Christine M. Baugh

The spectrum of disease in chronic traumatic encephalopathy

Chronic traumatic encephalopathy is a progressive tauopathy that occurs as a consequence of repetitive mild traumatic brain injury. We analysed post-mortem brains obtained from a cohort of 85 subjects with histories of repetitive mild traumatic brain injury and found evidence of chronic traumatic encephalopathy in 68 subjects: all males, ranging in age from 17 to 98 years (mean 59.5 years), including 64 athletes, 21 military veterans (86% of whom were also athletes) and one individual who engaged in self-injurious head banging behaviour. Eighteen age- and gender-matched individuals without a history of repetitive mild traumatic brain injury served as control subjects. In chronic traumatic encephalopathy, the spectrum of hyperphosphorylated tau pathology ranged in severity from focal perivascular epicentres of neurofibrillary tangles in the frontal neocortex to severe tauopathy affecting widespread brain regions, including the medial temporal lobe, thereby allowing a progressive staging of pathology from stages I-IV. Multifocal axonal varicosities and axonal loss were found in deep cortex and subcortical white matter at all stages of chronic traumatic encephalopathy. TAR DNA-binding protein 43 immunoreactive inclusions and neurites were also found in 85% of cases, ranging from focal pathology in stages I-III to widespread inclusions and neurites in stage IV. Symptoms in stage I chronic traumatic encephalopathy included headache and loss of attention and concentration. Additional symptoms in stage II included depression, explosivity and short-term memory loss. In stage III, executive dysfunction and cognitive impairment were found, and in stage IV, dementia, word-finding difficulty and aggression were characteristic. Data on athletic exposure were available for 34 American football players; the stage of chronic traumatic encephalopathy correlated with increased duration of football play, survival after football and age at death. Chronic traumatic encephalopathy was the sole diagnosis in 43 cases (63%); eight were also diagnosed with motor neuron disease (12%), seven with Alzheimers disease (11%), 11 with Lewy body disease (16%) and four with frontotemporal lobar degeneration (6%). There is an ordered and predictable progression of hyperphosphorylated tau abnormalities through the nervous system in chronic traumatic encephalopathy that occurs in conjunction with widespread axonal disruption and loss. The frequent association of chronic traumatic encephalopathy with other neurodegenerative disorders suggests that repetitive brain trauma and hyperphosphorylated tau protein deposition promote the accumulation of other abnormally aggregated proteins including TAR DNA-binding protein 43, amyloid beta protein and alpha-synuclein.

Chronic traumatic encephalopathy: neurodegeneration following repetitive concussive and subconcussive brain trauma

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease thought to be caused, at least in part, by repetitive brain trauma, including concussive and subconcussive injuries. It is thought to result in executive dysfunction, memory impairment, depression and suicidality, apathy, poor impulse control, and eventually dementia. Beyond repetitive brain trauma, the risk factors for CTE remain unknown. CTE is neuropathologically characterized by aggregation and accumulation of hyperphosphorylated tau and TDP-43. Recent postmortem findings indicate that CTE may affect a broader population than was initially conceptualized, particularly contact sport athletes and those with a history of military combat. Given the large population that could potentially be affected, CTE may represent an important issue in public health. Although there has been greater public awareness brought to the condition in recent years, there are still many research questions that remain. Thus far, CTE can only be diagnosed post-mortem. Current research efforts are focused on the creation of clinical diagnostic criteria, finding objective biomarkers for CTE, and understanding the additional risk factors and underlying mechanism that causes the disease. This review examines research to date and suggests future directions worthy of exploration.

Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football

Importance Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE). Objective To determine the neuropathological and clinical features of deceased football players with CTE. Design, Setting, and Participants Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history. Exposures Participation in American football at any level of play. Main Outcomes and Measures Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia. Results Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47-76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre–high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia. Conclusions and Relevance In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football.

Clinical subtypes of chronic traumatic encephalopathy: literature review and proposed research diagnostic criteria for traumatic encephalopathy syndrome

The long-term consequences of repetitive head impacts have been described since the early 20th century. Terms such as punch drunk and dementia pugilistica were first used to describe the clinical syndromes experienced by boxers. A more generic designation, chronic traumatic encephalopathy (CTE), has been employed since the mid-1900s and has been used in recent years to describe a neurodegenerative disease found not just in boxers but in American football players, other contact sport athletes, military veterans, and others with histories of repetitive brain trauma, including concussions and subconcussive trauma. This article reviews the literature of the clinical manifestations of CTE from 202 published cases. The clinical features include impairments in mood (for example, depression and hopelessness), behavior (for example, explosivity and violence), cognition (for example, impaired memory, executive functioning, attention, and dementia), and, less commonly, motor functioning (for example, parkinsonism, ataxia, and dysarthria). We present proposed research criteria for traumatic encephalopathy syndrome (TES) which consist of four variants or subtypes (TES behavioral/mood variant, TES cognitive variant, TES mixed variant, and TES dementia) as well as classifications of ‘probable CTE’ and ‘possible CTE’. These proposed criteria are expected to be modified and updated as new research findings become available. They are not meant to be used for a clinical diagnosis. Rather, they should be viewed as research criteria that can be employed in studies of the underlying causes, risk factors, differential diagnosis, prevention, and treatment of CTE and related disorders.

Age of first exposure to football and later-life cognitive impairment in former NFL players

Objective: To determine the relationship between exposure to repeated head impacts through tackle football prior to age 12, during a key period of brain development, and later-life executive function, memory, and estimated verbal IQ. Methods: Forty-two former National Football League (NFL) players ages 40–69 from the Diagnosing and Evaluating Traumatic Encephalopathy using Clinical Tests (DETECT) study were matched by age and divided into 2 groups based on their age of first exposure (AFE) to tackle football: AFE <12 and AFE ≥12. Participants completed the Wisconsin Card Sort Test (WCST), Neuropsychological Assessment Battery List Learning test (NAB-LL), and Wide Range Achievement Test, 4th edition (WRAT-4) Reading subtest as part of a larger neuropsychological testing battery. Results: Former NFL players in the AFE <12 group performed significantly worse than the AFE ≥12 group on all measures of the WCST, NAB-LL, and WRAT-4 Reading tests after controlling for total number of years of football played and age at the time of evaluation, indicating executive dysfunction, memory impairment, and lower estimated verbal IQ. Conclusions: There is an association between participation in tackle football prior to age 12 and greater later-life cognitive impairment measured using objective neuropsychological tests. These findings suggest that incurring repeated head impacts during a critical neurodevelopmental period may increase the risk of later-life cognitive impairment. If replicated with larger samples and longitudinal designs, these findings may have implications for safety recommendations for youth sports.

NCAA concussion education in ice hockey: an ineffective mandate

Background/aim Despite concussion education being increasingly mandated by states and sports leagues, there has been limited evaluation of what education is in fact effective. The National Collegiate Athletic Association (NCAA) currently mandates that institutions provide concussion education, without specifying content or delivery. The present study evaluated the effectiveness of this general mandate, as enacted for male collegiate ice hockey teams within one conference of competition. Methods In a prospective cohort design, 146 players from 6 male collegiate ice hockey teams in one Division 1 conference completed written surveys before and after receiving their institution-determined concussion education. Knowledge, attitudes, perceived norms and behavioural intention were assessed using validated measures. Education content and delivery was assessed by open-ended responses and consultation with team athletic trainers. Results All teams received concussion education material; however, content and delivery varied. Rates of material recall differed by delivery format. Considering all teams together, there were no significant improvements in knowledge and only a very small decrease in intention to continue playing while experiencing symptoms of a concussion. Pre-education and post-education, there were significant between-team differences in attitudes towards concussion reporting and behavioural intention. Conclusions The NCAAs general education mandate was divergently enacted; it did not significantly change the constructs of interest nor did it mitigate the pre-education team differences in these constructs. Existing educational materials should be evaluated, theory and evidence-driven materials developed, and mandates extended to, at a minimum, recommend materials found to be effective in changing concussion-reporting behaviour.

Helmets and mouth guards: the role of personal equipment in preventing sport-related concussions.

Millions of athletes in the United States experience concussions annually. Although helmets and mouth guards have decreased the risk of catastrophic head injuries, their protective effects on concussions are less clear. This article evaluates the current literature on the effect of equipment on concussions. Understanding the role that these equipment play in preventing concussions is complicated by many factors, such as selection bias in nonrandomized studies, variations in playing style, and risk compensation in sports with mandatory protective equipment. Improving coach and player education about proper concussion management, encouraging neck-strengthening exercises, and minimizing high-risk impacts may reduce concussions in sports.

Profile of self-reported problems with executive functioning in college and professional football players.

Repetitive mild traumatic brain injury (mTBI), such as that experienced by contact-sport athletes, has been associated with the development of chronic traumatic encephalopathy (CTE). Executive dysfunction is believed to be among the earliest symptoms of CTE, with these symptoms presenting in the fourth or fifth decade of life. The present study used a well-validated self-report measure to study executive functioning in football players, compared to healthy adults. Sixty-four college and professional football players were administered the Behavior Rating Inventory of Executive Function, adult version (BRIEF-A) to evaluate nine areas of executive functioning. Scores on the BRIEF-A were compared to published age-corrected normative scores for healthy adults Relative to healthy adults, the football players indicated significantly more problems overall and on seven of the nine clinical scales, including Inhibit, Shift, Emotional Control, Initiate, Working Memory, Plan/Organize, and Task Monitor. These symptoms were greater in athletes 40 and older, relative to younger players. In sum, football players reported more-frequent problems with executive functioning and these symptoms may develop or worsen in the fifth decade of life. The findings are in accord with a growing body of evidence that participation in football is associated with the development of cognitive changes and dementia as observed in CTE.

Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy

Background: Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer’s disease, there is a need for methods to diagnose CTE during life through objective biomarkers. Objective: The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker. Methods: Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau. Results: The NFL group had higher exosomal tau than the control group (p <  0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093). Conclusion: These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.

Self-reported concussion history: impact of providing a definition of concussion.

Background In recent years, the understanding of concussion has evolved in the research and medical communities to include more subtle and transient symptoms. The accepted definition of concussion in these communities has reflected this change. However, it is unclear whether this shift is also reflected in the understanding of the athletic community. What is known about the subject Self-reported concussion history is an inaccurate assessment of someone’s lifetime exposure to concussive brain trauma. However, unfortunately, in many cases it is the only available tool. Hypothesis/purpose We hypothesize that athletes’ self-reported concussion histories will be significantly greater after reading them the current definition of concussion, relative to the reporting when no definition was provided. An increase from baseline to post-definition response will suggest that athletes are unaware of the currently accepted medical definition. Study design Cross-sectional study of 472 current and former athletes. Methods Investigators conducted structured telephone interviews with current and former athletes between January 2010 and January 2013, asking participants to report how many concussions they had received in their lives. Interviewers then read participants a current definition of concussion, and asked them to re-estimate based on that definition. Results The two estimates were significantly different (Wilcoxon signed rank test: z=15.636, P<0.001). Comparison of the baseline and post-definition medians (7 and 15, respectively) indicated that the post-definition estimate was approximately twice the baseline. Follow-up analyses indicated that this effect was consistent across all levels of competition examined and across type of sport (contact versus non-contact). Conclusion Our results indicate that athletes’ current understandings of concussions are not consistent with a currently accepted medical definition. We strongly recommend that clinicians and researchers preface requests for self-reported concussion history with a definition. In addition, it is extremely important that researchers report the definition they used in published manuscripts of their work. What this study adds to existing knowledge Our study shows that unprompted reporting of concussion history produces results that are significantly different from those provided after a definition has been given, suggesting one possible mechanism to improve the reliability of self-reported concussion history across multiple individuals.