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
We have previously shown that myelin abnormalities characterize the normal aging process of the brain and that an age-associated reduction in Klotho is conserved across species. Predominantly generated in brain and kidney, Klotho overexpression extends life span, whereas loss of Klotho accelerates the development of aging-like phenotypes. Although the function of Klotho in brain is unknown, loss of Klotho expression leads to cognitive deficits. We found significant effects of Klotho on oligodendrocyte functions, including induced maturation of rat primary oligodendrocytic progenitor cells (OPCs) in vitro and myelination. Phosphoprotein analysis indicated that Klotho's downstream effects involve Akt and ERK signal pathways. Klotho increased OPC maturation, and inhibition of Akt or ERK function blocked this effect on OPCs. In vivo studies of Klotho knock-out mice and control littermates revealed that knock-out mice have a significant reduction in major myelin protein and gene expression. By immunohistochemistry, the number of total and mature oligodendrocytes was significantly lower in Klotho knock-out mice. Strikingly, at the ultrastructural level, Klotho knock-out mice exhibited significantly impaired myelination of the optic nerve and corpus callosum. These mice also displayed severe abnormalities at the nodes of Ranvier. To decipher the mechanisms by which Klotho affects oligodendrocytes, we used luciferase pathway reporters to identify the transcription factors involved. Together, these studies provide novel evidence for Klotho as a key player in myelin biology, which may thus be a useful therapeutic target in efforts to protect brain myelin against age-dependent changes and promote repair in multiple sclerosis.
Assuntos
Encéfalo/metabolismo , Glucuronidase/metabolismo , Bainha de Mielina/metabolismo , Fibras Nervosas Mielinizadas/metabolismo , Oligodendroglia/metabolismo , Animais , Contagem de Células , Sobrevivência Celular/fisiologia , Células Cultivadas , Corpo Caloso/metabolismo , Feminino , Glucuronidase/genética , Proteínas Klotho , Camundongos , Camundongos Knockout , Proteína Básica da Mielina/metabolismo , Células-Tronco Neurais/metabolismo , Nervo Óptico/metabolismo , Fosforilação , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT1/fisiologiaRESUMO
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.
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BACKGROUND: Our understanding of the molecular underpinnings of chronic traumatic encephalopathy (CTE) and its associated pathology in post-mortem brain is incomplete. Factors including years of play and genetic risk variants influence the extent of tau pathology associated with disease expression, but how these factors affect gene expression, and whether those effects are consistent across the development of disease, is unknown. METHODS: To address these questions, we conducted an analysis of the largest post-mortem brain CTE mRNASeq whole-transcriptome dataset available to date. We examined the genes and biological processes associated with disease by comparing individuals with CTE with control individuals with a history of repetitive head impacts that lack CTE pathology. We then identified genes and biological processes associated with total years of play as a measure of exposure, amount of tau pathology present at time of death, and the presence of APOE and TMEM106B risk variants. Samples were stratified into low and high pathology groups based on McKee CTE staging criteria to model early versus late changes in response to exposure, and the relative effects associated with these factors were compared between these groups. RESULTS: Substantial gene expression changes were associated with severe disease for most of these factors, primarily implicating diverse, strongly involved neuroinflammatory and neuroimmune processes. In contrast, low pathology groups had many fewer genes and processes implicated and show striking differences for some factors when compared with severe disease. Specifically, gene expression associated with amount of tau pathology showed a nearly perfect inverse relationship when compared between these two groups. CONCLUSIONS: Together, these results suggest the early CTE disease process may be mechanistically different than what occurs in late stages, that total years of play and tau pathology influence disease expression differently, and that related pathology-modifying risk variants may do so via distinct biological pathways.
Assuntos
Encefalopatia Traumática Crônica , Humanos , Encefalopatia Traumática Crônica/genética , Encefalopatia Traumática Crônica/metabolismo , Encefalopatia Traumática Crônica/patologia , Proteínas tau/genética , Proteínas tau/metabolismo , Encéfalo/metabolismo , Inflamação/metabolismo , Transcriptoma , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/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
BACKGROUND: Multiple studies have reported brain lipidomic abnormalities in Alzheimer's disease (AD) that affect glycerophospholipids, sphingolipids, and fatty acids. However, there is no consensus regarding the nature of these abnormalities, and it is unclear if they relate to disease progression. OBJECTIVE: Monogalactosyl diglycerides (MGDGs) are a class of lipids which have been recently detected in the human brain. We sought to measure their levels in postmortem human brain and determine if these levels correlate with the progression of the AD-related traits. METHODS: We measured MGDGs by ultrahigh performance liquid chromatography tandem mass spectrometry in postmortem dorsolateral prefrontal cortex gray matter and subcortical corona radiata white matter samples derived from three cohorts of participants: the Framingham Heart Study, the Boston University Alzheimer's Disease Research Center, and the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (total nâ=â288). RESULTS: We detected 40 molecular species of MGDGs (including diacyl and alkyl/acyl compounds) and found that the levels of 29 of them, as well as total MGDG levels, are positively associated with AD-related traits including pathologically confirmed AD diagnosis, clinical dementia rating, Braak and Braak stage, neuritic plaque score, phospho-Tau AT8 immunostaining density, levels of phospho-Tau396 and levels of Aß40. Increased MGDG levels were present in both gray and white matter, indicating that they are widespread and likely associated with myelin-producing oligodendrocytes-the principal cell type of white matter. CONCLUSIONS: Our data implicate the MGDG metabolic defect as a central correlate of clinical and pathological progression in AD.
Assuntos
Doença de Alzheimer , Substância Branca , Humanos , Doença de Alzheimer/patologia , Substância Branca/patologia , Diglicerídeos/metabolismo , Encéfalo/patologia , Envelhecimento/patologia , Substância Cinzenta/patologia , Progressão da DoençaRESUMO
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.
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Alzheimer disease (AD) is a chronic neurodegenerative disease with a multitude of contributing genetic factors, many of which are related to inflammation. The apolipoprotein E (APOE) ε4 allele is the most common genetic risk factor for AD and is related to a pro-inflammatory state. To test the hypothesis that microglia and AD-implicated cytokines were differentially associated with AD pathology based on the presence of APOE ε4, we examined the dorsolateral frontal cortex from deceased participants within a community-based aging cohort (n = 154). Cellular density of Iba1, a marker of microglia, was positively associated with tau pathology only in APOE ε4 positive participants (p = 0.001). The cytokines IL-10, IL-13, IL-4, and IL-1α were negatively associated with tau pathology, independent of Aß1-42 levels, only in APOE ε4 negative participants. Overall, the association of mostly anti-inflammatory cytokines with less tau pathology suggests a protective effect in APOE ε4 negative participants. These associations are largely absent in the presence of APOE ε4 where tau pathology was significantly associated with increased microglial cell density. Taken together, these results suggest that APOE ε4 mediates an altered inflammatory response and increased tau pathology independent of Aß1-42 pathology.
Assuntos
Apolipoproteína E4/genética , Encéfalo/patologia , Inflamação/genética , Inflamação/patologia , Idoso de 80 Anos ou mais , Alelos , Peptídeos beta-Amiloides/metabolismo , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biomarcadores/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Contagem de Células , Estudos de Coortes , Citocinas/metabolismo , Demência/patologia , Feminino , Genótipo , Humanos , Masculino , Proteínas dos Microfilamentos/metabolismo , Microglia/metabolismo , Microglia/patologia , Modelos Biológicos , Proteínas tau/metabolismoRESUMO
Lipid metabolism is abnormal in Alzheimer's disease (AD) brain leading to ceramide and sphingosine accumulation and reduced levels of brain sphingosine-1-phosphate (S1P). We hypothesize that changes in S1P signaling are central to the inflammatory and immune-pathogenesis of AD and the therapeutic benefits of fingolimod, a structural analog of sphingosine that is FDA approved for the treatment of multiple sclerosis. We recently reported that the neuroprotective effects of fingolimod in 5xFAD transgenic AD mice treated from 1-3 months of age were greater at 1 mg/kg/day than at 5 mg/kg/day. Here we performed a dose-response study using fingolimod from 0.03 to 1 mg/kg/day in 5xFAD mice treated from 1-8 months of age. At 1 mg/kg/day, fingolimod decreased both peripheral blood lymphocyte counts and brain Aß levels, but at the lowest dose tested (0.03 mg/kg/day), we detected improved memory, decreased activation of brain microglia and astrocytes, and restored hippocampal levels of GABA and glycerophosphocholine with no effect on circulating lymphocyte counts. These findings suggests that, unlike the case in multiple sclerosis, fingolimod may potentially have therapeutic benefits in AD at low doses that do not affect peripheral lymphocyte function.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Encéfalo/efeitos dos fármacos , Reposicionamento de Medicamentos , Cloridrato de Fingolimode/administração & dosagem , Fármacos Neuroprotetores/administração & dosagem , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Cloridrato de Fingolimode/uso terapêutico , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/patologia , Ácido gama-Aminobutírico/metabolismoRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular deposits of fibrillary ß-amyloid (Aß) plaques in the brain that initiate an inflammatory process resulting in neurodegeneration. The neuronal loss associated with AD results in gross atrophy of affected regions causing a progressive loss of cognitive ability and memory function, ultimately leading to dementia. Growing evidence suggests that vasoactive intestinal peptide (VIP) could be beneficial for various neurodegenerative diseases, including AD. The study investigated the effects of VIP on 5xFAD, a transgenic mouse model of AD. Toward this aim, we used 20 5xFAD mice in two groups (n = 10 each), VIP-treated (25 ng/kg i.p. injection, three times per week) and saline-treated (the drug's vehicle) following the same administration regimen. Treatment started at 1 month of age and ended 2 months later. After 2 months of treatment, the mice were euthanized, their brains dissected out, and immunohistochemically stained for Aß40 and Aß42 on serial sections. Then, plaque analysis and stereological morphometric analysis were performed in different brain regions. Chronic VIP administration in 5xFAD mice significantly decreased the levels of Aß40 and Aß42 plaques in the subiculum compared to the saline treated 5xFAD mice. VIP treatment also significantly decreased Aß40 and Aß42 plaques in cortical areas and significantly increased the hippocampus/cerebrum and corpus callosum/cerebrum ratio but not the cerebral cortex/cerebrum ratio. In summary, we found that chronic administration of VIP significantly decreased Aß plaques and preserved against atrophy for related brain regions in 5xFAD AD mice.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Peptídeo Intestinal Vasoativo/uso terapêutico , Peptídeos beta-Amiloides/metabolismo , Animais , Atrofia/tratamento farmacológico , Encéfalo/patologia , Feminino , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/farmacologia , Peptídeo Intestinal Vasoativo/administração & dosagem , Peptídeo Intestinal Vasoativo/farmacologiaRESUMO
The inflammatory system has been implicated in the pathophysiology of a variety of psychiatric conditions. Individuals with PTSD, depression, and other fear- and anxiety-related disorders exhibit alterations in peripheral circulating inflammatory markers, suggesting dysregulation of the inflammatory system. The relationship between inflammation and PTSD has been investigated almost exclusively in the periphery, and has not been extensively explored in human postmortem brain tissue. Interleukins (ILs) represent a subtype of cytokines and are key signaling proteins in the immune and inflammatory systems. Based on prior research implicating IL signaling in PTSD and depression, we performed a preliminary investigation of IL gene expression in a region of the cortex involved in emotion regulation and PTSD, the dorsolateral prefrontal cortex (dlPFC), using tissue from the newly established VA National PTSD Brain Bank. Gene expression analyses were conducted on post-mortem tissue from the dlPFC from 50 donors: 13 controls, 12 PTSD cases, and 25 depressed cases. RNA was extracted from frozen dlPFC tissue, reverse transcribed to cDNA, and quantitative polymerase chain reaction (qPCR) was performed to assess gene expression of IL1A, IL1B, IL6, IL8, IL10, IL13, and IL15. We found a multiple-testing corrected significant decrease in IL1A expression in the dlPFC for PTSD and depression cases compared to controls (p <â¯0.005) with age at death, sex, race and RNA integrity number (RIN) included as covariates. To our knowledge this finding is the first demonstration of altered IL expression in brain tissue from deceased individuals with histories of PTSD and/or depression.
Assuntos
Interleucina-1alfa/genética , Córtex Pré-Frontal/metabolismo , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Feminino , Expressão Gênica , Humanos , Inflamação/genética , Inflamação/metabolismo , Interleucina-1alfa/biossíntese , Masculino , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/metabolismo , TranscriptomaRESUMO
BACKGROUND: We compared the effect of temporary aneurysm clips on atherosclerotic and nonatherosclerotic CCA of rabbits by morphometric and ultrastructural methods. METHODS: The rabbits (N = 12) were divided into 2 groups: the first group was fed a 2% cholesterol diet, and the second group, a normal diet for 4 weeks. Atherosclerotic lesions developed after 4 weeks. Temporary aneurysm clips were placed on the left CCA of both groups; the right CCA of both groups served as control. Thus, a total of 4 groups were used: atherosclerotic (A), atherosclerotic/clip (AC), nonatherosclerotic (NA), and nonatherosclerotic/clip (NAC). Temporary aneurysm clips were applied for 1, 5, and 10 minutes in the AC and NAC groups. No temporary clip was placed on the right CCA (A and NA groups). The affected parts of the CCA via clips were examined under light microscope and SEM. RESULTS: Comparison of atherosclerotic and nonatherosclerotic CCA of rabbits under light microscope indicated that the wall of atherosclerotic CCA was thicker than that of nonatherosclerotic CCA. The difference between the thickness of atherosclerotic and nonatherosclerotic CCAs was significant. SEM analyses showed that in nonatherosclerotic CCAs, the effect of temporary aneurysm clips was seen after 10 minutes, but in atherosclerotic CCAs, the effect was seen within the 1st minute of clipping and continued in the 5th and 10th minutes. CONCLUSION: The duration of temporary clipping should be decreased for the neurovascular surgery of atherosclerotic patients.
Assuntos
Aterosclerose/patologia , Aterosclerose/cirurgia , Artéria Carótida Primitiva/patologia , Artéria Carótida Primitiva/cirurgia , Hemostasia Cirúrgica/instrumentação , Procedimentos Neurocirúrgicos/instrumentação , Aneurisma/cirurgia , Animais , Artéria Carótida Primitiva/ultraestrutura , Masculino , Coelhos , Fatores de Tempo , Túnica Íntima/patologia , Túnica Íntima/ultraestruturaRESUMO
In recent years, there has been increasing evidence that cholesterol plays a role in the pathology of Alzheimer disease. Since hypercholesterolemia was reported to increase the levels of reactive oxygen species and Alzheimer disease has clearly involved an oxidative component, it is possible that hypercholesterolemia is via increased oxidant production facilitating the disease development of the neurodegenerative disease. Therefore, we tested in an established model of enhanced cholesterol feed in rabbits the effects of serum cholesterol increase on oxidative stress parameters as well in serum as in the brain. In addition to that we tested the effects of vitamin E on the cholesterol-induced oxidative stress. Since Alzheimer disease is largely connected with increased protein oxidation whereas cholesterol is rather connected with lipid peroxidation processes, we tested both protein carbonyl levels and the formation of malondialdehyde, a marker of lipid peroxidation. We could clearly demonstrate an increase in serum malondialdehyde due to high cholesterol feeding, which is accompanied by an increase in protein oxidation parameters in the brain, especially in the hippocampus. Therefore, we suggest that specific neuropathological changes occur during the feeding of hypercholesterolemic diet.
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Encéfalo/metabolismo , Hipercolesterolemia/metabolismo , Estresse Oxidativo , Animais , Colesterol/sangue , Modelos Animais de Doenças , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/sangue , Complexo de Endopeptidases do Proteassoma/metabolismo , Carbonilação Proteica , Coelhos , Tirosina/análogos & derivados , Tirosina/metabolismo , Vitamina E/farmacologiaRESUMO
Dysfunction in the resolution of inflammation may play a key role in Alzheimer's disease (AD). In this study, we found that the levels of specialized pro-resolving lipid mediators (SPMs) in the hippocampus of 5xFAD mice are significantly lower than in non-transgenic littermates. We, therefore, tested the hypothesis that treatment with resolvin E1 (RvE1) and lipoxin A4 (LXA4) alone or in combination will reverse the neuroinflammatory process and decrease Aß pathology. 5xFAD mice were treated intraperitoneally starting at 1month of age with RvE1 or LXA4 alone or in combination at a dose of 1.5 µg/kg, 3 times a week until 3months of age. We found that treatment with RvE1 or LXA4 alone or in combination increased the concentration of RvE1, LXA4, and RvD2 in the hippocampus as measured by ELISA. Combination treatment of RvE1 and LXA4 had a more potent effect on the activation of microglia and astrocytes than either treatment alone, measured by immunohistochemistry with Iba1 and GFAP antibodies, respectively. The concentrations of Aß40 and Aß42 were measured by ELISA and the percentage of Aß plaques were analyzed by immunohistochemistry. All treatments single and in combination, decreased the measures of Aß pathology and restored the homeostasis reversing the inflammatory process for inflammatory cytokines and chemokines (GM-CSF, IFN-γ, IL-1ß, IL-6, IL-10, TNF-α, MCP-1, MIP-1α, MIP-1ß, and RANTES) as measured by multiplex immunoassay. Overall, the study showed that the levels of SPMs in the hippocampus of 5xFAD mice were significantly lower than in wild-type mice; that treatment with RvE1 and LXA4 restored the level of these compounds, reversed the inflammatory process, and decreased the neuroinflammation associated with Aß pathology in 5xFAD mice.
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Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Anti-Inflamatórios não Esteroides/administração & dosagem , Modelos Animais de Doenças , Ácido Eicosapentaenoico/análogos & derivados , Lipoxinas/administração & dosagem , Doença de Alzheimer/patologia , Animais , Quimioterapia Combinada , Ácido Eicosapentaenoico/administração & dosagem , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Camundongos , Camundongos TransgênicosRESUMO
The aim of the study was to describe the sociodemographic and clinical features of the mothers and their offspring staying with them in prison. The study was planned as a cross-sectional, single-center study of mothers residing in Tarsus Closed Women's Prison of Turkish Ministry of Justice along with their 0 to 6 years old offspring. Mothers were evaluated via Structured Clinical Interview for DSM-IV Axis I Disorders. A psychologist blind to maternal evaluations applied the Denver Developmental Screening Test II (DII-DST). Children/mothers were also evaluated by a child and adolescent psychiatrist via K-SADS-PL. Twenty-four mothers with a mean age of 29.3 years were included. Most common diagnoses in mothers were nicotine abuse (n = 17, 70.8%), specific phobia (n = 8, 33.3%), alcohol abuse (n = 7, 29.2%) and substance abuse (n = 5, 20.8%). Twenty-six children (53.9% female) were living with their mothers in prison, and the mean age of those was 26.3 months. Results of the D-II-DST were abnormal in 33.3% of the children. Most common diagnoses in children were adjustment disorder (n = 7, 26.9%) separation anxiety disorder (n = 3, 11.5%) and conduct disorder (n = 2, 7.7%). A multi-center study is necessary to reach that neglected/under-served population and address the inter-generational transmission of abuse, neglect, and psychopathology.
Assuntos
Filho de Pais com Deficiência/psicologia , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/epidemiologia , Mães/psicologia , Prisões , Psicometria/métodos , Adolescente , Adulto , Criança , Filho de Pais com Deficiência/estatística & dados numéricos , Pré-Escolar , Estudos Transversais , Deficiências do Desenvolvimento/psicologia , Manual Diagnóstico e Estatístico de Transtornos Mentais , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Mães/estatística & dados numéricos , Turquia/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: Attention deficit and hyperactivity disorder (ADHD) is a neuro-developmental disorder related to internalizing and externalizing disorders as well as somatic complaints and disorders. This study was conducted to evaluate the prevalence of headache subtypes, epilepsy, atopic disorders, motion sickness and recurrent abdominal pain among children and adolescents with ADHD and their parents. METHODS: In a multi-center, cross-sectional, familial association study using case-control design, treatment naïve children and adolescents between 6 and 18â¯years of age diagnosed with ADHD according to the DSM-5 criteria as well as age- and gender-matched healthy controls and their parents were evaluated by a neurologist and analyzed accordingly. RESULTS: 117 children and adolescents with ADHD and 111 controls were included. Headache disorder diagnosis was common for both patients and healthy controls (59.0% vs. 37.8%), with a significantly elevated rate in the ADHD group (pâ¯=â¯0.002). Migraine was found in 26.0% of ADHD patients and 9.9% of healthy controls. Tension headache was found in 32.4% of ADHD patients and 27.9% of healthy controls. Headache diagnosis was also found to be significantly more common in mothers of children with ADHD than control group mothers (90.5% vs. 36.6%, pâ¯<â¯0.001). CONCLUSION: Headache diagnoses and specifically migraines were significantly more common among children with ADHD and their mothers, while recurrent abdominal pain was elevated in both parents and ADHD patients. Migraine is an important part of ADHD comorbidity, not only for children but also for mothers. Motion sickness may be reduced among families of ADHD probands.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtornos de Enxaqueca/epidemiologia , Mães/estatística & dados numéricos , Cefaleia do Tipo Tensional/epidemiologia , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Comorbidade , Estudos Transversais , Feminino , Humanos , Masculino , Turquia/epidemiologiaRESUMO
Interest in brain-derived neurotrophic factor (BDNF) was greatly enhanced when it was recognized that its expression is reduced in neurodegenerative disorders, especially in Alzheimer's disease (AD). BDNF signaling through the TrkB receptor has a central role in promoting synaptic transmission, synaptogenesis, and facilitating synaptic plasticity making the BDNF-TrkB signaling pathway an attractive candidate for targeted therapies. Here we investigated the early effect of the small molecule TrkB agonist, 7,8 dihydroxyflavone (7,8-DHF), on AD-related pathology, dendritic arborization, synaptic density, and neurochemical changes in the 5xFAD mouse model of AD. We treated 5xFAD mice with 7,8-DHF for 2 months beginning at 1 month of age. We found that, in this model of AD, 7,8-DHF treatment decreased cortical Aß plaque deposition and protected cortical neurons against reduced dendritic arbor complexity but had no significant impact on the density of dendritic spines. In addition 7,8-DHF treatment protected against hippocampal increase in the level of choline-containing compounds and glutamate loss, but had no significant impact on hippocampal neurogenesis.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Flavonas/farmacologia , Fármacos Neuroprotetores/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Camundongos , Fragmentos de Peptídeos/metabolismoRESUMO
Gulf War Illness (GWI) is a chronic disease that affects the 1991 Gulf War (GW) veterans for which treatment is lacking. It has been hypothesized that drugs used to protect military personnel from chemical attacks and insects during the war: pyridostigmine bromide (PB),N, N-diethyl-m-toluamide (DEET), and permethrin (PER) together with stress may have contributed collectively and synergistically to generate GWI. There is a need to find markers of pathology to be used in pre-clinical trials. For this purpose we employed a previously validated mouse model of GWI evoked by daily exposure to PB (1.3â¯mg/kg), DEET (40â¯mg/kg), PER (0.13â¯mg/kg), and 5â¯min of restraint stress for 28â¯days to analyze behavior, brain pathology and neurochemical outcomes three months later. GWI-model mice were characterized by increased anxiety, decreased hippocampal levels of N-acetyl aspartate, GABA, the GABA-producing enzyme GAD-67 and microglial activation. We also observed that GWI model was sexually dimorphic on some measures: males had increased while females had decreased protein levels of the acetylcholine-synthesizing enzyme, choline acetyltransferase, in the septum and hippocampus and decreased levels of the receptor for brain-derived neurotrophic factor, TrkB140, in the hippocampus. Increased hippocampal levels of nerve growth factor were detected in males only. Together the data show behavioral and neuropathological abnormalities detected at 3â¯months post-exposure and that some of them are sexually dimorphic. Future preclinical studies for GWI may take advantage of this short latency model and should include both males and females as their response to treatment may differ.
Assuntos
Acetilcolina/metabolismo , Ansiedade/complicações , Modelos Animais de Doenças , Encefalite/complicações , Síndrome do Golfo Pérsico/etiologia , Ácido gama-Aminobutírico/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , DEET/administração & dosagem , Feminino , Masculino , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/metabolismo , Permetrina/administração & dosagem , Síndrome do Golfo Pérsico/metabolismo , Brometo de Piridostigmina/administração & dosagem , Estresse Psicológico/complicaçõesRESUMO
Traumatic brain injury has been associated with increased risk of Parkinson disease and parkinsonism, and parkinsonism and Lewy body disease (LBD) can occur with chronic traumatic encephalopathy (CTE). To test whether contact sports and CTE are associated with LBD, we compared deceased contact sports athletes (n = 269) to cohorts from the community (n = 164) and the Boston University Alzheimer disease (AD) Center (n = 261). Participants with CTE and LBD were more likely to have ß-amyloid deposition, dementia, and parkinsonism than CTE alone (p < 0.05). Traditional and hierarchical clustering showed a similar pattern of LBD distribution in CTE compared to LBD alone that was most frequently neocortical, limbic, or brainstem. In the community-based cohort, years of contact sports play were associated with neocortical LBD (OR = 1.30 per year, p = 0.012), and in a pooled analysis a threshold of >8 years of play best predicted neocortical LBD (ROC analysis, OR = 6.24, 95% CI = 1.5-25, p = 0.011), adjusting for age, sex, and APOE É4 allele status. Clinically, dementia was significantly associated with neocortical LBD, CTE stage, and AD; parkinsonism was associated with LBD pathology but not CTE stage. Contact sports participation may increase risk of developing neocortical LBD, and increased LBD frequency may partially explain extrapyramidal motor symptoms sometimes observed in CTE.