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.

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.

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

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

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

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

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

Former NFL Players with medium cognitive functioning and low concussion history with be included in this group.

Former NFL Players with medium cognitive functioning and medium concussion history with be included in this group.

Former NFL Players with medium cognitive functioning and high concussion history with be included in this group.

Former NFL Players with high cognitive functioning and high concussion history with be included in this group.

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.

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.

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.

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.

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.

The difference in Whole Brain standardized uptake values of SC11 PiB (Amyloid) between time points will be calculated after the second visit.

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.

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.

The difference in Whole Brain standardized uptake values of SC11 PiB (Amyloid) between time points will be calculated after the second visit.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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).

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.

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).

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).

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.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Change in neuro sensory exam findings between timepoints. An increase in number of abnormal findings on the sensory exam would be a negative outcome.

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.

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.

Change from Baseline to 3-Year Follow-Up in the NIH Toolbox Cognitive Composite Score to assess outcome.

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)

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