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Importance: Parkinsonism is associated with traumatic brain injury and chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head impact (RHI) exposure, but the neuropathologic substrates that underlie parkinsonism in individuals with CTE are yet to be defined., Objective: To evaluate the frequency of parkinsonism in individuals with CTE and the association of RHI and neuropathologic substrates with parkinsonism in these individuals., Design, Setting, and Participants: This cross-sectional study included brain donors with neuropathologically diagnosed CTE without other significant neurodegenerative disease and with information on parkinsonism from the Understanding Neurologic Injury and Traumatic Encephalopathy brain bank between July 2015 and May 2022., Exposure: Years of contact sports participation as a proxy for RHI., Main Outcomes and Measures: The main outcomes were frequency of parkinsonism in individuals with CTE and associations between (1) RHI with substantia nigra (SN) Lewy bodies (LBs) and neurofibrillary tangles (NFTs); (2) LBs, NFTs, and arteriolosclerosis with SN neuronal loss; and (3) SN neuronal loss, LBs, NFTs, and arteriolosclerosis with parkinsonism, tested by age-adjusted logistic regressions., Results: Of 481 male brain donors with neuropathologically diagnosed CTE, parkinsonism occurred frequently in individuals with CTE (119 [24.7%]; 362 [75.3%] did not have parkinsonism). Participants with parkinsonism had a higher mean (SD) age at death (71.5 [13.0] years) than participants without parkinsonism (54.1 [19.3] years) (P < .001) and higher rates of dementia (104 [87.4%] vs 105 [29.0%]), visual hallucinations (45 [37.8%] vs 51 [14.1%]), and probable rapid eye movement sleep behavior disorder (52 [43.7%] vs 58 [16.0%]) (P < .001 for all). Participants with parkinsonism had a more severe CTE stage (eg, stage IV: 35 [29.4%] vs 39 [10.8%]) and nigral pathology than those without parkinsonism (NFTs: 50 of 117 [42.7%] vs 103 of 344 [29.9%]; P = .01; neuronal loss: 61 of 117 [52.1%] vs 59 of 344 [17.1%]; P < .001; and LBs: 28 of 116 [24.1%] vs 20 of 342 [5.8%]; P < .001). Years of contact sports participation were associated with SN NFTs (adjusted odds ratio [AOR], 1.04; 95% CI, 1.00-1.07; P = .03) and neuronal loss (AOR, 1.05; 95% CI, 1.01-1.08; P = .02). Nigral neuronal loss (AOR, 2.61; 95% CI, 1.52-4.47; P < .001) and LBs (AOR, 2.29; 95% CI, 1.15-4.57; P = .02) were associated with parkinsonism. However, SN neuronal loss was associated with SN LBs (AOR, 4.48; 95% CI, 2.25-8.92; P < .001), SN NFTs (AOR, 2.51; 95% CI, 1.52-4.15; P < .001), and arteriolosclerosis (AOR, 2.27; 95% CI, 1.33-3.85; P = .002). In American football players, regression analysis demonstrated that SN NFTs and neuronal loss mediated the association between years of play and parkinsonism in the context of CTE (β, 0.012; 95% CI, 0.001-0.038)., Conclusions and Relevance: In this cross-sectional study of contact sports athletes with CTE, years of contact sports participation were associated with SN tau pathology and neuronal loss, and these pathologies were associated with parkinsonism. Repetitive head impacts may incite neuropathologic processes that lead to symptoms of parkinsonism in individuals with CTE.

Soccer is one of the most popular sports worldwide, played by over 270 million people and followed by many more. Several brain health benefits are promoted by practising soccer and physical exercise at large, which helps contrast the cognitive decline associated with ageing by enhancing neurogenesis processes. However, sport-related concussions have been increasingly recognised as a pressing public health concern, not only due to their acute impact but also, more importantly, due to mounting evidence indicating an elevated risk for the development of neurological sequelae following recurrent head traumas, especially chronic traumatic encephalopathy (CTE). While soccer players experience less frequent concussions compared with other contact or combat sports, such as American football or boxing, it stands alone in its purposeful use of the head to hit the ball (headings), setting its players apart as the only athletes exposed to intentional, sub-concussive head impacts. Additionally, an association between soccer and amyotrophic lateral sclerosis has been consistently observed, suggesting a potential "soccer-specific" risk factor. In this review, we discuss the neurological sequelae related to soccer playing, the emerging evidence of a detrimental effect related to recurrent headings, and the need for implementation of comprehensive strategies aimed at preventing and managing the burden of head impact in soccer., (© 2024. The Author(s).)

Traumatic brain injury (TBI) leads to progressive neurodegeneration that may be caused by chronic traumatic encephalopathy (CTE). However, the precise mechanism remains unclear. Herein, the study identifies a crucial protein, axonemal dynein light intermediate polypeptide 1 (DNALI1), and elucidated its potential pathogenic role in post-TBI neurodegeneration. The DNALI1 gene is systematically screened through analyses of Aging, Dementia, and TBI studies, confirming its elevated expression both in vitro and in vivo. Moreover, it is observed that altered DNALI1 expression under normal conditions has no discernible effect. However, upon overexpression, DNALI1 inhibits autophagosome-lysosome fusion, reduces autophagic flux, and exacerbates cell death under pathological conditions. DNALI1 silencing significantly enhances autophagic flux and alleviates neurodegeneration in a CTE model. These findings highlight DNALI1 as a potential key target for preventing TBI-related neurodegeneration., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

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.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition, in which the only known cause is exposure to repeated episodes of blunt head trauma. It most often occurs in professional and amateur athletes who have had frequent and repetitive cranial impacts during contact sports, but may also be found in victims of domestic violence, military personnel exposed to explosive devices and in individuals with severe epilepsy. The pathognomonic pathological findings are of neurofibrillary tangles and pretangles in the depths of the cerebral sulci caused by perivascular accumulation of phosphorylated Tau (pTau). Cases may be high profile requiring an evaluation of whether the neuropathological findings of CTE can be related to injuries previously sustained on the sporting field. Failure to examine the brain or to adequately sample appropriate areas at autopsy may lead to cases being overlooked and to an underestimation of the incidence of this condition in the community. Performing immunohistochemical staining for pTau in three areas from the neocortex has been found to be a useful screening tool for CTE. Ascertaining whether there is a history of head trauma, including exposure to contact sports, as a standard part of forensic clinical history protocols will help identify at-risk individuals so that Coronial consideration of the need for brain examination can be appropriately informed. Repetitive head trauma, particularly from contact sport, is being increasingly recognized as a cause of significant preventable neurodegeneration., (© 2023. The Author(s).)

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.

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by widespread accumulation of hyperphosphorylated tau that typically occurs in people who have suffered repetitive head impacts. To date, very few cases have been reported in association football players., Objectives: To describe the clinicopathological features of a case of CTE in an 84-year-old former football player who was clinically diagnosed as having dementia with Lewy bodies (DLB)., Methods: A retrospective review of the patient's primary care and hospital medical records was performed along with a comprehensive neuropathological examination., Results: This patient presented at age 84 with symmetrical parkinsonism and cognitive impairment that was exacerbated by prochlorperazine. His condition was rapidly progressive with recurrent falls within 1 year. Other features included headaches, depression, anxiety, suicidal ideation, disturbed sleep and aggression. He received a clinical diagnosis of DLB and died approximately 2 years after the onset of symptoms. A post-mortem examination revealed stage 4 CTE., Conclusions: While the contemporaneous onset of parkinsonism and cognitive symptoms in the context of possible neuroleptic sensitivity is suggestive of DLB, the additional symptoms of aggressive behavior, depression and suicidality in a former football player are consistent with the neuropathological diagnosis of CTE. This case, which is notable for the late presentation, demonstrates that CTE may masquerade as other dementias and highlights the importance of seeking a history of repetitive head impacts., (© 2023 International Parkinson and Movement Disorder Society.)

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., (© 2023. The Author(s).)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: Flourine-18-flortaucipir tau positron emission tomography (PET) was developed for the detection for Alzheimer's disease. Human imaging studies have begun to investigate its use in chronic traumatic encephalopathy (CTE). Flortaucipir-PET to autopsy correlation studies in CTE are needed for diagnostic validation. We examined the association between end-of-life flortaucipir PET and postmortem neuropathological measurements of CTE-related tau in six former American football players., Methods: Three former National Football League players and three former college football players who were part of the DIAGNOSE CTE Research Project died and agreed to have their brains donated. The six players had flortaucipir (tau) and florbetapir (amyloid) PET prior to death. All brains from the deceased participants were neuropathologically evaluated for the presence of CTE. On average, the participants were 59.0 (SD = 9.32) years of age at time of PET. PET scans were acquired 20.33 (SD = 13.08) months before their death. Using Spearman correlation analyses, we compared flortaucipir standard uptake value ratios (SUVRs) to digital slide-based AT8 phosphorylated tau (p-tau) density in a priori selected composite cortical, composite limbic, and thalamic regions-of-interest (ROIs)., Results: Four brain donors had autopsy-confirmed CTE, all with high stage disease (n = 3 stage III, n = 1 stage IV). Three of these four met criteria for the clinical syndrome of CTE, known as traumatic encephalopathy syndrome (TES). Two did not have CTE at autopsy and one of these met criteria for TES. Concomitant pathology was only present in one of the non-CTE cases (Lewy body) and one of the CTE cases (motor neuron disease). There was a strong association between flortaucipir SUVRs and p-tau density in the composite cortical (ρ = 0.71) and limbic (ρ = 0.77) ROIs. Although there was a strong association in the thalamic ROI (ρ = 0.83), this is a region with known off-target binding. SUVRs were modest and CTE and non-CTE cases had overlapping SUVRs and discordant p-tau density for some regions., Conclusions: Flortaucipir-PET could be useful for detecting high stage CTE neuropathology, but specificity to CTE p-tau is uncertain. Off-target flortaucipir binding in the hippocampus and thalamus complicates interpretation of these associations. In vivo biomarkers that can detect the specific p-tau of CTE across the disease continuum are needed., (© 2022. The Author(s).)

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.

The settlement of the National Football League (NFL) Players Concussion Litigation was founded on a unique set of circumstances: in essence that the NFL investigated the risk of Chronic Traumatic Encephalopathy-like harm and then denied the risk. These circumstances are unlikely to be repeated in any of the thousands of lawsuits presently proposed by "non-NFL athletes" around the globe. These athletes face the far more difficult task of proving their overseeing sporting organisation had, or should have had, knowledge that repeated head trauma in playing contact sport can cause severe long-term cognitive harm, but to do so relying on "archived" reports dating back decades., Competing Interests: None.

Background: Repetitive head injury in contact sports is associated with cognitive, neurobehavioral, and motor impairments and linked to a unique neurodegenerative disorder: chronic traumatic encephalopathy (CTE). As the clinical presentation is variable, risk factors are heterogeneous, and diagnostic biomarkers are not yet established, the diagnostic process of CTE remains a challenge. The general objective of the NEwTON study is to establish a prospective cohort of individuals with high risk for CTE, to phenotype the study population, to identify potential fluid and neuroimaging biomarkers, and to measure clinical progression of the disease. The present paper explains the protocol and design of this case-finding study., Methods: NEwTON is a prospective study that aims to recruit participants at risk for CTE, with features of the traumatic encephalopathy syndrome (exposed participants), and healthy unexposed control individuals. Subjects are invited to participate after diagnostic screening at our memory clinic or recruited by advertisement. Exposed participants receive a comprehensive baseline screening, including neurological examination, neuropsychological tests, questionnaires and brain MRI for anatomical imaging, diffusion tensor imaging (DTI), resting-state functional MRI (rsfMRI), and quantitative susceptibility mapping (QSM). Questionnaires include topics on life-time head injury, subjective cognitive change, and neuropsychiatric symptoms. Optionally, blood and cerebrospinal fluid are obtained for storage in the NEwTON biobank. Patients are informed about our brain donation program in collaboration with the Netherlands Brain Brank. Follow-up takes place annually and includes neuropsychological assessment, questionnaires, and optional blood draw. Testing of control subjects is limited to baseline neuropsychological tests, MRI scan, and also noncompulsory blood draw., Results: To date, 27 exposed participants have finished their baseline assessments. First baseline results are expected in 2023., Conclusions: The NEwTON study will assemble a unique cohort with prospective observational data of male and female individuals with high risk for CTE. This study is expected to be a primary explorative base and designed to share data with international CTE-related cohorts. Sub-studies may be added in the future with this cohort as backbone., (© 2022. The Author(s).)

Traumatic encephalopathy syndrome (TES) criteria were developed to aid diagnosis of chronic traumatic encephalopathy (CTE) pathology during life. Interpreting clinical and biomarker findings in patients with TES during life necessitates autopsy-based determination of the neuropathological profile. We report a clinicopathological series of nine patients with previous repetitive head impacts (RHI) classified retrospectively using the recent TES research framework (100% male and white/Caucasian, age at death 49-84) who completed antemortem neuropsychological evaluations, T1-weighted magnetic resonance imaging, diffusion tensor imaging ( n  = 6), (18)F-fluorodeoxyglucose-positron emission tomography ( n  = 5), and plasma measurement of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau ( n  = 8). Autopsies were performed on all patients. Cognitively, low test scores and longitudinal decline were relatively consistent for memory and executive function. Medial temporal lobe atrophy was observed in all nine patients. Poor white matter integrity was consistently found in the fornix. Glucose hypometabolism was most common in the medial temporal lobe and thalamus. Most patients had elevated plasma GFAP, NfL, and total tau at their initial visit and a subset showed longitudinally increasing concentrations. Neuropathologically, five of the nine patients had CTE pathology ( n  = 4 "High CTE"/McKee Stage III-IV, n  = 1 "Low CTE"/McKee Stage I). Primary neuropathological diagnoses (i.e., the disease considered most responsible for observed symptoms) were frontotemporal lobar degeneration ( n  = 2 FTLD-TDP, n  = 1 FTLD-tau), Alzheimer disease ( n  = 3), CTE ( n  = 2), and primary age-related tauopathy ( n  = 1). In addition, hippocampal sclerosis was a common neuropathological comorbidity ( n  = 5) and associated with limbic-predominant TDP-43 proteinopathy ( n  = 4) or FTLD-TDP ( n  = 1). Memory and executive function decline, limbic system brain changes (atrophy, decreased white matter integrity, hypometabolism), and plasma biomarker alterations are common in RHI and TES but may reflect multiple neuropathologies. In particular, the neuropathological differential for patients with RHI or TES presenting with medial temporal atrophy and memory loss should include limbic TDP-43. Researchers and clinicians should be cautious in attributing cognitive, neuroimaging, or other biomarker changes solely to CTE tau pathology based on previous RHI or a TES diagnosis alone.

Background: Persistent neuropsychiatric sequelae may develop in military personnel who are exposed to combat; such sequelae have been attributed in some cases to chronic traumatic encephalopathy (CTE). Only limited data regarding CTE in the brains of military service members are available., Methods: We performed neuropathological examinations for the presence of CTE in 225 consecutive brains from a brain bank dedicated to the study of deceased service members. In addition, we reviewed information obtained retrospectively regarding the decedents' histories of blast exposure, contact sports, other types of traumatic brain injury (TBI), and neuropsychiatric disorders., Results: Neuropathological findings of CTE were present in 10 of the 225 brains (4.4%) we examined; half the CTE cases had only a single pathognomonic lesion. Of the 45 brains from decedents who had a history of blast exposure, 3 had CTE, as compared with 7 of 180 brains from those without a history of blast exposure (relative risk, 1.71; 95% confidence interval [CI], 0.46 to 6.37); 3 of 21 brains from decedents with TBI from an injury during military service caused by the head striking a physical object without associated blast exposure (military impact TBI) had CTE, as compared with 7 of 204 without this exposure (relative risk, 4.16; 95% CI, 1.16 to 14.91). All brains with CTE were from decedents who had participated in contact sports; 10 of 60 contact-sports participants had CTE, as compared with 0 of 165 who had not participated in contact sports (point estimate of relative risk not computable; 95% CI, 6.16 to infinity). CTE was present in 8 of 44 brains from decedents with non-sports-related TBI in civilian life, as compared with 2 of 181 brains from those without such exposure in civilian life (relative risk, 16.45; 95% CI, 3.62 to 74.79)., Conclusions: Evidence of CTE was infrequently found in a series of brains from military personnel and was usually reflected by minimal neuropathologic changes. Risk ratios for CTE were numerically higher among decedents who had contact-sports exposure and other exposures to TBI in civilian life than among those who had blast exposure or other military TBI, but the small number of CTE cases and wide confidence intervals preclude causal conclusions. (Funded by the Department of Defense-Uniformed Services University Brain Tissue Repository and Neuropathology Program and the Henry M. Jackson Foundation for the Advancement of Military Medicine.)., (Copyright © 2022 Massachusetts Medical Society.)

Chronic Traumatic Encephalopathy, or CTE, is a neurodegenerative disease caused by traumatic brain injury and most frequently associated with contact sports such as American Football. Perhaps surprisingly, the woodpecker - an animal apparently immune to the effects of head impacts - has increasingly figured into debates surrounding CTE. On the one hand, the woodpecker is described as being contra-human and used to underscore the radical inappropriateness of humans playing football. On the other, there have been attempts to mitigate against the risk of CTE through the creation of biomimetic technologies inspired by woodpeckers. In this article I examine the highly politicized encounters between humans and woodpeckers and discuss how the politics of re-/dis-/en-tanglement during these interspecies relations is rendered meaningful. I show here, first, that those who seek to keep the human and the woodpecker apart envisage social overhaul while biomimetic technologies are put to work for the status quo. Second, I stress that different forms of entanglement have diverse sociopolitical consequences. I conclude by suggesting that the case of the woodpecker troubles a strand of contemporary scholarship in Science and Technology Studies that argues that biotechnologies are inherently transformatory and that foregrounding entanglement and interspecies relations is ethically generative. Instead, a discursive separation of nature and culture may be innovative.

Introduction: Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative syndrome, caused by single or repeated traumatic brain injuries. Since a few years ago, post mortem examination represented the only effective method to diagnose CTE through the detection of its peculiar neuropathological features (i.e. tau protein aggregates) at a macroscopic and microscopic level. Several efforts have been made to develop radiopharmaceuticals characterized by high affinity for tau aggregates, suitable for imaging through positron emission computed tomography (Tau-PET)., Areas Covered: The various radiopharmaceuticals utilized for the molecular imaging of CTE through Tau-PET are covered, with specific reference to their applications in clinical practice. Furthermore, PET probes binding to the translocator protein (TSPO), a marker of brain injury and repair, are reviewed as potential tools for the imaging of neuroinflammatory cascade associated with CTE., Expert Opinion: Molecular neuroimaging of CTE with Tau-PET is an intriguing, although still not completely explored, tool for the in vivo detection and monitoring of neuropathological hallmarks associated with CTE. Furthermore, some novel tracers, such as TSPO-ligands, hold the promise to get an insight into the complex physiopathological mechanisms leading from brain injury to symptomatic CTE.

Objective: To investigate factors associated with collegiate athletes' beliefs regarding chronic traumatic encephalopathy (CTE) mechanism., Design: Cross-sectional study., Methods: A total of 838 collegiate athletes (61.9% men) from seven institutions completed a 10-minute survey that captured information relative to demographics, diagnosed concussion history, formal sport-related concussion education, additional sources of concussion information, and beliefs about multiple concussions and premature return-to-play following a head impact as mechanisms for CTE., Results: More than half of collegiate athletes believed that multiple concussions (58.2%) and premature return-to-play (59.1%) may cause CTE. Those who reported getting concussion information from sports news had higher odds of believing multiple concussions and premature return-to-play were CTE mechanisms compared to those who did not get information from sports news sources. Additionally, CTE mechanism beliefs were significantly greater in collegiate athletes who were male, had sustained a previous diagnosed concussion, or had acquired concussion information from the NCAA., Conclusions: Sports news' reporting of CTE storylines, which highlight former male athletes with complex brain injury histories, may influence collegiate athletes' beliefs about concussion. Therefore, it is recommended that concussion awareness initiatives incorporate information related specifically to CTE to empower collegiate athletes with evidence-based, patient-oriented information and knowledge regarding this condition.

Objective: To determine whether an association exists between career duration or position played and the presence of chronic traumatic encephalopathy (CTE) at autopsy in a series of elite football and hockey players., Methods: This retrospective cohort study analyzed postmortem brains of 35 former football or hockey players (29 professional, 6 university varsity/major junior), with the presence of CTE at autopsy as the primary outcome. Position played (highest level), age at retirement (indicator of lifetime exposure to sport), and hockey fighting/penalization histories (surrogate marker for role/style of play) were collected. A blinded neuropathologic evaluation of each participant was performed, providing an assessment for neurodegenerative diseases including CTE, based on the 2015 National Institute of Neurological Disorders and Stroke/National Institute of Biomedical Imaging and Bioengineeringconsensus paper., Results: In total, 17 of 35 former players (48.6%) showed pathologic evidence of CTE. There was no correlation found between position played and CTE presence, nor between hockey fighting/penalization histories and CTE, in either the football or hockey groups ( p > 0.75, Mann-Whitney-Wilcoxon). Similarly, there was no association between age at retirement and CTE presence ( p > 0.5, Mann-Whitney-Wilcoxon). In 24 of 35 cases (68.6%), other neuropathologies were present, 13 of 24 (54.2%) of which were coexistent with CTE., Conclusion: In this cohort of 35 former collision sports athletes, no significant associations were found between career duration, position or role played, and CTE presence at autopsy. Although limited by the small and nonrepresentative sample studied, these findings suggest that nonsport factors may be important to understand differing susceptibilities among athletes to CTE., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Traumatic brain injury (TBI) is a risk factor for the later development of dementia, but although the evidence dates back to the early 20 th century, the nature of any association and its mechanistic pathways remain unclear. There has been greater focus on this subject over recent years, in part because of increasing reports around sports related TBIs, especially in the USA. Differences in research methods and clinical sampling remain the primary reason for the variable findings, although there is clearly increased prevalence of neurodegenerative disorders in general. Duration of follow up, definition of both TBI and dementia, and differences in the extent to which other dementia risk factors are controlled, as well as concerns about medical record accuracy are all issues yet to be resolved in TBI research, as is an absence pathological evidence. In addition, TBI has been reported to initiate a cascade of pathological processes related to several neurodegenerative disorders, and as such, it is likely that the risks vary between individuals. Given the evidence that dementia risk may increase with injury severity and frequency, a detailed account of age and type of injury, as well as lifetime TBI exposure is essential to document in future studies, and further longitudinal research with biomarker assessments are needed.

American football players are frequently exposed to head impacts, which can cause concussions and may lead to neurodegenerative diseases such as chronic traumatic encephalopathy (CTE). Player position appears to influence the risk of concussion but there is limited work on its effect on the risk of CTE. Computational modelling has shown that large brain deformations during head impacts co-localise with CTE pathology in sulci. Here we test whether player position has an effect on brain deformation within the sulci, a possible biomechanical trigger for CTE. We physically reconstructed 148 head impact events from video footage of American Football games. Players were separated into 3 different position profiles based on the magnitude and frequency of impacts. A detailed finite element model of TBI was then used to predict Green-Lagrange strain and strain rate across the brain and in sulci. Using a one-way ANOVA, we found that in positions where players were exposed to large magnitude and low frequency impacts (e.g. defensive back and wide receiver), strain and strain rate across the brain and in sulci were highest. We also found that rotational head motion is a key determinant in producing large strains and strain rates in the sulci. Our results suggest that player position has a significant effect on impact kinematics, influencing the magnitude of deformations within sulci, which spatially corresponds to where CTE pathology is observed. This work can inform future studies investigating different player-position risks for concussion and CTE and guide design of prevention systems., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Athletes, many comparatively young, are reported to have initiated legal action claiming their sporting organisation negligently failed to inform itself of the risk of chronic traumatic encephalopathy (CTE) and to warn its athletes of that risk when sufficient information to do so was available. This article considers the legal obligation of sporting organisations, perhaps through their medical staff, "to be informed" of the risk of CTE, to assess the risk, and to warn their athletes of that risk. The law pertaining to the "medical model", adjusted as to expertise, is proposed as the most suitable test of liability for failure to be informed and to warn. On the basis that CTE is a malady caused by repetitive head trauma, this article argues that delays in acquiring knowledge and warning of the risk of CTE deny athletes the opportunity to make a timely response to the risk of cognitive harm., Competing Interests: None.

Emerging evidence of brain injury on risk of neurodegenerative diseases such as Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE) have resulted in interest in therapeutic potential of omega-3 fatty acids (n-3FA). We conducted a systematic review of n-3FA therapeutic efficacy for ageing adults at risk of AD/CTE following a history of repeated head trauma. Databases for articles between 1980-June 2020 were examined for studies reporting on n-3 FAs in adults (≥ 45 years) with a history of repeated brain injury. Following an initial screen of 175 articles, 12 studies were considered but were eventually rejected, as they did not meet inclusion criteria. Our review could find no evidence to support, or disprove, effectiveness of n-3FA intervention in older adults with a history of head trauma. With animal studies showing neuro-restorative potential of n-3FA following brain injury, this review highlights the urgent need for human research in this area., Competing Interests: No specific funding was provided for the completion of this study. CP is CEO and Founder of Feedback Nutrition, which sell DHA supplements in Australia. He is also Independent Director of Sea Dragon, which sells refined omega-3 oils to the global infant formula market. ELH-Y is supported by an ARC Future Fellowship (FT160100126) and an RMIT Vice Chancellor’s Senior Research Fellowship. AJP currently receives partial research salary funding from Sports Health Check charity (Australia). AJP has previously received partial research funding from the Australian Football League (AFL), Impact Technologies Inc., and Samsung Corporation. Other authors declare that they have no competing interests.

This article presents a brief history and literature review of chronic traumatic encephalopathy (CTE) in professional athletes that played contact sports. The hypothesis that CTE results from concussion or sub-concussive blows is based largely on several case series investigations with considerable bias. Evidence of CTE in its clinical presentation has not been generally noted in studies of living retired athletes. However, these studies also demonstrated limitation in research methodology. This paper aims to present a balanced perspective amidst a politically charged subject matter., Competing Interests: Disclosure The authors have nothing to disclose., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Doubts can be raised about almost any assertion that a particular exposure can lead to an increase in a given adverse health effect. Even some of the most well-accepted causal associations in public health, such as that linking cigarette smoking to increased lung cancer risk, have intriguing research questions remaining to be answered. The inquiry whether an exposure causes a disease is never wholly a yes/no question but ought to follow from an appraisal of the weight of evidence supporting the positive conclusion in light of any coherent theories casting doubt on this evidence and the data supporting these. More importantly, such an appraisal cannot be made sensibly without considering the relative consequences to public health and economic welfare of specific actions based on unwarranted credulity (false positives) versus unwarranted skepticism (false negatives). Here we appraise the weight of evidence for the premise that repeated head impacts (RHIs) in professional football can increase the incidence of chronic traumatic encephalopathy (CTE) and, in turn, cause a variety of cognitive and behavioral symptoms. We first dismiss four logical fallacies that should not affect the appraisal of the weight of evidence. We then examine four alternative hypotheses in which RHI is not associated with CTE or symptoms (or both), and we conclude that the chances are small that the RHI→ CTE→ symptoms link is coincidental or artifactual. In particular, we observe that there are many specific interventions for which, even under a skeptical appraisal of the weight of evidence, the costs of a false positive are smaller than the false negative costs of refusing to intervene., Competing Interests: Dr. Finkel reports that in 2014 and 2015, he worked with the (former) Harvard Football Players Health Study to craft an article on legal and policy issues surrounding the possible OSHA regulation of football. The submitted article may differ from, or align with, views of individuals in the HFPHS, but his involvement with the study ended more than 3 years ago., (Thieme. All rights reserved.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

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., Competing Interests: None., (Thieme. All rights reserved.)

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease that has been neuropathologically diagnosed in contact and collision sport athletes, military veterans, and others with a history of exposure to repetitive head impacts (RHI). Identifying methods to diagnose and prevent CTE during life is a high priority. Timely diagnosis and implementation of treatment and preventative strategies for neurodegenerative diseases, including CTE, partially hinge upon early and accurate risk characterization. Here, we propose a framework of risk factors that influence the neuropathological development of CTE. We provide an up-to-date review of the literature examining cumulative exposure to RHI as the environmental trigger for CTE. Because not all individuals exposed to RHI develop CTE, the direct and/or indirect influence of nonhead trauma exposure characteristics (e.g., age, sex, race, genetics) on the pathological development of CTE is reviewed. We conclude with recommendations for future directions, as well as opinions for preventative strategies that could mitigate risk., Competing Interests: Dr. Stern reports grants from Avid Radiopharmaceuticals, Inc. (Philadelphia, PA); personal fees from Biogen (Cambridge, MA); personal fees from Eli Lilly (Indianapolis, IN); personal fees from Psychological Assessment Resources, Inc. (Lutz, FL); personal fees from King-Devick Technologies (Chicago, IL); outside the submitted work; and is a member of the Mackey-White Committee of the NFL Players Association., (Thieme. All rights reserved.)

Sports-related concussions (SRCs) are typically characterized by transient neurologic deficits due to physiologic and metabolic brain injury. However, following an SRC, subsequent insults may lead to severe and permanent injury in the affected brain cells. We present the case of a 15-year-old female scholastic wrestler who developed acute encephalopathy, macroscopic white matter injury on imaging, and chronic behavioral changes from inadequate neuro-recovery after a documented SRC. We also compare her case with established SRC data, demonstrating that wrestling-related concussions and repetitive head impacts can produce similar degrees of diffuse neuroinflammation, myelinated axonopathy, blood-brain barrier disruption, and post-concussive symptoms.

Over the past decade, concern for negative outcomes associated with concussive brain trauma has grown immensely. These neuropathologic changes, termed chronic traumatic encephalopathy (CTE), have been linked to patients who exhibit neuropsychiatric symptoms and have experienced repetitive brain trauma. Recent publicity has brought about renewed interest in this progressive neurodegenerative disorder. This article will share the advances that have been made with CTE.

Objective : To determine chronic traumatic encephalopathy (CTE)-related publication characteristics associated with higher Altmetric scores. Methods : A systematic review of the CTE literature was conducted using PubMed. Publications were coded for: journal impact factor (JIF); publication type (primary versus non-primary data collection); discussion of American football; contact sport-CTE association conclusion (yes versus no/neutral); and Altmetric score. Multivariable ordinal logistic regression identified predictors of higher Altmetric scores. Results : Most of the 270 CTE-related publications did not include primary data collection (60%). The median Altmetric score was 12 (range = 0-3745). Higher Altmetric scores were associated with primary data collection [Odds ratio (OR) Adjusted  = 2.29; 95% confidence interval (CI) = 1.35-3.89] and discussing American football (OR Adjusted  = 2.11; 95%CI = 1.24-3.59). Among publications concluding contact sport-CTE associations, higher Altmetric scores were associated with higher JIF (3-point-JIF-increase OR Adjusted = 2.11; 95%CI = 1.24-3.59); however, the association of higher Altmetric scores with higher JIF was not found among neutral publications or those concluding no contact sport-CTE associations (3-point-JIF-increase OR Adjusted  = 1.07; 95%CI = 0.94-1.22). Conclusions : Most CTE-related publications (60%) did not involve primary data collection. Publication characteristics such as higher JIF and concluding contact sport-CTE associations were associated with higher Altmetric scores. It is important for the academic community to consider strategies to counter publication and promotion bias in the presentation of CTE literature.

Collision sports are an integral part of Australian culture. The most common collision sports in Australia are Australian rules football, rugby union, and rugby league. Each of these sports often results in participants sustaining mild brain traumas, such as concussive and subconcussive injuries. However, the majority of previous studies and reviews pertaining to the neurological implications of sustaining mild brain traumas, while engaging in collision sports, have focused on those popular in North America and Europe. As part of this 2020 International Neurotrauma Symposium special issue, which highlights Australian neurotrauma research, this article will therefore review the burden of mild brain traumas in Australian collision sports athletes. Specifically, this review will first provide an overview of the consequences of mild brain trauma in Australian collision sports, followed by a summary of the previous studies that have investigated neurocognition, ocular motor function, neuroimaging, and fluid biomarkers, as well as neuropathological outcomes in Australian collision sports athletes. A review of the literature indicates that although Australians have contributed to the field, several knowledge gaps and limitations currently exist. These include important questions related to sex differences, the identification and implementation of blood and imaging biomarkers, the need for consistent study designs and common data elements, as well as more multi-modal studies. We conclude that although Australia has had an active history of investigating the neurological impact of collision sports participation, further research is clearly needed to better understand these consequences in Australian athletes and how they can be mitigated.

Chronic traumatic encephalopathy (CTE), a disease process well-recognized in boxers, American football players and military personnel, is a progressive neurodegenerative disease caused by repetitive blows to the head. Subjects with CTE can have a wide range of emotional, cognitive and physical symptoms. The cognitive group patients had a significantly higher probability of developing dementia in later years. Currently, there are no disease modifying regimen for CTE. Timely intervention of head blow could diminish the development of CTE. Low-intensity pulsed ultrasound (LIPUS) is a common adjunct used to promote bone healing for fresh fracture. Recent reports suggest that LIPUS can noninvasively modulate the cortical function and have neuroprotective effect in various animal models of traumatic brain injury, stroke, Alzheimer's disease and major depressive disorder. The multifunctional mechanisms of LIPUS neuroprotective effect include several trophic factor stimulations, anti-inflammatory properties and reduction of brain edema. From the above evidence, LIPUS intervention could be a strategy for the prevention of the clinical CTE sequelae of repetitive head blows. We hypothesized that due to its neuroprotective effects, the non-invasive and easy-to-use method of LIPUS brain stimulation could have a preventive effect on players who have head blows during the match. The development of a time sensitive protocol, resembling the therapeutic algorithm for traumatic brain injury, would potentially prevent the development of subsequent CTE adverse outcome. Further long-term longitudinal studies of LIPUS stimulation are warranted to verify the prevention efficacy of this intervention for CTE., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

In the 20th century, chronic traumatic encephalopathy (CTE) was conceptualized as a neurological disorder affecting some active and retired boxers who had tremendous exposure to neurotrauma. In recent years, the two research groups in the USA who have led the field have asserted definitively that CTE is a delayed-onset and progressive neurodegenerative disease, with symptoms appearing in midlife or decades after exposure. Between 2005 and 2012 autopsy cases of former boxers and American football players described neuropathology attributed to CTE that was broad and diverse. This pathology, resulting from multiple causes, was aggregated and referred to, in toto, as the pathology 'characteristic' of CTE. Preliminary consensus criteria for defining the neuropathology of CTE were forged in 2015 and published in 2016. Most of the macroscopic and microscopic neuropathological findings described as characteristic of CTE, in studies published before 2016, were not included in the new criteria for defining the pathology. In the past few years, there has been steadily emerging evidence that the neuropathology described as unique to CTE may not be unique. CTE pathology has been described in individuals with no known participation in collision or contact sports and no known exposure to repetitive neurotrauma. This pathology has been reported in individuals with substance abuse, temporal lobe epilepsy, amyotrophic lateral sclerosis, multiple system atrophy, and other neurodegenerative diseases. Moreover, throughout history, some clinical cases have been described as not being progressive, and there is now evidence that CTE neuropathology might not be progressive in some individuals. Considering the current state of knowledge, including the absence of a series of validated sensitive and specific biomarkers, CTE pathology might not be inexorably progressive or specific to those who have experienced repetitive neurotrauma., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Traumatic brain injury (TBI) is a leading cause of death and disability, contributing to ~30% of all injury-related deaths in the US. TBI occurs when a force transmitted to the head causes neuropathologic damage and impairment of brain function. TBI doubles risk of suicide and is the major determinant of acquired seizure disorders. TBI arising from closed head trauma (CHT) significantly increases the risk of developing Alzheimer's disease (AD), Parkinson's disease (PD) and chronic traumatic encephalopathy (CTE). Evidence for a possible role of TBI as a risk factor for sporadic amyotrophic lateral sclerosis (sALS) has been provided by studies of professional players of European football. Depending on age, genetic make-up (in particular, being a carrier of one or two ApoE4 alleles), the number of TBIs sustained, their severity, the time periods involved, and many other factors that affect vulnerability, decades may pass after occurrence of one or more TBIs before sequelae such as AD, PD, sALS or CTE become clinically evident. Among college and professional football players who experience repeated concussions and sub-concussive blows to the head, the risk of developing CTE increases with the number of years actively devoted to the sport, and the degree of exposure to physical impacts inherent in the position played. Following a moderate or severe concussion, or a series of mild blows to the head, the brain may undergo subtle pathophysiological changes that are unlikely to be detected with confidence using available diagnostic methods. Biomarkers are being sought that can help the attending physician infer the likely presence of an ongoing occult neurodegenerative process. One example of the adverse effect of collision on the brain is "heading" the soccer ball-a feat that, repeated over years of competition, has been found to produce severe brain damage in veteran players. CTE has attracted increasing national attention because of its devastating effects in a high proportion of retired professional players of American football. In a study of brains from deceased former football players, contributed mostly by family members, CTE was neuropathologically diagnosed in 110 of 111 of National Football League (NFL) veterans. In the CTE-positive subjects, the authors observed extensive brain atrophy, astrogliosis, myelinated axonopathy, microvascular injury, perivascular neuroinflammation, and phosphorylated tau protein pathology. CTE's neuropathology has been formally defined as a tauopathy characterized by a distinct perivascular accumulation of hyperphosphorylated tau in neurons and astrocytes within cerebral sulci. Although the mechanism that underlies the unforeseen emergence of CTE long after the occurrence of one or more closed head traumas is unknown, an explanation proposed by Albayram and associates is persuasive. They discovered TBI-induced neuronal production of the toxic compound cis P-tau, an abnormal and destructive isomer of the normal and benign trans P-tau, in mouse models of CTE. Cis P-tau produced a CTE-like syndrome via a process they termed cistauosis. Cistauosis can be blocked in laboratory animals by cis P-tau monoclonal antibody, which prevents later development of tau tangles, brain atrophy and virtual CTE. In a subsequent study, the same group found in human samples obtained post-TBI from a variety of causes, that cis P-tau is induced in cortical axons and cerebrospinal fluid and positively correlates with axonal injury and clinical outcome. Thus, cis P-tau appears to contribute to short-term and long-term sequelae after TBI, but may be subject to neutralization by cis-antibody treatment., (Copyright © 2019. Published by Elsevier Inc.)

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts. CTE has been linked to disruptions in cognition, mood, and behavior. Unfortunately, the diagnosis of CTE can only be made post-mortem. Neuropathological evidence suggests limbic structures may provide an opportunity to characterize CTE in the living. Using 3 T magnetic resonance imaging, we compared select limbic brain regional volumes - the amygdala, hippocampus, and cingulate gyrus - between symptomatic former National Football League (NFL) players (n = 86) and controls (n = 22). Moreover, within the group of former NFL players, we examined the relationship between those limbic structures and neurobehavioral functioning (n = 75). The former NFL group comprised eighty-six men (mean age = 55.2 ± 8.0 years) with at least 12 years of organized football experience, at least 2 years of active participation in the NFL, and self-reported declines in cognition, mood, and behavior within the last 6 months. The control group consisted of men (mean age = 57.0 ± 6.6 years) with no history of contact-sport involvement or traumatic brain injury. All control participants provided neurobehavioral data. Compared to controls, former NFL players exhibited reduced volumes of the amygdala, hippocampus, and cingulate gyrus. Within the NFL group, reduced bilateral cingulate gyrus volume was associated with worse attention and psychomotor speed (r = 0.4 (right), r = 0.42 (left); both p < 0.001), while decreased right hippocampal volume was associated with worse visual memory (r = 0.25, p = 0.027). Reduced volumes of limbic system structures in former NFL players are associated with neurocognitive features of CTE. Volume reductions in the amygdala, hippocampus, and cingulate gyrus may be potential biomarkers of neurodegeneration in those at risk for CTE.

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been associated with a history of repetitive head impacts. The neuropathological diagnosis is based on a specific pattern of tau deposition with minimal amyloid-beta deposition that differs from other disorders, including Alzheimer's disease. The feasibility of detecting tau and amyloid deposition in the brains of living persons at risk for CTE has not been well studied., Methods: We used flortaucipir positron-emission tomography (PET) and florbetapir PET to measure deposition of tau and amyloid-beta, respectively, in the brains of former National Football League (NFL) players with cognitive and neuropsychiatric symptoms and in asymptomatic men with no history of traumatic brain injury. Automated image-analysis algorithms were used to compare the regional tau standardized uptake value ratio (SUVR, the ratio of radioactivity in a cerebral region to that in the cerebellum as a reference) between the two groups and to explore the associations of SUVR with symptom severity and with years of football play in the former-player group., Results: A total of 26 former players and 31 controls were included in the analysis. The mean flortaucipir SUVR was higher among former players than among controls in three regions of the brain: bilateral superior frontal (1.09 vs. 0.98; adjusted mean difference, 0.13; 95% confidence interval [CI], 0.06 to 0.20; P<0.001), bilateral medial temporal (1.23 vs. 1.12; adjusted mean difference, 0.13; 95% CI, 0.05 to 0.21; P<0.001), and left parietal (1.12 vs. 1.01; adjusted mean difference, 0.12; 95% CI, 0.05 to 0.20; P = 0.002). In exploratory analyses, the correlation coefficients in these three regions between the SUVRs and years of play were 0.58 (95% CI, 0.25 to 0.79), 0.45 (95% CI, 0.07 to 0.71), and 0.50 (95% CI, 0.14 to 0.74), respectively. There was no association between tau deposition and scores on cognitive and neuropsychiatric tests. Only one former player had levels of amyloid-beta deposition similar to those in persons with Alzheimer's disease., Conclusions: A group of living former NFL players with cognitive and neuropsychiatric symptoms had higher tau levels measured by PET than controls in brain regions that are affected by CTE and did not have elevated amyloid-beta levels. Further studies are needed to determine whether elevated CTE-associated tau can be detected in individual persons. (Funded by Avid Radiopharmaceuticals and others.)., (Copyright © 2019 Massachusetts Medical Society.)

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.

Concussion is defined as a complex pathophysiological process that affects the brain as a result of traumatic biomechanical forces. Repeated unrecovered concussions can result in chronic brain injury syndrome which is referred to in the literature today as chronic traumatic encephalopathy." There is an exponential increase in public and political interest in this condition in the recent times resulting in a significant investment in research to improve the current understanding of the disease, ways to decrease its incidence and determine its prognosis. Broadly the research involves three main disciplines of medicine including neuropathology, neuroradiology and biological markers. Although progress has been made, to date there is no definite pathological, radiological or neurobiological marker which has shown consistent promise to make the diagnosis and prognosticate the disease. Possible reasons are multiple such as inconsistencies in the methods studies have used, different time periods in which the tests were conducted, the small numbers of subjects included in the studies, and inconsistencies in the definitions of concussion or mild traumatic brain injury. Herein, we present a comprehensive review of the current literature on this topic. Positron emission tomography scans with radioactive ligands such as T807 as an imaging biomarker, and neurofilament light and ubiquitin C-terminal hydrolase as serum biomarkers have shown some promise lately in diagnosing concussion and chronic traumatic encephalopathy and also determining their prognosis. Clin. Anat. 32:310-318, 2019. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

The term chronic traumatic encephalopathy (CTE) has recently entered public consciousness via media reports and even a Hollywood movie. However, in contrast to general impressions, the incidence of CTE is unknown, the clinical diagnostic criteria have not been agreed upon and the current neuropathological characterization of CTE is acknowledged as preliminary. Additionally, few studies have compared the pathologies of CTE with those of other neurodegenerative disorders or of age-matched controls. Consequently, disagreement continues about the neuropathological aspects that make CTE unique. Furthermore, CTE is widely considered to be a consequence of exposure to repeated head blows, but evidence suggests that a single moderate or severe traumatic brain injury can also induce progressive neuropathological changes. These unresolved aspects of CTE underlie disparate claims about its clinical and pathological features, leading to confusion among the public and health-care professionals alike.