The effects of cytomegalovirus on brain structure following sport-related concussion.

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.

Research Letter: Relationship of Blood Biomarkers of Inflammation With Acute Concussion Symptoms and Recovery in the CARE Consortium.

OBJECTIVE: Determine the association of inflammatory biomarkers with clinical measures and recovery in participants with concussion. SETTING: Multicenter study in National Collegiate Athletic Association member institutions including military service academies. PARTICIPANTS: Four hundred twenty-two participants with acute concussion. DESIGN: Clinical visits and blood draws were completed preinjury and at multiple visits postconcussion (0-12 hours, 12-36 hours, and 36-60 hours postinjury). Clinical measures included Sport Concussion Assessment Tool (SCAT) symptom severity, Balance Error Scoring System, Standardized Assessment of Concussion (SAC), Brief Symptom Inventory-18 (BSI-18) scores, time to initiation of graduated return-to-play (RTP) protocol, and time to RTP. Interleukin (IL)-6, IL-10, IL-8, IL-1 receptor antagonist (RA), tumor necrosis factor (TNF), c-reactive protein, and vascular endothelial growth factor (VEGF) were measured in serum. Prespecified analyses focused on IL-6 and IL-1RA at 0 to 12 hours; exploratory analyses were conducted with false discovery rate correction. RESULTS: For prespecified analyses, IL-1RA at 0 to 12 hours in female participants was positively associated with more errors on the SAC (B(standard error, SE) = 0.58(0.27), P < .05) and worse SCAT symptom severity (B(SE) = 0.96(0.44), P < .05). For exploratory analyses, higher levels of IL-1RA at 12 to 36 hours were associated with higher global (B(SE) = 0.55(0.14), q < 0.01), depression (B(SE) = 0.45(0.10), q < 0.005), and somatization scores on the BSI (B(SE) = 0.46(0.12), q < 0.01) in participants with concussion; Higher TNF at 12 to 36 hours was associated with fewer errors on the SAC (B(SE) = - 0.46(0.14), q < 0.05). Subanalyses showed similar results for male participants and participants who were athletes. No associations were discovered in nonathlete cadets. Higher IL-8 at 0 to 12 hours was associated with slower RTP in female participants (OR = 14.47; 95% confidence interval, 2.96-70.66, q < 0.05); no other associations with recovery were observed. CONCLUSIONS: Peripheral inflammatory markers are associated with clinical symptoms following concussion and potentially represent one mechanism for psychological symptoms observed postinjury. Current results do not provide strong support for a potential prognostic role for these markers.

Linking Rivermead Post Concussion Symptoms Questionnaire (RPQ) and Sport Concussion Assessment Tool (SCAT) scores with item response theory.

OBJECTIVE: Despite the public health burden of traumatic brain injury (TBI) across broader society, most TBI studies have been isolated to a distinct subpopulation. The TBI research literature is fragmented further because often studies of distinct populations have used different assessment procedures and instruments. Addressing calls to harmonize the literature will require tools to link data collected from different instruments that measure the same construct, such as civilian mild traumatic brain injury (mTBI) and sports concussion symptom inventories. METHOD: We used item response theory (IRT) to link scores from the Rivermead Post Concussion Symptoms Questionnaire (RPQ) and the Sport Concussion Assessment Tool (SCAT) symptom checklist, widely used instruments for assessing civilian and sport-related mTBI symptoms, respectively. The sample included data from n = 397 patients who suffered a sports-related concussion, civilian mTBI, orthopedic injury control, or non-athlete control and completed the SCAT and/or RPQ. RESULTS: The results of several analyses supported sufficient unidimensionality to treat the RPQ + SCAT combined item set as measuring a single construct. Fixed-parameter IRT was used to create a cross-walk table that maps RPQ total scores to SCAT symptom severity scores. Linked and observed scores were highly correlated (r = .92). Standard errors of the IRT scores were slightly higher for civilian mTBI patients and orthopedic controls, particularly for RPQ scores linked from the SCAT. CONCLUSION: By linking the RPQ to the SCAT we facilitated efforts to effectively combine samples and harmonize data relating to mTBI.

A dominance analysis of subjective cognitive complaint comorbidities in former professional football players with and without mild cognitive impairment.

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.

Salivary Cortisol Dynamics After Mild Traumatic Brain Injury.

OBJECTIVE: To assess mild traumatic brain injury (mTBI)-related alterations in baseline (resting) salivary cortisol and cortisol reactivity to cognitive and exercise stressors, which are frequently encountered during mTBI rehabilitation and recovery. SETTING: Persons with mTBI were recruited from a level 1 trauma center emergency department. Uninjured controls (UCs) were recruited from the community. PARTICIPANTS: Participants were 37 individuals with mTBI and 24 UCs. All patients with mTBI were enrolled at 7 ± 3 days post-injury, met the American Congress of Rehabilitation Medicine definition of mTBI, and had no acute intracranial findings on clinical neuroimaging (if performed). DESIGN: A prospective cohort study design was used. All participants provided saliva samples 10 times during each of 2 visits spaced 3 weeks apart (1 week and 1 month post-injury for the mTBI group). Each visit included baseline saliva sampling and sampling to evaluate reactivity to a cognitive stressor (Paced Auditory Serial Addition Test) and physical stressor (Buffalo Concussion Treadmill Test [BCTT]). MAIN OUTCOME MEASURE: Natural log-transformed salivary cortisol was measured by enzyme immunoassay. Cortisol was predicted using a linear mixed-effects model by group (mTBI and UC), visit (1 week and 1 month), and saliva sample. RESULTS: Mean salivary cortisol was higher in the mTBI group (1.67 nmol/L [95% CI 1.42-1.72]) than in controls (1.30 nmol/L [1.12-1.47]), without an mTBI × time interaction. At 1 week, the mTBI group had greater cortisol reactivity in response to the BCTT. CONCLUSIONS: Higher cortisol in individuals with mTBI at 1 week and 1 month post-injury extends previous findings into the subacute recovery period. Furthermore, the mTBI group demonstrated a greater cortisol response to mild-to-moderate aerobic exercise (BCTT) at 1 week post-injury. Given the increasing role of exercise in mTBI rehabilitation, further research is warranted to replicate these findings and identify the clinical implications, if any, of enhanced hypothalamic-pituitary-adrenal axis responses to exercise in civilians with recent mTBI.

Recommendations for Medical Discharge Documentation and Academic Supports for University Students Recovering From Concussion.

OBJECTIVE: This study sought to (1) collate the experiences of university students with concussion history and academic stakeholders through interviews and (2) develop concussion management recommendations for institutions of higher learning using a multidisciplinary Delphi procedure. SETTING: Remote semistructured interviews and online surveys. PARTICIPANTS: The first aim of this study included undergraduate university students with concussion history who did not participate in varsity athletics ( n = 21; 57.1% female), as well as academic faculty/staff with experience assisting university students with their postconcussion academic needs ( n = 7; 71.4% female). The second aim enrolled 22 participants (54.5% female) to serve on the Delphi panel including 9 clinicians, 8 researchers, and 5 academic faculty/staff. DESIGN: An exploratory-sequential mixed-methods approach. MAIN MEASURES: Semistructured interviews were conducted to unveil barriers regarding the return-to-learn (RTL) process after concussion, with emergent themes serving as a general framework for the Delphi procedure. Panelists participated in 3 stages of a modified Delphi process beginning with a series of open-ended questions regarding postconcussion management in higher education. The second stage included anonymous ratings of the recommendations, followed by an opportunity to review and/or modify responses based on the group's consensus. RESULTS: The results from the semistructured interviews indicated students felt supported by their instructors; however, academic faculty/staff lacked information on appropriate academic supports and/or pathways to facilitate the RTL process. Of the original 67 statements, 39 achieved consensus (58.2%) upon cessation of the Delphi procedure across 3 main categories: recommendations for discharge documentation (21 statements), guidelines to facilitate a multidisciplinary RTL approach (10 statements), and processes to obtain academic supports for students who require them after concussion (8 statements). CONCLUSIONS: These findings serve as a basis for future policy in higher education to standardize RTL processes for students who may need academic supports following concussion.

Incorporation of concussion history as part of the LIfestyle for BRAin Health (LIBRA) modifiable factors risk score and associations with cognition in older former National Football League players.

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.

Concussion Risk and Recovery in Athletes With Psychostimulant-Treated Attention-Deficit/Hyperactivity Disorder: Findings From the NCAA-DOD CARE Consortium.

The aim of the present study was to examine the effects of attention-deficit/hyperactivity disorder (ADHD) -related psychostimulant use in the context of concussion risk and symptom recovery. Data were obtained from the National Collegiate Athletic Association Department of Defense Grand Alliance Concussion Assessment, Research, and Education (NCAA-DOD CARE) Consortium from 2014 to 2017. Relative to individuals without diagnosed ADHD (i.e., control), both ADHD diagnosis and the combination of ADHD diagnosis and psychostimulant use were associated with a greater risk of incurring a concussive injury. Following a concussive injury, ADHD diagnosis was associated with longer symptom recovery time relative to the control group. However, individuals with ADHD who use psychostimulants did not take longer to resolve symptoms than controls, suggesting that psychostimulants may have a positive influence on recovery. Regardless of time point, ADHD diagnosis was associated with an elevated number of concussion-related symptoms; however, this effect appears mitigated by having used ADHD-related psychostimulants.

Cumulative Concussion and Odds of Stroke in Former National Football League Players.

BACKGROUND AND PURPOSE: Postmortem and experimental studies indicate a potential association between repeated concussions and stroke risk in older contact sport athletes. We examined the relationship between concussion and stroke history in former National Football League players aged ≥50 years. METHODS: Former professional football players aged ≥50 years who played ≥1 year in the National Football League were enrolled in the cross-sectional study. Indirect standardization was used to calculate overall and decade-specific standardized prevalence ratios. Logistic regression using Firth's bias reduction method examined the association between lifetime concussion history 0 (n=119; 12.2%), 1 to 2 (n=152; 15.5%), 3 to 5 (n=242; 24.7%), 6 to 9 (201; 20.5%), and 10+(n=265; 27.1%) and stroke. Adjusted odds ratios for stroke were calculated for concussion history groups, age, and coronary artery disease and/or myocardial infarction. RESULTS: The 979 participants who met inclusion criteria had a mean age of 65.0±9.0 years (range, 50-99). The prevalence of stroke was 3.4% (n=33), significantly lower than expected based on rates of stroke in US men aged 50 and over (standardized prevalence ratio=0.56, Z= -4.56, P<0.001). Greater odds of stroke history were associated with concussion history (10+ versus 0, adjusted odds ratio [95% CI]=5.51 [1.61-28.95]), cardiovascular disease (adjusted odds ratio [95% CI]=2.24 [1.01-4.77]), and age (1-year-increase adjusted odds ratio [95% CI]=1.07 [1.02-1.11]). CONCLUSIONS: The prevalence of stroke among former National Football League players aged ≥50 years was lower than the general population, with significantly increased risk among those with 10 or more prior concussions. Findings add to the evidence suggesting that traumatic brain injuries are associated with increased risk of stroke. Clinically, management of cardio- and cerebrovascular health may be pertinent to those with a history of multiple prior concussions.

Extracellular vesicle-associated cytokines in sport-related concussion.

Growing evidence suggests that sport-related concussion results in a robust inflammatory response that can be measured in serum or plasma and is predictive of symptom recovery. Recently, extracellular vesicles (EV) derived from serum or plasma have emerged as a promising source of biomarkers for neurological disorders like concussion because they may better reflect central immunological activity. However, the association of acute concussion with EV-associated cytokines has not yet been systematically studied in humans. We tested the hypothesis that EV-associated cytokines are elevated acutely and predictive of symptom duration following concussion in a cohort of high-school and collegiate football players. Players were enrolled and provided serum samples at a preseason baseline visit (N = 857). An additional blood draw was obtained in players that subsequently suffered a concussion (N = 23) within 6-hours post-injury and in matched, uninjured players (N = 44). Concentrations of Interleukin-6 (IL-6), IL-1ß, IL-1 receptor antagonist (IL-1RA), IL-10, and tumor necrosis factor were measured in EV and EV-depleted serum samples. EV-associated IL-6 was significantly elevated post-injury relative to baseline levels and controls (ps < 0.01). In EV-depleted samples, IL-1RA was significantly elevated post-injury relative to baseline levels and controls (ps < 0.01). Time-to-event analyses showed that post-injury EV-associated IL-6 levels were positively associated with the number of days that injured athletes reported symptoms (p < 0.05). These results highlight the potential of EV-associated cytokines as biomarkers of concussion.

Comparing Traumatic Brain Injury Symptoms Reported via Questionnaires Versus a Novel Structured Interview.

OBJECTIVE: Mild traumatic brain injury (mTBI) symptoms are typically assessed via questionnaires in research, yet questionnaires may be more prone to biases than direct clinical interviews. We compared mTBI symptoms reported on two widely used self-report inventories and the novel Structured Interview of TBI Symptoms (SITS). Second, we explored the association between acquiescence response bias and symptom reporting across modes of assessment. METHOD: Level 1 trauma center patients with mTBI (N = 73) were recruited within 2 weeks of injury, assessed at 3 months post-TBI, and produced nonacquiescent profiles. Assessments collected included the SITS (comprising open-ended and closed-ended questions), Rivermead Post Concussion Symptoms Questionnaire (RPQ), Sport Concussion Assessment Tool-3 (SCAT-3) symptom checklist, and Minnesota Multiphasic Personality Inventory-2 Restructured Form True Response Inconsistency (TRIN-r) scale. RESULTS: Current mTBI symptom burden and individual symptom endorsement were highly concordant between SITS closed-ended questions, the RPQ, and the SCAT-3. Within the SITS, participants reported significantly fewer mTBI symptoms to open-ended as compared to later closed-ended questions, and this difference was weakly correlated with TRIN-r. Symptom scales were weakly associated with TRIN-r. CONCLUSIONS: mTBI symptom reporting varies primarily by whether questioning is open- vs. closed-ended but not by mode of assessment (interview, questionnaire). Acquiescence response bias appears to play a measurable but small role in mTBI symptom reporting overall and the degree to which participants report more symptoms to closed- than open-ended questioning. These findings have important implications for mTBI research and support the validity of widely used TBI symptom inventories.

Association Between TBI-Related Hearing Impairment and Cognition: A TRACK-TBI Study.

OBJECTIVE: To examine the association between hearing impairment and cognitive function after traumatic brain injury (TBI). SETTING: A total of 18 level I trauma centers throughout the United States in the T ransforming R esearch a nd C linical K nowledge in TBI (TRACK-TBI) study. PARTICIPANTS: From February 2014 to June 2018, a total of 2697 participants with TBI were enrolled in TRACK-TBI. Key eligibility criteria included external force trauma to the head, presentation to a participating level I trauma center, and receipt of a clinically indicated head computed tomographic (CT) scan within 24 hours of injury. A total of 1267 participants were evaluated in the study, with 216 participants with hearing impairment and 1051 participants without hearing impairment. Those with missing or unknown hearing status or cognitive assessment were excluded from analysis. DESIGN: Prospective, observational cohort study. MAIN MEASURES: Hearing impairment at 2 weeks post-TBI was based on self-report. Participants who indicated worse hearing in one or both ears were defined as having hearing impairment, whereas those who denied worse hearing in either ear were defined as not having hearing impairment and served as the reference group. Cognitive outcomes at 6 months post-TBI included executive functioning and processing speed, as measured by the Trail Making Test (TMT) B/A and the Wechsler Adult Intelligence Scale, Fourth Edition, Processing Speed Index subscale (WAIS-IV PSI), respectively. RESULTS: TBI-related hearing impairment had a small but significantly greater TMT B/A ratio than without TBI-related hearing impairment: mean difference ( B ) = 0.25; 95% CI, 0.07 to 0.43; P = .005. No significant mean differences on WAIS-IV PSI scores were found between participants with and without TBI-related hearing impairment: B = 0.36; 95% CI, -2.07 to 2.60; P = .825. CONCLUSION: We conclude that TBI-related hearing impairment at 6 months postinjury was significantly associated with worse executive functioning but not cognitive processing speed.

The stability of self-reported professional football concussion history among former players: A longitudinal NFL-LONG study.

OBJECTIVES: To examine the stability of former National Football League (NFL) players' recall of professional football concussion. METHODS: Two-hundred-and-nine former NFL players (ceasing football participation before/in 2001) completed surveys in 2001, 2010, and 2019 and reported the number of concussions sustained during their professional careers (0, 1 … 10, >10). Participants were categorized into four 'recall stability' groups, based upon concussion recall [e.g., 'Same' (same number recalled), 'Increased' (more recalled than in prior time point)]. In 2019, participants completed measures of functioning (e.g., PROMIS Cognitive Function, Anxiety, Depression). Fleiss Kappa and generalized linear mixed models (GLMM)-based ordinal measures Kappa assessed stability across time points. 'Recall stability group' functioning scores were compared. RESULTS: Overall, 45.9% recalled more concussions over time; 14.8% reported the same number. Fleiss Kappa and GLMM-based ordinal measures Kappa suggested fair (0.22, 95% CI: 0.26, 0.38) and moderate stability (0.41, 95% CI: 0.35, 0.46), respectively. Higher cognitive functioning (P = 0.002), lower anxiety (P = 0.003), and lower depression (P = 0.007) were observed in the 'Same' vs 'Increased' groups. CONCLUSIONS: Despite subtle time-based variations in reporting, professional football concussion history recall was relatively stable. Better cognitive and psychological functioning was associated with greater stability in concussion recall.

Age-Group Differences and Annual Variation in Return-To-Play Practices After Sport-Related Concussion.

OBJECTIVE: To examine return-to-play (RTP) practice differences between high school and collegiate athletes, as well as the stability (ie, year-by-year) in these practices over a 5-year period. We hypothesized that similar protocols for treatment will be comparable across competition levels and that these practices will vary year-to-year. DESIGN: Prospective cohort study. SETTING: Nine high schools and 4 National Collegiate Athletic Association Division III colleges in Southeastern Wisconsin. PARTICIPANTS AND INDEPENDENT VARIABLES: Two-hundred seventy-three (N = 273) athletes with sport-related concussions (SRCs). Independent predictors included competition level (high school, n = 88 vs collegiate, n = 185) and year-of-injury. OUTCOME MEASURES: Athletes were evaluated prospectively for differences in symptom duration, symptom free waiting period (SFWP), and time to RTP, as well as longitudinal changes in management. RESULTS: High school and collegiate athletes experienced comparable median symptom duration (high school, 6.0 days, interquartile range (IQR) = 3.5-11.0; college, 6.0 days, IQR = 4.0-9.0, P = 0.95), SFWP (high school, 5.0 days, IQR = 3.0-8.0; college, 5.0 days, IQR = 3.0-7.0, P = 0.12), and total time to RTP (high school, 10.5 days, IQR = 7.0-16.0; college, 11.0 days, IQR = 8.0-14.0 days, P = 0.94). A Cox regression analysis revealed a nonsignificant trend toward longer SFWPs in high school athletes (P = 0.055; hazard ratio = 1.347, confidence interval = 0.99-1.83). Among football players, SFWPs in 2017 (Median = 3.5 days, IQR = 1.5-5.0 days) were significantly longer than those in 2014 (Median = 5.0 days, IQR = 4.0-8.5 days, P = 0.029) after correction for multiple comparisons. CONCLUSION: Similar postinjury and RTP management practices were observed at the high school and collegiate levels after SRCs. Symptom duration and time from injury to unrestricted RTP were comparable, although high school athletes may have longer SFWPs.

Transition-Related Psychosocial Factors and Mental Health Outcomes in Former National Football League Players: An NFL-LONG Study.

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.

A Prospective Study of Acute Blood-Based Biomarkers for Sport-Related Concussion.

OBJECTIVE: Prospectively characterize changes in serum proteins following sport-related concussion and determine whether candidate biomarkers discriminate concussed athletes from controls and are associated with duration of symptoms following concussion. METHODS: High school and collegiate athletes were enrolled between 2015 and 2018. Blood was collected at preinjury baseline and within 6 hours (early acute) and at 24 to 48 hours (late acute) following concussion in football players (n = 106), matched uninjured football players (n = 84), and non-contact-sport athletes (n = 50). Glial fibrillary acidic protein, ubiquitin c-terminal hydrolase-L1, S100 calcium binding protein B, alpha-II-spectrin breakdown product 150, interleukin 6, interleukin 1 receptor antagonist, and c-reactive protein were measured in serum. Linear models assessed changes in protein concentrations over time. Receiver operating curves quantified the discrimination of concussed athletes from controls. A Cox proportional hazard model determined whether proteins were associated with symptom recovery. RESULTS: All proteins except glial fibrillary acidic protein and c-reactive protein were significantly elevated at the early acute phase postinjury relative to baseline and both control groups and discriminated concussed athletes from controls with areas under the curve of 0.68 to 0.84. The candidate biomarkers also significantly improved the discrimination of concussed athletes from noncontact controls compared to symptom severity alone. Glial fibrillary acidic protein was elevated postinjury relative to baseline in concussed athletes with a loss of consciousness or amnesia. Finally, early acute levels of interleukin 1 receptor antagonist were associated with the number of days to symptom recovery. INTERPRETATION: Brain injury and inflammatory proteins show promise as objective diagnostic biomarkers for sport-related concussion, and inflammatory markers may provide prognostic value. ANN NEUROL 2020;87:907-920.

Distinct latent profiles based on neurobehavioural, physical and psychosocial functioning of former National Football League (NFL) players: an NFL-LONG Study.

OBJECTIVE: To identify subgroups of former National Football League (NFL) players using latent profile analysis (LPA) and examine their associations with total years of participation (TYP) and self-reported lifetime sport-related concussion history (SR-CHx). METHODS: Former NFL players (N=686) aged 50-70 years, with an average 18.0 TYP (±4.5) completed a questionnaire. SR-CHx distributions included: low (0-3; n=221); intermediate (4-8; n=209) and high (9+; n=256). LPA measures included: Quality of Life in Neurological Disorders Emotional-Behavioral Dyscontrol, Patient Reported Outcomes Measurement Information System Cognitive Function, Emotional Support, Self-Efficacy, Meaning and Purpose, Physical Function, Pain Interference, Participation in Social Roles and Activities, Anxiety, Depression, Fatigue, and Sleep Disturbance. Demographic, medical/psychiatric history, current psychosocial stressors, TYP and SR-CHx were compared across latent profiles (LPs). RESULTS: A five profile solution emerged: (LP1) global higher functioning (GHF; 26.5%); (LP2) average functioning (10.2%); (LP3) mild somatic (pain and physical functioning) concerns (22.0%); (LP4) somatic and cognitive difficulties with mild anxiety (SCA; 27.5%); LP5) global impaired functioning (GIF; 13.8%). The GIF and SCA groups reported the largest number ofe- medical/psychiatric conditions and higher psychosocial stressor levels. SR-CHx was associated with profile group (χ2(8)=100.38, p<0.001); with a higher proportion of GIF (72.6%) and SCA (43.1%) groups reporting being in the high SR-CHx category, compared with GHF (23.1%), average (31.4%) and somatic (27.8%) groups. TYP was not significantly associated with group (p=0.06), with greater TYP reported by the GHF group. CONCLUSIONS: Five distinct profiles of self-reported functioning were identified among former NFL players. Several comorbid factors (ie, medical/psychiatric diagnoses and psychosocial stressors) and SR-CHx were associated with greater neurobehavioural and psychosocial dysfunction.

Positive association between serum quinolinic acid and functional connectivity following concussion.

The molecular mechanisms underlying the diverse psychiatric and neuropathological sequalae documented in subsets of athletes with concussion have not been identified. We have previously reported elevated quinolinic acid (QuinA), a neurotoxic kynurenine pathway metabolite, acutely following concussion in football players with prior concussion. Similarly, work from our group and others has shown that increased functional connectivity strength, assessed using resting state fMRI, occurs following concussion and is associated with worse concussion-related symptoms and outcome. Moreover, other work has shown that repetitive concussion may have cumulative effects on functional connectivity and is a risk factor for adverse outcomes. Understanding the molecular mechanisms underlying these cumulative effects may ultimately be important for therapeutic interventions or the development of prognostic biomarkers. Thus, in this work, we tested the hypothesis that the relationship between QuinA in serum and functional connectivity following concussion would depend on the presence of a prior concussion. Concussed football players with prior concussion (N = 21) and without prior concussion (N = 16) completed a MRI session and provided a blood sample at approximately 1 days, 8 days, 15 days, and 45 days post-injury. Matched, uninjured football players with (N = 18) and without prior concussion (N = 24) completed similar visits. The association between QuinA and global connectivity strength differed based on group (F(3, 127) = 3.46, p = 0.019); post-hoc analyses showed a positive association between QuinA and connectivity strength in concussed athletes with prior concussion (B = 16.05, SE = 5.06, p = 0.002, 95%CI[6.06, 26.03]), but no relationship in concussed athletes without prior concussion or controls. Region-specific analyses showed that this association was strongest in bilateral orbitofrontal cortices, insulae, and basal ganglia. Finally, exploratory analyses found elevated global connectivity strength in concussed athletes with prior concussion who reported depressive symptoms at the 1-day visit compared to those who did not report depressive symptoms (t(15) = 2.37, mean difference = 13.50, SE = 5.69, p = 0.032, 95%CI[1.36, 25.63], Cohen's d = 1.15.). The results highlight a potential role of kynurenine pathway (KP) metabolites in altered functional connectivity following concussion and raise the possibility that repeated concussion has a "priming" effect on KP metabolism.

Personality Characteristics and Acute Symptom Response Predict Chronic Symptoms After Mild Traumatic Brain Injury.

OBJECTIVE: Despite consensus that personality influences mild traumatic brain injury (mTBI) recovery, it has been underexamined. We evaluated the extent to which diverse personality and psychiatric symptom dimensions predict mTBI recovery. METHODS: This prospective cohort study involved psychological assessments of hospital patients with mTBI (n = 75; median = 2 days post-injury, range = 0-12 days) and orthopedic trauma controls (OTC; n = 79) who were used for comparison in mediation modeling. Chronic symptoms were evaluated at 3 months after mTBI (n = 50) using the Sport Concussion Assessment Tool (SCAT) symptom checklist. Linear regression analyses were used to identify the predominant predictors of chronic symptoms in mTBI. Modern mediation analyses tested the hypothesis that personality traits predict chronic symptoms through acute psychological response to injury. RESULTS: In mTBI, trait psychoticism directly predicted chronic mTBI symptoms and was the strongest personality predictor overall. Furthermore, an internalizing personality dimension emphasizing negative affect/emotionality and detachment predicted chronic mTBI symptoms indirectly through enhancement of acute somatic complaints. In OTC, internalizing personality acted through the same mediator as in mTBI, whereas the effect of psychoticism was also mediated through acute somatic complaints. There was varying support for a moderated direct effect of personality traits at low levels of positive emotionality across models. CONCLUSION: These causal models provide novel insights about the role of personality in mTBI symptom recovery, highlighting the complexity of how psychological processes may interact to affect recovery and revealing that some of these processes may be non-specific to brain injury.