RESUMO
Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy more frequently found in deceased former football players. CTE has heterogeneous clinical presentations with multifactorial causes. Previous literature has shown substance use (alcohol/drug) can contribute to Alzheimer's disease and related tauopathies pathologically and clinically. Objective: To examine the association between substance use and clinical and neuropathological endpoints of CTE. Methods: Our sample included 429 deceased male football players. CTE was neuropathologically diagnosed. Informant interviews assessed features of substance use and history of treatment for substance use to define indicators: history of substance use treatment (yes vs no, primary variable), alcohol severity, and drug severity. Outcomes included scales that were completed by informants to assess cognition (Cognitive Difficulties Scale, BRIEF-A Metacognition Index), mood (Geriatric Depression Scale-15), behavioral regulation (BRIEF-A Behavioral Regulation Index, Barratt Impulsiveness Scale-11), functional ability (Functional Activities Questionnaire), as well as CTE status and cumulative p-tau burden. Regression models tested associations between substance use indicators and outcomes. Results: Of the 429 football players (mean ageâ=â62.07), 313 (73%) had autopsy confirmed CTE and 100 (23%) had substance use treatment history. Substance use treatment and alcohol/drug severity were associated with measures of behavioral regulation (FDR-p-values<0.05, ΔR2â=â0.04-0.18) and depression (FDR-p-values<0.05, ΔR2â=â0.02-0.05). Substance use indicators had minimal associations with cognitive scales, whereas p-tau burden was associated with all cognitive scales (p-values <0.05). Substance use treatment had no associations with neuropathological endpoints (FDR-p-values>0.05). Conclusions: Among deceased football players, substance use was common and associated with clinical symptoms.
Assuntos
Encefalopatia Traumática Crônica , Futebol Americano , Transtornos Relacionados ao Uso de Substâncias , Humanos , Masculino , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Pessoa de Meia-Idade , Futebol Americano/lesões , Encefalopatia Traumática Crônica/patologia , Idoso , Testes Neuropsicológicos , Estados Unidos/epidemiologia , Encéfalo/patologia , Proteínas tau/metabolismoRESUMO
Importance: Exposure to repetitive head impacts (RHI) is associated with increased risk for neurodegeneration. Accumulation of toxic proteins due to impaired brain clearance is suspected to play a role. Objective: To investigate whether perivascular space (PVS) volume is associated with lifetime exposure to RHI in individuals at risk for RHI-associated neurodegeneration. Design, Setting, and Participants: This cross-sectional study was part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project, a 7-year multicenter study consisting of 4 US study sites. Data were collected from September 2016 to February 2020 and analyses were performed between May 2021 and October 2023. After controlling for magnetic resonance image (MRI) and processing quality, former American football players and unexposed asymptomatic control participants were included in analyses. Exposure: Prior exposure to RHI while participating in American football was estimated using the 3 cumulative head impact indices (CHII-G, linear acceleration; CHII-R, rotational acceleration; and CHII, number of head impacts). Main Outcomes and Measures: Individual PVS volume was calculated in the white matter of structural MRI. Cognitive impairment was based on neuropsychological assessment. Linear regression models were used to assess associations of PVS volume with neuropsychological assessments in former American football players. All analyses were adjusted for confounders associated with PVS volume. Results: Analyses included 224 participants (median [IQR] age, 57 [51-65] years), with 170 male former football players (114 former professional athletes, 56 former collegiate athletes) and 54 male unexposed control participants. Former football players had larger PVS volume compared with the unexposed group (mean difference, 0.28 [95% CI, 0.00-0.56]; P = .05). Within the football group, PVS volume was associated with higher CHII-R (ß = 2.71 × 10-8 [95% CI, 0.50 × 10-8 to 4.93 × 10-8]; P = .03) and CHII-G (ß = 2.24 × 10-6 [95% CI, 0.35 × 10-6 to 4.13 × 10-6]; P = .03). Larger PVS volume was also associated with worse performance on cognitive functioning in former American football players (ß = -0.74 [95% CI, -1.35 to -0.13]; P = .04). Conclusions and Relevance: These findings suggest that impaired perivascular brain clearance, as indicated by larger PVS volume, may contribute to the association observed between RHI exposure and neurodegeneration.
Assuntos
Futebol Americano , Imageamento por Ressonância Magnética , Humanos , Masculino , Estudos Transversais , Futebol Americano/lesões , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética/métodos , Estados Unidos , Sistema Glinfático/diagnóstico por imagem , Concussão Encefálica/diagnóstico por imagem , Concussão Encefálica/fisiopatologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Adulto , Idoso , Encefalopatia Traumática Crônica/patologia , Encefalopatia Traumática Crônica/diagnóstico por imagemRESUMO
The history behind the biological, mechanistic, and clinical insights into concussion provides awareness of the current understanding and future areas for study. Although the initial description of concussion appeared in the 10th century, the potential long-term structural consequences were first defined by Harrison Martland, M.D., who performed a postmortem study of former boxers in 1928. He found evidence of perivascular microhemorrhage that he believed eventually evolved into a "replacement gliosis" underlying a clinical syndrome that he named "punch drunk," which was characterized by acute confusion with chronic cognitive and physical symptoms developing in those with prolonged exposure. Further research into the potential long-term consequences of repetitive concussions, particularly in athletics and the military, led to an understanding of chronic traumatic encephalopathy. To ameliorate possible long-term risks, research has been focused on preventative and therapeutic measures for concussion. In this review article, the authors present the history of concussion and the long-term sequelae of repeated head injury. Specifically, they consider how the understanding of concussion has evolved from antiquity into the modern era, and how this change in understanding of head injury has led to an appreciation of the fact that its long-term implications sometimes manifest as the clinical and histopathological entity of chronic traumatic encephalopathy.
Assuntos
Concussão Encefálica , Humanos , Concussão Encefálica/história , História do Século XX , História do Século XIX , História do Século XVIII , História Medieval , História do Século XVII , História do Século XVI , História do Século XXI , História Antiga , Traumatismos em Atletas/história , Encefalopatia Traumática Crônica/história , Encefalopatia Traumática Crônica/patologia , História do Século XVRESUMO
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 (ß, 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.
Assuntos
Encefalopatia Traumática Crônica , Transtornos Parkinsonianos , Substância Negra , Humanos , Encefalopatia Traumática Crônica/patologia , Encefalopatia Traumática Crônica/etiologia , Masculino , Substância Negra/patologia , Pessoa de Meia-Idade , Estudos Transversais , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/epidemiologia , Transtornos Parkinsonianos/etiologia , Feminino , Idoso , Adulto , Emaranhados Neurofibrilares/patologia , Traumatismos em Atletas/complicações , Traumatismos em Atletas/patologia , Corpos de Lewy/patologia , EsportesRESUMO
Dominantly inherited mutation D395G in the gene encoding valosin-containing protein causes vacuolar tauopathy, a type of behavioural-variant frontotemporal dementia, with marked vacuolation and abundant filamentous tau inclusions made of all six brain isoforms. Here we report that tau inclusions were concentrated in layers II/III of the frontotemporal cortex in a case of vacuolar tauopathy. By electron cryomicroscopy, tau filaments had the chronic traumatic encephalopathy (CTE) fold. Tau inclusions of vacuolar tauopathy share this cortical location and the tau fold with CTE, subacute sclerosing panencephalitis and amyotrophic lateral sclerosis/parkinsonism-dementia complex, which are believed to be environmentally induced. Vacuolar tauopathy is the first inherited disease with the CTE tau fold.
Assuntos
Encefalopatia Traumática Crônica , Mutação , Tauopatias , Proteína com Valosina , Proteínas tau , Humanos , Tauopatias/genética , Tauopatias/patologia , Encefalopatia Traumática Crônica/patologia , Encefalopatia Traumática Crônica/genética , Proteínas tau/genética , Proteínas tau/metabolismo , Proteína com Valosina/genética , Vacúolos/patologia , Vacúolos/ultraestrutura , Masculino , Adenosina Trifosfatases/genética , Proteínas de Ciclo Celular/genética , Pessoa de Meia-Idade , Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Encéfalo/patologia , FemininoRESUMO
This editorial investigates chronic traumatic encephalopathy (CTE) as a course of Alzheimer's disease (AD). CTE is a debilitating neurodegenerative disease that is the result of repeated mild traumatic brain injury (TBI). Many epidemiological studies show that experiencing a TBI in early or middle life is associated with an increased risk of dementia later in life. Chronic traumatic encephalopathy (CTE) and Alzheimer's disease (AD) present a series of similar neuropathological features that were investigated in this work like recombinant tau into filaments or the accumulation and aggregation of Aß protein. However, these two conditions differ from each other in brain-blood barrier damage. The purpose of this review was to evaluate information about CTE and AD from various articles, focusing especially on new therapeutic possibilities for the improvement in cognitive skills.
Assuntos
Doença de Alzheimer , Encefalopatia Traumática Crônica , Humanos , Doença de Alzheimer/complicações , Doença de Alzheimer/patologia , Doença de Alzheimer/etiologia , Encefalopatia Traumática Crônica/patologia , Encefalopatia Traumática Crônica/complicações , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologiaRESUMO
Chronic traumatic encephalopathy (CTE) is defined by perivascular neuronal phosphorylated-tau accumulation at cortical sulcal depths. CTE has been mainly described in the context of repetitive, impact-type traumatic brain injury (rTBI), principally from contact sports. Rarely, CTE has been associated with single TBIs, including in relationship to healed leucotomy sites in brains from formerly institutionalized psychiatric patients without documented rTBI. Given that leucotomy principally involves severing of white matter, this could suggest involvement of axonal injury in CTE pathophysiology. We present three cases wherein isolated CTE pathology was identified adjacent to distinct white matter lesions. Case 1 is a 41-year-old man with history of hereditary hemorrhagic telangiectasia and resection of a cerebral arteriovenous malformation (AVM). Case 2 is a 46-year-old man with glioblastoma. Case 3 is a 52-year-old man with a remote cerebral infarct. Isolated CTE lesions were found adjacent to the aforementioned pathologies in each case. Additional CTE lesions were not identified despite extensive sampling. Multiple age-related tau astrogliopathy (ARTAG)-like lesions were also identified at other sulcal depths near the AVM resection site in Case 1. These cases may provide insights regarding the pathophysiology of the CTE pathognomonic lesion and the development of ARTAG-like pathology adjacent to long-standing mass lesions.
Assuntos
Encefalopatia Traumática Crônica , Substância Branca , Humanos , Masculino , Pessoa de Meia-Idade , Substância Branca/patologia , Substância Branca/diagnóstico por imagem , Encefalopatia Traumática Crônica/patologia , Adulto , Encéfalo/patologia , Encéfalo/diagnóstico por imagemRESUMO
Exposure to repetitive head impacts in contact sports is associated with neurodegenerative disorders including chronic traumatic encephalopathy (CTE), which currently can be diagnosed only at post-mortem. American football players are at higher risk of developing CTE given their exposure to repetitive head impacts. One promising approach for diagnosing CTE in vivo is to explore known neuropathological abnormalities at post-mortem in living individuals using structural MRI. MRI brain morphometry was evaluated in 170 male former American football players ages 45-74 years (n = 114 professional; n = 56 college) and 54 same-age unexposed asymptomatic male controls (n = 54, age range 45-74). Cortical thickness and volume of regions of interest were selected based on established CTE pathology findings and were assessed using FreeSurfer. Group differences and interactions with age and exposure factors were evaluated using a generalized least squares model. A separate logistic regression and independent multinomial model were performed to predict each traumatic encephalopathy syndrome (TES) diagnosis, core clinical features and provisional level of certainty for CTE pathology using brain regions of interest. Former college and professional American football players (combined) showed significant cortical thickness and/or volume reductions compared to unexposed asymptomatic controls in the hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, insula, temporal pole and superior frontal gyrus. Post hoc analyses identified group-level differences between former professional players and unexposed asymptomatic controls in the hippocampus, amygdala, entorhinal cortex, parahippocampal gyrus, insula and superior frontal gyrus. Former college players showed significant volume reductions in the hippocampus, amygdala and superior frontal gyrus compared to the unexposed asymptomatic controls. We did not observe Age × Group interactions for brain morphometric measures. Interactions between morphometry and exposure measures were limited to a single significant positive association between the age of first exposure to organized tackle football and right insular volume. We found no significant relationship between brain morphometric measures and the TES diagnosis core clinical features and provisional level of certainty for CTE pathology outcomes. These findings suggested that MRI morphometrics detect abnormalities in individuals with a history of repetitive head impact exposure that resemble the anatomic distribution of pathological findings from post-mortem CTE studies. The lack of findings associating MRI measures with exposure metrics (except for one significant relationship) or TES diagnosis and core clinical features suggested that brain morphometry must be complemented by other types of measures to characterize individuals with repetitive head impacts.
Assuntos
Encéfalo , Encefalopatia Traumática Crônica , Futebol Americano , Imageamento por Ressonância Magnética , Humanos , Masculino , Pessoa de Meia-Idade , Futebol Americano/lesões , Idoso , Encefalopatia Traumática Crônica/patologia , Encefalopatia Traumática Crônica/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Estados UnidosAssuntos
Encefalopatia Traumática Crônica , Humanos , Encefalopatia Traumática Crônica/patologia , Encefalopatia Traumática Crônica/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Adulto , Feminino , Estudos Longitudinais , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , IdosoRESUMO
Repetitive head impacts (RHIs) from football are associated with the neurodegenerative tauopathy chronic traumatic encephalopathy (CTE). It is unclear whether a history of traumatic brain injury (TBI) is sufficient to precipitate CTE neuropathology. We examined the association between TBI and CTE neuropathology in 580 deceased individuals exposed to RHIs from football. TBI history was assessed using a modified version of the Ohio State University TBI Identification Method Short Form administered to informants. There were 22 donors who had no TBI, 213 who had at least one TBI without loss of consciousness (LOC), 345 who had TBI with LOC, and, of those with a history of TBI with LOC, 36 who had at least one moderate-to-severe TBI (msTBI, LOC >30 min). CTE neuropathology was diagnosed in 405. There was no association between CTE neuropathology status or severity and TBI with LOC (odds ratio [OR] = 0.95, 95% confidence interval [CI] = 0.64-1.41; OR = 1.22, 95% CI = 0.71-2.09) or msTBI (OR = 0.70, 95% CI = 0.33-1.50; OR = 1.01, 95% CI = 0.30-3.41). There were no associations with other neurodegenerative or cerebrovascular pathologies examined. TBI with LOC and msTBI were not associated with CTE neuropathology in this sample of brain donors exposed to RHIs from American football.
Assuntos
Lesões Encefálicas Traumáticas , Encefalopatia Traumática Crônica , Humanos , Masculino , Encefalopatia Traumática Crônica/patologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/patologia , Feminino , Pessoa de Meia-Idade , Adulto , Idoso , Futebol Americano/lesões , Idoso de 80 Anos ou mais , Adulto JovemRESUMO
This study examined the frequency of chronic traumatic encephalopathy-neuropathologic change (CTE-NC) and aging-related tau astrogliopathy (ARTAG) in community-dwelling older adults and tested the hypothesis that these tau pathologies are associated with a history of moderate-to-severe traumatic brain injury (msTBI), defined as a TBI with loss of consciousness >30 minutes. We evaluated CTE-NC, ARTAG, and Alzheimer disease pathologies in 94 participants with msTBI and 94 participants without TBI matched by age, sex, education, and dementia status TBI from the Rush community-based cohorts. Six (3%) of brains showed the pathognomonic lesion of CTE-NC; only 3 of these had a history of msTBI. In contrast, ARTAG was common in older brains (gray matter ARTAG = 77%; white matter ARTAG = 54%; subpial ARTAG = 51%); there were no differences in severity, type, or distribution of ARTAG pathology with respect to history of msTBI. Furthermore, those with msTBI did not have higher levels of PHF-tau tangles density but had higher levels of amyloid-ß load (Estimate = 0.339, SE = 0.164, p = 0.040). These findings suggest that CTE-NC is infrequent while ARTAG is common in the community and that both pathologies are unrelated to msTBI. The association of msTBI with amyloid-ß, rather than with tauopathies suggests differential mechanisms of neurodegeneration in msTBI.
Assuntos
Doença de Alzheimer , Lesões Encefálicas Traumáticas , Encefalopatia Traumática Crônica , Humanos , Idoso , Idoso de 80 Anos ou mais , Encefalopatia Traumática Crônica/patologia , Vida Independente , Astrócitos/patologia , Proteínas tau/metabolismo , Envelhecimento/patologia , Encéfalo/patologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/patologia , Doença de Alzheimer/patologia , Peptídeos beta-AmiloidesRESUMO
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.
Assuntos
Lesões Encefálicas Traumáticas , Encefalopatia Traumática Crônica , Humanos , Autofagossomos/metabolismo , Autofagossomos/patologia , Lesões Encefálicas Traumáticas/complicações , Encefalopatia Traumática Crônica/etiologia , Encefalopatia Traumática Crônica/patologia , Autofagia , Lisossomos/metabolismoRESUMO
BACKGROUND AND PURPOSE: Chronic traumatic encephalopathy (CTE) has gained widespread attention due to its association with multiple concussions and contact sports. However, CTE remains a postmortem diagnosis, and the link between clinical symptoms and CTE pathology is poorly understood. This study aimed to investigate the presence of copathologies and their impact on symptoms in former contact sports athletes. METHODS: This was a retrospective case series design of 12 consecutive cases of former contact sports athletes referred for autopsy. Analyses are descriptive and include clinical history as well as the pathological findings of the autopsied brains. RESULTS: All participants had a history of multiple concussions, and all but one had documented progressive cognitive, psychiatric, and/or motor symptoms. The results showed that 11 of the 12 participants had evidence of CTE in the brain, but also other copathologies, including different combinations of tauopathies, and other rare entities. CONCLUSIONS: The heterogeneity of symptoms after repetitive head injuries and the diverse pathological combinations accompanying CTE complicate the prediction of CTE in clinical practice. It is prudent to consider the possibility of multiple copathologies when clinically assessing patients with repetitive head injuries, especially as they age, and attributing neurological or cognitive symptoms solely to presumptive CTE in elderly patients should be discouraged.
Assuntos
Encefalopatia Traumática Crônica , Humanos , Encefalopatia Traumática Crônica/patologia , Encefalopatia Traumática Crônica/complicações , Masculino , Estudos Retrospectivos , Pessoa de Meia-Idade , Feminino , Idoso , Adulto , Traumatismos em Atletas/complicações , Concussão Encefálica/complicações , Concussão Encefálica/patologia , Atletas , Doenças Neurodegenerativas/patologia , Doenças Neurodegenerativas/complicações , Encéfalo/patologia , Encéfalo/diagnóstico por imagemRESUMO
BACKGROUND: Traumatic encephalopathy syndrome (TES) is defined as the clinical manifestation of the neuropathological entity chronic traumatic encephalopathy (CTE). A core feature of TES is neurobehavioral dysregulation (NBD), a neuropsychiatric syndrome in repetitive head impact (RHI)-exposed individuals, characterized by a poor regulation of emotions/behavior. To discover biological correlates for NBD, we investigated the association between biomarkers of inflammation (interleukin (IL)-1ß, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) in cerebrospinal fluid (CSF) and NBD symptoms in former American football players and unexposed individuals. METHODS: Our cohort consisted of former American football players, with (n = 104) or without (n = 76) NBD diagnosis, as well as asymptomatic unexposed individuals (n = 55) from the DIAGNOSE CTE Research Project. Specific measures for NBD were derived (i.e., explosivity, emotional dyscontrol, impulsivity, affective lability, and a total NBD score) from a factor analysis of multiple self-report neuropsychiatric measures. Analyses of covariance tested differences in biomarker concentrations between the three groups. Within former football players, multivariable linear regression models assessed relationships among log-transformed inflammatory biomarkers, proxies for RHI exposure (total years of football, cumulative head impact index), and NBD factor scores, adjusted for relevant confounding variables. Sensitivity analyses tested (1) differences in age subgroups (< 60, ≥ 60 years); (2) whether associations could be identified with plasma inflammatory biomarkers; (3) associations between neurodegeneration and NBD, using plasma neurofilament light (NfL) chain protein; and (4) associations between biomarkers and cognitive performance to explore broader clinical symptoms related to TES. RESULTS: CSF IL-6 was higher in former American football players with NBD diagnosis compared to players without NBD. Furthermore, elevated levels of CSF IL-6 were significantly associated with higher emotional dyscontrol, affective lability, impulsivity, and total NBD scores. In older football players, plasma NfL was associated with higher emotional dyscontrol and impulsivity, but also with worse executive function and processing speed. Proxies for RHI exposure were not significantly associated with biomarker concentrations. CONCLUSION: Specific NBD symptoms in former American football players may result from multiple factors, including neuroinflammation and neurodegeneration. Future studies need to unravel the exact link between NBD and RHI exposure, including the role of other pathophysiological pathways.
Assuntos
Lesões Encefálicas Traumáticas , Encefalopatia Traumática Crônica , Futebol Americano , Humanos , Idoso , Pessoa de Meia-Idade , Encefalopatia Traumática Crônica/patologia , Interleucina-6 , BiomarcadoresRESUMO
BACKGROUND: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by hyperphosphorylated tau (p-tau) accumulation. The clinical features associated with CTE pathology are unclear. In brain donors with autopsy-confirmed CTE, we investigated the association of CTE p-tau pathology density and location with cognitive, functional, and neuropsychiatric symptoms. METHODS: In 364 brain donors with autopsy confirmed CTE, semi-quantitative p-tau severity (range: 0-3) was assessed in 10 cortical and subcortical regions. We summed ratings across regions to form a p-tau severity global composite (range: 0-30). Informants completed standardized scales of cognition (Cognitive Difficulties Scale, CDS; BRIEF-A Metacognition Index, MI), activities of daily living (Functional Activities Questionnaire), neurobehavioral dysregulation (BRIEF-A Behavioral Regulation Index, BRI; Barratt Impulsiveness Scale, BIS-11), aggression (Brown-Goodwin Aggression Scale), depression (Geriatric Depression Scale-15, GDS-15), and apathy (Apathy Evaluation Scale, AES). Ordinary least squares regression models examined associations between global and regional p-tau severity (separate models for each region) with each clinical scale, adjusting for age at death, racial identity, education level, and history of hypertension, obstructive sleep apnea, and substance use treatment. Ridge regression models that incorporated p-tau severity across all regions in the same model assessed which regions showed independent effects. RESULTS: The sample was predominantly American football players (333; 91.2%); 140 (38.5%) had low CTE and 224 (61.5%) had high CTE. Global p-tau severity was associated with higher (i.e., worse) scores on the cognitive and functional scales: MI ([Formula: see text] standardized = 0.02, 95%CI = 0.01-0.04), CDS ([Formula: see text] standardized = 0.02, 95%CI = 0.01-0.04), and FAQ ([Formula: see text] standardized = 0.03, 95%CI = 0.01-0.04). After false-discovery rate correction, p-tau severity in the frontal, inferior parietal, and superior temporal cortex, and the amygdala was associated with higher CDS ([Formula: see text] sstandardized = 0.17-0.29, ps < 0.01) and FAQ ([Formula: see text] sstandardized = 0.21-0.26, ps < 0.01); frontal and inferior parietal cortex was associated with higher MI ([Formula: see text] sstandardized = 0.21-0.29, ps < 0.05); frontal cortex was associated with higher BRI ([Formula: see text] standardized = 0.21, p < 0.01). Regions with effects independent of other regions included frontal cortex (CDS, MI, FAQ, BRI), inferior parietal cortex (CDS) and amygdala (FAQ). P-tau explained 13-49% of variance in cognitive and functional scales and 6-14% of variance in neuropsychiatric scales. CONCLUSION: Accumulation of p-tau aggregates, especially in the frontal cortex, are associated with cognitive, functional, and certain neurobehavioral symptoms in CTE.
Assuntos
Encefalopatia Traumática Crônica , Doenças Neurodegenerativas , Humanos , Atividades Cotidianas , Autopsia , Encéfalo/metabolismo , Encefalopatia Traumática Crônica/patologia , Cognição , Doenças Neurodegenerativas/patologia , Proteínas tau/metabolismoRESUMO
OBJECTIVE: Exposure to repetitive sports-related concussions or (sub)concussive head trauma may lead to chronic traumatic encephalopathy (CTE). Which impact (heading or concussion) poses the greatest risk of CTE development in soccer players? DESIGN: Narrative review. SETTING: Teaching hospital and University of Applied sciences. PATIENTS: A literature search (PubMed) was conducted for neuropathologic studies in the period 2005-December 2022, investigating soccer players with dementia and a CTE diagnosis, limited to English language publications. 210 papers were selected for final inclusion, of which 7 papers described 14 soccer players. ASSESSMENT: Magnetic resonance imaging studies in soccer players show that lifetime estimates of heading numbers are inversely correlated with cortical thickness, grey matter volume, and density of the anterior temporal cortex. Using diffusion tensor imaging-magnetic resonance imaging, higher frequency of headings-particularly with rotational accelerations-are associated with impaired white matter integrity. Serum neurofilament light protein is elevated after heading. MAIN OUTCOME MEASURES: Chronic traumatic encephalopathy pathology, history of concussion, heading frequency. RESULTS: In 10 of 14 soccer players, CTE was the primary diagnosis. In 4 cases, other dementia types formed the primary diagnosis and CTE pathology was a concomitant finding. Remarkably, 6 of the 14 cases had no history of concussion, suggesting that frequent heading may be a risk for CTE in patients without symptomatic concussion. Rule changes in heading duels, management of concussion during the game, and limiting the number of high force headers during training are discussed. CONCLUSIONS: Data suggest that heading frequency and concussions are associated with higher risk of developing CTE in (retired) soccer players. However based on this review of only 14 players, questions persist as to whether or not heading is a risk factor for CTE or long-term cognitive decline.
Assuntos
Concussão Encefálica , Encefalopatia Traumática Crônica , Demência , Futebol , Humanos , Encefalopatia Traumática Crônica/patologia , Futebol/lesões , Imagem de Tensor de Difusão/efeitos adversos , Concussão Encefálica/diagnóstico , Demência/complicaçõesRESUMO
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.
Assuntos
Traumatismos em Atletas , Encefalopatia Traumática Crônica , Doenças Neurodegenerativas , Humanos , Encefalopatia Traumática Crônica/diagnóstico , Encefalopatia Traumática Crônica/etiologia , Encefalopatia Traumática Crônica/patologia , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/patologia , Traumatismos em Atletas/complicações , Traumatismos em Atletas/patologia , Encéfalo/patologia , CogniçãoRESUMO
OBJECTIVE: Exposure to repetitive head impacts (RHI) is associated with later-life cognitive symptoms and neuropathologies, including chronic traumatic encephalopathy (CTE). Cognitive decline in community cohorts is often due to multiple pathologies; however, the frequency and contributions of these pathologies to cognitive impairment in people exposed to RHI are unknown. Here, we examined the relative contributions of 13 neuropathologies to cognitive symptoms and dementia in RHI-exposed brain donors. METHODS: Neuropathologists examined brain tissue from 571 RHI-exposed donors and assessed for the presence of 13 neuropathologies, including CTE, Alzheimer disease (AD), Lewy body disease (LBD), and transactive response DNA-binding protein 43 (TDP-43) inclusions. Cognitive status was assessed by presence of dementia, Functional Activities Questionnaire, and Cognitive Difficulties Scale. Spearman rho was calculated to assess intercorrelation of pathologies. Additionally, frequencies of pathological co-occurrence were compared to a simulated distribution assuming no intercorrelation. Logistic and linear regressions tested associations between neuropathologies and dementia status and cognitive scale scores. RESULTS: The sample age range was 18-97 years (median = 65.0, interquartile range = 46.0-76.0). Of the donors, 77.2% had at least one moderate-severe neurodegenerative or cerebrovascular pathology. Stage III-IV CTE was the most common neurodegenerative disease (43.1%), followed by TDP-43 pathology, AD, and hippocampal sclerosis. Neuropathologies were intercorrelated, and there were fewer unique combinations than expected if pathologies were independent (p < 0.001). The greatest contributors to dementia were AD, neocortical LBD, hippocampal sclerosis, cerebral amyloid angiopathy, and CTE. INTERPRETATION: In this sample of RHI-exposed brain donors with wide-ranging ages, multiple neuropathologies were common and correlated. Mixed neuropathologies, including CTE, underlie cognitive impairment in contact sport athletes. ANN NEUROL 2024;95:314-324.