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AbstractObjectiveMethodsConclusionsThe long-recognized association of brain injury with increased risk of dementia has undergone significant refinement and more detailed study in recent decades. Chronic traumatic encephalopathy (CTE) is a specific neurodegenerative tauopathy related to prior exposure to repetitive head impacts (RHI). We aim to contextualize CTE within a historical perspective and among emerging data which highlights the scientific and conceptual evolution of CTE-related research in parallel with the broader field of neurodegenerative disease and dementia.We provide a narrative state-of-the-science update on CTE neuropathology, clinical manifestations, biomarkers, different types and patterns of head impact exposure relevant for CTE, and the complicated influence of neurodegenerative co-pathology on symptoms.Now almost 20 years since the initial case report of CTE in a former American football player, the field of CTE continues evolving with increasing clarity but also several ongoing controversies. Our understanding of CTE neuropathology outpaces that of disease-specific clinical correlates or the development of in-vivo biomarkers. Diagnostic criteria for symptoms attributable to CTE are still being validated, but leveraging increasingly available biomarkers for other conditions like Alzheimer’s disease may be helpful for informing the CTE differential diagnosis. As diagnostic refinement efforts advance, clinicians should provide care and/or referrals to providers best suited to treat an individual patient’s clinical symptoms, many of which have evidence-based behavioral treatment options that are etiologically agnostic. Several ongoing research initiatives and the gradual accrual of gold standard clinico-pathological data will pay dividends for advancing the many existing gaps in the field of CTE. [ABSTRACT FROM AUTHOR]

AbstractObjective: The long-term health of former athletes with a history of multiple concussions and/or repetitive head impact (RHI) exposure has been of growing interest among the public. The true proportion of dementia cases attributable to neurotrauma and the neurobehavioral profile/sequelae of multiple concussion and RHI exposure among athletes has been difficult to determine. Methods: Across three exposure paradigms (i.e. group comparisons of athletes vs. controls, number of prior concussions, and level of RHI exposure), this review characterizes the prevalence of neurodegenerative/neurological disease, changes in cognitive and psychiatric function, and alterations on neuroimaging. We highlight sources of variability across studies and provide suggested directions for future investigations. Results: The most robust finding reported in the literature suggests a higher level of symptom endorsement (general, psychiatric, and cognitive) among those with a greater history of sport-related concussion from adolescence to older adulthood. Pathological processes (e.g. atrophy, tau deposition, and hypometabolism) may be more likely to occur within select regions (frontal and temporal cortices) and structures (thalamus and hippocampus). However, studies examining concussion(s) and RHI exposure with imaging outcomes have yet to identify consistent associations or evidence of a dose-response relationship or a threshold at which associations are observed. Discussion: Studies have not observed a simple dose-response relationship between multiple concussions and/or RHI exposure with cognitive, psychiatric, or in vivo neurobiological outcomes, particularly at lower levels of play. The relationship between prior concussion and RHI exposure with long-term outcomes in former athletes is complex and likely influenced by ­several non-injury-related factors. [ABSTRACT FROM AUTHOR]

Studies have demonstrated associations between cumulative concussion and repetitive head impact exposure (RHI) through contact sports with white matter (WM) alterations later in life. The course of WM changes associated with exposure earlier in the lifespan is unclear. This study investigated alterations in white matter (WM hyperintensity [WMH] volume and microstructural changes) associated with concussion and RHI exposure from adolescence to early midlife, as well as the interaction between exposure and age cohort (i.e., adolescent/young adult compared with early midlife athlete cohorts) on WM outcomes. Participating football players included an adolescent/young adulthood cohort (n = 82; Mage = 18.4 ± 1.7) and an early midlife cohort (37 former collegiate players approximately 15 years removed from sport; Mage = 37.7 ± 1.4). Years of football participation and number of prior concussions were exposures of interest. White matter outcomes included log-transformed manually segmented total WMH volume and neurite orientation dispersion and density imaging metrics of microstructure/organization (isotropic volume fraction [Viso], intracellular volume fraction [Vic], and orientation dispersion [OD]). Regression models were fit to test the effects of concussion history, years of football participation, and age cohort by years of football participation with WM outcomes. Spearman's correlations assessed associations between significant WM metrics and measures of cognitive and psychological function. A significant age cohort by years of participation effect was observed for whole brain white matter OD, B = −0.002, SE = 0.001, p = 0.001. The interaction was driven by a negative association between years of participation and OD within the younger cohort, B = −0.001, SE = 0.0004, p = 0.008, whereas a positive association between participation and OD in the early midlife cohort, B = 0.001, SE = 0.0003, p = 0.039, was observed. Follow-up ROI analyses showed significant interaction effects for OD in the body of the corpus callosum, genu of the corpus callosum, cingulum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and posterior thalamic radiation (p values <0.05). Greater concussion history was significantly associated with greater Viso in the early midlife cohort, B = 0.001, SE = 0.0002, p = 0.010. Years of participation and concussion history were not associated with WMH volume, p values >0.05. Performance on a measure of executive function was significantly associated with years of participation, ρ = 0.34, p = 0.04, and a trend was observed for OD, ρ = 0.28, p = 0.09 in the early midlife cohort only. The global characterization of white matter changes associated with years of football participation were broadly similar and stable from adolescence through early midlife (i.e., microstructural alterations, but not macroscopic lesions). An inverse association between years of participation and orientation dispersion across age cohorts may represent a process of initial recovery/reorganization proximal to sport, followed by later reduction of white matter coherence. [ABSTRACT FROM AUTHOR]

Transition from professional sport to nonsport endeavors has implications for postcareer health and well-being of athletes. The purpose of the current study was to examine associations among transition-related psychosocial factors and current mental health outcomes in former National Football League (NFL) players. Participants were former NFL players (n = 1,784; mean age = 52.3 ± 16.3 years) who responded to a questionnaire assessing the nature of their discontinuation from professional football (i.e., any degree of voluntary choice vs. forced discontinuation), prediscontinuation transition planning (yes vs. no), and current symptoms of depression and anxiety. After adjusting for relevant covariates, having an involuntary discontinuation and no transition plan prior to discontinuation were associated with greater depressive and anxiety symptom severity. Autonomy in discontinuation and pretransition planning are important to former NFL football players' mental health. Increasing autonomy in the discontinuation decision and pretransition planning represent psychoeducational intervention targets for this population. [ABSTRACT FROM AUTHOR]

Sport-related concussion (SRC) is a complex injury, and SRCs are notably prevalent among National Collegiate Athletic Association (NCAA) athletes. We analysed SRCs and associated exposure data collected within the NCAA Injury Surveillance Program during 2014–2019. A total of 1,709 SRCs were reported with complete symptom profiles during the study period (Women's sports n = 499; Men's sports n = 1,210). Event type and academic class year most commonly predicted specific symptom presentations among athletes in men's sports, while symptom presentation among athletes in women's sports was most commonly predicted by class year and sport classification. We observed 78 and 69 significant pairwise symptom dependencies in men's and women's sports athletes, respectively; odds of longer symptom resolution time were higher with greater counts of symptoms with strongest cross-domain associations. Our findings highlight several contextual predictors of specific symptom presentations and identify parsimonious symptom subsets that may indicate protracted recovery among men's and women's sports athletes. [ABSTRACT FROM AUTHOR]

Objective Investigate the relationships between concussion history and years of football participation (repetitive head impact proxy) with alcohol use across multiple decades in former professional football players. Methods Participants (n  = 348; mean age = 49.0 ± 9.4) completed health questionnaires in 2001 and 2019, which included self-reported concussion history and years of participation. Alcohol use frequency and amount per occasion were reported for three timepoints: during professional career, 2001, and 2019. Ordinal logistic regression models were fit to test associations of concussion history and years of participation with alcohol use at each timepoint. Results There were no significant associations between either concussion history or years of football participation with alcohol use (frequency and amount per occasion) at any timepoint. Effect estimates for concussion history and years of football participation with alcohol use were generally comparable across timepoints. Conclusions Later life alcohol use by former American football players is not associated with concussion history or years of exposure to football. [ABSTRACT FROM AUTHOR]

Magnetic resonance imaging (MRI) diffusion studies have shown chronic microstructural tissue abnormalities in athletes with history of concussion, but with inconsistent findings. Concussions with post‐traumatic amnesia (PTA) and/or loss of consciousness (LOC) have been connected to greater physiological injury. The novel mean apparent propagator (MAP) MRI is expected to be more sensitive to such tissue injury than the conventional diffusion tensor imaging. This study examined effects of prior concussion severity on microstructure with MAP‐MRI. Collegiate‐aged athletes (N = 111, 38 females; ≥6 months since most recent concussion, if present) completed semistructured interviews to determine the presence of prior concussion and associated injury characteristics, including PTA and LOC. MAP‐MRI metrics (mean non‐Gaussian diffusion [NG Mean], return‐to‐origin probability [RTOP], and mean square displacement [MSD]) were calculated from multi‐shell diffusion data, then evaluated for associations with concussion severity through group comparisons in a primary model (athletes with/without prior concussion) and two secondary models (athletes with/without prior concussion with PTA and/or LOC, and athletes with/without prior concussion with LOC only). Bayesian multilevel modeling estimated models in regions of interest (ROI) in white matter and subcortical gray matter, separately. In gray matter, the primary model showed decreased NG Mean and RTOP in the bilateral pallidum and decreased NG Mean in the left putamen with prior concussion. In white matter, lower NG Mean with prior concussion was present in all ROI across all models and was further decreased with LOC. However, only prior concussion with LOC was associated with decreased RTOP and increased MSD across ROI. Exploratory analyses conducted separately in male and female athletes indicate associations in the primary model may differ by sex. Results suggest microstructural measures in gray matter are associated with a general history of concussion, while a severity‐dependent association of prior concussion may exist in white matter. [ABSTRACT FROM AUTHOR]

The neurotrophic herpes virus cytomegalovirus is a known cause of neuropathology in utero and in immunocompromised populations. Cytomegalovirus is reactivated by stress and inflammation, possibly explaining the emerging evidence linking it to subtle brain changes in the context of more minor disturbances of immune function. Even mild forms of traumatic brain injury, including sport-related concussion, are major physiological stressors that produce neuroinflammation. In theory, concussion could predispose to the reactivation of cytomegalovirus and amplify the effects of physical injury on brain structure. However, to our knowledge this hypothesis remains untested. This study evaluated the effect of cytomegalovirus serostatus on white and grey matter structure in a prospective study of athletes with concussion and matched contact-sport controls. Athletes who sustained concussion (n = 88) completed MRI at 1, 8, 15 and 45 days post-injury; matched uninjured athletes (n = 73) completed similar visits. Cytomegalovirus serostatus was determined by measuring serum IgG antibodies (n = 30 concussed athletes and n = 21 controls were seropositive). Inverse probability of treatment weighting was used to adjust for confounding factors between athletes with and without cytomegalovirus. White matter microstructure was assessed using diffusion kurtosis imaging metrics in regions previously shown to be sensitive to concussion. T1-weighted images were used to quantify mean cortical thickness and total surface area. Concussion-related symptoms, psychological distress, and serum concentration of C-reactive protein at 1 day post-injury were included as exploratory outcomes. Planned contrasts compared the effects of cytomegalovirus seropositivity in athletes with concussion and controls, separately. There was a significant effect of cytomegalovirus on axial and radial kurtosis in athletes with concussion but not controls. Cytomegalovirus positive athletes with concussion showed greater axial (P = 0.007, d = 0.44) and radial (P = 0.010, d = 0.41) kurtosis than cytomegalovirus negative athletes with concussion. Similarly, there was a significant association of cytomegalovirus with cortical thickness in athletes with concussion but not controls. Cytomegalovirus positive athletes with concussion had reduced mean cortical thickness of the right hemisphere (P = 0.009, d = 0.42) compared with cytomegalovirus negative athletes with concussion and showed a similar trend for the left hemisphere (P = 0.036, d = 0.33). There was no significant effect of cytomegalovirus on kurtosis fractional anisotropy, surface area, symptoms and C-reactive protein. The results raise the possibility that cytomegalovirus infection contributes to structural brain abnormalities in the aftermath of concussion perhaps via an amplification of concussion-associated neuroinflammation. More work is needed to identify the biological pathways underlying this process and to clarify the clinical relevance of this putative viral effect. [ABSTRACT FROM AUTHOR]

Background: The endorsement of symptoms upon initiation of a graduated return-to-activity (GRTA) protocol has been associated with prolonged protocols. It is unclear whether there are specific symptom clusters affecting protocol durations. Purpose: To describe the endorsement of specific concussion symptom clusters at GRTA protocol initiation and examine the association between symptom cluster endorsement and GRTA protocol duration. Study Design: Cohort study; Level of evidence, 2. Methods: This study was conducted among cadets enrolled at 3 US service academies. Participants completed an evaluation upon GRTA protocol initiation. Participants endorsing symptoms were binarized based on 6 symptom clusters (cognitive, emotional, insomnia, physical, sensitivity, and ungrouped). The primary outcome of interest was GRTA protocol duration based on symptom cluster endorsement severity. Prevalence rates were calculated to describe symptom cluster endorsement. Kaplan-Meier survival estimates and univariate and multivariable Cox proportional hazards regression models were calculated for all 6 symptom clusters to estimate GRTA protocol duration while controlling for significant covariates. Results: Data from 961 concussed participants were analyzed. Of these, 636 participants were asymptomatic upon GRTA protocol initiation. Among the 325 symptomatic participants, the physical symptom cluster (80%) was most endorsed, followed by the cognitive (29%), insomnia (23%), ungrouped (19%), sensitivity (15%), and emotional (9%) clusters. Univariate results revealed a significant association between endorsing cognitive (hazard ratio [HR], 0.79; p =.001), physical (HR, 0.84; p <.001), insomnia (HR, 0.83; p =.013), sensitivity (HR, 0.70; p <.001), and ungrouped (HR, 0.75; p =.005) symptom clusters and GRTA protocol duration. Endorsing physical (HR, 0.84; p <.001) and sensitivity (HR, 0.81; p =.036) clusters maintained a significant association with GRTA protocol duration in the multivariable models. Conclusion: Participants endorsing physical or sensitivity symptom clusters displayed GRTA protocols prolonged by 16% to 19% compared with participants not endorsing that respective cluster after controlling for significant covariates. [ABSTRACT FROM AUTHOR]

Objective Characterize the levels of various metrics of repetitive head impacts (RHI) in contact (CS) and non-contact (NCS) sport athletes and determine the extent to which they are associated with fluid cognition. Methods Collegiate-aged athletes (n  = 176) completed semi-structured interviews about participation in contact sport. RHI was operationalized based on current sport (CS/NCS), the cumulative number of years of participation, age at first exposure (AFE), and based on recently proposed traumatic encephalopathy syndrome (TES) categories. The NIH Toolbox Cognition Battery assessed fluid cognition. General linear models compared RHI metrics between CS and NCS athletes and tested associations of RHI measures with fluid cognition. Results CS athletes had more years of RHI exposure, higher rates of "extensive" exposure based on TES criteria, and were more likely to have AFE before age 12 relative to NCS (p s < .001). A subset of NCS athletes, however, reported prior RHI at levels categorized as being "extensive" based on TES criteria (5%), while a larger minority had AFE before 12 (34%). No adverse associations of RHI and fluid cognition were observed (p s > .05). Across all RHI metrics, more or earlier RHI was associated with better episodic memory (p s ≤ .05). Secondary analyses showed this effect was driven by women. Conclusions Current results find no evidence that RHI in collegiate-aged athletes is associated with worse neurocognition. Although there was extensive overlap among RHI measures, results demonstrate that categorizing athletes based on their current sport undercounts the lifetime RHI exposure in many NCS athletes. [ABSTRACT FROM AUTHOR]

ObjectiveThis study examined how associations of self-reported concussion history and depression vary based on different variable characterizations. Methods Former NFL players (n = 1,697) completed a General Health Survey, indicating the number of concussions they sustained during their football career and whether a physician had diagnosed them with depression, and the PROMIS 4-item Depression scale. Self-reported concussion history was characterized as: a 3-category variable (0, 1–2, 3+) with (1) indicator variables and (2) as an ordinal variable; a 5-category variable (0, 1–2, 3–5, 6–9, 10+) with (3) indicator variables and (4) as an ordinal variable; and (5) the original interval scale (0, 1, 2,..., 10, 10+). Depression was characterized as: (1) physician diagnosis (yes/no); and the PROMIS 4-item Depression scale treated as: (2) the original T-score variable and (3) using a cut-off of a T-score >60 versus ≤60. Regression models with various combinations of the characterizations, while adjusting for age, race/ethnicity, education, pain interference, and stress level, estimated prevalence ratios and mean differences for binary and continuous outcomes, respectively. Concussion history-related effect estimates were compared across all models. Results Self-reported concussion history emerged as a significant predictor of each depression measure. With a higher number of concussions reported, be it via the categories or the interval scale, stronger associations between self-reported concussion history and depression were observed. Conclusions The various approaches to characterize self-reported concussion history and depression provided evidence of significant associations between the two variables, with the degree of association varying based on characterization of each construct. [ABSTRACT FROM AUTHOR]

Objectives: Subjective cognitive difficulties (SCDs) are associated with factors commonly reported in older adults and former contact sport athletes, regardless of objective cognitive decline. We investigated the relative contribution of these factors to SCD in former National Football League (NFL)-players with and without a diagnosis of mild cognitive impairment (MCI). Methods: Former NFL players (n = 907) aged ≥ 50 years (mean = 64.7 ± 8.9), with (n = 165) and without (n = 742) a diagnosis of MCI completed health questionnaires. Multivariable regression and dominance analyses determined the relative importance of SCD factors on SCD: 1) depression, 2) anxiety, 3) sleep disturbance, 4) pain interference, 5) ability to participate in social roles and activities, 6) stress-related events, 7) fatigue, 8) concussion history, and 9) education. SCD outcomes included Neuro-QoL Emotional-Behavioral Dyscontrol and the PROMIS Cognitive Function. Fisher's z-transformation compared comorbid contributing factors to SCD across MCI and non-MCI groups. Results: Complete dominance of anxiety was established over most comorbid factors across the MCI and non-MCI groups. Fatigue also exhibited complete dominance over most comorbid factors, though its influence in the MCI group was less robust (general dominance). Average contributions to variance accounted for by comorbid factors to ratings of SCD across MCI and non-MCI groups did not statistically differ (Z-statistics <1.96, ps>.05). Conclusions: Anxiety and fatigue are the most robust factors associated with SCD in former professional football players across various combinations of clinical presentations (different combinations of comorbid factors), regardless of documented cognitive impairment. Self-reported deficits may be less reliable in detecting objective impairment in the presence of these factors, with multidimensional assessment being ideal. [ABSTRACT FROM AUTHOR]

Objective: Investigate associations between the LIfestyle for BRAin Health (LIBRA) risk score with odds of mild cognitive impairment (MCI) diagnosis and cognitive function, incorporating concussion history. Methods: Former National Football League (NFL) players (N = 1050; mean age = 64.8 ± 9.0‐years) completed initial testing for integration of concussion history into LIBRA scores (i.e., modified‐LIBRA) and completed the Brief Test of Adult Cognition by Telephone (BTACT). Modified‐LIBRA score (including concussion history) associations with odds of MCI and cognitive dysfunction were assessed via logistic and linear regression. Results: The highest quartile LIBRA scores were six times more likely to have a diagnosis of MCI compared to the lowest quartile (OR = 6.27[3.61, 10.91], p < 0.001). Modified‐LIBRA scores significantly improved model fit for odds of MCI above original LIBRA scores (χ2(1) = 7.76, p = 0.005) and accounted for a greater fraction of variance in executive function (ΔR2 = 0.02, p = 0.003) and episodic memory (ΔR2 = 0.02, p = 0.002). Conclusions: Modified‐LIBRA score, incorporating concussion history, may help monitoring risk status in former contact sport athletes, by targeting modifiable, lifestyle‐related risk factors. [ABSTRACT FROM AUTHOR]

Individuals with lower extremity osteoarthritis (OA) have a 25% greater risk of cardiovascular disease (CVD) than those without OA. The prevalence of traumatic joint injuries among National Football League (NFL) players exposes these athletes to an elevated risk for OA and potentially a greater risk of cardiovascular risk factors (CRFs) and CVD. To examine the associations between a history of lower extremity joint injury, lower extremity OA, and the prevalence of CRFs and CVD among former NFL athletes. Cross-sectional study. Former NFL players completed a comprehensive health questionnaire that was used in an ongoing study, the Neurologic Function Across the Lifespan: A Prospective, Longitudinal, and Translational Study for Former NFL Players (NFL-LONG). A subsample of 1738 former players reported lifetime medical diagnoses including CVD or CRFs. Crude and adjusted prevalence ratios (PRsadj) characterized the associations between CVD or CRFs and injury, OA diagnosis, or both among athletes who reported (1) no history of lower extremity joint injury or surgery and no diagnosed OA, (2) a history of lower extremity joint injury or surgery and no diagnosed OA, and (3) a history of lower extremity joint injury or surgery and diagnosed OA. Neither a history of lower extremity joint injury (PRadj = 1.34; 95% CI = 0.86, 2.07) nor a history of lower extremity joint injury and diagnosed OA (PRadj = 1.41; 95% CI = 0.89, 2.25) was significantly associated with CVD. However, CRFs were 30% and 53% more prevalent in former players with lower extremity joint injury and no diagnosed OA (PRadj = 1.30; 95% CI = 1.12, 1.50) and those with lower extremity joint injury and diagnosed OA (PRadj = 1.53; 95% CI = 1.31, 1.78), respectively, versus athletes with no history of either condition. The prevalence of CRFs was highest among former NFL athletes with a history of lower extremity joint injury and diagnosed OA. These findings provide insight regarding the potential pathways to chronic diseases that may be initiated by joint injury early in life. [ABSTRACT FROM AUTHOR]

Studies have observed variable associations of prior contact sport participation with subjective and objective measures of cognitive function. This study directly investigated the association between subjective self-report and objective performance-based cognition among former collegiate football players, as well as its relationship to self-reported concussion history. Former collegiate football players (N = 57; mean age = 37.9 years [SD = 1.49]) retired from sport 15-years prior were enrolled. Linear regression models examined associations between subjective cognition (Quality of Life in Neurological Disorders Cognitive Functioning-Short Form), and performance on a neuropsychological battery. Domain specific (executive function) metrics of subjective (Behavior Rating Inventory of Executive Function-Adult) and objective cognition were also exclusively examined. Associations between self-reported concussion history with subjective and objective measures were tested. Potential influential factors (sleep quality and distress) were included as covariates. Subjective cognition was not significantly associated with any objective measures of cognitive functioning (p's >.05). Greater self-reported concussion history was inversely associated with subjective cognition (B = −2.49, p =.004), but not objective performance-based cognition (p's >.05). Distress was significantly related to all metrics of subjective cognition (p's <.001) as well as performance on delayed recall and verbal fluency (p's <.05). Sleep quality was only significantly related to timed visuospatial sequencing (p =.033). Reliance on self-reported measures of cognitive functioning alone is insufficient when assessing cognition in former contact sport athletes. Assessment of other factors known to influence subjective cognitive complaints should also be examined in determining the presence of cognitive deficits. [ABSTRACT FROM AUTHOR]

Objective: To test the hypotheses that (1) higher neighborhood disadvantage is associated with greater injury-related symptom severity in civilians with mild traumatic brain injury (mTBI) and (2) neighborhood disadvantage remains predictive after controlling for other established predictors. Setting: Level 1 trauma center and affiliated academic medical center. Participants: N = 171 individuals with mTBI. Design: Prospective cohort study. Main Measures: Rivermead Post Concussion Symptoms Questionnaire (RPQ) total score assessed less than 24 hours and at 2 weeks, 3 months, and 6 months postinjury. Linear mixed-effects models were used to assess the relationship between predictor variables and mTBI-related symptom burden (RPQ score). Neighborhood disadvantage was quantified by the Area Deprivation Index (ADI), a composite of 17 markers of socioeconomic position (SEP) scored at the census block group level. Results: Individuals in the upper ADI quartile of the national distribution displayed higher RPQ symptoms than those in the lower 3 quartiles (P <.001), with a nonsignificant ADI × visit interaction (P =.903). In a multivariable model, the effect of ADI remained significant (P =.034) after adjusting for demographics, individual SEP, and injury factors. Other unique predictors in the multivariable model were gender (gender × visit P =.035), health insurance type (P =.017), and injury-related litigation (P =.012). Conclusion: Neighborhood disadvantage as quantified by the ADI is robustly associated with greater mTBI-related symptom burden throughout the first 6 months postinjury. That the effect of ADI remained after controlling for demographics, individual SEP, and injury characteristics implies that neighborhood disadvantage is an important, understudied factor contributing to clinical recovery from mTBI. [ABSTRACT FROM AUTHOR]