DNALI1 Promotes Neurodegeneration after Traumatic Brain Injury via Inhibition of Autophagosome-Lysosome Fusion.

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.

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

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

Leveraging football accelerometer data to quantify associations between repetitive head impacts and chronic traumatic encephalopathy in males.

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.

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

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

Chronic traumatic encephalopathy (CTE)-features and forensic considerations.

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.

Associations between near end-of-life flortaucipir PET and postmortem CTE-related tau neuropathology in six former American football players.

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.

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

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

[Chronic Traumatic Encephalopathy: Concussion].

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

Rationale and design of the "NEurodegeneration: Traumatic brain injury as Origin of the Neuropathology (NEwTON)" study: a prospective cohort study of individuals at risk for chronic traumatic encephalopathy.

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.

Chronic Traumatic Encephalopathy in the Brains of Military Personnel.

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.).

Multi-Modal Biomarkers of Repetitive Head Impacts and Traumatic Encephalopathy Syndrome: A Clinicopathological Case Series.

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.

Neuroimaging with PET/CT in chronic traumatic encephalopathy: what nuclear medicine can do to move the field forward.

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.

Knowledge of Chronic Traumatic Encephalopathy and Concussion Cannot Support a Negligence Suit against Major Sporting Organisations by Athletes. Or Can It?

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.

Consider the woodpecker: The contested more-than-human ethics of biomimetic technology and traumatic brain injury.

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.

[Experience with 4 clinical cases. Traumatic encephalopathy may be associated with a single traumatic brain injury?] / Experiencia con cuatro casos clínicos, ¿puede la encefalopatía traumática crónica estar asociada a un traumatismo craneoencefálico único?

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that affects people who had repetitive head trauma. Also, in single traumatic brain injury (TBI), changes may be found during the follow-up visits. We present four clinical cases of patients visited at the Institut Guttmann clinic between 2017 and 2019. They were affected by mild sequelae of severe and unique TBI who have subsequently developed a neurodegenerative disease without a specific diagnosis, and who could meet clinical criteria for chronic traumatic encephalopathy syndrome. Rehabilitation doctors are the professionals with the greatest possibility of identifying a suggestive clinic of this pathology, they can order the appropriate studies and indicate the new rehabilitation goals according to the new neurological situation.

The burden of unsubstantiated messaging: collegiate athletes' chronic traumatic encephalopathy mechanism beliefs.

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.

Concussion, Chronic Traumatic Encephalopathy, and the Legal Obligation of Sporting Organisations to be Informed of the Scientific Knowledge of the Day and to Warn of Material Risks.

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.