
Tract-Based Diffusion (Axial Diffusivity [AD]): 3-Year Follow-Up	Diffusion tensor imaging (DTI) data will be analyzed using tract-based spatial static analyses in order to study between-group differences. Within the white-matter skeleton, non-parametric permutation-based statistics will be employed in TBSS (i.e., the randomise command) will be used for voxelwise statistical analysis. White-matter voxels will be deemed significant if p < 0.05 after being adjusted for multiple comparisons by controlling false discovery rate (FDR). Lower AD values are considered a normal response to acute traumatic brain injury, and so lower AD in this study will be considered a worse outcome (e.g., residual effects of prior injury or head impact exposure). There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	3-Year Follow-Up
Change in Tract-Based Diffusion (Axial Diffusivity [AD]) between Time Points	The difference in Tract-Based Diffusion (Fractional Anisotropy [FA]) between time points will be assessed. Lower change in cortex volume would be considered a better outcome. Decreased AD values are considered a normal response to acute traumatic brain injury, and so larger changes in AD in this study will be considered a worse outcome (e.g., residual effects of prior injury or head impact exposure). There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline, 3-Year Follow-Up
Tract-Based Diffusion (Radial Diffusivity [RD]): Baseline	Diffusion tensor imaging (DTI) data will be analyzed using tract-based spatial static analyses in order to study between-group differences. Within the white-matter skeleton, non-parametric permutation-based statistics will be employed in TBSS (i.e., the randomise command) will be used for voxelwise statistical analysis. White-matter voxels will be deemed significant if p < 0.05 after being adjusted for multiple comparisons by controlling false discovery rate (FDR). Higher RD values are considered a normal response to acute traumatic brain injury, and so higher RD in this study will be considered a worse outcome (e.g., residual effects of prior injury or head impact exposure). There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline
Tract-Based Diffusion (Radial Diffusivity [RD]): 3-Year Follow-Up	Diffusion tensor imaging (DTI) data will be analyzed using tract-based spatial static analyses in order to study between-group differences. Within the white-matter skeleton, non-parametric permutation-based statistics will be employed in TBSS (i.e., the randomise command) will be used for voxelwise statistical analysis. White-matter voxels will be deemed significant if p < 0.05 after being adjusted for multiple comparisons by controlling false discovery rate (FDR). Higher RD values are considered a normal response to acute traumatic brain injury, and so higher RD in this study will be considered a worse outcome (e.g., residual effects of prior injury or head impact exposure). There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	3-Year Follow-Up
Change in Tract-Based Diffusion (Radial Diffusivity [RD]) between Time Points	The difference in Tract-Based Diffusion (Radial Diffusivity [RD]) between time points will be assessed. Lower change in cortex volume would be considered a better outcome. Higher RD values are considered a normal response to acute traumatic brain injury, and so higher RD changes in this study will be considered a worse outcome (e.g., residual effects of prior injury or head impact exposure). There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline, 3-Year Follow-Up
Resting-State Functional Connectivity (Whole Brain): Baseline	Resting-State Functional MRI (RS-fMRI) data will be processed using a modified Human Connectome Project (HCP) pipeline. The preprocessing steps will take into account the high temporal and spatial resolution nature of the data to effectively reduce noise and artifacts that may affect subsequent functional connectivity analyses. Traditional connectomes based on Pearson correlation, as well as dynamic high-order functional connectomes, will be constructed to comprehensively capture brain functional connectivity. Network-based statistics (NBS) will identify significant differences in components of the unthresholded, undirected connectivity matrices for the Craddock atlas. NBS is a nonparametric test that controls for family-wise error rate (FWER) at the network level using permutation testing. In this work, a primary threshold of t = 2.5 will be used at the edge level and 10,000 permutations will be used to identify significant clusters of supra-threshold nodes (i.e., ROI) at a one-sided	Baseline
Resting-State Functional Connectivity (Whole Brain): 3-Year Follow-Up	Resting-State Functional MRI (RS-fMRI) data will be processed using a modified Human Connectome Project (HCP) pipeline. The preprocessing steps will take into account the high temporal and spatial resolution nature of the data to effectively reduce noise and artifacts that may affect subsequent functional connectivity analyses. Traditional connectomes based on Pearson correlation, as well as dynamic high-order functional connectomes, will be constructed to comprehensively capture brain functional connectivity. Network-based statistics (NBS) will identify significant differences in components of the unthresholded, undirected connectivity matrices for the Craddock atlas. NBS is a nonparametric test that controls for family-wise error rate (FWER) at the network level using permutation testing. In this work, a primary threshold of t = 2.5 will be used at the edge level and 10,000 permutations will be used to identify significant clusters of supra-threshold nodes (i.e., ROI) at a one-sided	3-Year Follow-Up
Change in Whole Brain Resting-State Functional Connectivity between Time Points	The difference in Resting-State Functional Connectivity between time points will be assessed. Lower connectivity values are considered a negative outcome in studies of aging and cognitive function, so greater change in connectivity values in this study will be considered a worse outcome. There is no set range of values for this outcome, and both correlation and group differences will be taken into consideration for the purposes of statistical inference within this study.	Baseline, 3-Year Follow-Up
Collection of Plasma Aliquots at Baseline	At each in person visit a 20 mL of blood will be collected and processed to obtain plasma aliquots. Plasma will be tested for potential biomarkers, mainly proteins believed to be associated with concussion, and sub-concussive blows sustained during sports.	Baseline
Collection of Plasma Aliquots at 3-Year Follow-Up	During the in-person visit 20 mL of blood will be collected and processed to obtain plasma aliquots. Plasma will be tested for potential biomarkers, mainly proteins believed to be associated with concussion, and sub-concussive blows sustained during sports.	3-Year Follow-Up
Change in Plasma Aliquots between Timepoints	Change in plasma biomarker concentration and proteins will be assessed.	Baseline, 3-Year Follow-Up
Collection of Serum Aliquots at Baseline	During the in-person visit 10 mL of blood will be collected and processed to obtain serum aliquots. Serum will be tested for potential biomarkers, mainly proteins believed to be associated with concussion, and sub-concussive blows sustained during sports.	Baseline
Collection of Serum Aliquots at 3-Year Follow-Up	During the in-person visit 10 mL of blood will be collected and processed to obtain serum aliquots. Serum will be tested for potential biomarkers, mainly proteins believed to be associated with concussion, and sub-concussive blows sustained during sports.	3-Year Follow-Up
Change in Serum Aliquots between Timepoints	Change in serum biomarker concentration and proteins will be assessed.	Baseline, 3-Year Follow-Up
Collection of RNA at Baseline	During the in-person visit 2.5 mL of blood will be collected and processed for RNA extraction. RNA will be tested for potential biomarkers, mainly proteins believed to be associated with concussion, and sub-concussive blows sustained during sports.	Baseline
Collection of RNA at 3-Year Follow-Up	During the in-person visit 2.5 mL of blood will be collected and processed for RNA extraction. RNA will be tested for potential biomarkers, mainly proteins believed to be associated with concussion, and sub-concussive blows sustained during sports.	3-Year Follow-Up
Change in RNA between Timepoints	Change in RNA biomarker concentration and proteins will be assessed.	Baseline, 3-Year Follow-Up
Urine Collection at Baseline	During the in-person visit 60 mL of urine will be collected and processed to obtain aliquots. Urine will be tested for potential biomarkers, mainly proteins believed to be associated with concussion, and sub-concussive blows sustained during sports. Urine aliquots will be collected for biomarker assays.	Baseline
Urine Collection at 3-Year Follow-Up	During the in-person visit 60 mL of urine will be collected and processed to obtain aliquots. Urine will be tested for potential biomarkers, mainly proteins believed to be associated with concussion, and sub-concussive blows sustained during sports. Urine aliquots will be collected for biomarker assays.	3-Year Follow-Up
Change in urine collection between Timepoints	Change in urine biomarker concentration and proteins will be assessed.	Baseline, 3-Year Follow-Up
Saliva Collection at Baseline	Saliva will be collected using a salivate for cortisol determination.	Baseline
Saliva Collection at 3-Year Follow-Up	Saliva will be collected using a salivate for cortisol determination.	3-Year Follow-Up
Change in Saliva Collection between Timepoints	Change in cortisol determination based on saliva collected.	Baseline, 3-Year Follow-Up

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Motor Examination of Unified Parkinson's Disease Rating Scale (MDS UPDRS) at Baseline	The UPDRS is a measure originally developed for use in individual's with Parkinson's disease, but has been applied to a wide range of populations of neurodegenerative disorders and the older adult population in general. The MDS portion of the scale assess the motor signs. Scores range from 0 to 68. A higher score indicates greater impairment.	Baseline
Motor Examination of Unified Parkinson's Disease Rating Scale (MDS UPDRS) at 3-Year Follow-Up	The UPDRS is a measure originally developed for use in individual's with Parkinson's disease, but has been applied to a wide range of populations of neurodegenerative disorders and the older adult population in general. The MDS portion of the scale assess the motor signs. Scores range from 0 to 68. A higher score indicates greater impairment.	3-Year Follow-Up
Change in Motor Examination of Unified Parkinson's Disease Rating Scale (MDS UPDRS) between Timepoints	Change in MDS UPDRS scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Headache Impact Test (HIT-6) at Baseline	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). Total scores range from 36-78. Scores above the cut-off of 50 suggest that headaches are excessively impacting the subjects daily functional roles/abilities in a problematic way.	Baseline
Headache Impact Test (HIT-6) at 3-Year Follow-Up	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). Total scores range from 36-78. Scores above the cut-off of 50 suggest that headaches are excessively impacting the subjects daily functional roles/abilities in a problematic way.	3-Year Follow-Up
Change in Headache Impact Test (HIT-6) between Timepoints	Change in HIT-6 scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Structured Inventory of Malingered Symptomatology (SIMS) at Baseline	A 75 true-or-false item measure that assesses malingering psychopathology and neuropsychological symptoms. The measure provides an overall score (range 0-75; clinical cutoff >14) for probably malingering, as well as five subscales (each ranging from 0-15) including: Psychosis (clinical cutoff >1), Low Intelligence (clinical cutoff >2), Neurologic Impairment (clinical cutoff >2), Affective Disorders (clinical cutoff >5), and Amnestic Disorders (clinical cutoff >2). Higher scores indicate greater malingering psychopathology and neuropsychological symptoms.	Baseline
Structured Inventory of Malingered Symptomatology (SIMS) at 3-Year Follow-Up	A 75 true-or-false item measure that assesses malingering psychopathology and neuropsychological symptoms. The measure provides an overall score (range 0-75; clinical cutoff >14) for probably malingering, as well as five subscales (each ranging from 0-15) including: Psychosis (clinical cutoff >1), Low Intelligence (clinical cutoff >2), Neurologic Impairment (clinical cutoff >2), Affective Disorders (clinical cutoff >5), and Amnestic Disorders (clinical cutoff >2). Higher scores indicate greater malingering psychopathology and neuropsychological symptoms.	3-Year Follow-Up
Change in Structured Inventory of Malingered Symptomatology (SIMS) between Timepoints	Change in SIMS scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Wechsler Test of Premorbid Function (TOPF) at Baseline	The TOPF is a word recognition test that administered as an index of estimated premorbid level of intellectual functioning. Raw scores range from 0-70. Standard Score is calculated based on the raw score plus age and demographic questions. Higher scores indicate greater premorbid level of intellectual functioning.	Baseline
Wechsler Test of Premorbid Function (TOPF) at 3-Year Follow-Up	The TOPF is a word recognition test that administered as an index of estimated premorbid level of intellectual functioning. Raw scores range from 0-70. Standard Score is calculated based on the raw score plus age and demographic questions. Higher scores indicate greater premorbid level of intellectual functioning.	3-Year Follow-Up
Change in Wechsler Test of Premorbid Function (TOPF) between Timepoints	Change in TOPF scores between Baseline and the 3-Year Follow-Up will be assessed. A decrease in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Rey Auditory Verbal Learning Test (RAVLT) at Baseline	The RAVLT is a measure of auditory verbal learning, which is commonly affected among individuals with memory and other related cognitive disorders. Raw scores range from	Baseline
Rey Auditory Verbal Learning Test (RAVLT) at 3-Year Follow-Up	The RAVLT is a measure of auditory verbal learning, which is commonly affected among individuals with memory and other related cognitive disorders. Raw scores range from	3-Year Follow-Up
Change in Rey Auditory Verbal Learning Test (RAVLT) between Timepoints	Change in RAVLT scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Dot Counting Test at Baseline	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, which is an over learned skill that is persevered the majority of head injuries and neurological conditions. Poor performance on this measure is often indicative of suboptimal effort based on previously established cutoffs.	Baseline
Dot Counting Test at 3-Year Follow-Up	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, which is an over learned skill that is persevered the majority of head injuries and neurological conditions. Poor performance on this measure is often indicative of suboptimal effort based on previously established cutoffs.	3-Year Follow-Up
Change in Dot Counting Test between Timepoints	Change in Dot Counting scores between Baseline and the 3-Year Follow-Up will be assessed. A decrease in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Delis Kaplan Executive Function System (DKEFS) Trailmaking Test (TMT) at Baseline	The DKEFS is a measure that is comprised of tasks and items that are associated with integrity and functioning of the frontal system of the brain, or executive functioning. The DKEFS TMT is a paper-and-pencil test of speeded sequencing and set-shifting with documented sensitivity to sport-related concussion. There are four trials consisting of psychomotor speed, number sequencing, letter sequencing, and letter-number sequencing/shifting. Raw scores will be compared to age stratified normative data. There is no set range of outcome scores.	Baseline
Delis Kaplan Executive Function System (DKEFS) Trailmaking Test (TMT) at 3-Year Follow-Up	The DKEFS is a measure that is comprised of tasks and items that are associated with integrity and functioning of the frontal system of the brain, or executive functioning. The DKEFS TMT is a paper-and-pencil test of speeded sequencing and set-shifting with documented sensitivity to sport-related concussion. There are four trials consisting of psychomotor speed, number sequencing, letter sequencing, and letter-number sequencing/shifting. Raw scores will be compared to age stratified normative data. There is no set range of outcome scores.	3-Year Follow-Up
Change in Delis Kaplan Executive Function System (DKEFS) Trailmaking Test (TMT) between Timepoints	Change in DKEFS TMT scores between Baseline and the 3-Year Follow-Up will be assessed. A decrease in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Delis Kaplan Executive Function System (DKEFS) Color-Word Interference at Baseline	The DKEFS is a measure that is comprised of tasks and items that are associated with integrity and functioning of the frontal system of the brain, or executive functioning. DKEFS Color-Word Interference Test consists of four trials in which participants are timed in their ability to as quickly as possible state (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. Raw scores will be compared to age stratified normative data. There is no set range of outcome scores.	Baseline
Delis Kaplan Executive Function System (DKEFS) Color-Word Interference at 3-Year Follow-Up	The DKEFS is a measure that is comprised of tasks and items that are associated with integrity and functioning of the frontal system of the brain, or executive functioning. DKEFS Color-Word Interference Test consists of four trials in which participants are timed in their ability to as quickly as possible state (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. Raw scores will be compared to age stratified normative data. There is no set range of outcome scores.	3-Year Follow-Up
Change in Delis Kaplan Executive Function System (DKEFS) Color-Word Interference between Timepoints	Change in DKEFS Color-Word Interference scores between Baseline and the 3-Year Follow-Up will be assessed. A decrease in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Delis Kaplan Executive Function System (DKEFS) Verbal Fluency at Baseline	The DKEFS is a measure that is comprised of tasks and items that are associated with integrity and functioning of the frontal system of the brain, or executive functioning. Verbal fluency involves administration of three trials in which participants generate words based on letter prompts. Two additional trials involving participants generation of word lists based on categories is also including on the test. Raw scores will be compared to age stratified normative data. There is no set range of outcome scores.	Baseline
Delis Kaplan Executive Function System (DKEFS) Verbal Fluency at 3-Year Follow-Up	The DKEFS is a measure that is comprised of tasks and items that are associated with integrity and functioning of the frontal system of the brain, or executive functioning. Verbal fluency involves administration of three trials in which participants generate words based on letter prompts. Two additional trials involving participants generation of word lists based on categories is also including on the test. Raw scores will be compared to age stratified normative data. There is no set range of outcome scores.	3-Year Follow-Up
Change in Delis Kaplan Executive Function System (DKEFS) Verbal Fluency between Timepoints	Change in DKEFS Verbal Fluency scores between Baseline and the 3-Year Follow-Up will be assessed. A decrease in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) at Baseline	Within the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) are two subtests that make up the Processing Speed Index of the WAIS-IV, the coding subtest (raw score range from 0-135) and the symbol search subtest (raw score range from 0-60). Scores are then scaled based on raw scores.	Baseline
Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) at 3-Year Follow-Up	Within the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) are two subtests that make up the Processing Speed Index of the WAIS-IV, the coding subtest (raw score range from 0-135) and the symbol search subtest (raw score range from 0-60). Higher scores indicate greater processing speed. Scores are then scaled based on raw scores.	3-Year Follow-Up
Change in Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) between Timepoints	Change in WAIS-IV scores between Baseline and the 3-Year Follow-Up will be assessed. A decrease in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
PROMIS Cognitive Functioning Short form v2.0 at Baseline	The Patient-Reported Outcomes Measurement Information System (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-items scored on a 5-point Likert scale (5-never) to 1 (very often). Raw scores (range 4-20) are converted into T-scores for each participant. A T-score rescales the raw score into a standardized score with a distribution mean of 50 and a standard deviation (SD) of 10 according to values available on healthmeasures.net	Baseline
PROMIS Cognitive Functioning Short form v2.0 at 3-Year Follow-Up	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-items scored on a 5-point Likert scale (5-never) to 1 (very often). Raw scores (range 4-20) are converted into T-scores for each participant. A T-score rescales the raw score into a standardized score with a distribution mean of 50 and a standard deviation (SD) of 10 according to values available on healthmeasures.net	3-Year Follow-Up
Change in PROMIS Cognitive Functioning Short form v2.0 between Timepoints	Change in PROMIS Cognitive Functioning scores between Baseline and the 3-Year Follow-Up will be assessed. A decrease in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Neuro- Quality of Life (QOL) Cognitive Domain (short-form) at Baseline	This measure is designed for neurological impaired populations. Neuro-QOL seeks to incorporate patient reported outcomes of functioning, such as social, psychological, and mental well-being. The measure consists of 8-items reflecting these areas, with a five-point Likert scale response, ranging from 1 (very often/several times perf day) to 5 (never). Total raw score ranges from 8-40. A T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10 according to values available on healthmeasures.net.	Baseline
Neuro- Quality of Life (QOL) Cognitive Domain (short-form) at 3-Year Follow-Up	This measure is designed for neurological impaired populations. Neuro-QOL seeks to incorporate patient reported outcomes of functioning, such as social, psychological, and mental well-being. The measure consists of 8-items reflecting these areas, with a five-point Likert scale response, ranging from 1 (very often/several times perf day) to 5 (never). Total raw score ranges from 8-40. A T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10 according to values available on healthmeasures.net.	3-Year Follow-Up
Change in Neuro- Quality of Life (QOL) Cognitive Domain (short-form) between Timepoints	Change in Neuro- Quality of Life (QOL) Cognitive Domain scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Neuro-QOL: Emotional and Behavioral Dyscontrol Baseline	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). Total raw score ranges from 8-40. A T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10 according to values available on healthmeasures.net.	Baseline
Neuro-QOL: Emotional and Behavioral Dyscontrol at 3-Year Follow-Up	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). Total raw score ranges from 8-40. A T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10 according to values available on healthmeasures.net.	3-Year Follow-Up
Change in Neuro-QOL: Emotional and Behavioral Dyscontrol between Timepoints	Change in Neuro-QOL: Emotional and Behavioral Dyscontrol scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Frontal systems behavior scale (FrsBe) at Baseline	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
Frontal systems behavior scale (FrsBe) at 3-Year Follow-Up	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.	3-Year Follow-Up
Change in Frontal systems behavior scale (FrSBe) between Timepoints	Change in FrSBe scores between Baseline and the 3-Year Follow-Up will be assessed. A decrease in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Everyday Cognition Assessment (ECog) at Baseline	This measure is intended to be used as a measure of behaviors typically associated with forgetfulness and other cognitive difficulties. 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 range from 1-4 with greater scores indicating greater cognitive difficulties.	Baseline
Everyday Cognition Assessment (ECog) at 3-Year Follow-Up	This measure is intended to be used as a measure of behaviors typically associated with forgetfulness and other cognitive difficulties. 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) indicating with greater cognitive difficulties.	3-Year Follow-Up
Change in Everyday Cognition Assessment (ECog) between Timepoints	Change in ECog scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Minnesota Multiphasic Personality Inventory (MMPI)-2-RF Cognitive Complaints Scale at Baseline	The cognitive complaints scale is a subscale of the derived from the full MMPI-2-RF. Only the 10-items from the Cognitive Complaints Scale is administered in isolation for the current study. Raw score ranges from 0-10. A T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10.	Baseline
Minnesota Multiphasic Personality Inventory (MMPI)-2-RF Cognitive Complaints Scale at 3-Year Follow-Up	The cognitive complaints scale is a subscale of the derived from the full MMPI-2-RF. Only the 10-items from the Cognitive Complaints Scale is administered in isolation for the current study. Raw score ranges from 0-10. A T-score rescales the raw score into a standardized score with a mean of 50 and a standard deviation (SD) of 10.	3-Year Follow-Up
Change in Minnesota Multiphasic Personality Inventory (MMPI)-2-RF Cognitive Complaints Scale between Timepoints	Change in MMPI-2 RF scores between Baseline and the 3-Year Follow-Up will be assessed. A decrease in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
PROMIS 29 at Baseline	A self-report 29-item 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 (raw score range 4-20), anxiety (raw score range 4-20), depression (raw score range 4-20), fatigue (raw score range 4-20), sleep disturbance (raw score range 4-20), able to participate in social roles/activities (raw score range 4-20), pain interference (raw score range 4-20), and pain intensity (raw score range 0-10). 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 according to values available on healthmeasures.net.	Baseline
PROMIS 29 at 3-Year Follow-Up	A self-report 29-item 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 (raw score range 4-20), anxiety (raw score range 4-20), depression (raw score range 4-20), fatigue (raw score range 4-20), sleep disturbance (raw score range 4-20), able to participate in social roles/activities (raw score range 4-20), pain interference (raw score range 4-20), and pain intensity (raw score range 0-10). 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 according to values available on healthmeasures.net.	3-Year Follow-Up
Change in PROMIS 29 between Timepoints	Change in PROMIS 29 scores between Baseline and the 3-Year Follow-Up will be assessed. A decrease in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Beck Depression Inventory (BDI-II) at Baseline	The BDI-II is 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 (range 0-63) can be classified into severity categories, including normal (0-13), mild (14-19), moderate (20-28), and severe (29-63).	Baseline
Beck Depression Inventory (BDI-II) at 3-Year Follow-Up	The BDI-II is 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 (range 0-63) can be classified into severity categories, including normal (0-13), mild (14-19), moderate (20-28), and severe (29-63).	3-Year Follow-Up
Change in Beck Depression Inventory (BDI-II)	Change in BDI-II scores between Baseline and the 3-Year Follow-Up. An increase in score between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Beck Anxiety Inventory (BAI-II) at Baseline	The BAI-II is 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 (range 0-63) can be classified into severity categories, including minimal anxiety (0-7), mild anxiety (8-15), moderate (16-25), and severe (26-63).	Baseline
Beck Anxiety Inventory (BAI-II) at 3-Year Follow-Up	The BAI-II is 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 (range 0-63) can be classified into severity categories, including minimal anxiety (0-7), mild anxiety (8-15), moderate (16-25), and severe (26-63).	3-Year Follow-Up
Change in Beck Anxiety Inventory (BAI-II) between Timepoints	Change in BAI-II scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Neuropsychiatric Inventory Questionnaire (NPI-Q2) at Baseline	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
Neuropsychiatric Inventory Questionnaire (NPI-Q2) at 3-Year Follow-Up	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.	3-Year Follow-Up
Change in Neuropsychiatric Inventory Questionnaire (NPI-Q2) between Timepoints	Change in NPI-Q2 scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Satisfaction with Life Scale (SWLS) at Baseline	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
Satisfaction with Life Scale (SWLS) at 3-Year Follow-Up	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).	3-Year Follow-Up
Change in Satisfaction with Life Scale (SWLS) between Timepoints	Change in SWLS scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Alcohol Use Disorders Identification Test (AUDIT) at Baseline	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. A total score (range 0-40) can be calculated based on individual items. A score of 8 or more is associated with harmful or hazardous drinking, and 15 or more in men, is likely to indicate alcohol dependence.	Baseline
Alcohol Use Disorders Identification Test (AUDIT) at 3-Year Follow-Up	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. A total score (range 0-40) can be calculated based on individual items. A score of 8 or more is associated with harmful or hazardous drinking, and 15 or more in men, is likely to indicate alcohol dependence.	3-Year Follow-Up
Change in Alcohol Use Disorders Identification Test (AUDIT) between Timepoints	Change in AUDIT scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Drug Abuse Screening Test-10 (DAST-10) at Baseline	The DAST-10 is a measure inquiring about drug use (not including alcohol over the past 12 months. Questions are answered in a yes-no format and involve questions about use, behaviors, and consequences of use. Total scores range from 0-10 and a can be classified into no problems reported (0), low level (1-2), moderate level (3-5), substantial level (6-8), and severe level (9-10).	Baseline
Drug Abuse Screening Test-10 (DAST-10) at 3-Year Follow-Up	The DAST-10 is a measure inquiring about drug use (not including alcohol over the past 12 months. Questions are answered in a yes-no format and involve questions about use, behaviors, and consequences of use. Total scores range from 0-10 and a can be classified into no problems reported (0), low level (1-2), moderate level (3-5), substantial level (6-8), and severe level (9-10).	3-Year Follow-Up
Change in Drug Abuse Screening Test-10 (DAST-10) between Timepoints	Change in DAST-10 scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Pittsburgh Sleep Quality Inventory (PSQI) at Baseline	PSQI is an effective instrument used to measure the quality and patterns of sleep in adults. It differentiates "poor" from "good" sleep quality by measuring seven areas (components): subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction over the last month. Scoring of the answers is based on a 0 to 3 scale, whereby 3 reflects the negative extreme on the Likert Scale. A global sum of "5" or greater indicates a "poor" sleeper.	Baseline
Pittsburgh Sleep Quality Inventory (PSQI) at 3-Year Follow-Up	PSQI is an effective instrument used to measure the quality and patterns of sleep in adults. It differentiates "poor" from "good" sleep quality by measuring seven areas (components): subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction over the last month. Scoring of the answers is based on a 0 to 3 scale, whereby 3 reflects the negative extreme on the Likert Scale. A global sum of "5" or greater indicates a "poor" sleeper.	3-Year Follow-Up
Change in Pittsburgh Sleep Quality Inventory (PSQI) between Timepoints	Change in PSQI scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Circadian Sleep Inventory (REM 6 items) at Baseline	This is a 16-item measure attempting to assess sleep quantity, as well as quality. Items are scored in two ways, including how often and how severe each symptom/behavior is present. If symptoms are endorsed (yes/no), the frequency of symptoms, is measured on a scale ranging from 1 (less than once per week) to 4 (every day) with total score ranging from 0-40. Severity of symptoms is measured on a scale of 1 (mild-moderate) to 2 (moderate-severe) with a total score ranging from 0-24. Higher scores indicate more frequency of symptoms and/or greater severity of symptoms.	Baseline
Circadian Sleep Inventory (REM 6 items) at 3-Year Follow-Up	This is a 16-item measure attempting to assess sleep quantity, as well as quality. Items are scored in two ways, including how often and how severe each symptom/behavior is present. If symptoms are endorsed (yes/no), the frequency of symptoms, is measured on a scale ranging from 1 (less than once per week) to 4 (every day) with total score ranging from 0-40. Severity of symptoms is measured on a scale of 1 (mild-moderate) to 2 (moderate-severe) with a total score ranging from 0-24. Higher scores indicate more frequency of symptoms and/or greater severity of symptoms.	3-Year Follow-Up
Change in Circadian Sleep Inventory (REM 6 items) between Timepoints	Change in Circadian Sleep Inventory scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Social Readjustment Rating Scale (SRRS) at Baseline	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. 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
Social Readjustment Rating Scale (SRRS) at 3-Year Follow-Up	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. 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.	3-Year Follow-Up
Change in Social Readjustment Rating Scale (SRRS) between Timepoints	Change in SRRS scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Ascertain Dementia 8-Item (AD-8) Screening Interview Score at Baseline	This is a 8-item measure to help discriminate between signs of normal aging and mild dementia. The AD8 contains 8-items that test for memory, orientation, judgement, and function.Total score ranges from 0-16. Cut points for individual items are 0-1 normal cognition, or 2 or greater cognitive impairment. Scores in the impaired range indicate a need for further diagnostic assessment.	Baseline
Ascertain Dementia 8-Item (AD-8) Screening Interview Score at 3-Year Follow-Up	This is a 8-item measure to help discriminate between signs of normal aging and mild dementia. The AD8 contains 8-items that test for memory, orientation, judgement, and function.Total score ranges from 0-16. Cut points for individual items are 0-1 normal cognition, or 2 or greater cognitive impairment. Scores in the impaired range indicate a need for further diagnostic assessment.	3-Year Follow-Up
Change in Ascertain Dementia 8-Item (AD-8) Screening Interview between Timepoints	Change in AD8 scores between Baseline and the 3-Year Follow-Up will be assessed. An increase in scores between timepoints would be considered a worse outcome.	Baseline, 3-Year Follow-Up
Body Composition at Baseline	Body composition will be assessed using DEXA. The DEXA uses two, low-dose x-ray beams to measure differences in composition of different tissues in the body such as bones, muscle, and fat.	Baseline
Body Composition at 3-Year Follow-Up	Body composition will be assessed using DEXA. The DEXA uses two, low-dose x-ray beams to measure differences in composition of different tissues in the body such as bones, muscle, and fat.	3-Year Follow-Up
Change in Body Composition between Timepoints	Change in body composition based on the DEXA between Baseline and the 3-Year Follow-Upwill be assessed. An increase in body composition would be a negative outcome.	Baseline, 3-Year Follow-Up
Total Body Water Measurement at Baseline	Total body water measurement will be determined by sending a small electronic current through the body. This measure will be used with the DEXA scan to determine body composition.	Baseline
Total Body Water Measurement at 3-Year Follow-Up	Total body water measurement will be determined by sending a small electronic current through the body. This measure will be used with the DEXA scan to determine body composition.	3-Year Follow-Up
Change in Total Body Water Measurement between Timepoints	Change in body composition based on the total body water measurement between Baseline and the 3-Year Follow-Up will be assessed. An increase in body composition would be a negative outcome.	Baseline, 3-Year Follow-Up
Waist to Hip Ratio at Baseline	Waist to hip ratio is a measurement used to help determine obesity and can be an indicator of more serious health problems. This measurement will be used with the total body water measurement and the DEXA scan to determine overall body composition.	Baseline
Waist to Hip Ratio at 3-Year Follow-Up	Waist to hip ratio is a measurement used to help determine obesity and can be an indicator of more serious health problems. This measurement will be used with the total body water measurement and the DEXA scan to determine overall body composition.	3-Year Follow-Up
Change in Waist to Hip Ratio between Timepoints	Change in body composition waist to hip ratio between Baseline and the 3-Year Follow-Up will be assessed. An increase in body composition would be a negative outcome.	Baseline, 3-Year Follow-Up
Neuro Sensory Exam at Baseline	The sensory exam is a measurement used to determine neurological functioning and can be an indicator of more serious health problems. Findings on this measurement will be considered normal or abnormal, with abnormal findings being indicative of less neurological functioning.	Baseline
Neuro Sensory Exam at 3-Year Follow-Up	The sensory exam is a measurement used to determine neurological functioning and can be an indicator of more serious health problems. Findings on this measurement will be considered normal or abnormal, with abnormal findings being indicative of less neurological functioning.	3-Year Follow-Up
Change in Neuro Sensory Exam between Timepoints	Change in neuro sensory exam findings between timepoints. An increase in number of abnormal findings on the sensory exam would be a negative outcome.	Baseline, 3-Year Follow-Up
National Institute of Health (NIH) Toolbox Cognitive Battery at Baseline	A computerized measure of cognitive functioning across several domains of cognition developed by the NIH. A higher composite score indicates better cognitive performance. NIH Toolbox software calculates total composite score by averaging the normalized scores of each subscale and then deriving scale scores. The "NIH Toolbox Scoring and Interpretation Guide" (found online) doesn't indicate a total composite score range (because the score ranges are infinite), but describes scoring as follows: To get a normalized composite score, the score of the test taker is compared to the scores in the NIH Toolbox nationally representative normative sample. The mean score is 100 and the standard deviation (SD) is 15.	Baseline
NIH Toolbox Cognitive Battery at 3-Year Follow-Up	A computerized measure of cognitive functioning across several domains of cognition developed by the NIH. A higher composite score indicates better cognitive performance. NIH Toolbox software calculates total composite score by averaging the normalized scores of each subscale and then deriving scale scores. The "NIH Toolbox Scoring and Interpretation Guide" (found online) doesn't indicate a total composite score range (because the score ranges are infinite), but describes scoring as follows: To get a normalized composite score, the score of the test taker is compared to the scores in the NIH Toolbox nationally representative normative sample. The mean score is 100 and the standard deviation (SD) is 15.	3-Year Follow-Up
Change in NIH Toolbox Cognitive Battery between Timepoints	Change from Baseline to 3-Year Follow-Up in the NIH Toolbox Cognitive Composite Score to assess outcome.	Baseline, 3-Year Follow-Up

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Collaborators: Boston Children's Hospital; Medical College of Wisconsin; National Football League
• Investigators: Principal Investigator: William Meehan, MD, Boston Children's Hospital; Principal Investigator: Michael McCrea, PhD, Medical College of Wisconsin; Principal Investigator: Jason Mihalik, PhD, University of North Carolina, Chapel Hill

Publications and helpful links

General Publications

• Randolph C, Karantzoulis S, Guskiewicz K. Prevalence and characterization of mild cognitive impairment in retired national football league players. J Int Neuropsychol Soc. 2013 Sep;19(8):873-80. doi: 10.1017/S1355617713000805. Epub 2013 Aug 1.
• Guskiewicz KM, Marshall SW, Bailes J, McCrea M, Cantu RC, Randolph C, Jordan BD. Association between recurrent concussion and late-life cognitive impairment in retired professional football players. Neurosurgery. 2005 Oct;57(4):719-26; discussion 719-26. doi: 10.1093/neurosurgery/57.4.719.
• Kerr ZY, Marshall SW, Harding HP Jr, Guskiewicz KM. Nine-year risk of depression diagnosis increases with increasing self-reported concussions in retired professional football players. Am J Sports Med. 2012 Oct;40(10):2206-12. doi: 10.1177/0363546512456193. Epub 2012 Aug 24.
• Clark MD, Varangis EML, Champagne AA, Giovanello KS, Shi F, Kerr ZY, Smith JK, Guskiewicz KM. Effects of Career Duration, Concussion History, and Playing Position on White Matter Microstructure and Functional Neural Recruitment in Former College and Professional Football Athletes. Radiology. 2018 Mar;286(3):967-977. doi: 10.1148/radiol.2017170539. Epub 2017 Oct 31.
• Meehan WP 3rd, Taylor AM, Berkner P, Sandstrom NJ, Peluso MW, Kurtz MM, Pascual-Leone A, Mannix R. Division III Collision Sports Are Not Associated with Neurobehavioral Quality of Life. J Neurotrauma. 2016 Jan 15;33(2):254-9. doi: 10.1089/neu.2015.3930. Epub 2015 Jul 20.
• Mannix R, Meehan WP 3rd, Pascual-Leone A. Sports-related concussions - media, science and policy. Nat Rev Neurol. 2016 Aug;12(8):486-90. doi: 10.1038/nrneurol.2016.99. Epub 2016 Jul 1.
• Carson A. Concussion, dementia and CTE: are we getting it very wrong? J Neurol Neurosurg Psychiatry. 2017 Jun;88(6):462-464. doi: 10.1136/jnnp-2016-315510. Epub 2017 Apr 10. No abstract available. Erratum In: J Neurol Neurosurg Psychiatry. 2018 Aug;89(8):e7.
• Meehan W 3rd, Mannix R, Zafonte R, Pascual-Leone A. Chronic traumatic encephalopathy and athletes. Neurology. 2015 Oct 27;85(17):1504-11. doi: 10.1212/WNL.0000000000001893. Epub 2015 Aug 7.
• Deshpande SK, Hasegawa RB, Rabinowitz AR, Whyte J, Roan CL, Tabatabaei A, Baiocchi M, Karlawish JH, Master CL, Small DS. Association of Playing High School Football With Cognition and Mental Health Later in Life. JAMA Neurol. 2017 Aug 1;74(8):909-918. doi: 10.1001/jamaneurol.2017.1317.
• Baugh CM, Kroshus E, Kiernan PT, Mendel D, Meehan WP 3rd. Football Players' Perceptions of Future Risk of Concussion and Concussion-Related Health Outcomes. J Neurotrauma. 2017 Feb 15;34(4):790-797. doi: 10.1089/neu.2016.4585. Epub 2016 Sep 16.
• Zemlan FP, Jauch EC, Mulchahey JJ, Gabbita SP, Rosenberg WS, Speciale SG, Zuccarello M. C-tau biomarker of neuronal damage in severe brain injured patients: association with elevated intracranial pressure and clinical outcome. Brain Res. 2002 Aug 23;947(1):131-9. doi: 10.1016/s0006-8993(02)02920-7.
• Van Essen DC, Smith SM, Barch DM, Behrens TE, Yacoub E, Ugurbil K; WU-Minn HCP Consortium. The WU-Minn Human Connectome Project: an overview. Neuroimage. 2013 Oct 15;80:62-79. doi: 10.1016/j.neuroimage.2013.05.041. Epub 2013 May 16.
• Smith SM, Beckmann CF, Andersson J, Auerbach EJ, Bijsterbosch J, Douaud G, Duff E, Feinberg DA, Griffanti L, Harms MP, Kelly M, Laumann T, Miller KL, Moeller S, Petersen S, Power J, Salimi-Khorshidi G, Snyder AZ, Vu AT, Woolrich MW, Xu J, Yacoub E, Ugurbil K, Van Essen DC, Glasser MF; WU-Minn HCP Consortium. Resting-state fMRI in the Human Connectome Project. Neuroimage. 2013 Oct 15;80:144-68. doi: 10.1016/j.neuroimage.2013.05.039. Epub 2013 May 20.
• Glasser MF, Sotiropoulos SN, Wilson JA, Coalson TS, Fischl B, Andersson JL, Xu J, Jbabdi S, Webster M, Polimeni JR, Van Essen DC, Jenkinson M; WU-Minn HCP Consortium. The minimal preprocessing pipelines for the Human Connectome Project. Neuroimage. 2013 Oct 15;80:105-24. doi: 10.1016/j.neuroimage.2013.04.127. Epub 2013 May 11.
• Hampshire A, MacDonald A, Owen AM. Hypoconnectivity and hyperfrontality in retired American football players. Sci Rep. 2013 Oct 17;3:2972. doi: 10.1038/srep02972.
• Kaushal M, Espana LY, Nencka AS, Wang Y, Nelson LD, McCrea MA, Meier TB. Resting-state functional connectivity after concussion is associated with clinical recovery. Hum Brain Mapp. 2019 Mar;40(4):1211-1220. doi: 10.1002/hbm.24440. Epub 2018 Nov 19.

Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2020
• Primary Completion (Anticipated): December 1, 2025
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: January 31, 2020
• First Submitted That Met QC Criteria: February 6, 2020
• First Posted (Actual): February 10, 2020

Study Record Updates

• Last Update Posted (Estimate): December 7, 2022
• Last Update Submitted That Met QC Criteria: December 5, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: Concussion; Football; Former NFL Players; Neurologic; Sub-concussive Exposure
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Head Injuries, Closed; Wounds, Nonpenetrating; Brain Injuries; Brain Injuries, Traumatic; Brain Concussion
• Other Study ID Numbers: 19-1065

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No