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1.
Int J Mol Sci ; 22(12)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208374

RESUMO

Previous studies have demonstrated that pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, inhibits ischemia-induced brain injury. The present study was conducted to examine whether pioglitazone can reduce impairment of behavioral deficits mediated by inflammatory-induced brain white matter injury in neonatal rats. Intraperitoneal (i.p.) injection of lipopolysaccharide (LPS, 2 mg/kg) was administered to Sprague-Dawley rat pups on postnatal day 5 (P5), and i.p. administration of pioglitazone (20 mg/kg) or vehicle was performed 5 min after LPS injection. Sensorimotor behavioral tests were performed 24 h after LPS exposure, and changes in biochemistry of the brain was examined after these tests. The results show that systemic LPS exposure resulted in impaired sensorimotor behavioral performance, reduction of oligodendrocytes and mitochondrial activity, and increases in lipid peroxidation and brain inflammation, as indicated by the increment of interleukin-1ß (IL-1ß) levels and number of activated microglia in the neonatal rat brain. Pioglitazone treatment significantly improved LPS-induced neurobehavioral and physiological disturbances including the loss of body weight, hypothermia, righting reflex, wire-hanging maneuver, negative geotaxis, and hind-limb suspension in neonatal rats. The neuroprotective effect of pioglitazone against the loss of oligodendrocytes and mitochondrial activity was associated with attenuation of LPS-induced increment of thiobarbituric acid reactive substances (TBARS) content, IL-1ß levels and number of activated microglia in neonatal rats. Our results show that pioglitazone prevents neurobehavioral disturbances induced by systemic LPS exposure in neonatal rats, and its neuroprotective effects are associated with its impact on microglial activation, IL-1ß induction, lipid peroxidation, oligodendrocyte production and mitochondrial activity.


Assuntos
Comportamento Animal , Encefalite/tratamento farmacológico , Mitocôndrias/patologia , Pioglitazona/uso terapêutico , Substância Branca/patologia , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Citocinas/metabolismo , Complexo I de Transporte de Elétrons/metabolismo , Encefalite/patologia , Feminino , Hipotermia Induzida , Lipopolissacarídeos , Microglia/efeitos dos fármacos , Microglia/patologia , Mitocôndrias/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/patologia , Pioglitazona/farmacologia , Gravidez , Ratos Sprague-Dawley , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Perda de Peso/efeitos dos fármacos , Substância Branca/efeitos dos fármacos
2.
Neurology ; 97(6): e543-e553, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34088875

RESUMO

OBJECTIVE: To assess whether chronic white matter inflammation in patients with multiple sclerosis (MS) as detected in vivo by paramagnetic rim MRI lesions (PRLs) is associated with higher serum neurofilament light chain (sNfL) levels, a marker of neuroaxonal damage. METHODS: In 118 patients with MS with no gadolinium-enhancing lesions or recent relapses, we analyzed 3D-submillimeter phase MRI and sNfL levels. Histopathologic evaluation was performed in 25 MS lesions from 20 additional autopsy MS cases. RESULTS: In univariable analyses, participants with ≥2 PRLs (n = 43) compared to those with ≤1 PRL (n = 75) had higher age-adjusted sNfL percentiles (median, 91 and 68; p < 0.001) and higher Multiple Sclerosis Severity Scale scores (MSSS median, 4.3 and 2.4; p = 0.003). In multivariable analyses, sNfL percentile levels were higher in PRLs ≥2 cases (ßadd, 16.3; 95% confidence interval [CI], 4.6-28.0; p < 0.01), whereas disease-modifying treatment (DMT), Expanded Disability Status Scale (EDSS) score, and T2 lesion load did not affect sNfL. In a similar model, sNfL percentile levels were highest in cases with ≥4 PRLs (n = 30; ßadd, 30.4; 95% CI, 15.6-45.2; p < 0.01). Subsequent multivariable analysis revealed that PRLs ≥2 cases also had higher MSSS (ßadd, 1.1; 95% CI, 0.3-1.9; p < 0.01), whereas MSSS was not affected by DMT or T2 lesion load. On histopathology, both chronic active and smoldering lesions exhibited more severe acute axonal damage at the lesion edge than in the lesion center (edge vs center: p = 0.004 and p = 0.0002, respectively). CONCLUSION: Chronic white matter inflammation was associated with increased levels of sNfL and disease severity in nonacute MS, suggesting that PRL contribute to clinically relevant, inflammation-driven neurodegeneration.


Assuntos
Axônios/patologia , Inflamação , Esclerose Múltipla , Proteínas de Neurofilamentos/sangue , Substância Branca , Adulto , Feminino , Humanos , Inflamação/sangue , Inflamação/diagnóstico por imagem , Inflamação/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Esclerose Múltipla/fisiopatologia , Índice de Gravidade de Doença , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
3.
Neurology ; 97(8): e814-e824, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34099524

RESUMO

OBJECTIVE: To evaluate whether orthostatic hypotension (OH) or supine hypertension (SH) is associated with brain atrophy and white matter hyperintensities (WMH), we analyzed clinical and radiologic data from a large multicenter consortium of patients with Parkinson disease (PD) and dementia with Lewy bodies (DLB). METHODS: Supine and orthostatic blood pressure (BP) and structural MRI data were extracted from patients with PD and DLB evaluated at 8 tertiary-referral centers in the United States, Canada, Italy, and Japan. OH was defined as a systolic/diastolic BP fall ≥20/10 mm Hg within 3 minutes of standing from the supine position (severe ≥30/15 mm Hg) and SH as a BP ≥140/90 mm Hg with normal sitting BP. Diagnosis-, age-, sex-, and disease duration-adjusted differences in global and regional cerebral atrophy and WMH were appraised with validated semiquantitative rating scales. RESULTS: A total of 384 patients (310 with PD, 74 with DLB) met eligibility criteria, of whom 44.3% (n = 170) had OH, including 24.7% (n = 42) with severe OH and 41.7% (n = 71) with SH. OH was associated with global brain atrophy (p = 0.004) and regional atrophy involving the anterior-temporal (p = 0.001) and mediotemporal (p = 0.001) regions, greater in severe vs nonsevere OH (p = 0.001). The WMH burden was similar in those with and without OH (p = 0.49). SH was not associated with brain atrophy (p = 0.59) or WMH (p = 0.72). CONCLUSIONS: OH, but not SH, was associated with cerebral atrophy in Lewy body disorders, with prominent temporal region involvement. Neither OH nor SH was associated with WMH.


Assuntos
Hipotensão Ortostática/fisiopatologia , Doença por Corpos de Lewy/patologia , Doença de Parkinson/patologia , Lobo Temporal/patologia , Substância Branca/patologia , Idoso , Idoso de 80 Anos ou mais , Atrofia/patologia , Feminino , Humanos , Hipotensão Ortostática/etiologia , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Índice de Gravidade de Doença , Lobo Temporal/diagnóstico por imagem , Substância Branca/diagnóstico por imagem
4.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067023

RESUMO

Classical inflammation in response to bacterial, parasitic, or viral infections such as HIV includes local recruitment of neutrophils and macrophages and the production of proinflammatory cytokines and chemokines. Proposed biomarkers of organ integrity in Alcohol Use Disorders (AUD) include elevations in peripheral plasma levels of proinflammatory proteins. In testing this proposal, previous work included a group of human immunodeficiency virus (HIV)-infected individuals as positive controls and identified elevations in the soluble proteins TNFα and IP10; these cytokines were only elevated in AUD individuals seropositive for hepatitis C infection (HCV). The current observational, cross-sectional study evaluated whether higher levels of these proinflammatory cytokines would be associated with compromised brain integrity. Soluble protein levels were quantified in 86 healthy controls, 132 individuals with AUD, 54 individuals seropositive for HIV, and 49 individuals with AUD and HIV. Among the patient groups, HCV was present in 24 of the individuals with AUD, 13 individuals with HIV, and 20 of the individuals in the comorbid AUD and HIV group. Soluble protein levels were correlated to regional brain volumes as quantified with structural magnetic resonance imaging (MRI). In addition to higher levels of TNFα and IP10 in the 2 HIV groups and the HCV-seropositive AUD group, this study identified lower levels of IL1ß in the 3 patient groups relative to the control group. Only TNFα, however, showed a relationship with brain integrity: in HCV or HIV infection, higher peripheral levels of TNFα correlated with smaller subcortical white matter volume. These preliminary results highlight the privileged status of TNFα on brain integrity in the context of infection.


Assuntos
Alcoolismo/sangue , Infecções por HIV/sangue , Hepatite C/sangue , Fator de Necrose Tumoral alfa/sangue , Substância Branca/patologia , Alcoolismo/complicações , Comorbidade , Feminino , Infecções por HIV/complicações , Hepatite C/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Análise de Componente Principal , Solubilidade
5.
Medicine (Baltimore) ; 100(25): e26387, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160417

RESUMO

RATIONALE: Group B Streptococcus (GBS) remains a principal pathogen causing neonatal sepsis and meningitis, particularly in premature infants with relatively insufficient immunity. Recurrence may occur uncommonly, largely associated with subclinical mucosal persistence or repetitive exposure to exogenous sources. White matter injury (WMI) including cystic periventricular leukomalacia (PVL) has been associated with intrauterine infection/inflammation, and neonatal infection as a more significant predictor including postnatal sepsis and recurrent infection, even without microbial neuroinvasion. Furthermore, clinical and experimental evidence of WMI by some bacteria other than GBS without central nervous system invasion has been reported. However, there is little evidence of WMI associated with neonatal GBS sepsis in the absence of meningitis in the literature. PATIENT CONCERNS: A newborn at 30+4 weeks' gestation with low birthweight presented with 2 episodes (with a 13-day interval with no antibiotic therapy) of neonatal sepsis culture-proven for GBS with early-onset presentation after clinical chorioamnionitis via vertical GBS transmission and the associated conditions including prematurity-related neonatal immunodeficiency and persistent mucosal GBS carriage after the first antibiotic treatment. The perinatal GBS infection was complicated by progressive WMI presenting with ventriculomegaly and cystic PVL without a definite evidence of meningitis, intraventricular hemorrhage, and documented cerebral hypoxia or hypoperfusion conditions including septic shock. DIAGNOSES: Recurrent group B streptococcal sepsis and cystic PVL with ventriculomegaly. INTERVENTIONS: Two episodes of GBS sepsis were treated with 15-day parenteral antibiotic therapy, respectively. OUTCOMES: Resolution of the recurrent GBS sepsis without further relapses, however, complicated by WMI and subsequent about 6 months delay in motor development at 12 months' corrected age. LESSONS: This case suggests WMI associated with GBS bacteremia without central nervous system entry by viable GBS and also shows that in premature infants, intrauterine GBS infection with no interventions may lead to extensive and persistent GBS colonization, early-onset and recurrent GBS disease, and WMI. Postnatal as well as intrauterine infection/inflammation controls with maternal prophylaxis may be pivotal for prevention and limiting the magnitude of neurologic injury.


Assuntos
Leucomalácia Periventricular/microbiologia , Sepse Neonatal/microbiologia , Complicações Infecciosas na Gravidez/microbiologia , Infecções Estreptocócicas/complicações , Streptococcus agalactiae/isolamento & purificação , Administração Intravenosa , Antibacterianos/administração & dosagem , Corioamnionite/diagnóstico , Corioamnionite/microbiologia , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/microbiologia , Quimioterapia Combinada/métodos , Feminino , Humanos , Hidrocefalia/diagnóstico , Hidrocefalia/microbiologia , Lactente , Recém-Nascido de Baixo Peso , Recém-Nascido , Recém-Nascido Prematuro , Transmissão Vertical de Doenças Infecciosas , Leucomalácia Periventricular/diagnóstico , Leucomalácia Periventricular/patologia , Imageamento por Ressonância Magnética , Masculino , Idade Materna , Sepse Neonatal/diagnóstico , Sepse Neonatal/terapia , Gravidez , Complicações Infecciosas na Gravidez/diagnóstico , Recidiva , Infecções Estreptocócicas/diagnóstico , Infecções Estreptocócicas/microbiologia , Infecções Estreptocócicas/transmissão , Substância Branca/diagnóstico por imagem , Substância Branca/microbiologia , Substância Branca/patologia , Adulto Jovem
6.
Neuropsychology ; 35(3): 252-264, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33970659

RESUMO

Objective: Abnormal white matter (AWM) on magnetic resonance imaging is associated with cognitive performance in older adults. We explored cognitive associations with AWM during late-midlife. Method: Participants were community-dwelling men (n = 242; M = 61.90 years; range = 56-66). Linear-mixed effects regression models examined associations of total, periventricular, and deep AWM with cognitive performance, controlling for multiple comparisons. Models considering specific cognitive domains controlled for current general cognitive ability (GCA). We hypothesized that total AWM would be associated with worse processing speed, executive function, and current GCA; deep AWM would correlate with GCA and periventricular AWM would relate to specific cognitive abilities. We also assessed the potential influence of cognitive reserve by examining a moderation effect of early life (mean age of 20) cognition. Results: Greater total and deep AWM were associated with poorer current GCA. Periventricular AWM was associated with worse executive function, working memory, and episodic memory. When periventricular and deep AWM were modeled simultaneously, both retained their respective significant associations with cognitive performance. Cognitive reserve did not moderate associations. Conclusions: Our findings suggest that AWM contributes to poorer cognitive function in late-midlife. Examining only total AWM may obscure the potential differential impact of regional AWM. Separating total AWM into subtypes while controlling for current GCA revealed a dissociation in relationships with cognitive performance; deep AWM was associated with nonspecific cognitive ability whereas periventricular AWM was associated with specific frontal-related abilities and memory. Management of vascular or other risk factors that may increase the risk of AWM should begin during or before early late-midlife. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Cognição/fisiologia , Disfunção Cognitiva/diagnóstico por imagem , Função Executiva , Leucoencefalopatias/diagnóstico por imagem , Memória Episódica , Memória de Curto Prazo , Substância Branca/diagnóstico por imagem , Idoso , Disfunção Cognitiva/fisiopatologia , Humanos , Vida Independente , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Tamanho do Órgão , Fatores de Risco , Substância Branca/patologia
7.
Mol Genet Metab ; 133(2): 193-200, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33962822

RESUMO

OBJECTIVE: To quantify changes in segmented brain volumes over 12 months in children with mucopolysaccharidosis types IIIA and IIIB (MPS IIIA and IIIB). METHODS: In order to establish suitable outcome measures for clinical trials, twenty-five children greater than 2 years of age were enrolled in a prospective natural history study of MPS IIIA and IIIB at Nationwide Children's Hospital. Data from sedated non-contrast brain 3 T MRIs and neuropsychological measures were reviewed from the baseline visit and at 12-month follow-up. No intervention beyond standard clinical care was provided. Age- and sex-matched controls were gathered from the National Institute of Mental Health Data Archive. Automated brain volume segmentation with longitudinal processing was performed using FreeSurfer. RESULTS: Of the 25 subjects enrolled with MPS III, 17 children (4 females, 13 males) completed at least one MRI with interpretable volumetric data. The ages ranged from 2.8 to 13.7 years old (average 7.2 years old) at enrollment, including 8 with MPS IIIA and 9 with MPS IIIB. At baseline, individuals with MPS III demonstrated reduced cerebral white matter and corpus callosum volumes, but greater volumes of the lateral ventricles, cerebellar cortex, and cerebellar white matter compared to controls. Among the 13 individuals with MPS III with two interpretable MRIs, there were annualized losses or plateaus in supratentorial brain tissue volumes (cerebral cortex -42.10 ± 18.52 cm3/year [mean ± SD], cerebral white matter -4.37 ± 11.82 cm3/year, subcortical gray matter -6.54 ± 3.63 cm3/year, corpus callosum -0.18 ± 0.62 cm3/yr) and in cerebellar cortex (-0.49 ± 12.57 cm3/year), with a compensatory increase in lateral ventricular volume (7.17 ± 6.79 cm3/year). Reductions in the cerebral cortex and subcortical gray matter were more striking in individuals younger than 8 years of age. Greater cerebral cortex volume was associated with higher fine and gross motor functioning on the Mullen Scales of Early Learning, while greater subcortical gray matter volume was associated with higher nonverbal functioning on the Leiter International Performance Scale. Larger cerebellar cortex was associated with higher receptive language performance on the Mullen, but greater cerebellar white matter correlated with worse adaptive functioning on the Vineland Adaptive Behavioral Scales and visual problem-solving on the Mullen. CONCLUSIONS: Loss or plateauing of supratentorial brain tissue volumes may serve as longitudinal biomarkers of MPS III age-related disease progression compared to age-related growth in typically developing controls. Abnormally increased cerebellar white matter in MPS III, and its association with worse performance on neuropsychological measures, suggest the possibility of pathophysiological mechanisms distinct from neurodegeneration-associated atrophy that warrant further investigation.


Assuntos
Encéfalo/diagnóstico por imagem , Aprendizagem/fisiologia , Mucopolissacaridose III/diagnóstico por imagem , Adolescente , Encéfalo/metabolismo , Criança , Pré-Escolar , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/metabolismo , Corpo Caloso/patologia , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Mucopolissacaridose III/metabolismo , Mucopolissacaridose III/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Substância Branca/patologia
9.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33947043

RESUMO

Neonatal arterial ischemic stroke is one of the more severe birth complications. The injury can result in extensive neurological damage and is robustly associated with later diagnoses of cerebral palsy (CP). An important part of efforts to develop new therapies include the on-going refinement and understanding of animal models that capture relevant clinical features of neonatal brain injury leading to CP. The potent vasoconstrictor peptide, Endothelin-1 (ET-1), has previously been utilised in animal models to reduce local blood flow to levels that mimic ischemic stroke. Our previous work in this area has shown that it is an effective and technically simple approach for modelling ischemic injury at very early neonatal ages, resulting in stable deficits in motor function. Here, we aimed to extend this model to also examine the impact on cognitive function. We show that focal delivery of ET-1 to the cortex of Sprague Dawley rats on postnatal day 0 (P0) resulted in impaired learning in a touchscreen-based test of visual discrimination and correlated with important clinical features of CP including damage to large white matter structures.


Assuntos
Isquemia Encefálica/complicações , Paralisia Cerebral/etiologia , Modelos Animais de Doenças , Endotelina-1/toxicidade , Vasoconstritores/toxicidade , Animais , Animais Recém-Nascidos , Aprendizagem por Associação , Atrofia , Isquemia Encefálica/induzido quimicamente , Isquemia Encefálica/patologia , Contagem de Células , Córtex Cerebral/patologia , Paralisia Cerebral/patologia , Transtornos Cognitivos/etiologia , Corpo Estriado/patologia , Endotelina-1/administração & dosagem , Inflamação , Injeções , Microglia/patologia , Transtornos dos Movimentos/etiologia , Neurônios/patologia , Transtornos da Percepção/etiologia , Ratos , Ratos Sprague-Dawley , Teste de Desempenho do Rota-Rod , Vasoconstritores/administração & dosagem , Substância Branca/patologia
10.
AJNR Am J Neuroradiol ; 42(7): 1190-1195, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33888458

RESUMO

BACKGROUND: Neurologic events have been reported in patients with coronavirus disease 2019 (COVID-19). However, a model-based evaluation of the spatial distribution of these events is lacking. PURPOSE: Our aim was to quantitatively evaluate whether a network diffusion model can explain the spread of small neurologic events. DATA SOURCES: The MEDLINE, EMBASE, Scopus, and LitCovid data bases were searched from January 1, 2020, to July 19, 2020. STUDY SELECTION: Thirty-five case series and case studies reported 317 small neurologic events in 123 unique patients with COVID-19. DATA ANALYSIS: Neurologic events were localized to gray or white matter regions of the Illinois Institute of Technology (gray-matter and white matter) Human Brain Atlas using radiologic images and descriptions. The total proportion of events was calculated for each region. A network diffusion model was implemented, and any brain regions showing a significant association (P < .05, family-wise error-corrected) between predicted and measured events were considered epicenters. DATA SYNTHESIS: Within gray matter, neurologic events were widely distributed, with the largest number of events (∼10%) observed in the bilateral superior temporal, precentral, and lateral occipital cortices, respectively. Network diffusion modeling showed a significant association between predicted and measured gray matter events when the spread of pathology was seeded from the bilateral cerebellum (r = 0.51, P < .001, corrected) and putamen (r = 0.4, P = .02, corrected). In white matter, most events (∼26%) were observed within the bilateral corticospinal tracts. LIMITATIONS: The risk of bias was not considered because all studies were either case series or case studies. CONCLUSIONS: Transconnectome diffusion of pathology via the structural network of the brain may contribute to the spread of neurologic events in patients with COVID-19.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/patologia , COVID-19/diagnóstico por imagem , COVID-19/patologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
11.
Aging (Albany NY) ; 13(8): 11352-11362, 2021 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-33833133

RESUMO

BACKGROUND: Three polymorphisms in the Methylenetetrahydrofolate reductase (MTHFR) gene (C677T, A1298C, and A1793G) were reported associated with AD. However, their genotype distributions and associations with age at onset (AAO), homocysteine, and white matter lesions (WML) were unclear in the Chinese AD population. METHOD: We determined the presence of C677T, A1298C, and A1793G polymorphisms in the MTHFR gene using Sanger sequencing in a Chinese cohort comprising 721 AD patients (318 early-onset AD patients (EOAD) and 403 late-onset AD patients (LOAD)) and 365 elderly controls. Additionally, the homocysteine level and WML were evaluated in 121 AD patients. RESULTS: The frequency of allele T of C677T polymorphism was significantly higher in AD patients than in controls (P = 0.040), while no statistical difference was observed in A1298C and A1793G (P > 0.05). Besides, genotype distributions of C677T and A1298C polymorphisms statistically varied between AD patients and controls (P = 0.021, P = 0.012). Moreover, the AAO was significantly lower in CT/TT (C677T) genotypes carriers (P = 0.042) and higher in AC/CC (A1298C) and AG/GG (A1793G) genotypes carriers (P = 0.034, P = 0.009) in patients with LOAD. We also found that patients with CT/TT (C677T) genotypes were prone to present an increased homocysteine level (P = 0.036) and higher Fazekas score (P = 0.024). In comparison, patients with AG/GG genotypes (A1793G) had a significantly lower Fazekas score (P = 0.013). CONCLUSIONS: The genotype distributions of C677T and A1298C polymorphisms are associated with AD in the Chinese population. Moreover, AD patients with C677T polymorphism are prone to present an earlier onset, higher homocysteine level, and more severe WML.


Assuntos
Doença de Alzheimer/genética , Predisposição Genética para Doença , Homocisteína/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Substância Branca/patologia , Idade de Início , Idoso , Alelos , Doença de Alzheimer/sangue , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Feminino , Homocisteína/metabolismo , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
12.
Life Sci ; 278: 119526, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33894268

RESUMO

AIMS: White matter damage is the main pathological feature of chronic cerebral hypoperfusion (CCH) and glial activation is crucial in this process. Physical exercise has protective effects on CCH, but the mechanism is unclear. Therefore, this study focuses on investigating the influence of physical exercise on activated astrocytes polarization and its role in CCH. MAIN METHODS: Rats were given wheel running 48 h after 2VO (2 vessel occlusion) surgery. The cognitive function was evaluated by Morris water maze and novel object recognition test. Inflammatory cytokines expressions were detected by ELISA. Astrocytes polarization was analyzed by immunofluorescence. Myelin debris clearance and remyelination were detected by immunofluorescence and transmission electron microscopy. KEY FINDINGS: Astrocytes were activated and mainly switched to A1 phenotype in rats 2 and 3 months after 2VO. Myelin debris deposition and limited remyelination can be observed at the corresponding time. Whereas physical exercise can improve the cognitive function of 2VO rats, downregulate the expression of inflammatory factors IL-1α, C1q and TNF, upregulate the release of TGFß, and promote activated astrocytes transformation from A1 to A2 phenotype. In addition, it can also enhance myelin debris removal and remyelination. SIGNIFICANCE: These findings suggest that the benefits of physical exercise on white matter repair and cognition improvement may be related to its regulation of astrocytes polarization, which contributes to myelin debris clearance and effective remyelination in CCH.


Assuntos
Astrócitos/citologia , Astrócitos/metabolismo , Bainha de Mielina/química , Neuroglia/metabolismo , Condicionamento Físico Animal , Substância Branca/patologia , Animais , Isquemia Encefálica/patologia , Cognição/efeitos dos fármacos , Lobo Frontal/efeitos dos fármacos , Inflamação , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Microglia/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência , Atividade Motora , Reconhecimento Visual de Modelos , Perfusão , Fenótipo , Ratos , Ratos Wistar , Remielinização
13.
Aging (Albany NY) ; 13(8): 10973-10988, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33861727

RESUMO

Neuroimaging measures of Alzheimer's disease (AD) include grey matter volume (GMV) alterations in the Default Mode Network (DMN) and Executive Control Network (ECN). Small-vessel cerebrovascular disease, often visualised as white matter hyperintensities (WMH) on MRI, is often seen in AD. However, the relationship between WMH load and GMV needs further examination. We examined the load-dependent influence of WMH on GMV and cognition in 183 subjects. T1-MRI data from 93 Mild Cognitive Impairment (MCI) and 90 cognitively normal subjects were studied and WMH load was categorized into low, medium and high terciles. We examined how differing loads of WMH related to whole-brain voxel-wise and regional DMN and ECN GMV. We further investigated how regional GMV moderated the relationship between WMH and cognition. We found differential load-dependent effects of WMH burden on voxel-wise and regional atrophy in only MCI. At high load, as expected WMH negatively related to both ECN and DMN GMV, however at low load, WMH positively related to ECN GMV. Additionally, negative associations between WMH and memory and executive function were moderated by regional GMV. Our results demonstrate non-unidirectional relationships between WMH load, GMV and cognition in MCI.


Assuntos
Doença de Alzheimer/complicações , Disfunção Cognitiva/patologia , Substância Cinzenta/patologia , Substância Branca/patologia , Idoso , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Atrofia/diagnóstico , Atrofia/etiologia , Atrofia/patologia , Estudos de Casos e Controles , Cognição/fisiologia , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Função Executiva/fisiologia , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/fisiopatologia , Voluntários Saudáveis , Humanos , Imageamento por Ressonância Magnética , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Neuroimagem/métodos , Testes Neuropsicológicos , Substância Branca/diagnóstico por imagem , Substância Branca/fisiopatologia
14.
Int J Mol Sci ; 22(9)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925469

RESUMO

In multiple sclerosis (MS), oligodendrocyte precursor cells (OPCs) are recruited to the site of injury to remyelinate damaged axons; however, in patients this process is often ineffective due to defects in OPC maturation. The membrane receptor GPR17 timely regulates the early stages of OPC differentiation; however, after reaching its highest levels in immature oligodendrocytes, it has to be downregulated to allow terminal maturation. Since, in several animal models of disease GPR17 is upregulated, the aim of this work was to characterize GPR17 alterations in MS patients. We developed immunohistochemistry and immunofluorescence procedures for the detection of GPR17 in human tissues and stained post-mortem MS brain lesions from patients with secondary progressive MS and control subjects. The inflammatory activity in each lesion was evaluated by immunohistochemistry for the myelin protein MOG and the HLA antigen to classify them as active, chronic inactive or chronic active. Hence, we assessed the distribution of GPR17-positive cells in these lesions compared to normal appearing white matter (NAWM) and white matter (WM) of control subjects. Our data have shown a marked increase of GPR17-expressing oligodendroglial cells accumulating at NAWM, in which moderate inflammation was also found. Furthermore, we identified two distinct subpopulations of GPR17-expressing oligodendroglial cells, characterized by either ramified or rounded morphology, that differently populate the WM of healthy controls and MS patients. We concluded that the coordinated presence of GPR17 in OPCs at the lesion sites and inflamed NAWM areas suggests that GPR17 could be exploited to support endogenous remyelination through advanced pharmacological approaches.


Assuntos
Encefalite/metabolismo , Esclerose Múltipla/patologia , Receptores Acoplados a Proteínas G/metabolismo , Substância Branca/patologia , Adulto , Encefalite/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/metabolismo , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Substância Branca/metabolismo
15.
Medicine (Baltimore) ; 100(17): e25751, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33907171

RESUMO

ABSTRACT: Disrupted blood-brain barrier (BBB) in patients with ischemic stroke plays a critical role in malignant middle cerebral artery infarction (MMI) development.Cerebral white matter changes (WMC), particularly in the deep subcortical area or in severe one, may be also underlain by disrupted BBB. It is unclear whether the presence of WMC with potential premorbid disruption of BBB makes patients susceptible to MMI. Therefore, this study aimed to clarify any putative relationship between the MMI and WMC in terms of their severity and locations.In this case-control study, patients with infarction in the middle cerebral artery territory were retrospectively reviewed. Brain magnetic resonance images were analyzed according to Fazekas scale, and identified WMC were divided into periventricular WMC (PV-WMC) and deep subcortical WMC (deep-WMC). Patients were scored as having WMC, PV-WMC, deep-WMC, severe PV-WMC, and severe deep-WMC according to the severity and locations. Patients were defined as having MMI if either a progressive conscious disturbance or signs of uncal herniation was recorded in combination with a midline shift >5 mm identified on the follow-up computed tomography.Among 297 patients admitted between July 2009 and February 2015, 92 patients were eligible for final analysis. Compared to patients without MMI, patients with MMI had a higher score of National Institutes of Health Stroke Scale, a larger infarct volume, and an increasingly greater proportion of severe PV-WMC, deep-WMC, and severe deep-WMC, respectively. After adjustment for sex, age, infarct volume, and history of hypertension, severe deep-WMC (odds ratio [OR] = 6.362, 95% confidence interval [CI] = 1.444-28.023, P = .0144) and severe PV-WMC (odds ratio = 5.608, 95% confidence interval = 1.107-28.399, P = .0372) were significantly associated with MMI development.MMI and WMC are significantly associated such that MMI development is more likely when PV-WMC or deep-WMC is more severe. We hypothesize that Fazekas scale-defined severe deep-WMC and PV-WMC may be considered as clinically approachable predictors of MMI development. These findings support that the WMC with potential premorbid disrupted BBB may make patients susceptible to MMI, and further prospective study should be conducted to clarify this hypothesis.


Assuntos
Barreira Hematoencefálica/fisiopatologia , Infarto da Artéria Cerebral Média , AVC Isquêmico , Substância Branca , Idoso , Estudos de Casos e Controles , Correlação de Dados , Imagem de Difusão por Ressonância Magnética/métodos , Suscetibilidade a Doenças , Feminino , Humanos , Infarto da Artéria Cerebral Média/diagnóstico , Infarto da Artéria Cerebral Média/epidemiologia , Infarto da Artéria Cerebral Média/fisiopatologia , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/patologia , Masculino , Índice de Gravidade de Doença , Taiwan/epidemiologia , Tomografia Computadorizada por Raios X/métodos , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Substância Branca/fisiopatologia
16.
Molecules ; 26(6)2021 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-33802165

RESUMO

Dementia is one of the most disabling non-motor symptoms in Parkinson's disease (PD). Unlike in Alzheimer's disease, the vascular pathology in PD is less documented. Due to the uncertain role of commonly investigated metabolic or vascular factors, e.g., hypertension or diabetes, other factors corresponding to PD dementia have been proposed. Associated dysautonomia and dopaminergic treatment seem to have an impact on diurnal blood pressure (BP) variability, which may presumably contribute to white matter hyperintensities (WMH) development and cognitive decline. We aim to review possible vascular and metabolic factors: Renin-angiotensin-aldosterone system, vascular endothelial growth factor (VEGF), hyperhomocysteinemia (HHcy), as well as the dopaminergic treatment, in the etiopathogenesis of PD dementia. Additionally, we focus on the role of polymorphisms within the genes for catechol-O-methyltransferase (COMT), apolipoprotein E (APOE), vascular endothelial growth factor (VEGF), and for renin-angiotensin-aldosterone system components, and their contribution to cognitive decline in PD. Determining vascular risk factors and their contribution to the cognitive impairment in PD may result in screening, as well as preventive measures.


Assuntos
Disfunção Cognitiva/fisiopatologia , Doença de Parkinson/fisiopatologia , Apolipoproteínas E/genética , Pressão Arterial/fisiologia , Catecol O-Metiltransferase/genética , Catecol O-Metiltransferase/metabolismo , Disfunção Cognitiva/sangue , Humanos , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/fisiopatologia , Doença de Parkinson/sangue , Sistema Renina-Angiotensina/fisiologia , Fatores de Risco , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/fisiologia , Substância Branca/patologia
17.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802612

RESUMO

Frontotemporal dementia (FTD) is a common cause of presenile dementia and is characterized by behavioural and/or language changes and progressive cognitive deficits. Genetics is an important component in the aetiology of FTD, with positive family history of dementia reported for 40% of cases. This review synthesizes current knowledge of the known major FTD genes, including C9orf72 (chromosome 9 open reading frame 72), MAPT (microtubule-associated protein tau) and GRN (granulin), and their impact on neuronal and glial pathology. Further, evidence for white matter dysfunction in the aetiology of FTD and the clinical, neuroimaging and genetic overlap between FTD and leukodystrophy/leukoencephalopathy are discussed. The review highlights the role of common variants and mutations in genes such as CSF1R (colony-stimulating factor 1 receptor), CYP27A1 (cytochrome P450 family 27 subfamily A member 1), TREM2 (triggering receptor expressed on myeloid cells 2) and TMEM106B (transmembrane protein 106B) that play an integral role in microglia and oligodendrocyte function. Finally, pharmacological and non-pharmacological approaches for enhancing remyelination are discussed in terms of future treatments of FTD.


Assuntos
Demência Frontotemporal/genética , Demência Frontotemporal/patologia , Leucoencefalopatias/genética , Leucoencefalopatias/patologia , Substância Branca/patologia , Animais , Humanos , Microglia/patologia , Mutação/genética , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia
18.
BMC Neurol ; 21(1): 156, 2021 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-33838643

RESUMO

BACKGROUND: Colony-stimulating factor 1 receptor (CSF1R)-related leukoencephalopathy is a rare and rapidly progressive leukoencephalopathy characterized by cognitive, motor, and neuropsychiatric symptoms, which is often misdiagnosed. Magnetic resonance imaging (MRI) signs and follow-up MRI of CSF1R-related leukoencephalopathy could help in establishing a diagnosis, but these features are not widely known by general neurologists. CASE PRESENTATION: A 34-year-old man was admitted for progressive weakness of the right limbs over 8 months. His father and sister had a similar clinical evolution. The primary neurological signs were hemiplegia, cognitive decline, dysarthria, pyramidal signs, ataxia and parkinsonism, and rapid disease progression. Cerebrospinal fluid analysis results were normal. Despite receiving treatment for improving cerebral metabolism and relieving the muscle spasm, his symptoms did not improve significantly. Brain MRI showed lesions concentrated in the corpus callosum and the deep white matter of the bilateral parieto-occipital lobes, periventricular areas, and corticospinal tracts. There was an enhanced lesion after a gadolinium-enhanced MRI scan. Over the 8-month progression, the lesions always exhibited restricted diffusion. The diffuse lesions gradually increased as the disease progressed. Genetic sequencing results showed a novel heterozygous missense mutation (c.2267 T > C p.L756P) in the CSF1R gene. The patient was treated with citicoline and idebenone for 4 days to improve cerebral metabolism, but his symptoms did not improve significantly. CONCLUSION: The multiple lesions involving the pyramidal tract and white matter showed continuously restricted diffusion on brain imaging and gradually increased with disease progression.


Assuntos
Corpo Caloso/diagnóstico por imagem , Leucoencefalopatias/diagnóstico por imagem , Tratos Piramidais/diagnóstico por imagem , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Substância Branca/diagnóstico por imagem , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Corpo Caloso/patologia , Heterozigoto , Humanos , Leucoencefalopatias/genética , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Mutação , Mutação de Sentido Incorreto , Tratos Piramidais/patologia , Irmãos , Substância Branca/patologia
19.
Pediatr Infect Dis J ; 40(7): e268-e269, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-33902081

RESUMO

Coronavirus disease 2019 (COVID-19) symptoms in newborn infants are incompletely described. We present the first case of neuroradiologic abnormality associated with COVID-19 in a newborn infant with afebrile seizure. This case underlines the possible neurologic involvement of severe acute respiratory syndrome coronavirus 2 in this age group.


Assuntos
COVID-19/complicações , Convulsões/virologia , Substância Branca/patologia , Substância Branca/virologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/virologia , COVID-19/diagnóstico , COVID-19/fisiopatologia , Febre , Humanos , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Convulsões/etiologia
20.
Nutrients ; 13(4)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919810

RESUMO

Although l-carnitine alleviated white-matter lesions in an experimental study, the treatment effects of l-carnitine on white-matter microstructural damage and cognitive decline in hemodialysis patients are unknown. Using novel diffusion magnetic resonance imaging (dMRI) techniques, white-matter microstructural changes together with cognitive decline in hemodialysis patients and the effects of l-carnitine on such disorders were investigated. Fourteen hemodialysis patients underwent dMRI and laboratory and neuropsychological tests, which were compared across seven patients each in two groups according to duration of l-carnitine treatment: (1) no or short-term l-carnitine treatment (NSTLC), and (2) long-term l-carnitine treatment (LTLC). Ten age- and sex-matched controls were enrolled. Compared to controls, microstructural disorders of white matter were widely detected on dMRI of patients. An autopsy study of one patient in the NSTLC group showed rarefaction of myelinated fibers in white matter. With LTLC, microstructural damage on dMRI was alleviated along with lower levels of high-sensitivity C-reactive protein and substantial increases in carnitine levels. The LTLC group showed better achievement on trail making test A, which was correlated with amelioration of disorders in some white-matter tracts. Novel dMRI tractography detected abnormalities of white-matter tracts after hemodialysis. Long-term treatment with l-carnitine might alleviate white-matter microstructural damage and cognitive impairment in hemodialysis patients.


Assuntos
Carnitina/administração & dosagem , Disfunção Cognitiva/prevenção & controle , Demência Vascular/prevenção & controle , Falência Renal Crônica/terapia , Fármacos Neuroprotetores/administração & dosagem , Diálise Renal/efeitos adversos , Administração Oral , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Estudos Transversais , Demência Vascular/diagnóstico , Demência Vascular/etiologia , Demência Vascular/patologia , Imagem de Tensor de Difusão , Esquema de Medicação , Feminino , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fatores de Tempo , Resultado do Tratamento , Substância Branca/diagnóstico por imagem , Substância Branca/efeitos dos fármacos , Substância Branca/patologia
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