Chronic traumatic encephalopathy (CTE) is a neuropathologically defined disease reportedly linked to a history of repetitive brain trauma. As such, retired collision sport athletes are likely at heightened risk for developing CTE. Researchers have described distinct pathological features of CTE as well a wide range of clinical symptom presentations, recently termed traumatic encephalopathy syndrome (TES). These clinical symptoms are highly variable, non-specific to individuals described as having CTE pathology in case reports, and are often associated with many other factors. This review describes the cognitive, emotional, and behavioral changes associated with 1) developmental and demographic factors, 2) neurodevelopmental disorders, 3) normal aging, 4) adjusting to retirement, 5) drug and alcohol abuse, 6) surgeries and anesthesia, and 7) sleep difficulties, as well as the relationship between these factors and risk for developing dementia-related neurodegenerative disease. We discuss why some professional athletes may be particularly susceptible to many of these effects and the importance of choosing appropriate controls groups when designing research protocols. We conclude that these factors should be considered as modifiers predominantly of the clinical outcomes associated with repetitive brain trauma within a broader biopsychosocial framework when interpreting and attributing symptom development, though also note potential effects on neuropathological outcomes. Importantly, this could have significant treatment implications for improving quality of life.

Introduction: It remains unclear if tau imaging may assist diagnosis of chronic traumatic encephalopathy (CTE). Flortaucipir PET has shown superior frontal with medial temporal tau binding consistent with the provisional neuropathological criteria for mid-stage CTE in group-level analyses of retired symptomatic NFL players and in one individual with pathologically confirmed CTE. 18F-MK6240 is a new PET ligand that has high affinity for tau. We present the case of a 63-year-old cognitively impaired, former Australian rules football player with distinct superior frontal and medial temporal 18F-MK6240 binding and show it to be significantly different to the pattern seen in prodromal Alzheimer's disease (AD). Findings: The participant was recruited for a study of amyloid-β and tau several decades after traumatic brain injury. He had multiple concussions during his football career but no cognitive complaints at retirement. A thalamic stroke in his mid 50s left stable mild cognitive deficits but family members reported further short-term memory, behavioral, and personality decline preceding the study. Imaging showed extensive small vessel disease on MRI, a moderate burden of amyloid-β plaques, and 18F-MK6240 binding in bilateral superior frontal and medial temporal cortices. Voxel-wise analysis demonstrated that the frontally predominant pattern of the participant was significantly different to the posterior temporo-parietal predominant pattern of prodromal AD. Conclusion: Although lacking neuropathological examination to distinguish CTE from a variant of AD, the clear demonstration of a CTE-like tau pattern in a single at-risk individual suggests further research on the potential of 18F-MK6240 PET for identifying CTE is warranted.

<h4>Background and objectives</h4>Clinical features of individuals with autopsy findings of chronic traumatic encephalopathy (CTE) have been described for 50 years. Clinical criteria have been proposed, although cognitive correlates of CTE remain unknown. This study examined whether CTE was related to dementia and patterns of cognitive impairment to summarize the clinicopathologic evidence.<h4>Methods</h4>A systematic review and meta-analysis was performed, composed of a multicenter interdisciplinary team. Five databases were searched from their inception to March 2025. Original studies involving participants with neuropathologic findings of CTE and neuropsychological data were included. A multistage selection approach was used, including a review by neuropathologists to ensure that studies conformed to CTE consensus criteria. Methodological quality was rated from 9 items using a modified Murad Case Report Methodological Quality Tool. The main outcomes of interest were domains of cognitive functioning, based on objective testing, and prevalence of dementia-related clinical diagnoses in individuals with CTE. A random-effects meta-analysis examined prevalence of dementia-related diagnoses, and meta-regression examined whether Alzheimer-type neuropathology or any comorbid neuropathology was a moderator.<h4>Results</h4>A total of 36 studies comprising 563 unique CTE cases were included. Only 22 CTE cases (<5%) had objective neuropsychological data available from studies (k = 10) of acceptable quality. Deficits in memory, language, and attention were the most prevalent cognitive features, but all cases had comorbid non-CTE neuropathologies that may have been associated with cognitive impairment. Diverse neuropsychological impairments were observed, resulting in no consistent cognitive pattern, even for high CTE severity. Dementia-related diagnoses were prevalent (62%; 95% CI 48%-75%) in the meta-analysis (k = 13; n = 492), yet not strongly related to non-CTE neuropathologies recorded (estimate = 0.14, 95% CI -0.62 to 0.91; <i>p</i> = 0.714), including Alzheimer-type neuropathology (estimate = 0.21, 95% CI -0.03 to 0.45; <i>p</i> = 0.084).<h4>Discussion</h4>Limited CTE cases have been published with objective neuropsychological information. CTE cases show cognitive deficits resembling Alzheimer dementia, but a direct clinicopathologic link is inconclusive. While the meta-analytic findings suggest that CTE may be associated with cognitive impairment, further investigation is needed because heterogeneity in study designs prohibits clear conclusions. To realize any clinicopathologic links and inform future iterations of clinical criteria, a transition in how cognition is investigated in CTE will be needed and several research directions are proposed.

Chronic traumatic encephalopathy (CTE) is a progressive tauopathy causally linked to repetitive mild traumatic brain injury. Currently, there are no established clinical diagnostic criteria for CTE, making post-mortem neuropathological examination essential for diagnosis. The pathological hallmark of CTE is the presence of perivascular neuronal p-tau aggregates at cortical sulcal depths. In this commentary, we share our diagnostic experience, highlight emerging diagnostic protocols for CTE, and discuss the challenges in CTE diagnosis and its differentiation from comorbid conditions. Beyond the neuropathological insights, we explore the broader implications of CTE for the community, including the need for prevention strategies and the role of public health policy. By advancing understanding of CTE pathology, neuropathologists are positioned to inform prevention and treatment efforts, ultimately contributing to the mitigation of this preventable disease.

Recent reports have highlighted a troubling pattern of athletes exhibiting pronounced and unexplained behavioral changes. This phenomenon is often linked to chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder associated with repeated head injuries in contact sports, and is characterized by the accumulation of abnormal tau protein in the brain. This paper provides a focused review of the neurological and neurobehavioral mechanisms, prevention and treatments, and the role of animal models in advancing our understanding of CTE. Key findings have identified the accumulation of tau proteins and neuroinflammation as major contributing factors in the development of CTE. However, gaps in the literature, including the need for standardized injury models and biomarkers for diagnosing CTE in living individuals, point to future directions in refining diagnostic tools and developing targeted therapeutic interventions.

Chronic Traumatic Encephalopathy (CTE) is a progressive neurodegenerative tauopathy associated with repetitive head impacts (RHI), yet it remains diagnosable only at post-mortem. Tau, a microtubule-associated protein, normally stabilizes neuronal microtubules and regulates cytoskeletal dynamics. Mechanical strain from RHI is thought to disrupt calcium homeostasis and kinase-phosphatase balance, driving hyperphosphorylation and phosphorylated-tau (p-tau) formation. This results in detachment from microtubules and subsequent p-tau aggregation. These mechanically-induced biochemical changes produce CTE's characteristic lesion: perivascular p-tau deposition in the depths of cortical sulci, reflecting the non-uniform mechanical loading experienced by brain tissue following head impacts. Advances in molecular neuropathology have revealed that CTE tau filaments adopt a unique conformational fold, and that early tau species may contribute to neurotoxicity. Despite this growing understanding, antemortem diagnosis remains challenging. Structural MRI demonstrates frontotemporal atrophy and white-matter abnormalities in impact-exposed individuals, but these findings lack disease specificity. Tau-PET tracers developed for Alzheimer's disease (AD) show limited affinity for the distinct CTE tau fold, while fluid biomarkers variably reflect cumulative exposure but cannot yet discriminate CTE from other tauopathies. Future progress will depend on mechanistically informed diagnostic tools, including conformation-specific biomarkers and PET radiotracers tailored to CTE-specific tau. Multimodal approaches integrating neuroimaging, molecular profiling, exposure metrics, and computational modelling will be essential for early detection, disease monitoring, and informed public health policy around repetitive head impacts.

by chronic traumatic brain injury (CTBI), which causes cognitive, behavioral, and physical impairments. Dementia pugilistica, also called chronic traumatic Traumatic brain injury (TBI, physical trauma to the brain) can cause a variety of complications, health effects that are not TBI themselves but that result from it. The risk of complications increases with the severity of the trauma; however even mild traumatic brain injury can result in disabilities that interfere with social interactions, employment, and everyday living. TBI can cause a variety M…