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Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head trauma. Brain pathology in CTE is characterized by neuronal loss, gliosis, and a distinctive pattern of neuronal accumulation of hyper-phosphorylated tau (p-tau) and phospho-TDP43 (p-TDP43). Visual anomalies have been reported by patients with CTE, but the ocular pathology underlying these symptoms is unknown. We evaluated retinal pathology in post-mortem eyes collected from 8 contact sport athletes with brain autopsy-confirmed stage IV CTE and compared their findings to retinas from 8 control patients without CTE and with no known history of head injury. Pupil-optic nerve cross sections were prepared and stained with hematoxylin and eosin (H&E), p-tau, p-TDP43, and total TDP43 by immunohistochemistry. No significant retinal degeneration was observed in CTE eyes compared to control eyes by H&E. Strong cytoplasmic p-TDP43 and total TDP43 staining was found in 6/8 CTE eyes in a subset of inner nuclear layer interneurons (INL) of the retina, while only 1/8 control eyes showed similar p-TDP43 pathology. The morphology and location of these inner nuclear layer interneurons were most compatible with retinal horizontal cells, although other retinal cell types present in INL could not be ruled out. No p-tau pathology was observed in CTE or control retinas. These findings identify novel retinal TDP43 pathology in CTE retinas and support further investigation into the role of p-TDP43 in producing visual deficits in patients with CTE.

The 6th Consensus Statement on Concussion in Sport is authored by the Concussion in Sport Group (CiSG) and intends to provide evidence-based recommendations on concussion management for the welfare of sports participants. However, the authors of the Consensus Statement have declared many competing links to third-party groups. While the declaration of an author's competing interests is now a widely accepted practice within academic publishing aimed at greater transparency and research integrity, it is not a measure to remove the potential influence of third-party links. In the case of the Consensus Statement, this leaves uncertainty about how the potential sources of third-party bias declared by individual members of the CiSG may have influenced the CiSG's interpretation of the existing state of evidence on concussion management and impacted the content of the recommendations contained with the Consensus Statement. Openly declaring third-party links falls short of securing trustworthiness in the Consensus Statement recommendations since it leaves end-users of the Consensus Statement with the task of interpreting the impact(s) of these competing interests with little information to guide them. This is because the authors themselves offer neither explanation nor guidance concerning potential bias arising from the competing interests that they have declared, which impinges upon the ability of readers to evaluate the trustworthiness of the content. The status quo could be improved by excluding researchers who have conflicts of interest. Nevertheless, if authors with competing interests are permitted to be part of the CiSG (as is the status quo), then I propose a novel option for increasing transparency that would require authors of the Consensus Statements to provide a reflexive explanation, not simply a declaration, of their competing interests. [ABSTRACT FROM AUTHOR]

Background: Traumatic brain injury (TBI) is a major cause of morbidity and mortality, affecting millions annually worldwide. Although the majority of TBI patients return to premorbid baseline, a subset of patient can develop persistent and often debilitating neurocognitive and behavioral changes. The etiology of TBI within the clinical setting is inherently heterogenous, ranging from sport related injuries, fall related injuries and motor vehicle accidents in the civilian setting, to blast injuries in the military setting. Objective: Animal models of TBI, offer the distinct advantage of controlling for injury modality, duration and severity. Furthermore, preclinical models of TBI have provided the necessary temporal opportunity to study the chronic neuropathological sequelae of TBI, including neurodegenerative sequelae such as tauopathy and neuroinflammation within the finite experimental timeline. Despite the high prevalence of TBI, there are currently no disease modifying regimen for TBI, and the current clinical treatments remain largely symptom based. The preclinical models have provided the necessary biological substrate to examine the disease modifying effect of various pharmacological agents and have imperative translational value. Methods: The current review will include a comprehensive survey of well- established preclinical models, including classic preclinical models including weight drop, blast injury, fluid percussion injury, controlled cortical impact injury, as well as more novel injury models including closed-head impact model of engineered rotational acceleration (CHIMERA) models and closed- head projectile concussive impact model (PCI). In addition to rodent preclinical models, the review will include an overview of other species including large animal models and Drosophila. Results: There are major neuropathological perturbations post TBI captured in various preclinical models, which include neuroinflammation, calcium dysregulation, tauopathy, mitochondrial dysfunction and oxidative stress, axonopathy, as well as glymphatic system disruption. Conclusion: The preclinical models of TBI continue to offer valuable translational insight, as well as essential neurobiological basis to examine specific disease modifying therapeutic regimen. [ABSTRACT FROM AUTHOR]

Abstract Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head trauma. Brain pathology in CTE is characterized by neuronal loss, gliosis, and a distinctive pattern of neuronal accumulation of hyper-phosphorylated tau (p-tau) and phospho-TDP43 (p-TDP43). Visual anomalies have been reported by patients with CTE, but the ocular pathology underlying these symptoms is unknown. We evaluated retinal pathology in post-mortem eyes collected from 8 contact sport athletes with brain autopsy-confirmed stage IV CTE and compared their findings to retinas from 8 control patients without CTE and with no known history of head injury. Pupil-optic nerve cross sections were prepared and stained with hematoxylin and eosin (H&E), p-tau, p-TDP43, and total TDP43 by immunohistochemistry. No significant retinal degeneration was observed in CTE eyes compared to control eyes by H&E. Strong cytoplasmic p-TDP43 and total TDP43 staining was found in 6/8 CTE eyes in a subset of inner nuclear layer interneurons (INL) of the retina, while only 1/8 control eyes showed similar p-TDP43 pathology. The morphology and location of these inner nuclear layer interneurons were most compatible with retinal horizontal cells, although other retinal cell types present in INL could not be ruled out. No p-tau pathology was observed in CTE or control retinas. These findings identify novel retinal TDP43 pathology in CTE retinas and support further investigation into the role of p-TDP43 in producing visual deficits in patients with CTE.

BackgroundTraumatic brain injury (TBI) is a major cause of morbidity and mortality, affecting millions annually worldwide. Although the majority of TBI patients return to premorbid baseline, a subset of patient can develop persistent and often debilitating neurocognitive and behavioral changes. The etiology of TBI within the clinical setting is inherently heterogenous, ranging from sport related injuries, fall related injuries and motor vehicle accidents in the civilian setting, to blast injuries in the military setting.ObjectiveAnimal models of TBI, offer the distinct advantage of controlling for injury modality, duration and severity. Furthermore, preclinical models of TBI have provided the necessary temporal opportunity to study the chronic neuropathological sequelae of TBI, including neurodegenerative sequelae such as tauopathy and neuroinflammation within the finite experimental timeline. Despite the high prevalence of TBI, there are currently no disease modifying regimen for TBI, and the current clinical treatments remain largely symptom based. The preclinical models have provided the necessary biological substrate to examine the disease modifying effect of various pharmacological agents and have imperative translational value.MethodsThe current review will include a comprehensive survey of well-established preclinical models, including classic preclinical models including weight drop, blast injury, fluid percussion injury, controlled cortical impact injury, as well as more novel injury models including closed-head impact model of engineered rotational acceleration (CHIMERA) models and closed-head projectile concussive impact model (PCI). In addition to rodent preclinical models, the review will include an overview of other species including large animal models and Drosophila.ResultsThere are major neuropathological perturbations post TBI captured in various preclinical models, which include neuroinflammation, calcium dysregulation, tauopathy, mitochondrial dysfunction and oxidative stress, axonopathy, as well as glymphatic system disruption.ConclusionThe preclinical models of TBI continue to offer valuable translational insight, as well as essential neurobiological basis to examine specific disease modifying therapeutic regimen.

Chronic traumatic encephalopathy (CTE) is a unique neurodegenerative disease that is associated with repetitive head impacts (RHI) in both civilian and military settings. In 2014, the research criteria for the clinical manifestation of CTE, traumatic encephalopathy syndrome (TES), were proposed to improve the clinical identification and understanding of the complex neuropathological phenomena underlying CTE. This review provides a comprehensive overview of the current understanding of the neuropathological and clinical features of CTE, proposed biomarkers of traumatic brain injury (TBI) in both research and clinical settings, and a range of treatments based on previous preclinical and clinical research studies. Due to the heterogeneity of TBI, there is no universally agreed-upon serum, CSF, or neuroimaging marker for its diagnosis. However, as our understanding of this complex disease continues to evolve, it is likely that there will be more robust, early diagnostic methods and effective clinical treatments. This is especially important given the increasing evidence of a correlation between TBI and neurodegenerative conditions, such as Alzheimer's disease and CTE. As public awareness of these conditions grows, it is imperative to prioritize both basic and clinical research, as well as the implementation of necessary safe and preventative measures. [ABSTRACT FROM AUTHOR]

Background: A 2021 National Institute for Neurological Disorders and Stroke (NINDS) consensus panel proposed a set of clinical diagnostic criteria for traumatic encephalopathy syndrome (TES) and determined provisional levels of certainty for chronic traumatic encephalopathy (CTE) pathology based on neuropathological evidence. The panel suggested the criteria needed to be validated by clinical studies of living populations exposed to repetitive head impacts (RHIs). Hypothesis: As the consensus criteria were developed solely from neuropathologically diagnosed cases of CTE, we hypothesized that they may not be readily applicable to the clinical impressions developed from the histories and examination findings of living patients whose neuropathology was unknown. Study Design: We applied the consensus criteria to 4 groups of living retired contact sports athletes collected from previously published articles in the medical literature. Level of Evidence: Level 4. Methods: Clinical evidence from 4 groups of living retired athletes (boxers and American football players) with extensive RHI exposure was available. We used the NINDS consensus criteria to determine for each athlete whether or not they met the criteria for TES. For those who met the criteria, we determined their provisional level of certainty for CTE pathology. Results: Among all 80 subjects, the prevalence of TES was 21.3% (17 of 80), the prevalence of possible CTE was 12.5% (10 of 80), and the prevalence of probable CTE was 2.5% (2 of 80). Among the 45 retired football players, the prevalence of TES was 24.4% (11 of 45) and the prevalence of possible CTE was 17.7% (8 of 45). None of the retired football players met the criteria for probable CTE. Among the 35 total retired boxers (from all 3 groups), the prevalence of TES was 17.1% (6 of 35), the prevalence of possible CTE was 5.7% (2 of 35), and the prevalence of probable CTE was 5.7% (2 of 35). Conclusion: Applying the NINDS consensus criteria to this historical cohort of living retired athletes with extensive RHI exposure resulted in a relatively low prevalence of TES and possible/probable certainties of CTE pathology, which might suggest limitations on the sensitivity of the NINDS criteria. Clinical Relevance: Physicians are often asked by retired contact sports athletes and their families to determine if their clinical picture is related to TES and/or CTE. Physicians may turn to the NINDS consensus criteria for guidance in making such determinations. The data presented here may assist physicians in evaluating the reliability and validity of using the consensus criteria in living subjects. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine athletic training students' media consumption to advance our understanding of the role the media play in reported incidences of sport-related concussion (SRC) and chronic traumatic encephalopathy (CTE) in American football and how media coverage of those injuries may potentially influence public perception. Participants who consumed more hours of television per day were more likely to disagree with the statements that reporting on SRC has helped to accurately educate the public, H(2) = 11.06, p = .01, and that reporting on CTE has helped to accurately educate the public, H(2) = 8.67, p = .01. Respondents who consumed more hours of Internet per day were more likely to disagree with the statements that accurate terminology is used to report SRC, H(2) = 7.78, p = .02, and that reporting of SRCs has helped to accurately educate the public, H(2) = 8.27, p = .02. [ABSTRACT FROM AUTHOR]

Chronic traumatic encephalopathy (CTE) is a unique neurodegenerative disease that is associated with repetitive head impacts (RHI) in both civilian and military settings. In 2014, the research criteria for the clinical manifestation of CTE, traumatic encephalopathy syndrome (TES), were proposed to improve the clinical identification and understanding of the complex neuropathological phenomena underlying CTE. This review provides a comprehensive overview of the current understanding of the neuropathological and clinical features of CTE, proposed biomarkers of traumatic brain injury (TBI) in both research and clinical settings, and a range of treatments based on previous preclinical and clinical research studies. Due to the heterogeneity of TBI, there is no universally agreed-upon serum, CSF, or neuroimaging marker for its diagnosis. However, as our understanding of this complex disease continues to evolve, it is likely that there will be more robust, early diagnostic methods and effective clinical treatments. This is especially important given the increasing evidence of a correlation between TBI and neurodegenerative conditions, such as Alzheimer’s disease and CTE. As public awareness of these conditions grows, it is imperative to prioritize both basic and clinical research, as well as the implementation of necessary safe and preventative measures.

This study examines CTE-related knowledge and information-seeking behaviors of caregivers of persons who are at high risk of CTE. Online survey responses were collected from 64 females, ages 18-74, who were married to former college, semiprofessional, or professional football players and were fluent in English. Ranging from 0 to 18, a score was calculated to represent level of CTE knowledge. Participants were classified into groups based on their spouse's reported symptoms and diagnosis. Approximately 87% of participants reported that their spouses have been diagnosed with a football-related concussion and were significantly more likely to seek out information from a healthcare provider, a scientific journal or article, and post/comment on social media compared to spouses of symptomatic/undiagnosed and non-symptomatic groups. Participants reported 77% of available information as probably true, with social media thought to be highly credible. Highest levels of dissatisfaction were reported for league-sponsored websites and physicians/healthcare providers. Although the majority of participants sought CTE related information on regular or social media, and the internet, information sources differed amongst the groups. These findings may help healthcare providers and organizations develop more effective health-related educational programs that will help the wives make informed decisions regarding care for their spouses with respect to CTE. [ABSTRACT FROM AUTHOR]

Abstract Background There is an association between repetitive head injury (RHI) and a pathologic diagnosis of chronic traumatic encephalopathy (CTE) characterized by the aggregation of proteins including tau. The underlying molecular events that cause these abnormal protein accumulations remain unclear. Here, we hypothesized that identifying the human brain proteome from serial CTE stages (CTE I-IV) would provide critical new insights into CTE pathogenesis. Brain samples from frontotemporal lobar degeneration due to microtubule associated protein tau (FTLD-MAPT) mutations were also included as a distinct tauopathy phenotype for comparison. Methods Isobaric tandem mass tagged labeling and mass spectrometry (TMT-MS) followed by integrated differential and co-expression analysis (i.e., weighted gene co-expression network analysis (WGCNA)) was used to define modules of highly correlated proteins associated with clinical and pathological phenotypes in control (n = 23), CTE (n = 43), and FTLD-MAPT (n = 12) post-mortem cortical tissues. We also compared these findings to network analysis of AD brain. Results We identified over 6000 unique proteins across all four CTE stages which sorted into 28 WGCNA modules. Consistent with Alzheimer’s disease, specific modules demonstrated reduced neuronal protein levels, suggesting a neurodegeneration phenotype, while other modules were increased, including proteins associated with inflammation and glial cell proliferation. Notably, unique CTE-specific modules demonstrated prominent enrichment of immunoglobulins, including IGHM and IGLL5, and extracellular matrix (ECM) proteins as well as progressive protein changes with increasing CTE pathologic stage. Finally, aggregate cell subtype (i.e., neurons, microglia, astrocytes) protein abundance levels in CTE cases were similar in expression to AD, but at intermediate levels between controls and the more exaggerated phenotype of FTLD-MAPT, especially in astrocytes. Conclusions Overall, we identified thousands of protein changes in CTE postmortem brain and demonstrated that CTE has a pattern of neurodegeneration in neuronal-synaptic and inflammation modules similar to AD. We also identified unique CTE progressive changes, including the enrichment of immunoglobulins and ECM proteins even in early CTE stages. Early and sustained changes in astrocyte modules were also observed. Overall, the prominent overlap with FTLD-MAPT cases confirmed that CTE is on the tauopathy continuum and identified CTE stage specific molecular phenotypes that provide novel insights into disease pathogenesis.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with a history of repetitive head impacts (RHI). CTE was described in boxers as early as the 1920s and by the 1950s it was widely accepted that hits to the head caused some boxers to become "punch drunk." However, the recent discovery of CTE in American and Australian-rules football, soccer, rugby, ice hockey, and other sports has resulted in renewed debate on whether the relationship between RHI and CTE is causal. Identifying the strength of the evidential relationship between CTE and RHI has implications for public health and medico-legal issues. From a public health perspective, environmentally caused diseases can be mitigated or prevented. Medico-legally, millions of children are exposed to RHI through sports participation; this demographic is too young to legally consent to any potential long-term risks associated with this exposure. To better understand the strength of evidence underlying the possible causal relationship between RHI and CTE, we examined the medical literature through the Bradford Hill criteria for causation. The Bradford Hill criteria, first proposed in 1965 by Sir Austin Bradford Hill, provide a framework to determine if one can justifiably move from an observed association to a verdict of causation. The Bradford Hill criteria include nine viewpoints by which to evaluate human epidemiologic evidence to determine if causation can be deduced: strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy. We explored the question of causation by evaluating studies on CTE as it relates to RHI exposure. Through this lens, we found convincing evidence of a causal relationship between RHI and CTE, as well as an absence of evidence-based alternative explanations. By organizing the CTE literature through this framework, we hope to advance the global conversation on CTE mitigation efforts. [ABSTRACT FROM AUTHOR]

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is frequently found in athletes and those who have experienced repetitive head traumas. CTE is associated with a variety of neuropathologies, which cause cognitive and behavioral impairments in CTE patients. However, currently, CTE can only be diagnosed after death via brain autopsy, and it is challenging to distinguish it from other neurodegenerative diseases with similar clinical features. To better understand this multifaceted disease and identify metabolic differences in the postmortem brain tissues of CTE patients and control subjects, we performed ultra-high performance liquid chromatography–mass spectrometry (UPLC-MS)-based non-targeted metabolomics. Through multivariate and pathway analysis, we found that the brains of CTE patients had significant changes in the metabolites involved in astrocyte activation, phenylalanine, and tyrosine metabolism. The unique metabolic characteristics of CTE identified in this study were associated with cognitive dysfunction, amyloid-beta deposition, and neuroinflammation. Altogether, this study provided new insights into the pathogenesis of CTE and suggested appealing targets for both diagnosis and treatment for the disease. [ABSTRACT FROM AUTHOR]

CTE, or chronic traumatic encephalopathy, is caused by repetitive head trauma and detected by a distinctive stain for a protein called 'tau' in autopsied brain tissue. While the number of diagnosed patients is only in the hundreds, the cultural footprint of the disease in North America is huge, both because those diagnosed are often celebrity-athletes and because millions of children, adolescents and young men and women play collision sports like football and hockey. We argue that the widespread attention to CTE provides a useful wedge to crack open another, heretofore neglected public health concern: repetitive acts of violence in and around hypermasculine sports create subjects whose brains—and characters—are materially shaped by that violence. Brains change materially when delivering blows as well as receiving them, when participating in degrading hazing rituals as victim or assailant, when belittled or assaulted by a coach, when approaching an upcoming game riddled with fear. We adopt a biosocial model of the brain's becoming to intervene in a linear discourse around CTE that medicalizes and oversimplifies violence, a story that prematurely dissects one slice of the problem from a noxious whole. [ABSTRACT FROM AUTHOR]

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with a history of repetitive head impacts (RHI). CTE was described in boxers as early as the 1920s and by the 1950s it was widely accepted that hits to the head caused some boxers to become “punch drunk.” However, the recent discovery of CTE in American and Australian-rules football, soccer, rugby, ice hockey, and other sports has resulted in renewed debate on whether the relationship between RHI and CTE is causal. Identifying the strength of the evidential relationship between CTE and RHI has implications for public health and medico-legal issues. From a public health perspective, environmentally caused diseases can be mitigated or prevented. Medico-legally, millions of children are exposed to RHI through sports participation; this demographic is too young to legally consent to any potential long-term risks associated with this exposure. To better understand the strength of evidence underlying the possible causal relationship between RHI and CTE, we examined the medical literature through the Bradford Hill criteria for causation. The Bradford Hill criteria, first proposed in 1965 by Sir Austin Bradford Hill, provide a framework to determine if one can justifiably move from an observed association to a verdict of causation. The Bradford Hill criteria include nine viewpoints by which to evaluate human epidemiologic evidence to determine if causation can be deduced: strength, consistency, specificity, temporality, biological gradient, plausibility, coherence, experiment, and analogy. We explored the question of causation by evaluating studies on CTE as it relates to RHI exposure. Through this lens, we found convincing evidence of a causal relationship between RHI and CTE, as well as an absence of evidence-based alternative explanations. By organizing the CTE literature through this framework, we hope to advance the global conversation on CTE mitigation efforts.

Chronic traumatic encephalopathy (CTE) is a progressive and fatal neurological disorder linked to repeated traumatic brain injuries (TBIs), including concussions and blows to the head. This condition is characterized by the accumulation of abnormally structured hyperphosphorylated tau proteins (p-tau), forming neurofibrillary tangles, astrocytic tangles, and neurites in the brain. CTE is often diagnosed post-mortem, making it challenging to diagnose and predict its progression in living individuals. Despite recent advancements, no definitive pathological, radiological, or neurobiological marker consistently shows promise in diagnosing and predicting the disease. This review aims to summarize the available techniques and advancements in imaging-based, genetic, neuropsychological, and fluid biomarkers for CTE, evaluating their specificity and sensitivity. It will also highlight the limitations of each marker in diagnosing CTE and provide future research directions to enhance the accuracy of CTE diagnosis in living individuals., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Majeed et al.)

A controversial theory proposes that playing tackle football before the age of 12 causes later in life brain health problems. This theory arose from a small study of 42 retired National Football League (NFL) players, which reported that those who started playing tackle football at a younger age performed worse on selected neuropsychological tests and a word reading test. The authors concluded that these differences were likely due to greater exposure to repetitive neurotrauma during a developmentally sensitive maturational period in their lives. Several subsequent studies of current high school and collegiate contact/collision sports athletes, and former high school, collegiate, and professional tackle football players have not replicated these findings. This narrative review aims to (i) discuss the fundamental concepts, issues, and controversies surrounding existing research on age of first exposure (AFE) to contact/collision sport, and (ii) provide a balanced interpretation, including risk of bias assessment findings, of this body of evidence. Among 21 studies, 11 studies examined former athletes, 8 studies examined current athletes, and 2 studies examined both former and current athletes. Although the literature on whether younger AFE to tackle football is associated with later in life cognitive, neurobehavioral, or mental health problems in former NFL players is mixed, the largest study of retired NFL players (N = 3,506) suggested there was not a significant association between earlier AFE to organized tackle football and worse subjectively experienced cognitive functioning, depression, or anxiety. Furthermore, no published studies of current athletes show a significant association between playing tackle football (or other contact/collision sports) before the age of 12 and cognitive, neurobehavioral, or mental health problems. It is important to note that all studies were judged to be at high overall risk of bias, indicating that more methodologically rigorous research is needed to understand whether there is an association between AFE to contact/collision sports and later in life brain health. The accumulated research to date suggests that earlier AFE to contact/collision sports is not associated with worse cognitive functioning or mental health in (i) current high school athletes, (ii) current collegiate athletes, or (iii) middle-aged men who played high school football. The literature on former NFL players is mixed and does not, at present, clearly support the theory that exposure to tackle football before age 12 is associated with later in life cognitive impairment or mental health problems.

A controversial theory proposes that playing tackle football before the age of 12 causes later in life brain health problems. This theory arose from a small study of 42 retired National Football League (NFL) players, which reported that those who started playing tackle football at a younger age performed worse on selected neuropsychological tests and a word reading test. The authors concluded that these differences were likely due to greater exposure to repetitive neurotrauma during a developmentally sensitive maturational period in their lives. Several subsequent studies of current high school and collegiate contact/collision sports athletes, and former high school, collegiate, and professional tackle football players have not replicated these findings. This narrative review aims to (i) discuss the fundamental concepts, issues, and controversies surrounding existing research on age of first exposure (AFE) to contact/collision sport, and (ii) provide a balanced interpretation, including risk of bias assessment findings, of this body of evidence. Among 21 studies, 11 studies examined former athletes, 8 studies examined current athletes, and 2 studies examined both former and current athletes. Although the literature on whether younger AFE to tackle football is associated with later in life cognitive, neurobehavioral, or mental health problems in former NFL players is mixed, the largest study of retired NFL players (N = 3,506) suggested there was not a significant association between earlier AFE to organized tackle football and worse subjectively experienced cognitive functioning, depression, or anxiety. Furthermore, no published studies of current athletes show a significant association between playing tackle football (or other contact/collision sports) before the age of 12 and cognitive, neurobehavioral, or mental health problems. It is important to note that all studies were judged to be at high overall risk of bias, indicating that more methodologically rigorous research is needed to understand whether there is an association between AFE to contact/collision sports and later in life brain health. The accumulated research to date suggests that earlier AFE to contact/collision sports is not associated with worse cognitive functioning or mental health in (i) current high school athletes, (ii) current collegiate athletes, or (iii) middle-aged men who played high school football. The literature on former NFL players is mixed and does not, at present, clearly support the theory that exposure to tackle football before age 12 is associated with later in life cognitive impairment or mental health problems. [ABSTRACT FROM AUTHOR]

Traumatic Brain Injuries (TBIs) are often connected to the development of Chronic Traumatic Encephalopathy (CTE), a degenerative brain disease commonly found in athletes, military veterans, and others that have a history of repetitive brain trauma. This formative exploratory study looked at person-centred design techniques for a person with CTE. The person-centred design method used for this study was based on a two-tiered reductionist approach; the first tier was to identify common symptoms and concerns associated with CTE from the literature. This information provided specific symptoms that were addressed through brainstorming ideations. Each singular ideation accommodated the singular, or small cluster of symptoms, that affected a person with CTE in a residential environment. This method of understanding a health condition through its symptoms, and then designing for those symptoms can extend the practice of interior design by providing probable solutions to specific health symptoms, thereby including designers into the healthcare team. Commonly identified behavioural and physical symptoms of CTE served as the factors of analysis and thus a variable of design. The health condition symptoms became the variables of design, and each symptom was assessed through additional data obtained from the literature for environmental causality, mitigation, or accommodation. Once the outcomes were determined, each design implication was assessed for its relationship to specific design actions.

Background: There is an association between repetitive head injury (RHI) and a pathologic diagnosis of chronic traumatic encephalopathy (CTE) characterized by the aggregation of proteins including tau. The underlying molecular events that cause these abnormal protein accumulations remain unclear. Here, we hypothesized that identifying the human brain proteome from serial CTE stages (CTE I-IV) would provide critical new insights into CTE pathogenesis. Brain samples from frontotemporal lobar degeneration due to microtubule associated protein tau (FTLD-MAPT) mutations were also included as a distinct tauopathy phenotype for comparison. Methods: Isobaric tandem mass tagged labeling and mass spectrometry (TMT-MS) followed by integrated differential and co-expression analysis (i.e., weighted gene co-expression network analysis (WGCNA)) was used to define modules of highly correlated proteins associated with clinical and pathological phenotypes in control (n = 23), CTE (n = 43), and FTLD-MAPT (n = 12) post-mortem cortical tissues. We also compared these findings to network analysis of AD brain. Results: We identified over 6000 unique proteins across all four CTE stages which sorted into 28 WGCNA modules. Consistent with Alzheimer's disease, specific modules demonstrated reduced neuronal protein levels, suggesting a neurodegeneration phenotype, while other modules were increased, including proteins associated with inflammation and glial cell proliferation. Notably, unique CTE-specific modules demonstrated prominent enrichment of immunoglobulins, including IGHM and IGLL5, and extracellular matrix (ECM) proteins as well as progressive protein changes with increasing CTE pathologic stage. Finally, aggregate cell subtype (i.e., neurons, microglia, astrocytes) protein abundance levels in CTE cases were similar in expression to AD, but at intermediate levels between controls and the more exaggerated phenotype of FTLD-MAPT, especially in astrocytes. Conclusions: Overall, we identified thousands of protein changes in CTE postmortem brain and demonstrated that CTE has a pattern of neurodegeneration in neuronal-synaptic and inflammation modules similar to AD. We also identified unique CTE progressive changes, including the enrichment of immunoglobulins and ECM proteins even in early CTE stages. Early and sustained changes in astrocyte modules were also observed. Overall, the prominent overlap with FTLD-MAPT cases confirmed that CTE is on the tauopathy continuum and identified CTE stage specific molecular phenotypes that provide novel insights into disease pathogenesis. [ABSTRACT FROM AUTHOR]

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is frequently found in athletes and those who have experienced repetitive head traumas. CTE is associated with a variety of neuropathologies, which cause cognitive and behavioral impairments in CTE patients. However, currently, CTE can only be diagnosed after death via brain autopsy, and it is challenging to distinguish it from other neurodegenerative diseases with similar clinical features. To better understand this multifaceted disease and identify metabolic differences in the postmortem brain tissues of CTE patients and control subjects, we performed ultra-high performance liquid chromatography–mass spectrometry (UPLC-MS)-based non-targeted metabolomics. Through multivariate and pathway analysis, we found that the brains of CTE patients had significant changes in the metabolites involved in astrocyte activation, phenylalanine, and tyrosine metabolism. The unique metabolic characteristics of CTE identified in this study were associated with cognitive dysfunction, amyloid-beta deposition, and neuroinflammation. Altogether, this study provided new insights into the pathogenesis of CTE and suggested appealing targets for both diagnosis and treatment for the disease.

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.

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. [ABSTRACT FROM AUTHOR]

Exposure to repetitive neurotrauma increases lifetime risk for developing progressive cognitive deficits, neurobehavioral abnormalities, and chronic traumatic encephalopathy (CTE). CTE is a tau protein neurodegenerative disease first identified in boxers and recently described in athletes participating in other contact sports (notably American football, ice hockey, rugby, and wrestling) and in military veterans with blast exposure. Currently, CTE can only be diagnosed by neuropathological examination of the brain after death. The defining diagnostic lesion of CTE consists of patchy perivascular accumulations of hyperphosphorylated tau protein that localize in the sulcal depths of the cerebral cortex. Neuronal abnormalities, axonopathy, neurovascular dysfunction, and neuroinflammation are triggered by repetitive head impacts (RHIs) and likely act as catalysts for CTE pathogenesis and progression. However, the specific mechanisms that link RHI to CTE are unknown. This review will explore two important areas of CTE pathobiology. First, we will review what is known about the biomechanical properties of RHI that initiate CTE-related pathologies. Second, we will provide an overview of key features of CTE neuropathology and how these contribute to abnormal tau hyperphosphorylation, accumulation, and spread. [ABSTRACT FROM AUTHOR]

There has been considerable public interest in the topic of traumatic brain injury (TBI) as a risk factor for development of late-life dementia. A review was performed on empirical studies examining the relationship between these two conditions. Although results from a number of studies clearly demonstrate that TBI is a positive risk factor for developing dementia, there are an equivalent number of studies that obtain inconclusive or negative findings. Inconsistencies across studies are often the result of methodological findings including the nature of the investigational design, choice of comparison groups, and criteria used to define cases. In many studies, the diagnosis of TBI is obtained retrospectively in a manner that is subject to bias. Accurate identification of dementia cases is often compromised by the use of inappropriately brief follow-up periods and variations in diagnostic methods. There remains no universally accepted neurobiological mechanism to explain the transition from acute TBI to the chronic effects of dementia. Studies of specialty populations, including athletes and military personnel are beset by secular and cohort effects, raising questions about the applicability of findings to the general population. No existing studies have been able to exclude the possible effects of confounding medical or lifestyle factors in facilitating the onset of dementia following TBI. Although the research findings suggest a general association between TBI and dementia, the specifics of the relationship remain poorly defined. [ABSTRACT FROM AUTHOR]

Tau deposits is a core feature of neurodegenerative disorder following traumatic brain injury (TBI). Despite ample evidence from post-mortem studies demonstrating exposure to both mild-repetitive and severe TBIs are linked to tau depositions, associations of topology of tau lesions with late-onset psychiatric symptoms due to TBI have not been explored. To address this issue, we assessed tau deposits in long-term survivors of TBI by PET with 11C-PBB3, and evaluated those associations with late-life neuropsychiatric outcomes. PET data were acquired from 27 subjects in the chronic stage following mild-repetitive or severe TBI and 15 healthy control subjects. Among the TBI patients, 14 were diagnosed as having late-onset symptoms based on the criteria of traumatic encephalopathy syndrome. For quantification of tau burden in TBI brains, we calculated 11C-PBB3 binding capacity (cm3), which is a summed voxel value of binding potentials (BP*ND) multiplied by voxel volume. Main outcomes of the present study were differences in 11C-PBB3 binding capacity between groups, and the association of regional 11C-PBB3 binding capacity with neuropsychiatric symptoms. To confirm 11C-PBB3 binding to tau deposits in TBI brains, we conducted in vitro PBB3 fluorescence and phospho-tau antibody immunofluorescence labelling of brain sections of chronic traumatic encephalopathy obtained from the Brain Bank. Our results showed that patients with TBI had higher 11C-PBB3 binding capacities in the neocortical grey and white matter segments than healthy control subjects. Furthermore, TBI patients with traumatic encephalopathy syndrome showed higher 11C-PBB3 binding capacity in the white matter segment than those without traumatic encephalopathy syndrome, and regional assessments revealed that subgroup difference was also significant in the frontal white matter. 11C-PBB3 binding capacity in the white matter segment correlated with the severity of psychosis. In vitro assays demonstrated PBB3-positive tau inclusions at the depth of neocortical sulci, confirming 11C-PBB3 binding to tau lesions. In conclusion, increased 11C-PBB3 binding capacity is associated with late-onset neuropsychiatric symptoms following TBI, and a close correlation was found between psychosis and 11C-PBB3 binding capacity in the white matter. [ABSTRACT FROM AUTHOR]

Introduction: Chronic Traumatic Encephalopathy (CTE) is a neuropathological disease defined by perivascular hyperphosphorylated tau protein depositions in a patchy distribution at the depths of cortical sulci in the brain. Presently, in living individuals, it cannot be precisely diagnosed or differentiated from other neurodegenerative diseases nor are there treatments for the underlying disease process. There are non-pharmacologic and pharmacologic treatments for the symptoms of CTE that improve the quality of daily life. That is the primary focus of this review article that used Pub Med and other standard databases but drew heavily from the author's personal experience managing patients at risk for CTE. Areas covered: The history and pathology of CTE, aiding the clinician diagnosing CTE as unlikely, possible, or probable in the living, and symptom treatment are the major areas discussed. Expert opinion: Diagnosing CTE during life with sensitive and specific biomarkers is the next critical step and only then will its incidence and prevalence, risk factors, and clinical features due to tauopathy versus axonopathy or other features be known. [ABSTRACT FROM AUTHOR]

Aims: Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease thought to be caused by repetitive traumatic brain injury (TBI) and subconcussive injuries. While hyperphosphorylation of tau (p-Tau), which is attributed to astrocytic tangles (ATs) and neurofibrillary tangles, is known to be involved in CTE, there are limited neuropathological or molecular data. By utilizing repetitive mild TBI (rmTBI) mouse models, our aim was to examine the pathological changes of CTE-associated structures, specifically the ATs. Results: Our rmTBI mouse models showed symptoms of depressive behavior and memory deficit, alongside an increased p-Tau expression in their neurons and astrocytes in both the hippocampus and cortex. rmTBI induced oxidative stress in endothelial cells and nitric oxide (NO) generation in astrocytes, which were mediated by hypoxia and increased hypoxia-inducible factor 1-α (HIF1α). There was also correlated decreased regional cerebral tissue perfusion units, mild activation of astrocytes and NFκB phosphorylation, increased expression of inducible nitric oxide synthase (iNOS), increased endothelial nitric oxide synthase (eNOS) uncoupling with decreased tetrahydrobiopterin, and increased expression of nitrotyrosine, NADPH oxidase 2 (Nox2)/nuclear factor (erythroid-derived 2) factor 2 (Nrf2) signaling proteins. Combined, these effects induced peroxynitrite formation and hyperphosphorylation of tau in the hippocampus and cortex toward the formation of ATs. Innovation: Our model features molecular pathogenesis events of CTE with clinically relevant latency periods. In particular, this is the first demonstration of an increased astrocytic iNOS expression in an in vivo model. Conclusion: We propose a novel mechanism of uncoupled eNOS and NO contribution to Tau phosphorylation and AT formation in rmTBI brain, toward an increased molecular understanding of the pathophysiology of human CTE. [ABSTRACT FROM AUTHOR]

In a recent article in this journal, Lopez Frias and McNamee (2017) raise some concerns about an argument presented in Corlett (2014), also published in this journal. This article is a detailed response to Lopez Frias and McNamee (2017) in clarification and defense of the argument in question in Corlett (2014). The discussion concerns the questions of whether or not inter-collegiate football ought to and will be eliminated, and why or why not. More specifically, the discussion concerns the health care and medical costs to others argument for the elimination of inter-collegiate football articulated in Corlett (2014). [ABSTRACT FROM AUTHOR]

How should science and policy interpret the recent finding that 110 of 111 former National Football League (NFL) players had brain pathology known as chronic traumatic encephalopathy (CTE) at autopsy? Some physicians view this (and related epidemiologic and mechanistic evidence) skeptically, emphasizing that the association between repeated head trauma (RHT) and CTE may be artifactual, that this "incidence" is biased by self-selection of players with cognitive or emotional symptoms, and that even if RHT causes CTE, the lesions themselves may be inconsequential. Public health scientists look at this emerging evidence quite differently; in particular, they tend not to fall prey to certain illogical arguments justifying inaction. We present a quantitative risk assessment showing that even accounting for the non-representativeness of the 110 cases, the risk of CTE in the NFL workforce amply meets both parts of the test for "a significant risk of material impairment of health" that would permit the U.S. Occupational Safety and Health Administration to intervene to reduce RHT exposure. We further conclude that according to available evidence, CTE is a public health problem, and that lawyers and physicians need to understand that this conclusion is based on standards of evidence at least as longstanding and robust as their own. [ABSTRACT FROM AUTHOR]

Objectives: An observational study to compare the laminar distributions in frontal and temporal cortex of the tau-immunoreactive pathologies in chronic traumatic encephalopathy (CTE) and Alzheimer's disease neuropathologic change (ADNC).Patients: Post-mortem material of (1) four cases of CTE without ADNC, (2) seven cases of CTE with ADNC (CTE/ADNC), and (3) seven cases of ADNC alone.Results: In CTE and CTE/ADNC, neurofibrillary tangles (NFT), neuropil threads (NT), and dot-like grains (DLG) were distributed either in upper cortex or across all layers. Low densities of astrocytic tangles (AT) and abnormally enlarged neurons (EN) were not localized to any specific layer. Surviving neurons exhibited peaks of density in both upper and lower cortex, and vacuole density was greatest in superficial layers. In ADNC, neuritic plaques (NP) were more frequent, AT rare, NFT and NT were more widely distributed, NT affected lower layers more frequently, and surviving neurons were less frequently bimodal than in CTE and CTE/ADNC.Conclusion: Tau pathology in CTE and CTE/ADNC consistently affected the upper cortex but was more widely distributed in ADNC. The presence of CTE may encourage the development of ADNC pathology later in the course of the disease. [ABSTRACT FROM AUTHOR]

Concussion or mild traumatic brain injury (mTBI) is associated with long-term impairments in military personnel. Diagnosis of the condition remains clinically challenging. Neurological examination and cognitive symptoms may not accurately map the nature and severity of underlying brain injury. Neuroimaging techniques, such as diffusion tensor imaging (DTI), show promise as an effective tool in delineating the microstructural neural changes and corresponding clinical consequences following mTBI. This paper discusses the diagnosis and management of concussion, in the military context, using two cases of veterans who suffered blast-related mTBI. Insights on an integrated approach to concussion in the military, incorporating thorough neurological and neuropsychological examination and application of advanced neuroimaging are presented. [ABSTRACT FROM AUTHOR]

Tauopathies are a diverse group of diseases featuring progressive dying-back neurodegeneration of specific neuronal populations in association with accumulation of abnormal forms of the microtubule-associated protein tau. It is well-established that the clinical symptoms characteristic of tauopathies correlate with deficits in synaptic function and neuritic connectivity early in the course of disease, but mechanisms underlying these critical pathogenic events are not fully understood. Biochemical in vitro evidence fueled the widespread notion that microtubule stabilization represents tau's primary biological role and that the marked atrophy of neurites observed in tauopathies results from loss of microtubule stability. However, this notion contrasts with the mild phenotype associated with tau deletion. Instead, an analysis of cellular hallmarks common to different tauopathies, including aberrant patterns of protein phosphorylation and early degeneration of axons, suggests that alterations in kinase-based signaling pathways and deficits in axonal transport (AT) associated with such alterations contribute to the loss of neuronal connectivity triggered by pathogenic forms of tau. Here, we review a body of literature providing evidence that axonal pathology represents an early and common pathogenic event among human tauopathies. Observations of axonal degeneration in animal models of specific tauopathies are discussed and similarities to human disease highlighted. Finally, we discuss potential mechanistic pathways other than microtubule destabilization by which disease-related forms of tau may promote axonopathy.

Tauopathies are a diverse group of diseases featuring progressive dying-back neurodegeneration of specific neuronal populations in association with accumulation of abnormal forms of the microtubule-associated protein tau. It is well-established that the clinical symptoms characteristic of tauopathies correlate with deficits in synaptic function and neuritic connectivity early in the course of disease, but mechanisms underlying these critical pathogenic events are not fully understood. Biochemical in vitro evidence fueled the widespread notion that microtubule stabilization represents tau's primary biological role and that the marked atrophy of neurites observed in tauopathies results from loss of microtubule stability. However, this notion contrasts with the mild phenotype associated with tau deletion. Instead, an analysis of cellular hallmarks common to different tauopathies, including aberrant patterns of protein phosphorylation and early degeneration of axons, suggests that alterations in kinase-based signaling pathways and deficits in axonal transport (AT) associated with such alterations contribute to the loss of neuronal connectivity triggered by pathogenic forms of tau. Here, we review a body of literature providing evidence that axonal pathology represents an early and common pathogenic event among human tauopathies. Observations of axonal degeneration in animal models of specific tauopathies are discussed and similarities to human disease highlighted. Finally, we discuss potential mechanistic pathways other than microtubule destabilization by which disease-related forms of tau may promote axonopathy. [ABSTRACT FROM AUTHOR]

The potential relationship between chronic traumatic encephalopathy (CTE) and head injuries such as blast-related traumatic brain injury (TBI) is an important area of study, particularly for military and contact sports populations, yet little is known about this relationship. To address this topic, the Department of Defense (DoD) Blast Injury Research Program Coordinating Office organized the 2015 International State-of-the-Science Meeting, which brought together subject matter experts from the DoD, other federal agencies, academia, industry, foreign allies, and the sports community. Over the course of the meeting, this community of experts reached a consensus regarding the current body of knowledge and the future of the field. The overarching finding was that there is insufficient existing scientific evidence to link blast-related TBI with CTE. The meeting's Expert Panel also agreed on 13 additional findings describing research and knowledge gaps, clinical gaps, and research opportunities that, if addressed with focused effort, would further the understanding of the relationship between blast-related TBI and CTE. To this end, the Expert Panel also developed six recommendations for advancing research, each with short- and long-term goals. Among the six recommendations, the Expert Panel identified the first four as highest priority for addressing pressing research needs. These four high-priority recommendations include, in order of priority: (1) more collection and study of clinical neuropathology samples, (2) standardization of clinical diagnostic criteria, (3) development of clinically appropriate and standardized animal models, and (4) development of noninvasive serial assessment strategies (i.e., imaging or biospecimen biomarkers). [ABSTRACT FROM AUTHOR]