Validity of the 2014 traumatic encephalopathy syndrome criteria for CTE pathology.

INTRODUCTION: Validity of the 2014 traumatic encephalopathy syndrome (TES) criteria, proposed to diagnose chronic traumatic encephalopathy (CTE) in life, has not been assessed. METHODS: A total of 336 consecutive brain donors exposed to repetitive head impacts from contact sports, military service, and/or physical violence were included. Blinded to clinical information, neuropathologists applied National Institute on Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineering CTE criteria. Blinded to neuropathological information, clinicians interviewed informants and reviewed medical records. An expert panel adjudicated TES diagnoses. RESULTS: A total of 309 donors were diagnosed with TES; 244 donors had CTE pathology. TES criteria demonstrated sensitivity and specificity of 0.97 and 0.21, respectively. Cognitive (odds ratio [OR] = 3.6; 95% confidence interval [CI]: 1.2-5.1), but not mood/behavior or motor symptoms, were significantly associated with CTE pathology. Having Alzheimer's disease (AD) pathology was significantly associated with reduced TES accuracy (OR = 0.27; 95% CI: 0.12-0.59). DISCUSSION: TES criteria provided good evidence to rule out, but limited evidence to rule in, CTE pathology. Requiring cognitive symptoms in revised criteria and using AD biomarkers may improve CTE pathology prediction.

Efficacy of Guardian Cap Soft-Shell Padding on Head Impact Kinematics in American Football: Pilot Findings.

Sport-related concussion prevention strategies in collision sports are a primary interest for sporting organizations and policy makers. After-market soft-shell padding purports to augment the protective capabilities of standard football helmets and to reduce head impact severity. We compared head impact kinematics [peak linear acceleration (PLA) and peak rotational acceleration (PRA)] in athletes wearing Guardian Cap soft-shell padding to teammates without soft-shell padding. Ten Division I college football players were enrolled [soft-shell padding (SHELL) included four defensive linemen and one tight end; non-soft-shell (CONTROL) included two offensive linemen, two defensive linemen, and one tight end]. Participants wore helmets equipped with the Head Impact Telemetry System to quantify PLA (g) and PRA (rad/s2) during 14 practices. Two-way ANOVAs were conducted to compare log-transformed PLA and PRA between groups across helmet location and gameplay characteristics. In total, 968 video-confirmed head impacts between SHELL (n = 421) and CONTROL (n = 547) were analyzed. We observed a Group x Stance interaction for PRA (F1,963 = 7.21; p = 0.007) indicating greater PRA by SHELL during 2-point stance and lower PRA during 3- or 4-point stances compared to CONTROL. There were no between-group main effects. Protective soft-shell padding did not reduce head impact kinematic outcomes among college football athletes.

Effects of purposeful soccer heading on circulating small extracellular vesicle concentration and cargo.

BACKGROUND: Considering the potential cumulative effects of repetitive head impact (HI) exposure, we need sensitive biomarkers to track short- and long-term effects. Circulating small extracellular vesicles (sEVs) (<200 nm) traffic biological molecules throughout the body and may have diagnostic value as biomarkers for disease. The purpose of this study was to identify the microRNA (miRNA) profile in circulating sEVs derived from human plasma following repetitive HI exposure. METHODS: Healthy adult (aged 18-35 years) soccer players were randomly assigned to one of 3 groups: the HI group performed 10 standing headers, the leg impact group performed 10 soccer ball trapping maneuvers over 10 min, and the control group did not participate in any soccer drills. Plasma was collected before testing and 24 h afterward, and sEVs were isolated and characterized via nanoparticle tracking analysis. Next-generation sequencing was utilized to identify candidate miRNAs isolated from sEVs, and candidate microRNAs were analyzed via quantitative polymerase chain reaction. In silico target prediction was performed using TargetScan (Version 7.0; targetscan.org) and miRWalk (http://mirwalk.umm.uni-heidelberg.de/) programs, and target validation was performed using luciferase reporter vectors with a miR-7844-5p mimic in human embryonic kidney (HEK) 293T/17 cells. RESULTS: Plasma sEV concentration and size were not affected across time and group following repetitive HI exposure. After 24 h, the HI read count from next-generation sequencing showed a 4-fold or greater increase in miR-92b-5p, miR-423-5p, and miR-24-3p and a 3-fold or greater decrease in miR-7844-5p, miR-144-5p, miR-221-5p, and miR-22-3p. Analysis of quantitative polymerase chain reaction revealed that leg impact did not alter the candidate miRNA levels. To our knowledge, miR-7844-5p is a previously unknown miRNA. We identified 8 miR-7844-5p mRNA targets: protein phosphatase 1 regulatory inhibitor subunit 1B (PPP1R1B), LIM and senescent cell antigen-like domains 1 (LIMS1), autophagy-related 12 (ATG12), microtubule-associated protein 1 light chain 3 beta (MAP1LC3B), integrin subunit alpha-1 (ITGA1), mitogen-activated protein kinase 1 (MAPK1), glycogen synthase kinase 3ß (GSK3ß), and mitogen-activated protein kinase 8 (MAPK8). CONCLUSION: Collectively, these data indicate repetitive HI exposure alters plasma sEV miRNA content, but not sEV size or number. Furthermore, for the first time we demonstrate that previously unknown miR-7844-5p targets mRNAs known to be involved in mitochondrial apoptosis, autophagy regulation, mood disorders, and neurodegenerative disease.

On-field Characteristics and Head Impact Magnitude in Youth Tackle Football.

BACKGROUND: This study determined the effect of video-verified collision characteristics on head impact magnitudes in male youth tackle football. METHODS: Participants (n = 23, age = 10.9 ± 0.3 years, height = 150.0 ± 8.3 cm, mass = 41.6 ± 8.4 kg) wore Triax Sim-G sensors throughout the fall 2019 season. Ten filmed games were used to identify nine different collision characteristics: mechanism, preparedness, head direction, struck versus striking activity, stance, play type, closing distance, penalty, and quarter. Random-effects general linear models and Cohen d effect sizes were used to examine differences in log-transformed peak linear (PLA; g) and rotational (PRA; rad/s2) accelerations across characteristics. The 10 games produced 533 total video-verified impacts and 23.2 ± 7.2 impacts per athlete. RESULTS: PLA (P range: 0.107 to 0.923) and PRA (P range: 0.057 to 0.768) did not differ across characteristics. Struck players (3370 rads/s2, 95% confidence interval [CI] = 2986 to 3808) had a small effect for higher PRA compared with striking players (3037 rads/s2, 95% CI = 2713 to 3404, d = 0.251), but negligible effect for simultaneous struck-striking players (3340 rad/s2, 95% CI = 2945 to 3792, d = 0.018). Fourth quarter impacts (3490 rads/s2, 95% CI = 3083 to 3951) had a small effect for higher PRA compared with first (2945 rads/s2, 95% CI = 2596 to 3337, d = 0.404), second (3196 rads/s2, 95% CI = 2832 to 3604, d = 0.219), and third quarters (3241 rads/s2, 95% CI = 2841 to 3699, d = 0.144). CONCLUSION: Youth tackle football characteristics did not significantly affect head impact magnitudes during games. More research is needed to explore additional factors that could be modified for sport safety rather than mitigating impact mechanism.

Word-reading ability as a "hold test" in cognitively normal young adults with history of concussion and repetitive head impact exposure: A CARE Consortium Study.

Objective: Neuropsychological evaluations include hold tests like word-reading ability as estimates of premorbid intellect thought to be resilient to the effects of neurologic insult. We tested the alternative hypothesis that exposure to concussion or repetitive subclinical head impacts throughout early life may stunt acquisition of word-reading skills.Method: Data were obtained from student-athletes within the CARE Consortium that completed the Wechsler Test of Adult Reading (WTAR). Measures of head trauma burden included self-reported concussion history and cumulative years of exposure to collision sports. We evaluated the effects of head trauma, sociodemographic (race, SES), and academic (SAT/ACT scores, learning disorder) variables on WTAR standard score using linear regression. Analyses were repeated in a football-only subsample estimating age of first exposure to football as a predictor.Results: We analyzed data from 6,598 participants (72.2% white, 39.6% female, mean ± SD age = 18.8 ± 1.2 years). Head trauma variables collectively explained 0.1% of the variance in WTAR standard scores, with years of collision sport exposure weakly predicting lower WTAR standard scores (ß = .026-.035, very small effect). In contrast, sociodemographic and academic variables collectively explained 20.9-22.5% of WTAR standard score variance, with strongest effects noted for SAT/ACT scores (ß = .313-.337, medium effect), LD diagnosis (ß = -.115 to -.131, small effect), and SES (ß = .101-.108, small effect). Age of first exposure to football did not affect WTAR scores in a football-only sample.Conclusion: Wechsler Test of Adult Reading performance appears unrelated to history of self-reported concussion(s) and/or repetitive subclinical head trauma exposure in current collegiate athletes. Sociodemographic and academic variables should be incorporated in test score interpretations for diverse populations like athletes.

Academic aptitude mediates the relationship between socioeconomic status and race in predicting ImPACT scores in college athletes.

Objective: To evaluate the influences of sociodemographic factors, estimated head impact exposure, and academic aptitude on ImPACT scores in college athletes.Methods: Data were reported on 18,886 participants (58% male) from the NCAA/DoD CARE Consortium. Race, SES, concussion history, estimated repetitive head impact exposure (eRHIE), and academic aptitude (SAT or ACT score) were our predictors of interest. Cognition was measured using ImPACT composite scores. We evaluated the mediating effects of academic aptitude on sociodemographic predictors and eRHIE on ImPACT scores. We then evaluated a football-only subsample and added age of first exposure to football (AFE) to the model. Males, females, and football players were analyzed separately using structural equation modeling.Results: Academic aptitude was associated with Black/African American race, SES, and each of the ImPACT composite scores. There were significant indirect effects of Black/African American race and SES on all ImPACT composite scores. Academic aptitude fully mediated SES effects and either fully or partially mediated race effects. Contrary to expectation, greater concussion history and eRHIE predicted better ImPACT scores.Conclusions: Academic aptitude, a stable indicator of premorbid cognitive function, consistently and most strongly predicted baseline ImPACT scores in collegiate student-athletes. Concussion and eRHIE history demonstrated a small positive, but non-significant, relationship with cognitive scores at the time of college athletic participation. This study suggests that attempts to characterize cognitive ability across the lifespan must consider premorbid functioning and sociodemographic variables.

Drill-Specific Head Impacts in Collegiate Football Practice: Implications for Reducing "Friendly Fire" Exposure.

This study investigated drill-specific head impact biomechanics in a Division 1 collegiate football team using the Head Impact Telemetry System (HITS). A total of 32,083 impacts were recorded across 2 years of practices. Precise tracking of instrumented athletes, head impacts, and drill participation allowed quantification of hits sustained per person per minute (H/P/M) for each specific drill. We found significant H/P/M variability between 14 drills and player position, ranging from 0.02 to 0.41 H/P/M for Linemen and 0.01 to 0.15 H/P/M for Non-Linemen. Impact magnitude data are also reported for practice term (Spring, Training Camp, In-Season) and dress-type (Helmets Only, Spyders, Shells, Full Pads). Recommendations for shortening high-risk drills, based on H/P/M drill impact frequencies, suggest possible "friendly fire" reductions of 1000 impacts for Linemen and 300 impacts for Non-Linemen over their collegiate career. Over 80% of potentially avoidable head impacts were attributable to just three drills-"Team Run," "Move the Field," and "Team." Recommending drill-specific modifications based on practical considerations (the drill's impact frequency, dress-types when performing the drill, and duration) could improve acceptance from coaches and efficiently reduce head impact exposure without drastically altering overall practice structure.

Comparison of Head Impact Exposure Between Concussed Football Athletes and Matched Controls: Evidence for a Possible Second Mechanism of Sport-Related Concussion.

Studies of football athletes have implicated repetitive head impact exposure in the onset of cognitive and brain structural changes, even in the absence of diagnosed concussion. Those studies imply accumulating damage from successive head impacts reduces tolerance and increases risk for concussion. Support for this premise is that biomechanics of head impacts resulting in concussion are often not remarkable when compared to impacts sustained by athletes without diagnosed concussion. Accordingly, this analysis quantified repetitive head impact exposure in a cohort of 50 concussed NCAA Division I FBS college football athletes compared to controls that were matched for team and position group. The analysis quantified the number of head impacts and risk weighted exposure both on the day of injury and for the season to the date of injury. 43% of concussed athletes had the most severe head impact exposure on the day of injury compared to their matched control group and 46% of concussed athletes had the most severe head impact exposure for the season to the date of injury compared to their matched control group. When accounting for date of injury or season to date of injury, 72% of all concussed athletes had the most or second most severe head impact exposure compared to their matched control group. These trends associating cumulative head impact exposure with concussion onset were stronger for athletes that participated in a greater number of contact activities. For example, 77% of athletes that participated in ten or more days of contact activities had greater head impact exposure than their matched control group. This unique analysis provided further evidence for the role of repetitive head impact exposure as a predisposing factor for the onset of concussion. The clinical implication of these findings supports contemporary trends of limiting head impact exposure for college football athletes during practice activities in an effort to also reduce risk of concussive injury.

Sport-Related Concussion Alters Indices of Dynamic Cerebral Autoregulation.

Sport-related concussion is known to affect a variety of brain functions. However, the impact of this brain injury on cerebral autoregulation (CA) is poorly understood. Thus, the goal of the current study was to determine the acute and cumulative effects of sport-related concussion on indices of dynamic CA. Toward this end, 179 elite, junior-level (age 19.6 ± 1.5 years) contact sport (ice hockey, American football) athletes were recruited for preseason testing, 42 with zero prior concussions and 31 with three or more previous concussions. Eighteen athletes sustained a concussion during that competitive season and completed follow-up testing at 72 h, 2 weeks, and 1 month post injury. Beat-by-beat arterial blood pressure (BP) and middle cerebral artery blood velocity (MCAv) were recorded using finger photoplethysmography and transcranial Doppler ultrasound, respectively. Five minutes of repetitive squat-stand maneuvers induced BP oscillations at 0.05 and 0.10 Hz (20- and 10-s cycles, respectively). The BP-MCAv relationship was quantified using transfer function analysis to estimate Coherence (correlation), Gain (amplitude ratio), and Phase (timing offset). At a group level, repeated-measures ANOVA indicated that 0.10 Hz Phase was significantly reduced following an acute concussion, compared to preseason, by 23% (-0.136 ± 0.033 rads) at 72 h and by 18% (-0.105 ± 0.029 rads) at 2 weeks post injury, indicating impaired autoregulatory functioning; recovery to preseason values occurred by 1 month. Athletes were cleared to return to competition after a median of 14 days (range 7-35), implying that physiologic dysfunction persisted beyond clinical recovery in many cases. When comparing dynamic pressure buffering between athletes with zero prior concussions and those with three or more, no differences were observed. Sustaining an acute sport-related concussion induces transient impairments in the capabilities of the cerebrovascular pressure-buffering system that may persist beyond 2 weeks and may be due to a period of autonomic dysregulation. Athletes with a history of three or more concussions did not exhibit impairments relative to those with zero prior concussions, suggesting recovery of function over time. Findings from this study support the potential need to consider physiological recovery in deciding when patients should return to play following a concussion.