RESUMO
Hippocampal sclerosis (HS) is associated with advanced age as well as transactive response DNA-binding protein with 43 kDa (TDP-43) deposits. Both hippocampal sclerosis and TDP-43 proteinopathy have also been described in chronic traumatic encephalopathy (CTE), a neurodegenerative disease linked to exposure to repetitive head impacts (RHI). However, the prevalence of HS in CTE, the pattern of TDP-43 pathology, and associations of HS and TDP-43 with RHI are unknown. A group of participants with a history of RHI and CTE at autopsy (n = 401) as well as a group with HS-aging without CTE (n = 33) was examined to determine the prevalence of HS and TDP-43 inclusions in CTE and to compare the clinical and pathological features of HS and TDP-43 inclusions in CTE to HS-aging. In CTE, HS was present in 23.4%, and TDP-43 inclusions were present in 43.3% of participants. HS in CTE occurred at a relatively young age (mean 77.0 years) and was associated with a greater number of years of RHI than CTE without HS adjusting for age (p = 0.029). In CTE, TDP-43 inclusions occurred frequently in the frontal cortex and occurred both with and without limbic TDP-43. Additionally, structural equation modeling demonstrated that RHI exposure years were associated with hippocampal TDP-43 inclusions (p < 0.001) through increased CTE stage (p < 0.001). Overall, RHI and the development of CTE pathology may contribute to TDP-43 deposition and hippocampal sclerosis.
Assuntos
Encefalopatia Traumática Crônica , Esclerose Hipocampal , Doenças Neurodegenerativas , Proteinopatias TDP-43 , Humanos , Idoso , Encefalopatia Traumática Crônica/patologia , Envelhecimento , Proteinopatias TDP-43/patologia , Proteínas de Ligação a DNA/metabolismoRESUMO
Probable rapid eye movement (REM) sleep behavior disorder (pRBD) is a synucleinopathy-associated parasomnia in which loss of REM sleep muscle atonia results in motor behavior during REM sleep, including dream enactment. Traumatic brain injury is independently associated with increased risk of pRBD and Lewy body disease, and both pRBD and Lewy body disease are often observed in chronic traumatic encephalopathy (CTE). However, the frequency and pathological substrate of pRBD in CTE have not been formally studied and remain unknown. Of the total sample of 247 men, age at death of 63.1 ± 18.8 years (mean ± SD), 80 [32%] were determined by informant report to have symptoms of pRBD. These participants had played more years of contact sports (18.3 ± 11.4) than those without pRBD (15.1 ± 6.5; P = 0.02) and had an increased frequency of Lewy body disease (26/80 [33%] vs 28/167 [17%], P = 0.005). Of the 80 participants with pRBD, 54 [68%] did not have Lewy body disease; these participants were more likely to have neurofibrillary tangles and pretangles in the dorsal and median raphe (41 of 49 [84%] non-LBD participants with pRBD symptoms vs 90 of 136 [66%] non-LBD participants without pRBD symptoms, P = 0.02), brainstem nuclei with sleep regulatory function. Binary logistic regression modeling in the total study sample showed that pRBD in CTE was associated with dorsal and median raphe nuclei neurofibrillary tangles (OR = 3.96, 95% CI [1.43, 10.96], P = 0.008), Lewy body pathology (OR = 2.36, 95% CI [1.18, 4.72], P = 0.02), and years of contact sports participation (OR = 1.04, 95% CI [1.00, 1.08], P = 0.04). Overall, pRBD in CTE is associated with increased years of contact sports participation and may be attributable to Lewy body and brainstem tau pathologies.
Assuntos
Encefalopatia Traumática Crônica/patologia , Doença por Corpos de Lewy/patologia , Emaranhados Neurofibrilares/patologia , Transtorno do Comportamento do Sono REM/etiologia , Transtorno do Comportamento do Sono REM/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Encefalopatia Traumática Crônica/complicações , Humanos , Corpos de Lewy/patologia , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Transtorno do Comportamento do Sono REM/diagnósticoRESUMO
The Wnt receptor Ryk is an evolutionary-conserved protein important during neuronal differentiation through several mechanisms, including γ-secretase cleavage and nuclear translocation of its intracellular domain (Ryk-ICD). Although the Wnt pathway may be neuroprotective, the role of Ryk in neurodegenerative disease remains unknown. We found that Ryk is up-regulated in neurons expressing mutant huntingtin (HTT) in several models of Huntington's disease (HD). Further investigation in Caenorhabditis elegans and mouse striatal cell models of HD provided a model in which the early-stage increase of Ryk promotes neuronal dysfunction by repressing the neuroprotective activity of the longevity-promoting factor FOXO through a noncanonical mechanism that implicates the Ryk-ICD fragment and its binding to the FOXO co-factor ß-catenin. The Ryk-ICD fragment suppressed neuroprotection by lin-18/Ryk loss-of-function in expanded-polyQ nematodes, repressed FOXO transcriptional activity, and abolished ß-catenin protection of mutant htt striatal cells against cell death vulnerability. Additionally, Ryk-ICD was increased in the nucleus of mutant htt cells, and reducing γ-secretase PS1 levels compensated for the cytotoxicity of full-length Ryk in these cells. These findings reveal that the Ryk-ICD pathway may impair FOXO protective activity in mutant polyglutamine neurons, suggesting that neurons are unable to efficiently maintain function and resist disease from the earliest phases of the pathogenic process in HD.
Assuntos
Fatores de Transcrição Forkhead/metabolismo , Doença de Huntington/etiologia , Neurônios/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Wnt/metabolismo , Idoso , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Linhagem Celular , Feminino , Humanos , Doença de Huntington/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Presenilina-1/metabolismo , Receptores Proteína Tirosina Quinases/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Via de Sinalização WntRESUMO
Importance: Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE). Objective: To determine the neuropathological and clinical features of deceased football players with CTE. Design, Setting, and Participants: Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history. Exposures: Participation in American football at any level of play. Main Outcomes and Measures: Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia. Results: Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47-76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre-high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia. Conclusions and Relevance: In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football.
Assuntos
Traumatismos em Atletas/patologia , Encéfalo/patologia , Encefalopatia Traumática Crônica/patologia , Futebol Americano/lesões , Adulto , Idoso , Atletas , Traumatismos em Atletas/complicações , Concussão Encefálica/epidemiologia , Causas de Morte , Encefalopatia Traumática Crônica/diagnóstico , Encefalopatia Traumática Crônica/etiologia , Transtornos Cognitivos/etiologia , Humanos , Masculino , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Transtornos Relacionados ao Uso de Substâncias/etiologia , Estados Unidos , Proteínas tau/análiseRESUMO
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder linked to repetitive traumatic brain injury (TBI) and characterized by deposition of hyperphosphorylated tau at the depths of sulci. We sought to determine the presence of CTE pathology in a brain bank for neurodegenerative disorders for individuals with and without a history of contact sports participation. Available medical records of 1721 men were reviewed for evidence of past history of injury or participation in contact sports. Subsequently, cerebral cortical samples were processed for tau immunohistochemistry in cases with a documented history of sports exposure as well as age- and disease-matched men and women without such exposure. For cases with available frozen tissue, genetic analysis was performed for variants in APOE, MAPT, and TMEM106B. Immunohistochemistry revealed 21 of 66 former athletes had cortical tau pathology consistent with CTE. CTE pathology was not detected in 198 individuals without exposure to contact sports, including 33 individuals with documented single-incident TBI sustained from falls, motor vehicle accidents, domestic violence, or assaults. Among those exposed to contact sports, those with CTE pathology did not differ from those without CTE pathology with respect to noted clinicopathologic features. There were no significant differences in genetic variants for those with CTE pathology, but we observed a slight increase in MAPT H1 haplotype, and there tended to be fewer homozygous carriers of the protective TMEM106B rs3173615 minor allele in those with sports exposure and CTE pathology compared to those without CTE pathology. In conclusion, this study has identified a small, yet significant, subset of individuals with neurodegenerative disorders and concomitant CTE pathology. CTE pathology was only detected in individuals with documented participation in contact sports. Exposure to contact sports was the greatest risk factor for CTE pathology. Future studies addressing clinical correlates of CTE pathology are needed.
Assuntos
Lesão Encefálica Crônica/etiologia , Lesão Encefálica Crônica/patologia , Encéfalo/patologia , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/patologia , Idoso , Apolipoproteínas E/genética , Traumatismos em Atletas/complicações , Traumatismos em Atletas/genética , Traumatismos em Atletas/metabolismo , Traumatismos em Atletas/patologia , Encéfalo/metabolismo , Lesão Encefálica Crônica/genética , Lesão Encefálica Crônica/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Estudos Retrospectivos , Bancos de Tecidos , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive mild traumatic brain injury. It is defined pathologically by the abnormal accumulation of tau in a unique pattern that is distinct from other tauopathies, including Alzheimer's disease (AD). Although trauma has been suggested to increase amyloid ß peptide (Aß) levels, the extent of Aß deposition in CTE has not been thoroughly characterized. We studied a heterogeneous cohort of deceased athletes and military veterans with neuropathologically diagnosed CTE (n = 114, mean age at death = 60) to test the hypothesis that Aß deposition is altered in CTE and associated with more severe pathology and worse clinical outcomes. We found that Aß deposition, either as diffuse or neuritic plaques, was present in 52 % of CTE subjects. Moreover, Aß deposition in CTE occurred at an accelerated rate and with altered dynamics in CTE compared to a normal aging population (OR = 3.8, p < 0.001). We also found a clear pathological and clinical dichotomy between those CTE cases with Aß plaques and those without. Aß deposition was significantly associated with the presence of the APOE ε4 allele (p = 0.035), older age at symptom onset (p < 0.001), and older age at death (p < 0.001). In addition, when controlling for age, neuritic plaques were significantly associated with increased CTE tauopathy stage (ß = 2.43, p = 0.018), co-morbid Lewy body disease (OR = 5.01, p = 0.009), and dementia (OR = 4.45, p = 0.012). A subset of subjects met the diagnostic criteria for both CTE and AD, and in these subjects both Aß plaques and total levels of Aß1-40 were increased at the depths of the cortical sulcus compared to the gyral crests. Overall, these findings suggest that Aß deposition is altered and accelerated in a cohort of CTE subjects compared to normal aging and that Aß is associated with both pathological and clinical progression of CTE independent of age.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Lesão Encefálica Crônica/patologia , Encéfalo/patologia , Doenças Neurodegenerativas/patologia , Proteínas tau/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/genética , Atletas , Traumatismos em Atletas/epidemiologia , Traumatismos em Atletas/genética , Traumatismos em Atletas/metabolismo , Traumatismos em Atletas/patologia , Encéfalo/metabolismo , Lesão Encefálica Crônica/epidemiologia , Lesão Encefálica Crônica/genética , Lesão Encefálica Crônica/metabolismo , Estudos de Coortes , Comorbidade , Humanos , Pessoa de Meia-Idade , Doenças Neurodegenerativas/epidemiologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Placa Amiloide/etiologia , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Índice de Gravidade de Doença , Veteranos , Lesões Relacionadas à Guerra/epidemiologia , Lesões Relacionadas à Guerra/genética , Lesões Relacionadas à Guerra/metabolismo , Lesões Relacionadas à Guerra/patologiaRESUMO
Chronic traumatic encephalopathy is a progressive tauopathy that occurs as a consequence of repetitive mild traumatic brain injury. We analysed post-mortem brains obtained from a cohort of 85 subjects with histories of repetitive mild traumatic brain injury and found evidence of chronic traumatic encephalopathy in 68 subjects: all males, ranging in age from 17 to 98 years (mean 59.5 years), including 64 athletes, 21 military veterans (86% of whom were also athletes) and one individual who engaged in self-injurious head banging behaviour. Eighteen age- and gender-matched individuals without a history of repetitive mild traumatic brain injury served as control subjects. In chronic traumatic encephalopathy, the spectrum of hyperphosphorylated tau pathology ranged in severity from focal perivascular epicentres of neurofibrillary tangles in the frontal neocortex to severe tauopathy affecting widespread brain regions, including the medial temporal lobe, thereby allowing a progressive staging of pathology from stages I-IV. Multifocal axonal varicosities and axonal loss were found in deep cortex and subcortical white matter at all stages of chronic traumatic encephalopathy. TAR DNA-binding protein 43 immunoreactive inclusions and neurites were also found in 85% of cases, ranging from focal pathology in stages I-III to widespread inclusions and neurites in stage IV. Symptoms in stage I chronic traumatic encephalopathy included headache and loss of attention and concentration. Additional symptoms in stage II included depression, explosivity and short-term memory loss. In stage III, executive dysfunction and cognitive impairment were found, and in stage IV, dementia, word-finding difficulty and aggression were characteristic. Data on athletic exposure were available for 34 American football players; the stage of chronic traumatic encephalopathy correlated with increased duration of football play, survival after football and age at death. Chronic traumatic encephalopathy was the sole diagnosis in 43 cases (63%); eight were also diagnosed with motor neuron disease (12%), seven with Alzheimer's disease (11%), 11 with Lewy body disease (16%) and four with frontotemporal lobar degeneration (6%). There is an ordered and predictable progression of hyperphosphorylated tau abnormalities through the nervous system in chronic traumatic encephalopathy that occurs in conjunction with widespread axonal disruption and loss. The frequent association of chronic traumatic encephalopathy with other neurodegenerative disorders suggests that repetitive brain trauma and hyperphosphorylated tau protein deposition promote the accumulation of other abnormally aggregated proteins including TAR DNA-binding protein 43, amyloid beta protein and alpha-synuclein.
Assuntos
Lesão Encefálica Crônica/patologia , Encéfalo/patologia , Tauopatias/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Atletas , Encéfalo/metabolismo , Lesão Encefálica Crônica/metabolismo , Progressão da Doença , Futebol Americano , Humanos , Masculino , Pessoa de Meia-Idade , Emaranhados Neurofibrilares/metabolismo , Emaranhados Neurofibrilares/patologia , Tauopatias/metabolismo , Veteranos , Proteínas tau/metabolismoRESUMO
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.
RESUMO
Caspase-mediated cell death contributes to the pathogenesis of motor neuron degeneration in the mutant SOD1(G93A) transgenic mouse model of amyotrophic lateral sclerosis (ALS), along with other factors such as inflammation and oxidative damage. By screening a drug library, we found that melatonin, a pineal hormone, inhibited cytochrome c release in purified mitochondria and prevented cell death in cultured neurons. In this study, we evaluated whether melatonin would slow disease progression in SOD1(G93A) mice. We demonstrate that melatonin significantly delayed disease onset, neurological deterioration and mortality in ALS mice. ALS-associated ventral horn atrophy and motor neuron death were also inhibited by melatonin treatment. Melatonin inhibited Rip2/caspase-1 pathway activation, blocked the release of mitochondrial cytochrome c, and reduced the overexpression and activation of caspase-3. Moreover, for the first time, we determined that disease progression was associated with the loss of both melatonin and the melatonin receptor 1A (MT1) in the spinal cord of ALS mice. These results demonstrate that melatonin is neuroprotective in transgenic ALS mice, and this protective effect is mediated through its effects on the caspase-mediated cell death pathway. Furthermore, our data suggest that melatonin and MT1 receptor loss may play a role in the pathological phenotype observed in ALS. The above observations indicate that melatonin and modulation of Rip2/caspase-1/cytochrome c or MT1 pathways may be promising therapeutic approaches for ALS.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Antioxidantes/uso terapêutico , Morte Celular/efeitos dos fármacos , Morte Celular/ética , Melatonina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Esclerose Lateral Amiotrófica/genética , Análise de Variância , Animais , Caspase 3/metabolismo , Citocromos c/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Camundongos , Camundongos Transgênicos , Receptor MT1 de Melatonina/metabolismo , Superóxido Dismutase/genéticaRESUMO
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease linked to repetitive head impacts (RHI) and characterized by perivascular hyperphosphorylated tau (p-tau) deposits. The role of vascular injury, blood-brain barrier leakage, and neuroinflammation in CTE pathogenesis is not well understood. We performed quantitative immunoassays for intercellular adhesion molecule 1 (ICAM1), vascular cellular adhesion molecule 1 (VCAM1), and C-reactive protein (CRP) within the postmortem dorsolateral frontal cortex of participants with and without a history of RHI and CTE (n = 156), and tested for associations with RHI, microgliosis, and tau pathology measures. Levels of vascular injury-associated markers ICAM1, VCAM1, and CRP were increased in CTE compared to RHI-exposed and -naïve controls. ICAM1 and CRP increased with RHI exposure duration (p < 0.01) and were associated with increased microglial density (p < 0.001) and tau pathology (AT8, p-tau396, p-tau202; p < 0.05). Histologically, there was significantly increased ICAM1 staining of the microvasculature, extracellular space, and astrocytes at the sulcal depths in high stage CTE compared to both low stage CTE and controls. Multifocal perivascular immunoreactivity for serum albumin was present in all RHI-exposed individuals. These findings demonstrate that vascular injury markers are associated with RHI exposure, duration, and microgliosis, are elevated in CTE, and increase with disease severity.
Assuntos
Encefalopatia Traumática Crônica , Doenças Neurodegenerativas , Lesões do Sistema Vascular , Humanos , Encefalopatia Traumática Crônica/patologia , Lesões do Sistema Vascular/complicações , Lobo Frontal/metabolismo , Barreira Hematoencefálica/patologia , Proteínas tau/metabolismoRESUMO
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI) and characterized by perivascular accumulations of hyperphosphorylated tau protein (p-tau) at the depths of the cortical sulci. Studies of living athletes exposed to RHI, including concussive and nonconcussive impacts, have shown increased blood-brain barrier permeability, reduced cerebral blood flow, and alterations in vasoreactivity. Blood-brain barrier abnormalities have also been reported in individuals neuropathologically diagnosed with CTE. To further investigate the three-dimensional microvascular changes in individuals diagnosed with CTE and controls, we used SHIELD tissue processing and passive delipidation to optically clear and label blocks of postmortem human dorsolateral frontal cortex. We used fluorescent confocal microscopy to quantitate vascular branch density and fraction volume. We compared the findings in 41 male brain donors, age at death 31-89 years, mean age 64 years, including 12 donors with low CTE (McKee stage I-II), 13 with high CTE (McKee stage III-IV) to 16 age- and sex-matched non-CTE controls (7 with RHI exposure and 9 with no RHI exposure). The density of vessel branches in the gray matter sulcus was significantly greater in CTE cases than in controls. The ratios of sulcus versus gyrus vessel branch density and fraction volume were also greater in CTE than in controls and significantly above one for the CTE group. Hyperphosphorylated tau pathology density correlated with gray matter sulcus fraction volume. These findings point towards increased vascular coverage and branching in the dorsolateral frontal cortex (DLF) sulci in CTE, that correlates with p-tau pathology.
Assuntos
Encefalopatia Traumática Crônica , Doenças Neurodegenerativas , Humanos , Masculino , Pessoa de Meia-Idade , Adulto , Idoso , Idoso de 80 Anos ou mais , Encefalopatia Traumática Crônica/patologia , Doenças Neurodegenerativas/patologia , Encéfalo/patologia , Proteínas tau/metabolismo , Lobo Frontal/metabolismo , AtletasRESUMO
Importance: Young contact sport athletes may be at risk for long-term neuropathologic disorders, including chronic traumatic encephalopathy (CTE). Objective: To characterize the neuropathologic and clinical symptoms of young brain donors who were contact sport athletes. Design, Setting, and Participants: This case series analyzes findings from 152 of 156 brain donors younger than 30 years identified through the Understanding Neurologic Injury and Traumatic Encephalopathy (UNITE) Brain Bank who donated their brains from February 1, 2008, to September 31, 2022. Neuropathologic evaluations, retrospective telephone clinical assessments, and online questionnaires with informants were performed blinded. Data analysis was conducted between August 2021 and June 2023. Exposures: Repetitive head impacts from contact sports. Main Outcomes and Measures: Gross and microscopic neuropathologic assessment, including diagnosis of CTE, based on defined diagnostic criteria; and informant-reported athletic history and informant-completed scales that assess cognitive symptoms, mood disturbances, and neurobehavioral dysregulation. Results: Among the 152 deceased contact sports participants (mean [SD] age, 22.97 [4.31] years; 141 [92.8%] male) included in the study, CTE was diagnosed in 63 (41.4%; median [IQR] age, 26 [24-27] years). Of the 63 brain donors diagnosed with CTE, 60 (95.2%) were diagnosed with mild CTE (stages I or II). Brain donors who had CTE were more likely to be older (mean difference, 3.92 years; 95% CI, 2.74-5.10 years) Of the 63 athletes with CTE, 45 (71.4%) were men who played amateur sports, including American football, ice hockey, soccer, rugby, and wrestling; 1 woman with CTE played collegiate soccer. For those who played football, duration of playing career was significantly longer in those with vs without CTE (mean difference, 2.81 years; 95% CI, 1.15-4.48 years). Athletes with CTE had more ventricular dilatation, cavum septum pellucidum, thalamic notching, and perivascular pigment-laden macrophages in the frontal white matter than those without CTE. Cognitive and neurobehavioral symptoms were frequent among all brain donors. Suicide was the most common cause of death, followed by unintentional overdose; there were no differences in cause of death or clinical symptoms based on CTE status. Conclusions and Relevance: This case series found that young brain donors exposed to repetitive head impacts were highly symptomatic regardless of CTE status, and the causes of symptoms in this sample are likely multifactorial. Future studies that include young brain donors unexposed to repetitive head impacts are needed to clarify the association among exposure, white matter and microvascular pathologic findings, CTE, and clinical symptoms.
Assuntos
Traumatismos em Atletas , Encefalopatia Traumática Crônica , Futebol , Feminino , Humanos , Masculino , Adulto Jovem , Adulto , Estudos Retrospectivos , Encefalopatia Traumática Crônica/diagnóstico , Encéfalo/patologia , Atletas , Traumatismos em Atletas/complicações , Traumatismos em Atletas/patologiaRESUMO
Melatonin mediates neuroprotection in several experimental models of neurodegeneration. It is not yet known, however, whether melatonin provides neuroprotection in genetic models of Huntington's disease (HD). We report that melatonin delays disease onset and mortality in a transgenic mouse model of HD. Moreover, mutant huntingtin (htt)-mediated toxicity in cells, mice, and humans is associated with loss of the type 1 melatonin receptor (MT1). We observe high levels of MT1 receptor in mitochondria from the brains of wild-type mice but much less in brains from HD mice. Moreover, we demonstrate that melatonin inhibits mutant htt-induced caspase activation and preserves MT1 receptor expression. This observation is critical, because melatonin-mediated protection is dependent on the presence and activation of the MT1 receptor. In summary, we delineate a pathologic process whereby mutant htt-induced loss of the mitochondrial MT1 receptor enhances neuronal vulnerability and potentially accelerates the neurodegenerative process.
Assuntos
Doença de Huntington/metabolismo , Melatonina/farmacologia , Mutação/genética , Proteínas do Tecido Nervoso/genética , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Proteínas Nucleares/genética , Receptor MT1 de Melatonina/metabolismo , Análise de Variância , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Caspase 3/análise , Caspase 3/metabolismo , Caspase 9/análise , Caspase 9/metabolismo , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Células Cultivadas , Modelos Animais de Doenças , Embrião de Mamíferos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Humanos , Proteína Huntingtina , Doença de Huntington/tratamento farmacológico , Doença de Huntington/patologia , Peróxido de Hidrogênio/toxicidade , Masculino , Melatonina/uso terapêutico , Camundongos , Camundongos Mutantes , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/ultraestrutura , Proteínas Nucleares/metabolismo , Mudanças Depois da Morte , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/farmacologia , Ratos , Receptor MT1 de Melatonina/genética , Receptor MT2 de Melatonina/genética , Receptor MT2 de Melatonina/metabolismo , Estatísticas não Paramétricas , Fatores de Tempo , Transfecção/métodosRESUMO
Although a direct causative pathway from the gene mutation to the selective neostriatal neurodegeneration remains unclear in Huntington's disease (HD), one putative pathological mechanism reported to play a prominent role in the pathogenesis of this neurological disorder is mitochondrial dysfunction. We examined mitochondria in preferentially vulnerable striatal calbindin-positive neurons in moderate-to-severe grade HD patients, using antisera against mitochondrial markers of COX2, SOD2 and cytochrome c. Combined calbindin and mitochondrial marker immunofluorescence showed a significant and progressive grade-dependent reduction in the number of mitochondria in spiny striatal neurons, with marked alteration in size. Consistent with mitochondrial loss, there was a reduction in COX2 protein levels using western analysis that corresponded with disease severity. In addition, both mitochondrial transcription factor A, a regulator of mtDNA, and peroxisome proliferator-activated receptor-co-activator gamma-1 alpha, a key transcriptional regulator of energy metabolism and mitochondrial biogenesis, were also significantly reduced with increasing disease severity. Abnormalities in mitochondrial dynamics were observed, showing a significant increase in the fission protein Drp1 and a reduction in the expression of the fusion protein mitofusin 1. Lastly, mitochondrial PCR array profiling in HD caudate nucleus specimens showed increased mRNA expression of proteins involved in mitochondrial localization, membrane translocation and polarization and transport that paralleled mitochondrial derangement. These findings reveal that there are both mitochondrial loss and altered mitochondrial morphogenesis with increased mitochondrial fission and reduced fusion in HD. These findings provide further evidence that mitochondrial dysfunction plays a critical role in the pathogenesis of HD.
Assuntos
Doença de Huntington/metabolismo , Doença de Huntington/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neostriado/metabolismo , Neostriado/ultraestrutura , Calbindinas , Citocromos c/análise , Citocromos c/imunologia , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Proteínas de Ligação a DNA/metabolismo , Dinaminas , Complexo IV da Cadeia de Transporte de Elétrons/análise , Metabolismo Energético , Imunofluorescência , GTP Fosfo-Hidrolases/metabolismo , Expressão Gênica , Perfilação da Expressão Gênica , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Potencial da Membrana Mitocondrial , Proteínas de Membrana Transportadoras/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Mitocôndrias/genética , Proteínas de Transporte da Membrana Mitocondrial , Proteínas Mitocondriais/metabolismo , Proteínas do Tecido Nervoso/genética , Neurônios/química , Neurônios/patologia , Proteínas Nucleares/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Reação em Cadeia da Polimerase , Proteína G de Ligação ao Cálcio S100/análise , Superóxido Dismutase/análise , Superóxido Dismutase/imunologia , Fatores de Transcrição/metabolismoRESUMO
Huntington's disease (HD) is a neurodegenerative disorder previously thought to be of primary neuronal origin, despite ubiquitous expression of mutant huntingtin (mHtt). We tested the hypothesis that mHtt expressed in astrocytes may contribute to the pathogenesis of HD. To better understand the contribution of astrocytes in HD in vivo, we developed a novel mouse model using lentiviral vectors that results in selective expression of mHtt into striatal astrocytes. Astrocytes expressing mHtt developed a progressive phenotype of reactive astrocytes that was characterized by a marked decreased expression of both glutamate transporters, GLAST and GLT-1, and of glutamate uptake. These effects were associated with neuronal dysfunction, as observed by a reduction in DARPP-32 and NR2B expression. Parallel studies in brain samples from HD subjects revealed early glial fibrillary acidic protein expression in striatal astrocytes from Grade 0 HD cases. Astrogliosis was associated with morphological changes that increased with severity of disease, from Grades 0 through 4 and was more prominent in the putamen. Combined immunofluorescence showed co-localization of mHtt in astrocytes in all striatal HD specimens, inclusive of Grade 0 HD. Consistent with the findings from experimental mice, there was a significant grade-dependent decrease in striatal GLT-1 expression from HD subjects. These findings suggest that the presence of mHtt in astrocytes alters glial glutamate transport capacity early in the disease process and may contribute to HD pathogenesis.
Assuntos
Astrócitos/metabolismo , Ácido Glutâmico/metabolismo , Doença de Huntington/metabolismo , Neostriado/patologia , Peptídeos/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Expansão das Repetições de Trinucleotídeos/genética , Idoso , Sistema X-AG de Transporte de Aminoácidos/metabolismo , Animais , Astrócitos/patologia , Transporte Biológico , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Regulação para Baixo , Imunofluorescência , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Doença de Huntington/patologia , Lentivirus/genética , Camundongos , Pessoa de Meia-Idade , Proteínas Mutantes/metabolismo , Neostriado/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Fenótipo , Receptores de N-Metil-D-Aspartato/metabolismo , Fatores de TempoRESUMO
Repetitive head impacts (RHI) and traumatic brain injuries are risk factors for the neurodegenerative diseases chronic traumatic encephalopathy (CTE) and amyotrophic lateral sclerosis (ALS). ALS and CTE are distinct disorders, yet in some instances, share pathology, affect similar brain regions, and occur together. The pathways involved and biomarkers for diagnosis of both diseases are largely unknown. MicroRNAs (miRNAs) involved in gene regulation may be altered in neurodegeneration and be useful as stable biomarkers. Thus, we set out to determine associations between miRNA levels and disease state within the prefrontal cortex in a group of brain donors with CTE, ALS, CTE + ALS and controls. Of 47 miRNAs previously implicated in neurological disease and tested here, 28 (60%) were significantly different between pathology groups. Of these, 21 (75%) were upregulated in both ALS and CTE, including miRNAs involved in inflammatory, apoptotic, and cell growth/differentiation pathways. The most significant change occurred in miR-10b, which was significantly increased in ALS, but not CTE or CTE + ALS. Overall, we found patterns of miRNA expression that are common and unique to CTE and ALS and that suggest shared and distinct mechanisms of pathogenesis.
RESUMO
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder. Oxidative damage has been associated with pathological neuronal loss in HD. The therapeutic modulation of oxidative stress and mitochondrial function using low molecular weight compounds may be an important strategy for delaying the onset and slowing the progression of HD. In the present study, we found a marked increase of 4-hydroxy-2-nonenal (4-HNE) adducts, a lipid peroxidation marker, in the caudate and putamen of HD brains and in the striatum of HD mice. Notably, 4-HNE immunoreactivity was colocalized with mutant huntingtin inclusions in the striatal neurons of R6/2 HD mice. Administration of nordihydroguaiaretic acid (NDGA), an antioxidant that functions by inhibiting lipid peroxidation, markedly reduced 4-HNE adduct formation in the nuclear inclusions of R6/2 striatal neurons. NDGA also protected cultured neurons against oxidative stress-induced cell death by improving ATP generation and mitochondrial morphology and function. In addition, NDGA restored mitochondrial membrane potential, mitochondrial structure, and synapse structure in the striatum of R6/2 mice and increased their lifespan. The present findings suggest that further therapeutic studies using NDGA are warranted in HD and other neurodegenerative diseases characterized by increased oxidative stress and altered mitochondrial function.
Assuntos
Doença de Huntington/patologia , Peroxidação de Lipídeos/fisiologia , Mitocôndrias/patologia , Neostriado/patologia , Trifosfato de Adenosina/metabolismo , Fatores Etários , Aldeídos/metabolismo , Análise de Variância , Animais , Células Cultivadas , Córtex Cerebral/citologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Ácido Glutâmico/farmacologia , Humanos , Proteína Huntingtina , Doença de Huntington/tratamento farmacológico , Doença de Huntington/genética , Imageamento Tridimensional/métodos , Marcação In Situ das Extremidades Cortadas/métodos , Indóis , Peroxidação de Lipídeos/efeitos dos fármacos , Inibidores de Lipoxigenase/uso terapêutico , Masculino , Masoprocol/uso terapêutico , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Potencial da Membrana Mitocondrial/genética , Camundongos , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão/métodos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/ultraestrutura , Neostriado/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Neurônios/patologia , Neurônios/ultraestrutura , Proteínas Nucleares/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Sinapses/efeitos dos fármacos , Sinapses/patologia , Sinapses/ultraestrutura , Sais de Tetrazólio , Tiazóis , Expansão das Repetições de Trinucleotídeos/genéticaRESUMO
Chromatin remodeling is tightly controlled under physiological conditions. Alterations in chromatin structure are involved in the pathogenesis of neuronal systems. We found that the monoallelic deletion of CREB binding protein (CBP) results in the induction of ERG-associated protein with SET domain (ESET) and increases trimethylation of histone H3 (K9) and condensation of pericentromeric heterochromatin structure in neurons. Nested deletion and mutational analysis of the ESET promoter further demonstrated that the Ets-2 transcription factor regulates transcriptional activity of the ESET gene. In CBP+/- mice, Ets-2 occupancy in the ESET promoter DNA was markedly elevated. Our results suggest that CBP is a transcriptional repressor of ESET gene expression by limiting Ets-2 transcriptional activity, while CBP siRNA enhances basal and Ets-2-dependent ESET transcriptional activity. Altered expression of the ESET gene and hypertrimethylation of H3 (K9) correlate with striatal neuron atrophy and dysfunction in CBP+/- mice. These results establish an alternative pathway that loss of CBP leads to the pericentric heterochromatin condensation through ESET expression and trimethylation of H3 (K9).
Assuntos
Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/metabolismo , Heterocromatina/metabolismo , Histonas/metabolismo , Neurônios/metabolismo , Proteínas Metiltransferases/metabolismo , Animais , Deleção de Genes , Histona-Lisina N-Metiltransferase , Metilação , Camundongos , Camundongos Endogâmicos C57BLRESUMO
There is strong evidence from studies in humans and animal models to suggest the involvement of energy metabolism defects in neurodegenerative diseases. Uridine, a pyrimidine nucleoside, has been suggested to be neuroprotective in neurological disorders by improving bioenergetic effects, increasing ATP levels and enhancing glycolytic energy production. We assessed whether uridine treatment extended survival and improved the behavioral and neuropathological phenotype observed in G93A-ALS mice. In vitro and in vivo pharmacokinetic analyses in mutant SOD models provided optimal dose and assurance that uridine entered the brain. A dose-ranging efficacy trial in G93A mice was performed using survival, body weight, open-field analysis, and neuropathology as outcome measures. Urinary levels of 8-hydroxy-2'-deoxyguanosine, identifying DNA oxidative damage, were measured and used as a pharmacodynamic biomarker. Uridine administration significantly extended survival in a dose-dependent manner in G93A mice, while improving the behavioral and neuropathological phenotype. Uridine increased survival by 17.4%, ameliorated body weight loss, enhanced motor performance, reduced gross lumbar and ventral horn atrophy, attenuated lumbar ventral horn neuronal cell death, and decreased reactive astrogliosis. Consistent with a therapeutic effect, uridine significantly reduced urinary 8-hydroxy-2'-deoxyguanosine in G93A mice. These data suggest that uridine may be a therapeutic candidate in ALS patients.
Assuntos
Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/patologia , Esclerose Lateral Amiotrófica/fisiopatologia , Fármacos Neuroprotetores/uso terapêutico , Superóxido Dismutase/metabolismo , Uridina/uso terapêutico , 8-Hidroxi-2'-Desoxiguanosina , Esclerose Lateral Amiotrófica/genética , Animais , Células do Corno Anterior/efeitos dos fármacos , Células do Corno Anterior/metabolismo , Células do Corno Anterior/patologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Peso Corporal/efeitos dos fármacos , Desoxiguanosina/análogos & derivados , Desoxiguanosina/urina , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Metabolismo Energético/fisiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Medula Espinal/citologia , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Superóxido Dismutase/genética , Taxa de Sobrevida , Uridina/farmacologiaRESUMO
A large body of evidence indicates that dysregulation of cerebral biometals (Fe, Cu, Zn) and their interactions with amyloid precursor protein (APP) and Aß amyloid may contribute to the Alzheimer's disease (AD) Aß amyloid pathology. However, the molecular underpinnings associated with the interactions are still not fully understood. Herein we have further validated the exacerbation of Aß oligomerization by Cu and H2O2 in vitro. We have also reported that Cu enhanced APP translations via its 5' untranslated region (5'UTR) of mRNA in SH-SY5Y cells, and increased Aß amyloidosis and expression of associated pro-inflammatory cytokines such as MCP-5 in Alzheimer's APP/PS1 doubly transgenic mice. This preliminary study may further unravel the pathogenic role of Cu in Alzheimer's Aß amyloid pathogenesis, warranting further investigation.