Examining the New Consensus Criteria for Traumatic Encephalopathy Syndrome in Community-Dwelling Older Adults.

In 2021, an expert panel of clinician-scientists published the first consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), a clinical condition thought to be associated with chronic traumatic encephalopathy neuropathological change. This study evaluated the TES criteria in older adults and assessed associations between TES criteria and a history of repetitive head impacts. This cross-sectional, survey-based study examined the symptoms of TES, previous repetitive head impacts, and a variety of current health difficulties. To meet symptom criteria for TES, participants had to report progressive changes with memory, executive functioning, and/or neurobehavioral dysregulation. To meet the criterion for substantial exposure to repetitive head impacts via contact sports, participants reported at least 5 years of contact sport exposure (with 2+ years in high school or beyond). A sample of 507 older adults (mean age = 70.0 years, 65% women) completed the survey and 26.2% endorsed having one or more of the progressive core clinical features of TES. Those who had a significant history of contact sport exposure were not significantly more likely to meet TES criteria compared with those who did not (31.3% vs. 25.3%, p = 0.46). In a binary logistic regression predicting TES status, current depression or anxiety (odds ratio [OR] = 12.55; 95% confidence interval [CI] = 4.43-35.51), history of psychiatric disorders (OR = 2.07, 95% CI = 1.22-3.49), male sex (OR = 1.87), and sleep problems (OR = 1.71, 95% CI = 1.01-2.91) were associated with meeting TES criteria. The sport exposure criterion, age, and current pain were not significantly associated with TES status (ps > 0.05). A significant minority of participants with no history of neurotrauma endorsed symptoms consistent with TES (22.0% of men and 19.8% of women). Nearly 80% of neurotrauma naïve participants with clinically significant anxiety/depression met criteria for TES. In summary, approximately one in four older adults met the symptom criteria for TES, many of whom had no history of repetitive neurotrauma. Mental health problems and sleep issues were associated with TES, whereas having a history of repetitive head impacts in contact sports was not. These data suggest that the new consensus diagnostic criteria for TES may have low specificity and may carry a higher risk of misdiagnosing those with other physical and mental health conditions as having TES.

Public Chronic Traumatic Encephalopathy Knowledge: Sources, Accuracy and Confidence.

ABSTRACT: The goal of this study was to examine the general public's level of accuracy and confidence in knowledge of chronic traumatic encephalopathy (CTE), as well as information sources. This study also explored how these factors affected comfort in allowing children to play a high-contact sport. This study utilized online surveys and included 529 participants. Overall, CTE knowledge accuracy was 48.02% (standard deviation = 0.23). Inaccuracies regarding the etiology and diagnosis of CTE were most common, whereas the symptoms and lack of treatments for CTE were more widely known. Despite overall low CTE knowledge accuracy, CTE knowledge confidence was positively correlated with comfort in allowing children to play a high-contact sport (r = 0.199, P ≤ 0.001). Participants identified television/movies followed by web sites and social media as the most utilized CTE information sources. These results further support the need for clinicians and researchers to address misconceptions about CTE.

Is contact sport participation associated with chronic traumatic encephalopathy or neurodegenerative decline? A systematic review and meta-analysis.

INTRODUCTION: We sought to evaluate a potential association between contact vs. non-contact sport participation and long-term neurologic outcomes and chronic traumatic encephalopathy (CTE). EVIDENCE ACQUISITION: PubMed/Embase/PsycINFO/CINAHL databases were queried for studies between 1950-2020 with contact and non-contact sports, longitudinal assessment >10 years, and long-term neurologic outcomes in four-domains: I) clinical diagnosis; II) CTE neuropathology; III) neurocognition; and IV) neuroimaging. EVIDENCE SYNTHESIS: Of 2561 studies, 37 met inclusion criteria, and 19 contained homogenous outcomes usable in the meta-analysis. Domain I: Across six studies, no significant relationship was seen between contact sport participation and antemortem diagnosis of neurodegenerative disease or death related to such a diagnosis (RR1.88, P=0.054, 95%CI0.99, 3.49); however, marginal significance (P<0.10) was obtained. Domain II: Across three autopsy studies, no significant relationship was seen between contact sport participation and CTE neuropathology (RR42.39, P=0.086, 95%CI0.59, 3057.46); however, marginal significance (P<0.10) was obtained. Domain III: Across five cognitive studies, no significant relationship was seen between contact sport participation and cognitive function on the Trail Making Test (TMT) scores A/B (A:d=0.17, P=0.275,95% CI-0.13, 0.47; B:d=0.13, P=0.310, 95%CI-0.12, 0.38). Domain IV: In 10 brain imaging-based studies, 32% comparisons showed significant differences between those with a history of contact sport vs. those without. CONCLUSIONS: No statistically significant increased risk of neurodegenerative diagnosis, CTE neuropathology, or neurocognitive changes was found to be associated with contact sport participation, yet marginal significance was obtained in two domains. A minority of imaging comparisons showed differences of uncertain clinical significance. These results highlight the need for longitudinal investigations using standardized contact sport participation and neurodegenerative criteria.

Examination of parkinsonism in former elite American football players.

BACKGROUND: Former American football players are at risk for chronic traumatic encephalopathy (CTE) which may have parkinsonism as a clinical feature. OBJECTIVE: Former football players were prospectively assessed for parkinsonism. METHODS: 120 former professional football players, 58 former college football players, and 60 same-age asymptomatic men without repetitive head impacts, 45-74 years, were studied using the MDS-UPDRS to assess for parkinsonism, and the Timed Up and Go (TUG). Traumatic encephalopathy syndrome (TES), the clinical syndrome of CTE, was adjudicated and includes parkinsonism diagnosis. Fisher's Exact Test compared groups on parkinsonism due to small cell sizes; analysis of covariance or linear regressions controlling for age and body mass index were used otherwise. RESULTS: Twenty-two (12.4%) football players (13.3% professional, 10.3% college) met parkinsonism criteria compared with two (3.3%) in the unexposed group. Parkinsonism was higher in professional (p = 0.037) but not college players (p = 0.16). There were no differences on the MDS-UPDRS Part III total scores. Scores on the individual MDS-UPDRS items were low. TUG times were longer in former professional but not college players compared with unexposed men (13.09 versus 11.35 s, p < 0.01). There were no associations between years of football, age of first exposure, position or level of play on motor outcomes. TES status was not associated with motor outcomes. CONCLUSIONS: Parkinsonism rates in this sample of football players was low and highest in the professional football players. The association between football and parkinsonism is inconclusive and depends on factors related to sample selection, comparison groups, and exposure characteristics.

Interaction of Medical Conditions and Football Exposures Associated with Premortem Chronic Traumatic Encephalopathy Diagnosis in Former Professional American Football Players.

BACKGROUND AND OBJECTIVE: Despite being a postmortem diagnosis, former professional American-style football players report receiving chronic traumatic encephalopathy (CTE) diagnoses from medical care providers. However, many players also report other health conditions that manifest with cognitive and psychological symptoms. The purpose of this study was to identify how medical conditions, psychological disorders, and football exposure combinations are associated with former athletes reporting a premortem CTE diagnosis. METHODS: This study was a cross-sectional cohort survey from 2015 to 2019 of 4033 former professional American-style football players. Demographics (age, race, domestic status, primary care recipient), football-related factors (position, years of professional play, burden of symptoms following head impacts, performance-enhancing drug use), and comorbidities (sleep apnea, psychological disorder status [depression and anxiety; either depression or anxiety; neither depression nor anxiety], diabetes mellitus, attention-deficit/hyperactivity disorder, hypertension, heart conditions, high cholesterol, stroke, cancer, low testosterone, chronic pain, current and maximum body mass index) were recorded. A Chi-square automatic interaction detection (CHAID) decision tree model identified interactive effects between demographics, health conditions, and football exposures on the CTE diagnosis. RESULTS: Depression showed the strongest univariate association with premortem CTE diagnoses (odds ratio [OR] = 9.5, 95% confidence interval [CI] 6.0-15.3). CHAID differentiated participants with premortem CTE diagnoses with 98.2% accuracy and area under the curve = 0.81. Participants reporting both depression and anxiety were more likely to have a CTE diagnosis compared with participants who reported no psychological disorders (OR = 12.2; 95% CI 7.3-21.1) or one psychological disorder (OR = 4.5; 95% CI 1.9-13.0). Sleep apnea was also associated with a CTE diagnosis amongst those with both depression and anxiety (OR = 2.7; 95% CI 1.4-5.2). CONCLUSIONS: Clinical phenotypes including psychological disorders and sleep apnea were strongly associated with an increased likelihood of having received a pre-mortem CTE diagnosis in former professional football players. Depression, anxiety, and sleep apnea produce cognitive symptoms, are treatable conditions, and should be distinguished from neurodegenerative disease.

Blood-Based Biomarkers in the Diagnosis of Chronic Traumatic Encephalopathy: Research to Date and Future Directions.

Chronic Traumatic Encephalopathy (CTE) is a neurodegenerative disease consistently associated with repetitive traumatic brain injuries (TBIs), which makes multiple professions, such as contact sports athletes and the military, especially susceptible to its onset. There are currently no approved biomarkers to diagnose CTE, thus it can only be confirmed through a post-mortem brain autopsy. Several imaging and cerebrospinal fluid biomarkers have shown promise in the diagnosis. However, blood-based biomarkers can be more easily obtained and quantified, increasing their clinical feasibility and potential for prophylactic use. This article aimed to comprehensively review the studies into potential blood-based biomarkers of CTE, discussing common themes and limitations, as well as suggesting future research directions. While the interest in blood-based biomarkers of CTE has recently increased, the research is still in its early stages. The main issue for many proposed biomarkers is their lack of selectivity for CTE. However, several molecules, such as different phosphorylated tau isoforms, were able to discern CTE from different neurodegenerative diseases. Further, the results from studies on exosomal biomarkers suggest that exosomes are a promising source of biomarkers, reflective of the internal environment of the brain. Nonetheless, more longitudinal studies combining imaging, neurobehavioral, and biochemical approaches are warranted to establish robust biomarkers for CTE.

Neuropathologic and Clinical Findings in Young Contact Sport Athletes Exposed to Repetitive Head Impacts.

Importance: Young contact sport athletes may be at risk for long-term neuropathologic disorders, including chronic traumatic encephalopathy (CTE). Objective: To characterize the neuropathologic and clinical symptoms of young brain donors who were contact sport athletes. Design, Setting, and Participants: This case series analyzes findings from 152 of 156 brain donors younger than 30 years identified through the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank who donated their brains from February 1, 2008, to September 31, 2022. Neuropathologic evaluations, retrospective telephone clinical assessments, and online questionnaires with informants were performed blinded. Data analysis was conducted between August 2021 and June 2023. Exposures: Repetitive head impacts from contact sports. Main Outcomes and Measures: Gross and microscopic neuropathologic assessment, including diagnosis of CTE, based on defined diagnostic criteria; and informant-reported athletic history and informant-completed scales that assess cognitive symptoms, mood disturbances, and neurobehavioral dysregulation. Results: Among the 152 deceased contact sports participants (mean [SD] age, 22.97 [4.31] years; 141 [92.8%] male) included in the study, CTE was diagnosed in 63 (41.4%; median [IQR] age, 26 [24-27] years). Of the 63 brain donors diagnosed with CTE, 60 (95.2%) were diagnosed with mild CTE (stages I or II). Brain donors who had CTE were more likely to be older (mean difference, 3.92 years; 95% CI, 2.74-5.10 years) Of the 63 athletes with CTE, 45 (71.4%) were men who played amateur sports, including American football, ice hockey, soccer, rugby, and wrestling; 1 woman with CTE played collegiate soccer. For those who played football, duration of playing career was significantly longer in those with vs without CTE (mean difference, 2.81 years; 95% CI, 1.15-4.48 years). Athletes with CTE had more ventricular dilatation, cavum septum pellucidum, thalamic notching, and perivascular pigment-laden macrophages in the frontal white matter than those without CTE. Cognitive and neurobehavioral symptoms were frequent among all brain donors. Suicide was the most common cause of death, followed by unintentional overdose; there were no differences in cause of death or clinical symptoms based on CTE status. Conclusions and Relevance: This case series found that young brain donors exposed to repetitive head impacts were highly symptomatic regardless of CTE status, and the causes of symptoms in this sample are likely multifactorial. Future studies that include young brain donors unexposed to repetitive head impacts are needed to clarify the association among exposure, white matter and microvascular pathologic findings, CTE, and clinical symptoms.

Emerging Symptomatic Treatment of Chronic Traumatic Encephalopathy (CTE): a narrative review.

INTRODUCTION: Chronic traumatic encephalopathy (CTE) is an emergent neurodegenerative tauopathy well characterized pathologically but with limited consensus about clinical criteria. The clinical features include cognitive, behavioral, and motor symptoms such as parkinsonism, gait, balance disorder, and bulbar impairment. Their recognition derives from retrospective studies in pathologically confirmed CTE patients. This is one of the main reasons for the lack of specific pharmacological studies targeting symptoms or pathologic pathways of this disease. AREAS COVERED: In this narrative review, we overview the possible symptomatic treatment options for CTE, based on pathological similarities with other neurodegenerative diseases that may share common pathological pathways with CTE. The PubMed database was screened for articles addressing the symptomatic treatment of CTE and Traumatic Encephalopathy Syndrome (TES). Additional references were retrieved by reference cross-check and retained if pertinent to the subject. The clinicaltrials.gov database was screened for ongoing trials on the treatment of CTE. EXPERT OPINION: The similarities with the other tauopathies allow us, in the absence of disease-specific evidence, to translate some knowledge from these neurodegenerative disorders to CTE's symptomatic treatment, but any conclusion should be drawn cautiously and a patient-tailored strategy should be always preferred balancing the risks and benefits of each treatment.

Challenges in the pharmacological treatment of patients under suspicion of chronic traumatic encephalopathy: A review.

Chronic traumatic encephalopathy (CTE) is caused by progressive neurodegeneration associated with repetitive head impacts. This disease is more common in professionals who practice contact sports, resulting in a concussion and subconcussive trauma. CTE is characterized by the accumulation of hyperphosphorylated tau protein in neurons, astrocytes, and frontotemporal lobe degeneration. Symptoms are usually nonspecific and overlap with other neurodegenerative diseases, such as Alzheimer's disease and frontotemporal dementia, making it difficult to provide drug treatment for patients with this comorbidity. Therefore, the objective of this article is to present an updated review of the pharmacological treatment of chronic traumatic encephalopathy and its challenges.

Sports Concussion and Chronic Traumatic Encephalopathy: Finding a Path Forward.

Sports concussion has recently assumed special importance because of the widely publicized entity of chronic traumatic encephalopathy (CTE). Identified primarily in former contact sports athletes with repeated mild traumatic brain injury (mTBI), CTE is a distinct tauopathy that can only be diagnosed postmortem and for which no specific treatment is available. Although the hazards of repeated mTBI are generally acknowledged, a spirited controversy has developed because a firm link between sports concussion and CTE has been questioned. We briefly review the history of CTE, discuss areas of uncertainty, and offer suggestions to assist neurologists confronting these issues and advance understanding of this vexing problem. ANN NEUROL 2023;93:222-225.

[Chronic Traumatic Encephalopathy: Concussion].

I present Concussion, a 2015 film based on a true story, and produced in the United States. This film not only helps us understand how chronic traumatic encephalopathy (CTE) became a social issue in that country but also makes us think about the attitude of scientists toward the truth. In this article, I would like to introduce the history and current status of CTE research.

A systematic review on the risk of neurodegenerative diseases and neurocognitive disorders in professional and varsity athletes.

OBJECTIVE: The aim of this systematic review (SR) was to gather all available epidemiological evidence on former participation in any type of sport, at a professional and varsity level, as a potential risk factor for neurodegenerative diseases (NDs) and neurocognitive disorders (NCDs). DESIGN: Systematic searches were performed on PubMed, the Cochrane databases, and the ISI Web of Knowledge databases. Included studies were assessed using the NOS checklist. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: All epidemiological studies reporting data on the possible association between a clinical diagnosis of amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND), dementia or mild cognitive impairment (MCI), Parkinson's disease (PD), chronic traumatic encephalopathy (CTE) at any stage and with any clinical pattern and the former participation in any types of sport at a varsity and professional level were included. RESULTS: Data from the 17 included studies showed a higher frequency of NDs and NCDs in former soccer and American football players. Updating the previous SR confirmed a higher frequency of ALS/MND in former soccer players. Data reported a significantly higher risk of dementia/AD in former soccer players, and of MCI in former American football players. Results also showed a significantly higher risk of PD in former soccer and American football players, and a significantly higher risk of CTE in former boxers and American football players. This SR confirmed a higher risk of NDs and NCDs in former professional/varsity athletes. However, the pathological mechanisms underlying this association remain unclear, and further high-quality studies should be performed to clarify whether the association could be sport specific.

Association of APOE Genotypes and Chronic Traumatic Encephalopathy.

Importance: Repetitive head impact (RHI) exposure is the chief risk factor for chronic traumatic encephalopathy (CTE). However, the occurrence and severity of CTE varies widely among those with similar RHI exposure. Limited evidence suggests that the APOEε4 allele may confer risk for CTE, but previous studies were small with limited scope. Objective: To test the association between APOE genotype and CTE neuropathology and related endophenotypes. Design, Setting, and Participants: This cross-sectional genetic association study analyzed brain donors from February 2008 to August 2019 from the Veterans Affairs-Boston University-Concussion Legacy Foundation Brain Bank. All donors had exposure to RHI from contact sports or military service. All eligible donors were included. Analysis took place between June 2020 and April 2022. Exposures: One or more APOEε4 or APOEε2 alleles. Main Outcomes and Measures: CTE neuropathological status, CTE stage (0-IV), semiquantitative phosphorylated tau (p-tau) burden in 11 brain regions (0-3), quantitative p-tau burden in the dorsolateral frontal lobe (log-transformed AT8+ pixel count per mm2), and dementia. Results: Of 364 consecutive brain donors (100% male; 53 [14.6%] self-identified as Black and 311 [85.4%] as White; median [IQR] age, 65 [47-77] years) 20 years or older, there were 294 individuals with CTE and 70 controls. Among donors older than 65 years, APOEε4 status was significantly associated with CTE stage (odds ratio [OR], 2.34 [95% CI, 1.30-4.20]; false discovery rate [FDR]-corrected P = .01) and quantitative p-tau burden in the dorsolateral frontal lobe (ß, 1.39 [95% CI, 0.83-1.94]; FDR-corrected P = 2.37 × 10-5). There was a nonsignificant association between APOEε4 status and dementia (OR, 2.64 [95% CI, 1.06-6.61]; FDR-corrected P = .08). Across 11 brain regions, significant associations were observed for semiquantitative p-tau burden in the frontal and parietal cortices, amygdala, and entorhinal cortex (OR range, 2.45-3.26). Among football players, the APOEε4 association size for CTE stage was similar to playing more than 7 years of football. Associations were significantly larger in the older half of the sample. There was no significant association for CTE status. Association sizes were similar when donors with an Alzheimer disease neuropathological diagnosis were excluded and were reduced but remained significant after adjusting for neuritic and diffuse amyloid plaques. No associations were observed for APOEε2 status. Models were adjusted for age at death and race. Conclusions and Relevance: APOEε4 may confer increased risk for CTE-related neuropathological and clinical outcomes among older individuals with RHI exposure. Further work is required to validate these findings in an independent sample.

Relationship Between Level of American Football Playing and Diagnosis of Chronic Traumatic Encephalopathy in a Selection Bias Analysis.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts such as those from American football. Our understanding of this association is based on research in autopsied brains, since CTE can only be diagnosed postmortem. Such studies are susceptible to selection bias, which needs to be accounted for to ensure a generalizable estimate of the association between repetitive head impacts and CTE. We evaluated the relationship between level of American football playing and CTE diagnosis after adjusting for selection bias. The sample included 290 deceased male former American football players who donated their brains to the Veterans Affairs-Boston University-Concussion Legacy Foundation (VA-BU-CLF) Brain Bank between 2008 and 2019. After adjustment for selection bias, college-level and professional football players had 2.38 (95% simulation interval (SI): 1.16, 5.94) and 2.47 (95% SI: 1.46, 4.79) times the risk of being diagnosed with CTE as high-school-level players, respectively; these estimates are larger than estimates with no selection bias adjustment. Since CTE is currently diagnosed only postmortem, we additionally provide plausible scenarios for CTE risk ratios for each level of play during the former players' lifetime. This study provides further evidence to support a dose-response relationship between American football playing and CTE.

Detection of astrocytic tau pathology facilitates recognition of chronic traumatic encephalopathy neuropathologic change.

Traumatic brain injury (TBI) is associated with the development of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy (CTE). Current consensus diagnostic criteria define the pathognomonic cortical lesion of CTE neuropathologic change (CTE-NC) as a patchy deposition of hyperphosphorylated tau in neurons, with or without glial tau in thorn-shaped astrocytes, typically towards the depths of sulci and clustered around small blood vessels. Nevertheless, although incorporated into consensus diagnostic criteria, the contribution of the individual cellular components to identification of CTE-NC has not been formally evaluated. To address this, from the Glasgow TBI Archive, cortical tissue blocks were selected from consecutive brain donations from contact sports athletes in which there was known to be either CTE-NC (n = 12) or Alzheimer's disease neuropathologic change  (n = 4). From these tissue blocks, adjacent tissue sections were stained for tau antibodies selected to reveal either solely neuronal pathology (3R tau; GT-38) or mixed neuronal and astroglial pathologies (4R tau; PHF-1). These stained sections were then randomised and independently assessed by a panel of expert neuropathologists, blind to patient clinical history and primary antibody applied to each section, who were asked to record whether CTE-NC was present. Results demonstrate that, in sections stained for either 4R tau or PHF-1, consensus recognition of CTE-NC was high. In contrast, recognition of CTE-NC in sections stained for 3R tau or GT-38 was poor; in the former no better than chance. Our observations demonstrate that the presence of both neuronal and astroglial tau pathologies facilitates detection of CTE-NC, with its detection less consistent when neuronal tau pathology alone is visible. The combination of both glial and neuronal pathologies, therefore, may be required for detection of CTE-NC.