Chronic traumatic encephalopathy.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repeated traumatic brain injury (TBI). This disorder is mainly observed in subjects at risk for brain traumatisms including boxers, American football and European football (soccer) players, as well as war veterans. Neuropathological findings are marked by abnormally phosphorylated tau accumulations at the depth of cerebral sulci, as well as TDP43, Aß and α-synuclein positive staining. It has been described 3 clinical variants: the behavioural/mood variant, the cognitive variant and the mixed behavioural/cognitive variant. Cerebral MRI revealed signs of diffuse atrophy with abnormal axonal findings using the diffusion tensor imaging methods. Cerebral PET tau revealed increased standardised uptake value ratio (SUVR) levels in various brain regions of CTE patients compared to controls. The place of CTE among other neurodegenerative diseases is still debated. The focus of CTE management must be on prevention. The best way to prevent CTE in athletes is to put in place strict and appropriate measures by physicians. An individual with concussion should not be allowed to play again immediately (and sometimes never) in cases of abnormal neurological symptoms or imaging abnormalities.

A Review of the Role of Chronic Traumatic Encephalopathy in Criminal Court.

Chronic traumatic encephalopathy (CTE) is believed to be a degenerative brain disease characterized by repetitive brain trauma resulting in a specific pattern of neuropathological changes, which some have linked to functional disturbance and aggression. The diagnosis has gained greater public attention after these same neuropathological changes were discovered in multiple deceased National Football League (NFL) players, many of whom had exhibited signs of aggression, impulsivity, and poor executive functioning, according to a widely publicized study. When an NFL player convicted of murder was found to have the neuropathological changes associated with CTE following his suicide, the New York Times editorial section asked whether CTE was a defense for murder. This idea raises an interesting legal and philosophical question about whether an individual's criminal actions can be determined by something outside their control, such as past head trauma. To begin to attempt an answer, this article reviews what is currently known about the neurobiology of traumatic brain injury, CTE, and morality. By looking at how U.S. criminal law courts have handled cases of dementia and traumatic brain injury in the past, we can better understand how to consider this postmortem diagnosis in its forensic context.

Clinical and neuropsychological profile of patients with dementia and chronic traumatic encephalopathy.

OBJECTIVE: To determine whether subjects with chronic traumatic encephalopathy (CTE) and dementia have distinct clinical features compared to subjects with pathologically confirmed Alzheimer's disease (AD). METHODS: Among 339 subjects assessed for CTE in the National Alzheimer's Coordinating Center dataset, 6 subjects with CTE and 25 subjects with AD neuropathologic change matched for age (±5 years) and sex were identified. All subjects had a clinical diagnosis of dementia. Neurological examination, neuropsychological testing and emotional/behavioural data were compared between CTE and AD subjects at the time of dementia diagnosis and last clinical visit near death. RESULTS: A history of traumatic brain injury with loss of consciousness (LOC) was reported in one CTE and one AD subject; information about injuries without LOC or multiple injuries was unavailable. CTE and AD subjects did not differ significantly at the time of diagnosis or last visit on the Unified Parkinson's Disease Rating Scale-Motor Exam, global measures of cognitive functioning (Mini-Mental State Exam and Clinical Dementia Rating Scale), emotional/behaviour symptoms as assessed with the Neuropsychiatric Inventory questionnaire or across neuropsychological measures. All CTE participants had co-occurring neuropathologic processes, including AD and most had TAR DNA-binding protein 43 (TDP-43) neuropathology. CONCLUSIONS: CTE pathology was rare in a large multicentre national dataset, and when present, was accompanied by AD and TDP-43 pathologies. CTE was not associated with a different clinical presentation from AD or with greater cognitive impairment or neurobehavioral symptoms. These findings suggest that CTE may not have a distinct clinical profile when other neuropathologic processes are coexistent with CTE pathology.

Premortem Chronic Traumatic Encephalopathy Diagnoses in Professional Football.

OBJECTIVE: American-style football (ASF) has gained attention because of possible links between repetitive head injury and neurodegenerative diseases. Although postmortem pathologic changes consistent with chronic traumatic encephalopathy (CTE) have been reported in ASF players, there are currently no established premortem diagnostic criteria for CTE. Nevertheless, presented with symptoms of cognitive impairment, clinicians treating former players may be inclined to suggest CTE without a thorough exploration of comorbid factors that demonstrate similar clinical phenotypes to putative CTE. METHODS: A survey of 3,913 former ASF players aged 24 to 89 was conducted for those who responded by March 2019. RESULTS: Despite being a postmortem diagnosis, 108 players (2.8%) self-reported clinician-diagnosed CTE. The percentage of players under age 60 years reporting a CTE diagnosis was 2.3% versus 3.7% in participants age 60 or older. Comorbidities in participants self-reporting CTE were significantly more common, including sleep apnea, hypercholesterolemia, obesity, indicators of past or current depression, hypertension, prescription pain medication use, heart conditions, and low testosterone when compared to non-CTE respondents. Patterns of reporting for obesity, hypertension, heart conditions, or hypercholesterolemia differed between older and younger participants. Cognitive impairment symptoms were significantly higher in participants self-reporting CTE. INTERPRETATION: Some former professional football players have been clinically diagnosed with CTE, a postmortem condition. Comorbidities that can affect cognition were associated with CTE diagnoses in both older and younger players. Although underlying neuropathology cannot be ruled out, treatable conditions should be explored in former athletes demonstrating CTE-linked clinical phenotypes or symptoms as a means of improving cognitive health in these patients. ANN NEUROL 2020 ANN NEUROL 2020;88:106-112.

Chronic traumatic encephalopathy: understanding the facts and debate.

PURPOSE OF REVIEW: Chronic traumatic encephalopathy (CTE) is hypothesized to be a progressive neurodegenerative disease leading to dementia after repetitive head impacts. This review summarizes the recent evidence on CTE to highlight the facts currently known and the areas that remain poorly understood. RECENT FINDINGS: Increasing evidence suggests that many of the prior assertions about CTE in relation to repetitive head trauma are premature. First, CTE lesions have been observed in individuals with no history of head trauma/impacts. In addition, attempts to characterize possible clinical markers of CTE have had several shortcomings, notably an absence of detailed clinical assessments during life, vague/nonspecific symptom reports, and crude methodology. Moreover, recent studies demonstrate that current CTE pathological criteria have limitations and are in need of refinement/validation. SUMMARY: CTE is still in the early stages of research as a neuropathological condition and no specific clinical criteria exist. Claims about CTE being a progressive disease entity and caused exclusively by head trauma/impacts are not well supported at present. Such assertions may have impeded our understanding of the frequency and significance of this disorder. Refining diagnostic criteria to reduce ambiguity in classifying cases will be essential before risk factors and/or possible clinical markers may be identified.

Retired National Football League Players are Not at Greater Risk for Suicide.

OBJECTIVE: Some researchers have claimed that former National Football League (NFL) players are at increased risk for suicide as a clinical feature of chronic traumatic encephalopathy (CTE). This review examines the literature on risk for suicide in former professional football players, and the association between suicide and CTE. METHOD: A narrative review of the literature published between 1928 and 2018. RESULTS: Between 1928 and 2009, suicide was not considered to be a clinical feature of CTE in the literature. The best available evidence from epidemiological studies suggests that former NFL football players are at lesser risk for suicide, not greater risk, compared to men in the general population. However, surveys have revealed that a substantial minority of former NFL players have depression and other mental health problems, chronic pain and opioid use is relatively common, and those with depression and chronic pain also have greater life stress and financial difficulties. That minority would be at increased risk for suicidal thoughts and behaviors. CONCLUSIONS: Researchers and clinicians are encouraged to be cautious and circumspect when considering the clinical presentation of former athletes, and to not assume that depression and suicidality are caused by specific types of neuropathology. This represents a reductionistic and Procrustean view. Some former football players have mental health problems, but it should not be assumed uncritically that the underlying cause is an inexorably progressive neurodegenerative disease. Providing evidence-informed and evidence-supported treatments for depression and suicidality might reduce suffering and improve their functioning.

Tau PET and multimodal brain imaging in patients at risk for chronic traumatic encephalopathy.

OBJECTIVE: To characterize individual and group-level neuroimaging findings in patients at risk for Chronic Traumatic Encephalopathy (CTE). METHODS: Eleven male patients meeting criteria for Traumatic Encephalopathy Syndrome (TES, median age: 64) underwent neurologic evaluation, 3-Tesla MRI, and PET with [18F]-Flortaucipir (FTP, tau-PET) and [11C]-Pittsburgh compound B (PIB, amyloid-PET). Six patients underwent [18F]-Fluorodeoxyglucose-PET (FDG, glucose metabolism). We assessed imaging findings at the individual patient level, and in group-level comparisons with modality-specific groups of cognitively normal older adults (CN). Tau-PET findings in patients with TES were also compared to a matched group of patients with mild cognitive impairment or dementia due to Alzheimer's disease (AD). RESULTS: All patients with TES sustained repetitive head injury participating in impact sports, ten in American football. Three patients met criteria for dementia and eight had mild cognitive impairment. Two patients were amyloid-PET positive and harbored the most severe MRI atrophy, FDG hypometabolism, and FTP-tau PET binding. Among the nine amyloid-negative patients, tau-PET showed either mildly elevated frontotemporal binding, a "dot-like" pattern, or no elevated binding. Medial temporal FTP was mildly elevated in a subset of amyloid-negative patients, but values were considerably lower than in AD. Voxelwise analyses revealed a convergence of imaging abnormalities (higher FTP binding, lower FDG, lower gray matter volumes) in frontotemporal areas in TES compared to controls. CONCLUSIONS: Mildly elevated tau-PET binding was observed in a subset of amyloid-negative patients at risk for CTE, in a distribution consistent with CTE pathology stages III-IV. FTP-PET may be useful as a biomarker of tau pathology in CTE but is unlikely to be sensitive to early disease stages.

The psychometric validation of the Dutch version of the Rivermead Post-Concussion Symptoms Questionnaire (RPQ) after traumatic brain injury (TBI).

BACKGROUND: Traumatic brain injury (TBI) is one of the most common neurological conditions. It can have wide-ranging physical, cognitive and psychosocial effects. Most people recover within weeks to months after the injury, but a substantial proportion are at risk of developing lasting post-concussion symptoms. The Rivermead Post-Concussion Syndrome Questionnaire (RPQ) is a short validated 16-items self-report instrument to evaluate post-concussive symptoms. The aim of this study was to test psychometrics characteristics of the current Dutch translation of the RPQ. METHODS: To determine the psychometric characteristics of the Dutch RPQ, 472 consecutive patients six months after they presented with a traumatic brain injury in seven medical centers in the Netherlands (N = 397), and in two in Belgium (Flanders) (N = 75) took part in the study which is part of the large prospective longitudinal observational CENTER-TBI-EU-study. Psychometric properties at six months post TBI, were assessed using exploratory and confirmatory factor analyses. Sensitivity was analyzed by comparing RPQ scores and self-reported recovery status of patients with mild vs. moderate and severe TBI. FINDINGS: The Dutch version of RPQ proved good, showing excellent psychometric characteristics: high internal consistency (Cronbach's α .93), and good construct validity, being sensitive to self-reported recovery status at six months post TBI. Moreover, data showed a good fit to the three dimensional structure of separate cognitive, emotional and somatic factors (Chi2 = 119; df = 117; p = .4; CFI = .99; RMSEA = .006), reported earlier in the literature. DISCUSSION: Psychometric characteristics of the Dutch version of RPQ proved excellent to good, and can the instrument therefore be applied for research purposes and in daily clinical practice.

Chronic Traumatic Encephalopathy (CTE) Is Absent From a European Community-Based Aging Cohort While Cortical Aging-Related Tau Astrogliopathy (ARTAG) Is Highly Prevalent.

This study determined the prevalence of chronic traumatic encephalopathy (CTE) and cortical aging-related tau astrogliopathy (ARTAG) in a European community-based population (n = 310). The frontal, parietal, and temporal cortices, representing initial stages of CTE were assessed. No case fulfilling CTE consensus criteria was found. However, isolated astroglial or neuronal tau pathologies were recognized in the depths of cortical sulci (<2%). A single case (female, 85 years) without a history of traumatic brain injury (TBI) showed combined tau-immunoreactive features confined to frontal sulci without perivascular accumulation. Another 24 cases had single tau pathologies in cortical sulci. ARTAG was identified in 117 cases (38%), with a similar regional prevalence. Gray matter ARTAG was the most common followed by subpial, white matter, and perivascular. The presence of any type of ARTAG was strongly associated with having another type of ARTAG in the same region (p < 0.05). In summary, although isolated tau pathologies in the depths of cortical sulci were identified, no case fulfilled diagnostic criteria of CTE. Cortical ARTAG in this population is common and contrasts the high prevalence of CTE in individuals with repeated mild TBI. ARTAG in isolation might not be indicative of CTE although commonalities in pathogenesis should be considered.

Chronic traumatic encephalopathy is not a real disease.

There was a long-lasting debate during the first half of the 1900s about whether boxers suffered from a condition called "dementia pugilistica". This included arguments as to whether there was such a distinct clinical condition, whether it was static or progressive, and whether boxers were actually at any increased risk of any neurological issues at all. The debate was never resolved, but was resuscitated in 2005 with the speculation that a similar condition, dubbed "chronic traumatic encephalopathy (CTE)" existed in retired National Football League (NFL) players. A specific pattern of p-tau deposition has been identified in the brains of NFL retirees, and also identifiable in the brains of at least a percentage of individuals exposed to contact sports in general. Advocates of CTE as a disease describe it as presenting with behavioral disturbance, increased suicidality and neurodegeneration leading to dementia. The evidence to date, however, does not rise to the level of a verifiable disease, and remains at the level of case report. To assume that CTE pathology represents a neurodegenerative disease flies in the face of a number of facts, including that traumatic brain injury does not cause neurodegeneration, protein deposits in the brain are a poor predictor of behavioral symptoms, p-tau is not necessarily toxic or self-propagating, and retired NFL players are actually much physically and mentally healthier than men of their demographic background. They have an all-cause mortality rate that is 50% of that expected, and a suicide rate that is 40% of that expected. The most parsimonious explanation of the evidence to date is that repetitive head trauma may result in p-tau deposition, but that this isoform of p-tau is inert and has no toxic or self-propagating effects.

A novel repetitive mild traumatic brain injury mouse model for chronic traumatic encephalopathy research.

BACKGROUND: Athletes, military personnel and mobility-declined elderly people are prone to repetitive mild traumatic brain injury (rmTBI). The injury does not cause acute pathological changes, but leads to chronic neurodegeneration, long-term cognitive dysfunction and even chronic traumatic encephalopathy (CTE). Many existing rmTBI animal models reported uncontrollable adverse effects and long experiment period. Therefore, an improved model needs to be designed. NEW METHOD: Our rmTBI mouse model is a modification of the closed head injury method using electronic controlled cortical impact system. Discontinuous 4 impacts with 48-h interval were performed. A key facet of the model is the use of our designed molded acrylic cast and concave metal disc (as a helmet). They could scatter and transmit hitting power to the whole brain, thus produced a mild diffused injury. The procedure does not require scalp incision or craniotomy, which allows the impacting to be completed in 2 min. RESULTS: Our model did not induce acute macroscopic brain damage and brain edema. It could lead to sustained neuroinflammation and chronic neurodegeneration in injured brain, and resulted in cognitive dysfunction within 5 weeks post-injury. COMPARISON WITH EXISTING METHODS: Previously reported adverse effects including skull fractures, hemorrhage and brain tissue loss were not observed in our model. An experiment period of 5 weeks was allowed for observing chronic neurodegeneration and cognitive dysfunction. CONCLUSIONS: Our model is beneficial to use for simplicity, reproducibility and time saver. It could serve as a platform for research on the pathogenesis, diagnosis and potential therapeutics for rmTBI and CTE.

Diagnosis makes a difference: Perceptions of older persons with dementia symptoms.

Background/Study Context: Employing the stereotype content model and terror management theory, we examined whether stereotypes and feelings about persons with dementia vary depending on the type of dementia diagnosis and purported causes of the dementia. METHODS: Participants were randomly assigned to read one of four vignettes that depicted a man who consulted his doctor because of memory problems. All vignettes described the same symptoms and diagnostic tests, but each of four groups read a different result: all tests normal (Normal); Alzheimer's disease (AD); Wernicke-Korsakoff Syndrome (WKS) associated with alcohol abuse; and chronic traumatic encephalopathy (CTE) associated with head injuries from playing football in high school and college. Measures included a word fragment completion task, a stereotype content scale, and an emotions scale. RESULTS: Results showed no differences in the number of death-related words generated in the word fragment completion task and no differences in assessment of competence across the four groups. Those in the Normal, AD, and CTE groups evaluated the man as warmer than those in the WKS group. Participants in the AD condition showed more empathy than those in the WKS group. There were no differences in pity or fear but the CTE condition produced more envy and admiration and the WKS condition produced more contempt. CONCLUSION: These results suggest that different forms of dementia elicit varying emotional and cognitive responses.

Research Gaps and Controversies in Chronic Traumatic Encephalopathy: A Review.

Importance: Scientific and lay interest in negative outcomes associated with exposure to repetitive brain trauma (RBT) continues to strengthen. Concerns about the association between RBT and dementia began more than a century ago, but have resurfaced in the last decade with the more recently described chronic traumatic encephalopathy (CTE). Chronic traumatic encephalopathy is a tauopathy associated with RBT that has become inextricably linked to conversations about sport-related concussion and mild traumatic brain injury. Accordingly, specific populations such as collision sport athletes and certain military personnel are of particular interest owing to their unique exposure to RBT. The gaps and controversies in our understanding of the epidemiologic factors, mechanism, and clinicopathological correlates of CTE reflect the current reliance on postmortem case series investigations. This review discusses the state of the science of CTE and raises considerations for researching and interpreting cognitive changes in members of at-risk populations. Observations: The recent development of pathological diagnostic criteria for CTE represented an important step for differentiating CTE from other neurodegenerative diseases. By comparison, defining the clinical syndrome(s) associated with CTE and the necessary and sufficient symptoms needed for its diagnosis lags behind. The absence of validated in vivo biomarkers of pathological characteristics of CTE and longitudinal tracking with neuropsychological evaluation remains a significant hurdle. Attribution of candidate symptoms in retired athletes to CTE is complicated by the presence of multiple premorbid and comorbid factors affecting cognitive reserve that influence normal or expected cognitive functioning. This is a critical issue in appropriately defining reference groups for normative comparisons. Conclusions and Relevance: Available data, while limited and complicated by selection bias, indicate that exposure to RBT represents the greatest risk factor for CTE pathological features, although clinicopathological correlates and the nature of onset and progression of symptoms are largely unknown. Considering aspects of cognitive reserve is likely essential for both interpreting cognitive outcomes associated with CTE and for developing preventive treatment programs. Research on CTE would benefit greatly from incorporating principles established within other areas of neurodegenerative disease and the nuances of clinicopathological considerations.

Longitudinal changes in linguistic complexity among professional football players.

Reductions in spoken language complexity have been associated with the onset of various neurological disorders. The objective of this study is to analyze whether similar trends are found in professional football players who are at risk for chronic traumatic encephalopathy. We compare changes in linguistic complexity (as indexed by the type-to-token ratio and lexical density) measured from the interview transcripts of players in the National Football League (NFL) to those measured from interview transcripts of coaches and/or front-office NFL executives who have never played professional football. A multilevel mixed model analysis reveals that exposure to the high-impact sport (vs no exposure) was associated with an overall decline in language complexity scores over time. This trend persists even after controlling for age as a potential confound. The results set the stage for a prospective study to test the hypothesis that language complexity decline is a harbinger of chronic traumatic encephalopathy.

Does a Unique Neuropsychiatric Profile Currently Exist for Chronic Traumatic Encephalopathy?

There is evidence that repetitive mild traumatic brain injury leads to specific patterns of neuropathological findings, labeled chronic traumatic encephalopathy (CTE). However, questions remain about whether these neuropathological changes produce changes in behavior, cognition, and emotional status that are associated with a unique neuropsychiatric profile that can be assessed using currently available clinical tools. Our review of the literature indicates that insufficient evidence currently exists to suggest a distinct neuropsychiatric profile for CTE. Major limitations to the field presently include the relatively nascent nature of the topic, reliance on retrospective next-of-kin reporting, the lack of prospective studies, and similarities in neuropsychiatric symptoms between CTE, other neurodegenerative disorders and forms of psychopathology. Clinicians and researchers alike have a responsibility to adopt a cautious and balanced approach for antemortem assessments to minimize the potential unintended negative consequences of both overdiagnosing and underdiagnosing a clinical entity that has yet to be clearly established.

Football Players' Perceptions of Future Risk of Concussion and Concussion-Related Health Outcomes.

Concussion is increasingly recognized as a risk of participation in contact and collision sports. There have been few examinations of athletes' perceptions of their susceptibility to concussion or concussion-related health consequences. We examine college football players' perceptions of their risk of sustaining a concussion and concussion-related health consequences in their future, whether these perceptions change over time, and how concussion history is related to perceived future risk of concussion and concussion-related health consequences. A survey was administered to National Collegiate Athletic Association Division I Football Championship Series athletes on 10 teams in 2013 and to nine of those teams in 2014. Athletes answered questions assessing their perceptions of concussion and potential concussion-related health consequences. Approximately 40% of athletes believed there was a strong possibility that they would sustain a concussion in the future, while approximately one-in-four thought a concussion would make them miss a few games. About one-in-10 athletes predicted dementia, Alzheimer's disease, or chronic traumatic encephalopathy would develop from concussions. These beliefs were stronger among athletes who had sustained previous concussions. Across the two years studied, athletes' perceptions of the risk of concussion and missing a few games because of concussion decreased significantly. Overall, a substantial proportion of college football players believe they will have long-term health consequences as a result of sustaining sport-related concussions. The true incidence and prevalence of many of these outcomes are unknown. Further research is needed to determine whether athletes have an accurate perception of the risks of these outcomes developing.

Cognitive Reserve as a Modifier of Clinical Expression in Chronic Traumatic Encephalopathy: A Preliminary Examination.

This study conducted a preliminary examination on cognitive reserve (CR) as a modifier of symptom expression in subjects with autopsy-confirmed chronic traumatic encephalopathy (CTE). The sample included 25 former professional football players neuropathologically diagnosed with CTE stage III or IV. Next of kin interviews ascertained age at cognitive and behavioral/mood symptom onset and demographic/athletic characteristics. Years of education and occupational attainment defined CR. High occupational achievement predicted later age at cognitive (p=0.02) and behavioral/mood (p=0.02) onset. Education was not an individual predictor. These preliminary findings suggest that CR may forestall the clinical manifestation of CTE.

Progressive Focal Gray Matter Volume Loss in a Former High School Football Player: A Possible Magnetic Resonance Imaging Volumetric Signature for Chronic Traumatic Encephalopathy.

Here a case is presented of a 51-year-old former high school football player with multiple concussions, including one episode with loss of consciousness. The patient experienced 6 years of cognitive and mood decline, and his wife corroborated increasing memory loss, attentional difficulties, and depressed mood without suicidal ideation. He had been unable to maintain full-time employment because of progressive decline. Based on his presentation, he had been previously diagnosed with attention deficit hyperactivity disorder and bipolar disorder, type II. Neuropsychological tests indicated domain-specific cognitive impairment, and longitudinal volumetric magnetic resonance imaging (MRI) of the brain showed progressive brainstem, diencephalic, and frontal lobe atrophy. This regional volume loss correlated with the increased signal seen on tau and amyloid imaging (FDDNP-PET scan) of a separate case of suspected chronic traumatic encephalopathy (CTE). Visual assessment of the MRI also showed evidence of old petechial hemorrhages in the frontal and temporal-parietal lobe white matter. This case raises the possibility of distinct quantitative and visual brain MRI findings in suspected CTE.