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The term “repetitive head impacts” (RHI) refers to the cumulative exposure to concussive and subconcussive events. Although RHI are believed to increase risk for later-life neurological consequences (including chronic traumatic encephalopathy), quantitative analysis of this relationship has not yet been examined because of the lack of validated tools to quantify lifetime RHI exposure. The objectives of this study were: 1) to develop a metric to quantify cumulative RHI exposure from football, which we term the “cumulative head impact index” (CHII); 2) to use the CHII to examine the association between RHI exposure and long-term clinical outcomes; and 3) to evaluate its predictive properties relative to other exposure metrics (i.e., duration of play, age of first exposure, concussion history). Participants included 93 former high school and collegiate football players who completed objective cognitive and self-reported behavioral/mood tests as part of a larger ongoing longitudinal study. Using established cutoff scores, we transformed continuous outcomes into dichotomous variables (normal vs. impaired). The CHII was computed for each participant and derived from a combination of self-reported athletic history (i.e., number of seasons, position[s], levels played), and impact frequencies reported in helmet accelerometer studies. A bivariate probit, instrumental variable model revealed a threshold dose-response relationship between the CHII and risk for later-life cognitive impairment (p < 0.0001), self-reported executive dysfunction (p < 0.0001), depression (p < 0.0001), apathy (p = 0.0161), and behavioral dysregulation (p < 0.0001). Ultimately, the CHII demonstrated greater predictive validity than other individual exposure metrics.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impacts (RHI), but the components of RHI exposure underlying this relationship are unclear. We create a position exposure matrix (PEM), composed of American football helmet sensor data, summarized from literature review by player position and level of play. Using this PEM, we estimate measures of lifetime RHI exposure for a separate cohort of 631 football playing brain donors. Separate models examine the relationship between CTE pathology and players’ concussion count, athletic positions, years of football, and PEM-derived measures, including estimated cumulative head impacts, linear accelerations, and rotational accelerations. Only duration of play and PEM-derived measures are significantly associated with CTE pathology. Models incorporating cumulative linear or rotational acceleration have better model fit and are better predictors of CTE pathology than duration of play or cumulative head impacts alone. These findings implicate cumulative head impact intensity in CTE pathogenesis. The relationship between the components of repetitive head impacts and chronic traumatic encephalopathy (CTE) remains unclear. Here, the authors use American football helmet sensor data to show that duration of play, cumulative head impacts and linear and rotational accelerations are significantly associated with CTE pathology.

Epidemiological evidence suggests that the incidence of amyotrophic lateral sclerosis is increased in association with head injury. Repetitive head injury is also associated with the development of chronic traumatic encephalopathy (CTE), a tauopathy characterized by neurofibrillary tangles throughout the brain in the relative absence of β-amyloid deposits. We examined 12 cases of CTE and, in 10, found a widespread TAR DNA-binding protein of approximately 43kd (TDP-43) proteinopathy affecting the frontal and temporal cortices, medial temporal lobe, basal ganglia, diencephalon, and brainstem. Three athletes with CTE also developed a progressive motor neuron disease with profound weakness, atrophy, spasticity, and fasciculations several years before death. In these 3 cases, there were abundant TDP-43-positive inclusions and neurites in the spinal cord in addition to tau neurofibrillary changes, motor neuron loss, and corticospinal tract degeneration. The TDP-43 proteinopathy associated with CTE is similar to that found in frontotemporal lobar degeneration with TDP-43 inclusions, in that widespread regions of the brain are affected. Akin to frontotemporal lobar degeneration with TDP-43 inclusions, in some individuals with CTE, the TDP-43 proteinopathy extends to involve the spinal cord and is associated with motor neuron disease. This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease.

CCL11, a protein previously associated with age-associated cognitive decline, is observed to be increased in the brain and cerebrospinal fluid (CSF) in chronic traumatic encephalopathy (CTE) compared to Alzheimer's disease (AD). Using a cohort of 23 deceased American football players with neuropathologically verified CTE, 50 subjects with neuropathologically diagnosed AD, and 18 non-athlete controls, CCL11 was measured with ELISA in the dorsolateral frontal cortex (DLFC) and CSF. CCL11 levels were significantly increased in the DLFC in subjects with CTE (fold change = 1.234, p < 0.050) compared to non-athlete controls and AD subjects with out a history of head trauma. This increase was also seen to correlate with years of exposure to American football (β = 0.426, p = 0.048) independent of age (β = -0.046, p = 0.824). Preliminary analyses of a subset of subjects with available post-mortem CSF showed a trend for increased CCL11 among individuals with CTE (p = 0.069) mirroring the increase in the DLFC. Furthermore, an association between CSF CCL11 levels and the number of years exposed to football (β = 0.685, p = 0.040) was observed independent of age (β = -0.103, p = 0.716). Finally, a receiver operating characteristic (ROC) curve analysis demonstrated CSF CCL11 accurately distinguished CTE subjects from non-athlete controls and AD subjects (AUC = 0.839, 95% CI 0.62-1.058, p = 0.028). Overall, the current findings provide preliminary evidence that CCL11 may be a novel target for future CTE biomarker studies.

Background Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by hyperphosphorylated tau (p-tau) accumulation. The clinical features associated with CTE pathology are unclear. In brain donors with autopsy-confirmed CTE, we investigated the association of CTE p-tau pathology density and location with cognitive, functional, and neuropsychiatric symptoms. Methods In 364 brain donors with autopsy confirmed CTE, semi-quantitative p-tau severity (range: 0–3) was assessed in 10 cortical and subcortical regions. We summed ratings across regions to form a p-tau severity global composite (range: 0–30). Informants completed standardized scales of cognition (Cognitive Difficulties Scale, CDS; BRIEF-A Metacognition Index, MI), activities of daily living (Functional Activities Questionnaire), neurobehavioral dysregulation (BRIEF-A Behavioral Regulation Index, BRI; Barratt Impulsiveness Scale, BIS-11), aggression (Brown-Goodwin Aggression Scale), depression (Geriatric Depression Scale-15, GDS-15), and apathy (Apathy Evaluation Scale, AES). Ordinary least squares regression models examined associations between global and regional p-tau severity (separate models for each region) with each clinical scale, adjusting for age at death, racial identity, education level, and history of hypertension, obstructive sleep apnea, and substance use treatment. Ridge regression models that incorporated p-tau severity across all regions in the same model assessed which regions showed independent effects. Results The sample was predominantly American football players (333; 91.2%); 140 (38.5%) had low CTE and 224 (61.5%) had high CTE. Global p-tau severity was associated with higher (i.e., worse) scores on the cognitive and functional scales: MI ( β standardized  = 0.02, 95%CI = 0.01–0.04), CDS ( β standardized  = 0.02, 95%CI = 0.01–0.04), and FAQ ( β standardized  = 0.03, 95%CI = 0.01–0.04). After false-discovery rate correction, p-tau severity in the frontal, inferior parietal, and superior temporal cortex, and the amygdala was associated with higher CDS ( β s standardized  = 0.17–0.29, ps < 0.01) and FAQ ( β s standardized  = 0.21–0.26, ps < 0.01); frontal and inferior parietal cortex was associated with higher MI ( β s standardized  = 0.21–0.29, ps < 0.05); frontal cortex was associated with higher BRI ( β standardized  = 0.21, p  < 0.01). Regions with effects independent of other regions included frontal cortex (CDS, MI, FAQ, BRI), inferior parietal cortex (CDS) and amygdala (FAQ). P-tau explained 13–49% of variance in cognitive and functional scales and 6–14% of variance in neuropsychiatric scales. Conclusion Accumulation of p-tau aggregates, especially in the frontal cortex, are associated with cognitive, functional, and certain neurobehavioral symptoms in CTE.

Background Chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, cannot currently be diagnosed during life. Atrophy patterns on magnetic resonance imaging could be an effective in vivo biomarker of CTE, but have not been characterized. Mechanisms of neurodegeneration in CTE are unknown. Here, we characterized macrostructural magnetic resonance imaging features of brain donors with autopsy-confirmed CTE. The association between hyperphosphorylated tau (p-tau) and atrophy on magnetic resonance imaging was examined. Methods Magnetic resonance imaging scans were obtained by medical record requests for 55 deceased symptomatic men with autopsy-confirmed CTE and 31 men ( n = 11 deceased) with normal cognition at the time of the scan, all > 60 years Three neuroradiologists visually rated regional atrophy and microvascular disease (0 [none]–4 [severe]), microbleeds, and cavum septum pellucidum presence. Neuropathologists rated tau severity and atrophy at autopsy using semi-quantitative scales. Results Compared to unimpaired males, donors with CTE (45/55=stage III/IV) had greater atrophy of the orbital-frontal (mean diff.=1.29), dorsolateral frontal (mean diff.=1.31), superior frontal (mean diff.=1.05), anterior temporal (mean diff.=1.57), and medial temporal lobes (mean diff.=1.60), and larger lateral (mean diff.=1.72) and third (mean diff.=0.80) ventricles, controlling for age at scan (ps<0.05). There were no effects for posterior atrophy or microvascular disease. Donors with CTE had increased odds of a cavum septum pellucidum (OR = 6.7, p < 0.05). Among donors with CTE, greater tau severity across 14 regions corresponded to greater atrophy on magnetic resonance imaging (beta = 0.68, p < 0.01). Conclusions These findings support frontal-temporal atrophy as a magnetic resonance imaging finding of CTE and show p-tau accumulation is associated with atrophy in CTE.

BackgroundPatient-Reported Outcome Measures (PROMs) are vital for patient-centred care but face implementation challenges. Within the participating academic medical centre’s spine care and pain management clinics, PROMs were collected but underused, indicating a quality gap.ObjectiveTo identify and compare physician and patient perspectives on priorities, barriers and preferences for PROM implementation to inform a quality improvement initiative.MethodsWe conducted a mixed-methods evaluation (October 2024–December 2024) in two outpatient clinics. Data included quantitative surveys assessing priorities and challenges from physicians (N=8) and patients (N=35), and qualitative data from physician meeting field notes, patient interaction field notes and open-ended survey responses. Quantitative data were analysed descriptively; qualitative data underwent thematic analysis. Findings were integrated using triangulation.ResultsPhysicians and patients aligned on prioritising pain interference and physical function. However, patients prioritised pain severity and personal goals more highly than physicians. While 70% of patients found PROMs useful, only 24% reported discussing PROM findings with providers, and 75% of clinicians responded ‘not at all confident’ to a question about score interpretation. Implementation challenges diverged significantly: physicians universally (100%) cited perceived patient time burden as a barrier, but this concern was infrequently shared by patients (11.4%). Physicians also cited workflow integration as a barrier (87.5%), while patients primarily prioritised PROM format/design (37.1%) and relevance (28.6%). Five qualitative themes emerged across patients and physicians: (1) critiques of PROM content/fidelity; (2) disconnect between data collection and clinical integration; (3) prioritising function and patient-centred goals; (4) need for flexibility, customisation and communication and (5) system-level barriers influencing implementation.ConclusionsGaps exist between PROM collection and meaningful clinical use in this setting, driven by content limitations, workflow barriers, system issues and divergent stakeholder perspectives. Improving PROM implementation requires a multistakeholder approach prioritising function-focused, relevant measures integrated effectively into clinical workflows and support by system-level changes.

Over the last 17 years, there has been a remarkable increase in scientific research concerning chronic traumatic encephalopathy (CTE). Since the publication of NINDS–NIBIB criteria for the neuropathological diagnosis of CTE in 2016, and diagnostic refinements in 2021, hundreds of contact sport athletes and others have been diagnosed at postmortem examination with CTE. CTE has been reported in amateur and professional athletes, including a bull rider, boxers, wrestlers, and American, Canadian, and Australian rules football, rugby union, rugby league, soccer, and ice hockey players. The pathology of CTE is unique, characterized by a pathognomonic lesion consisting of a perivascular accumulation of neuronal phosphorylated tau (p-tau) variably alongside astrocytic aggregates at the depths of the cortical sulci, and a distinctive molecular structural configuration of p-tau fibrils that is unlike the changes observed with aging, Alzheimer’s disease, or any other tauopathy. Computational 3-D and finite element models predict the perivascular and sulcal location of p-tau pathology as these brain regions undergo the greatest mechanical deformation during head impact injury. Presently, CTE can be definitively diagnosed only by postmortem neuropathological examination; the corresponding clinical condition is known as traumatic encephalopathy syndrome (TES). Over 97% of CTE cases published have been reported in individuals with known exposure to repetitive head impacts (RHI), including concussions and nonconcussive impacts, most often experienced through participation in contact sports. While some suggest there is uncertainty whether a causal relationship exists between RHI and CTE, the preponderance of the evidence suggests a high likelihood of a causal relationship, a conclusion that is strengthened by the absence of any evidence for plausible alternative hypotheses. There is a robust dose–response relationship between CTE and years of American football play, a relationship that remains consistent even when rigorously accounting for selection bias. Furthermore, a recent study suggests that selection bias underestimates the observed risk. Here, we present the advances in the neuropathological diagnosis of CTE culminating with the development of the NINDS–NIBIB criteria, the multiple international studies that have used these criteria to report CTE in hundreds of contact sports players and others, and the evidence for a robust dose–response relationship between RHI and CTE.

The benefits of regular exercise, physical fitness and sports participation on cardiovascular and brain health are undeniable. Physical activity reduces the risk for cardiovascular disease, type 2 diabetes, hypertension, obesity, and stroke, and produces beneficial effects on cholesterol levels, antioxidant systems, inflammation, and vascular function. Exercise also enhances psychological health, reduces age-related loss of brain volume, improves cognition, reduces the risk of developing dementia, and impedes neurodegeneration. Nonetheless, the play of sports is associated with risks, including a risk for mild TBI (mTBI) and, rarely, catastrophic traumatic injury and death. There is also growing awareness that repetitive mTBIs, such as concussion and subconcussion, can occasionally produce persistent cognitive, behavioral, and psychiatric problems as well as lead to the development of a neurodegeneration, chronic traumatic encephalopathy (CTE). In this review, we summarize the beneficial aspects of sports participation on psychological, emotional, physical and cognitive health, and specifically analyze some of the less common adverse neuropathological outcomes, including concussion, second-impact syndrome, juvenile head trauma syndrome, catastrophic sudden death, and CTE. CTE is a latent neurodegeneration clinically associated with behavioral changes, executive dysfunction and cognitive impairments, and pathologically characterized by frontal and temporal lobe atrophy, neuronal and axonal loss, and abnormal deposits of paired helical filament (PHF)-tau and 43 kDa TAR deoxyribonucleic acid (DNA)-binding protein (TDP-43). CTE often occurs as a sole diagnosis, but may be associated with other neurodegenerative disorders, including motor neuron disease (CTE-MND). Although the incidence and prevalence of CTE are not known, CTE has been reported most frequently in American football players and boxers. Other sports associated with CTE include ice hockey, professional wrestling, soccer, rugby, and baseball.

Background/Objectives: Diagnosing concussions is problematic, in part due to the invisible nature of concussion symptoms, in addition to personal and interpersonal factors that influence symptom reporting. As a result, observable signs of concussion can ensure concussions are identified and appropriately treated. Here, we define a potential novel sign, the spontaneous headshake after a kinematic event (SHAAKE) and evaluate its utility in the diagnosis of concussion. Methods: A cross-sectional survey study of 347 athletes (age 27, IQR: 25–29; 47.6% female; highest level of play: college—46.1%, high school—41.2%) identified whether SHAAKE occurred, the reasons underlying SHAAKEs, and its utility for self-reported concussion. Sensitivity and positive predictive value were calculated across all sports and these parameters, as well as estimates for specificity and negative predictive value leveraging published helmet sensor data, were calculated for football players. Results: The median number of times participants reported SHAAKE was 5 (IQR: 3–10), with 4 (IQR: 2–7) associated with a self-reported concussion. Overall, 84.9% of participants reported concussion symptoms as the most common reason for their SHAAKEs. Across all sports, SHAAKE had a sensitivity of 49.6% and positive predictive value 72.4% for diagnosing concussion. In football players, SHAAKE had a sensitivity of 52.3%, estimated specificity of 99.9%, positive predictive value of 91.9%, and estimated negative predictive value of 99.5% for diagnosing self-reported concussion. Conclusions: These results demonstrate that nearly three-quarters of athletes reported a SHAAKE associated with a self-reported concussion, which supports the potential for SHAAKE to be used as a concussion screening tool.