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1.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445515

RESUMO

The impacts of sex differences on the biology of various organ systems and the influences of sex hormones on modulating health and disease have become increasingly relevant in clinical and biomedical research. A growing body of evidence has recently suggested fundamental sex differences in cardiovascular and cognitive function, including anatomy, pathophysiology, incidence and age of disease onset, symptoms affecting disease diagnosis, disease severity, progression, and treatment responses and outcomes. Atrial fibrillation (AF) is currently recognized as the most prevalent sustained arrhythmia and might contribute to the pathogenesis and progression of vascular cognitive impairment (VCI), including a range of cognitive deficits, from mild cognitive impairment to dementia. In this review, we describe sex-based differences and sex hormone functions in the physiology of the brain and vasculature and the pathophysiology of disorders therein, with special emphasis on AF and VCI. Deciphering how sex hormones and their receptor signaling (estrogen and androgen receptors) potentially impact on sex differences could help to reveal disease links between AF and VCI and identify therapeutic targets that may lead to potentially novel therapeutic interventions early in the disease course of AF and VCI.


Assuntos
Fibrilação Atrial/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Demência Vascular/fisiopatologia , Hormônios Esteroides Gonadais/metabolismo , Feminino , Humanos , Masculino , Fatores Sexuais
2.
Medicine (Baltimore) ; 100(32): e26914, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397930

RESUMO

ABSTRACT: Atrial fibrillation is considered to be the most common arrhythmia in the clinic, and it gradually increases with age. In recent years, there has been increasing evidence that atrial fibrillation may exacerbate the progression of cognitive dysfunction. The current guidelines recommend ablation for drug-refractory atrial fibrillation.We aimed to prospectively analyze changes in cognitive function in patients with atrial fibrillation following treatment using different ablation methods.A total of 139 patients, with non-valvular atrial fibrillation, were included in the study. The patients were divided into the drug therapy (n = 41) and catheter ablation (n = 98) groups, with the catheter ablation group further subdivided into radiofrequency ablation (n = 68) and cryoballoon (CY) ablation (n = 30). We evaluated cognitive function at baseline, 3- and 12-months follow-up using the Telephone Interview for Cognitive Status-modified (TICS-m) test, then analyzed differences in cognitive function between the drug therapy and catheter ablation groups, to reveal the effect of the different ablation methods.We observed a significantly higher TICS-m score (39.56 ±â€Š3.198) in the catheter ablation group at 12-month follow-up (P < .001), than the drug treatment group was. Additionally, we found no statistically significant differences in TICS-m scores between the radiofrequency ablation and CY groups at 3- and 12-month postoperatively (P > .05), although the two subgroups showed statistically significant cognitive function (P < .001).Overall, these findings indicated that radiofrequency and CY ablation improve cognitive function in patients with atrial fibrillation.


Assuntos
Fibrilação Atrial/cirurgia , Ablação por Cateter/métodos , Cognição/fisiologia , Disfunção Cognitiva/etiologia , Criocirurgia/métodos , Fibrilação Atrial/complicações , Fibrilação Atrial/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Feminino , Seguimentos , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Veias Pulmonares/cirurgia , Estudos Retrospectivos , Resultado do Tratamento
3.
Neurology ; 97(7): e706-e719, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34400568

RESUMO

OBJECTIVE: To determine similarities and differences in key predictors of recovery of bimanual hand use and unimanual motor impairment after stroke. METHOD: In this prospective longitudinal study, 89 patients with first-ever stroke with arm paresis were assessed at 3 weeks and 3 and 6 months after stroke onset. Bimanual activity performance was assessed with the Adult Assisting Hand Assessment Stroke (Ad-AHA), and unimanual motor impairment was assessed with the Fugl-Meyer Assessment (FMA). Candidate predictors included shoulder abduction and finger extension measured by the corresponding FMA items (FMA-SAFE; range 0-4) and sensory and cognitive impairment. MRI was used to measure weighted corticospinal tract lesion load (wCST-LL) and resting-state interhemispheric functional connectivity (FC). RESULTS: Initial Ad-AHA performance was poor but improved over time in all (mild-severe) impairment subgroups. Ad-AHA correlated with FMA at each time point (r > 0.88, p < 0.001), and recovery trajectories were similar. In patients with moderate to severe initial FMA, FMA-SAFE score was the strongest predictor of Ad-AHA outcome (R 2 = 0.81) and degree of recovery (R 2 = 0.64). Two-point discrimination explained additional variance in Ad-AHA outcome (R 2 = 0.05). Repeated analyses without FMA-SAFE score identified wCST-LL and cognitive impairment as additional predictors. A wCST-LL >5.5 cm3 strongly predicted low to minimal FMA/Ad-AHA recovery (≤10 and 20 points respectively, specificity = 0.91). FC explained some additional variance to FMA-SAFE score only in unimanual recovery. CONCLUSION: Although recovery of bimanual activity depends on the extent of corticospinal tract injury and initial sensory and cognitive impairments, FMA-SAFE score captures most of the variance explained by these mechanisms. FMA-SAFE score, a straightforward clinical measure, strongly predicts bimanual recovery. CLINICALTRIALSGOV IDENTIFIER: NCT02878304. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that the FMA-SAFE score predicts bimanual recovery after stroke.


Assuntos
Disfunção Cognitiva/fisiopatologia , Conectoma , Mãos/fisiopatologia , Avaliação de Resultados em Cuidados de Saúde , Paresia/fisiopatologia , Desempenho Psicomotor/fisiologia , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Adulto , Idoso , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Paresia/diagnóstico , Paresia/etiologia , Prognóstico , Índice de Gravidade de Doença , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico
4.
Neuron ; 109(16): 2590-2603.e13, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34197733

RESUMO

Neuropsychiatric disorders are often accompanied by cognitive impairments/intellectual disability (ID). It is not clear whether there are converging mechanisms underlying these debilitating impairments. We found that many autism and schizophrenia risk genes are expressed in the anterodorsal subdivision (AD) of anterior thalamic nuclei, which has reciprocal connectivity with learning and memory structures. CRISPR-Cas9 knockdown of multiple risk genes selectively in AD thalamus led to memory deficits. While the AD is necessary for contextual memory encoding, the neighboring anteroventral subdivision (AV) regulates memory specificity. These distinct functions of AD and AV are mediated through their projections to retrosplenial cortex, using differential mechanisms. Furthermore, knockdown of autism and schizophrenia risk genes PTCHD1, YWHAG, or HERC1 from AD led to neuronal hyperexcitability, and normalization of hyperexcitability rescued memory deficits in these models. This study identifies converging cellular to circuit mechanisms underlying cognitive deficits in a subset of neuropsychiatric disease models.


Assuntos
Núcleos Anteriores do Tálamo/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Vias Neurais/fisiopatologia , Núcleos Talâmicos/fisiopatologia , Animais , Núcleos Anteriores do Tálamo/fisiologia , Córtex Cerebral/fisiopatologia , Cognição/fisiologia , Camundongos , Vias Neurais/fisiologia , Núcleos Talâmicos/fisiologia
5.
Neurology ; 97(8): e836-e848, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34210821

RESUMO

OBJECTIVE: To assess the role of biomarkers of Alzheimer disease (AD), neurodegeneration, and small vessel disease (SVD) as mediators in the association between diabetes mellitus and cognition. METHODS: The study sample was derived from MEMENTO, a cohort of French adults recruited in memory clinics and screened for either isolated subjective cognitive complaints or mild cognitive impairment. Diabetes was defined based on blood glucose assessment, use of antidiabetic agent, or self-report. We used structural equation modeling to assess whether latent variables of AD pathology (PET mean amyloid uptake, Aß42/Aß40 ratio, and CSF phosphorylated tau), SVD (white matter hyperintensities volume and visual grading), and neurodegeneration (mean cortical thickness, brain parenchymal fraction, hippocampal volume, and mean fluorodeoxyglucose uptake) mediate the association between diabetes and a latent variable of cognition (5 neuropsychological tests), adjusting for potential confounders. RESULTS: There were 254 (11.1%) participants with diabetes among 2,288 participants (median age 71.6 years; 61.8% women). The association between diabetes and lower cognition was significantly mediated by higher neurodegeneration (standardized indirect effect: -0.061, 95% confidence interval: -0.089, -0.032), but not mediated by SVD and AD markers. Results were similar when considering latent variables of memory or executive functioning. CONCLUSION: In a large clinical cohort in the elderly, diabetes is associated with lower cognition through neurodegeneration, independently of SVD and AD biomarkers.


Assuntos
Doença de Alzheimer/diagnóstico , Doenças de Pequenos Vasos Cerebrais/diagnóstico , Disfunção Cognitiva/diagnóstico , Diabetes Mellitus/diagnóstico , Degeneração Neural/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores , Doenças de Pequenos Vasos Cerebrais/epidemiologia , Doenças de Pequenos Vasos Cerebrais/metabolismo , Doenças de Pequenos Vasos Cerebrais/fisiopatologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Estudos de Coortes , Comorbidade , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Feminino , França/epidemiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Degeneração Neural/epidemiologia , Degeneração Neural/metabolismo , Degeneração Neural/fisiopatologia , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons
6.
Nat Commun ; 12(1): 4623, 2021 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-34330904

RESUMO

Visceral obesity increases risk of cognitive decline in humans, but subcutaneous adiposity does not. Here, we report that beige adipocytes are indispensable for the neuroprotective and anti-inflammatory effects of subcutaneous fat. Mice lacking functional beige fat exhibit accelerated cognitive dysfunction and microglial activation with dietary obesity. Subcutaneous fat transplantation also protects against chronic obesity in wildtype mice via beige fat-dependent mechanisms. Beige adipocytes restore hippocampal synaptic plasticity following transplantation, and these effects require the anti-inflammatory cytokine interleukin-4 (IL4). After observing beige fat-mediated induction of IL4 in meningeal T-cells, we investigated the contributions of peripheral lymphocytes in donor fat. There was no sign of donor-derived lymphocyte trafficking between fat and brain, but recipient-derived lymphocytes were required for the effects of transplantation on cognition and microglial morphology. These findings indicate that beige adipocytes oppose obesity-induced cognitive impairment, with a potential role for IL4 in the relationship between beige fat and brain function.


Assuntos
Adipócitos Bege/metabolismo , Tecido Adiposo Bege/metabolismo , Adiposidade , Obesidade/metabolismo , Gordura Subcutânea/metabolismo , Adipócitos Bege/citologia , Animais , Anti-Inflamatórios/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Dieta Hiperlipídica/efeitos adversos , Humanos , Interleucina-4/metabolismo , Camundongos Obesos , Plasticidade Neuronal/fisiologia , Fármacos Neuroprotetores/metabolismo , Obesidade/etiologia , Obesidade/fisiopatologia , Gordura Subcutânea/transplante , Linfócitos T/metabolismo
7.
Theranostics ; 11(14): 6644-6667, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093845

RESUMO

Mouse models of Alzheimer's disease (AD) are valuable but do not fully recapitulate human AD pathology, such as spontaneous Tau fibril accumulation and neuronal loss, necessitating the development of new AD models. The transgenic (TG) TgF344-AD rat has been reported to develop age-dependent AD features including neuronal loss and neurofibrillary tangles, despite only expressing APP and PSEN1 mutations, suggesting an improved modelling of AD hallmarks. Alterations in neuronal networks as well as learning performance and cognition tasks have been reported in this model, but none have combined a longitudinal, multimodal approach across multiple centres, which mimics the approaches commonly taken in clinical studies. We therefore aimed to further characterise the progression of AD-like pathology and cognition in the TgF344-AD rat from young-adults (6 months (m)) to mid- (12 m) and advanced-stage (18 m, 25 m) of the disease. Methods: TgF344-AD rats and wild-type (WT) littermates were imaged at 6 m, 12 m and 18 m with [18F]DPA-714 (TSPO, neuroinflammation), [18F]Florbetaben (Aß) and [18F]ASEM (α7-nicotinic acetylcholine receptor) and with magnetic resonance spectroscopy (MRS) and with (S)-[18F]THK5117 (Tau) at 15 and 25 m. Behaviour tests were also performed at 6 m, 12 m and 18 m. Immunohistochemistry (CD11b, GFAP, Aß, NeuN, NeuroChrom) and Tau (S)-[18F]THK5117 autoradiography, immunohistochemistry and Western blot were also performed. Results: [18F]DPA-714 positron emission tomography (PET) showed an increase in neuroinflammation in TG vs wildtype animals from 12 m in the hippocampus (+11%), and at the advanced-stage AD in the hippocampus (+12%), the thalamus (+11%) and frontal cortex (+14%). This finding coincided with strong increases in brain microgliosis (CD11b) and astrogliosis (GFAP) at these time-points as assessed by immunohistochemistry. In vivo [18F]ASEM PET revealed an age-dependent increase uptake in the striatum and pallidum/nucleus basalis of Meynert in WT only, similar to that observed with this tracer in humans, resulting in TG being significantly lower than WT by 18 m. In vivo [18F]Florbetaben PET scanning detected Aß accumulation at 18 m, and (S)-[18F]THK5117 PET revealed subsequent Tau accumulation at 25m in hippocampal and cortical regions. Aß plaques were low but detectable by immunohistochemistry from 6 m, increasing further at 12 and 18 m with Tau-positive neurons adjacent to Aß plaques at 18 m. NeuroChrom (a pan neuronal marker) immunohistochemistry revealed a loss of neuronal staining at the Aß plaques locations, while NeuN labelling revealed an age-dependent decrease in hippocampal neuron number in both genotypes. Behavioural assessment using the novel object recognition task revealed that both WT & TgF344-AD animals discriminated the novel from familiar object at 3 m and 6 m of age. However, low levels of exploration observed in both genotypes at later time-points resulted in neither genotype successfully completing the task. Deficits in social interaction were only observed at 3 m in the TgF344-AD animals. By in vivo MRS, we showed a decrease in neuronal marker N-acetyl-aspartate in the hippocampus at 18 m (-18% vs age-matched WT, and -31% vs 6 m TG) and increased Taurine in the cortex of TG (+35% vs age-matched WT, and +55% vs 6 m TG). Conclusions: This multi-centre multi-modal study demonstrates, for the first time, alterations in brain metabolites, cholinergic receptors and neuroinflammation in vivo in this model, validated by robust ex vivo approaches. Our data confirm that, unlike mouse models, the TgF344-AD express Tau pathology that can be detected via PET, albeit later than by ex vivo techniques, and is a useful model to assess and longitudinally monitor early neurotransmission dysfunction and neuroinflammation in AD.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Espectroscopia de Ressonância Magnética , Placa Amiloide/metabolismo , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismo , Envelhecimento/metabolismo , Envelhecimento/fisiologia , Doença de Alzheimer/patologia , Animais , Escala de Avaliação Comportamental , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Feminino , Radioisótopos de Flúor , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Gliose/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Imuno-Histoquímica , Inflamação/metabolismo , Locomoção/genética , Locomoção/fisiologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Ratos , Ratos Transgênicos , Receptores Colinérgicos/metabolismo , Tálamo/metabolismo , Tálamo/patologia
8.
Neurology ; 97(7): e739-e746, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34099525

RESUMO

OBJECTIVE: To investigate the relationship between late-life duration of poverty exposure and cognitive function and decline among older adults in China. METHODS: Data were from 3,209 participants ≥64 years of age in the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Duration of poverty, defined according to urban and rural regional standards from the China Statistical Yearbook, was assessed according to annual household income from 2005 to 2011 (never in poverty; one-third of the period in poverty; two-thirds or more of the period in poverty). Cognitive function was measured by the Chinese Mini-Mental State Examination (CMMSE) from 2011 to 2018. We used attrition-weighted, multivariable mixed-effects Tobit regression to examine the association of duration of poverty with cognitive function and rate of decline. RESULTS: A total of 1,162 individuals (36.21%) were never in poverty over the period from 2005 to 2011; 1,172 (36.52%) were in poverty one-third of the period; and 875 (27.27%) were in poverty two-thirds or more of the period. A longer poverty duration was associated with lower subsequent CMMSE scores with a dose-response relationship (one-third vs never in poverty: ß = -0.98; 95% confidence interval -1.61 to -0.35; two-thirds or more vs never in poverty: ß = -1.55; 95% confidence interval -2.29 to -0.81). However, a longer duration of poverty was associated with a slower rate of CMMSE score decline over time from 2011 to 2018. CONCLUSION: These findings provide valuable evidence for the role of cumulative late-life poverty in relation to cognitive health among older adults in a rapidly urbanizing and aging middle-income country. Our findings may support a compensation hypothesis for cognitive reserve in this setting.


Assuntos
Envelhecimento/fisiologia , Cognição/fisiologia , Disfunção Cognitiva/fisiopatologia , Pobreza/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , China/epidemiologia , Disfunção Cognitiva/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Fatores de Tempo
9.
Neurology ; 97(8): e794-e802, 2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34099528

RESUMO

OBJECTIVE: To characterize functional network changes related to conversion to cognitive impairment in a large sample of patients with multiple sclerosis (MS) over a period of 5 years. METHODS: Two hundred twenty-seven patients with MS and 59 healthy controls of the Amsterdam MS cohort underwent neuropsychological testing and resting-state fMRI at 2 time points (time interval 4.9 ± 0.9 years). At both baseline and follow-up, patients were categorized as cognitively preserved (CP; n = 123), mildly impaired (MCI; z < -1.5 on ≥2 cognitive tests, n = 32), or impaired (CI; z < -2 on ≥2 tests, n = 72), and longitudinal conversion between groups was determined. Network function was quantified with eigenvector centrality, a measure of regional network importance, which was computed for individual resting-state networks at both time points. RESULTS: Over time, 18.9% of patients converted to a worse phenotype; 22 of 123 patients who were CP (17.9%) converted from CP to MCI, 10 of 123 from CP to CI (8.1%), and 12 of 32 patients with MCI converted to CI (37.5%). At baseline, default-mode network (DMN) centrality was higher in CI individuals compared to controls (p = 0.05). Longitudinally, ventral attention network (VAN) importance increased in CP, driven by stable CP and CP-to-MCI converters (p < 0.05). CONCLUSIONS: Of all patients, 19% worsened in their cognitive status over 5 years. Conversion from intact cognition to impairment is related to an initial disturbed functioning of the VAN, then shifting toward DMN dysfunction in CI. Because the VAN normally relays information to the DMN, these results could indicate that in MS normal processes crucial for maintaining overall network stability are progressively disrupted as patients clinically progress.


Assuntos
Encéfalo , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/fisiopatologia , Rede de Modo Padrão/fisiopatologia , Progressão da Doença , Esclerose Múltipla/diagnóstico , Rede Nervosa/fisiopatologia , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/fisiopatologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Rede de Modo Padrão/diagnóstico por imagem , Feminino , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/complicações , Rede Nervosa/diagnóstico por imagem , Índice de Gravidade de Doença
10.
Aging (Albany NY) ; 13(12): 16353-16366, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135129

RESUMO

ApoE gene polymorphism may be involved in the change in blood lipid profile and cognitive impairment of the general population. However, few studies explored the effects of ApoE gene polymorphism on blood lipid levels and cognition in schizophrenia. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was employed to evaluate the cognition and the SNPStats was used to investigate the association of ApoE rs429358 with schizophrenia. The models of analysis of covariance and multivariate analysis were conducted to investigate the effect of ApoE rs429358 on cognition in schizophrenia. Altogether, 637 patients with schizophrenia and 467 healthy controls were recruited in this study. The findings in the case group found that both the ApoA1 and ApoB levels were predictors for RBANS total score (p < 0.001 vs. p = 0.011), immediate memory (p < 0.001 vs. p = 0.019), language (p < 0.001 vs. p = 0.013), attention (p < 0.001 vs. p < 0.001), except ApoA1 level only was a predictor for visuospatial/constructional (p = 0.014) and delayed memory (p < 0.001). When the association was examined in different ApoE rs429358 genotype subgroups, the association between ApoA1 level and RBANS scores (except for the language score) or between ApoB level and RBANS scores (except for the attention score) was regulated by ApoE rs429358. Our results suggest that patients with schizophrenia have broad cognitive impairment compared with healthy controls. For patients with schizophrenia, both ApoA1 and ApoB levels were positively associated with cognition. There was a significant association between ApoA1 or ApoB levels and cognition in schizophrenia, which was regulated by the ApoE rs429358.


Assuntos
Apolipoproteína A-I/sangue , Apolipoproteína B-100/sangue , Apolipoproteínas E/genética , Disfunção Cognitiva/sangue , Estudos de Associação Genética , Polimorfismo de Nucleotídeo Único/genética , Esquizofrenia/sangue , Esquizofrenia/genética , Adulto , Estudos de Casos e Controles , Doença Crônica , Cognição , Disfunção Cognitiva/fisiopatologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Esquizofrenia/fisiopatologia
11.
Aging (Albany NY) ; 13(12): 16088-16104, 2021 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-34176788

RESUMO

Traumatic brain injury (TBI) is a highly lethal event with a poor prognosis. Recovering residual neuronal function in the intermediate stage of TBI is important for treatment; however, neuroinflammation and neuronal apoptosis impede residual neuronal repair processes. Considering that hyperglycemia influences inflammatory processes and neuronal survival, we examined the effects of high glucose on neuroinflammation and neuronal death during the intermediate phase of TBI. Rat models of type 2 diabetes mellitus and/or TBI were developed and behaviorally assessed. Neurological function and cognitive abilities were impaired in TBI rats and worsened by type 2 diabetes mellitus. Histopathological staining and analyses of serum and hippocampal mRNA and protein levels indicated that neuroinflammation and apoptosis were induced in TBI rats and exacerbated by hyperglycemia. Hyperglycemia inhibited hippocampal mitogen-activated protein kinase kinase 5 (MEK5) phosphorylation in TBI rats. In vitro assays were used to assess inflammatory factor expression, apoptotic protein levels and neuronal survival after MEK5 activation in TBI- and/or high-glucose-treated neurons. MEK5/extracellular signal-regulated kinase 5 (ERK5) pathway activation reduced the inflammation, cleaved caspase-3 expression, Bax/Bcl-2 ratio and apoptosis of TBI neurons, even under high-glucose conditions. Thus, high glucose exacerbated neuroinflammation and apoptosis in the intermediate stage post-TBI by inhibiting the MEK5/ERK5 pathway.


Assuntos
Apoptose/efeitos dos fármacos , Lesões Encefálicas Traumáticas/patologia , Progressão da Doença , Glucose/toxicidade , Inflamação/patologia , Neurônios/patologia , Animais , Lesões Encefálicas Traumáticas/fisiopatologia , Sobrevivência Celular , Disfunção Cognitiva/complicações , Disfunção Cognitiva/fisiopatologia , Regulação para Baixo/genética , Hiperglicemia/complicações , Hiperglicemia/fisiopatologia , Mediadores da Inflamação/metabolismo , MAP Quinase Quinase 5/metabolismo , Sistema de Sinalização das MAP Quinases , Masculino , Modelos Biológicos , Fosforilação , Ratos Sprague-Dawley , Regulação para Cima/genética
12.
Aging (Albany NY) ; 13(11): 14816-14828, 2021 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-34091444

RESUMO

As a symptomatic predementia stage with progressive cognitive decline, mild cognitive impairment (MCI) is common with aging. How changes in self-reported sleep duration affect MCI risk in the older adults remains unclear. Participants aged ≥ 65 years and enrolled at least two waves in the Chinese Longitudinal Healthy Longevity Survey were included in present longitudinal study. Changes in sleep duration were calculated as the difference between two waves and categorized into five groups: decreased >2 h, decreased 0-2h, stable, increased 0-2 h, and increased >2 h. MCI was measured by the Chinese version of the Mini-Mental State Examination. Generalized estimating equation model and restricted cubic spline function was applied to investigate the association. Among 9,005 participants (mean age, 81.19 years; 4,391 male), 2,877 developed MCI. Comparing with individuals with stable sleep duration, MCI risk [odds ratio (95% confidence intervals)] was: 1.15 (0.99-1.34) for decreased >2 h, 0.99 (0.87-1.13) for decreased 0-2h, 1.09 (0.95-1.24) for increased 0-2 h, and 1.57 (1.36-1.81) for increased >2 h, respectively. Similar patterns were observed among subgroup analyses by sex, age, and sleep quality at baseline. For participants with long sleep duration at baseline (>8h), further increased >2 h was associated with higher MCI risk [2.23 (1.55-3.21)]. Either in the whole or subgroup population, a U-shaped association was observed (Pnon-linearity<0.05). In conclusion, changes in self-reported sleep duration were associated with MCI risk in a U-shaped pattern. Strategies that shifting sleep duration into normal range and keeping it stable are essential to prevent MCI in clinical practice.


Assuntos
Disfunção Cognitiva/fisiopatologia , Autorrelato , Sono/fisiologia , Idoso , Idoso de 80 Anos ou mais , China , Feminino , Humanos , Estudos Longitudinais , Masculino , Fatores de Risco
13.
Aging (Albany NY) ; 13(11): 15400-15412, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34114969

RESUMO

Metabolic syndrome (MetS) brings considerable effects on cognitive function, but trajectories within remain unclear. We investigated the interactions between distinct MetS components and cognitive domains. A total of 5693 participants from the Taiwan biobank during 2008-2018 were enrolled. Participants were classified as either normal or as having MetS at two time points; i.e., study entry and follow-up. At both the time points, cognitive evaluations using the Mini-Mental State Examination (MMSE) were conducted. The hazard ratios (HRs) of mild cognitive impairment (MCI) and dementia were higher in participants meeting more diagnostic components of MetS. Of the five criteria of MetS, three were significantly associated with MCI and dementia: high blood pressure (MCI: HR = 1.203, p < 0.001; dementia: HR = 1.345, p < 0.001), abdominal obesity (MCI: HR = 1.137, p = 0.006; dementia: HR = 1.442, p < 0.001), and low high-density lipoprotein (HDL) level (MCI: HR = 1.149, p = 0.007; dementia: HR = 1.364, p < 0.001). Of the cognitive domains measured, three were significantly associated with MetS; namely, orientation, language, and visuospatial abilities. Participants who were initially diagnosed with MetS but were normal at follow-up had an HR of 1.374 for dementia (p = 0.019), which was beyond our expectations. The undiminished risk of cognitive decline in subjects returning to normal status illustrated that neural injury caused by MetS takes a long time to get repaired. Consequently, earlier detection and management of adjustable risk factors of MetS should be encouraged to minimize the damage.


Assuntos
Bancos de Espécimes Biológicos , Cognição/fisiologia , Síndrome Metabólica/fisiopatologia , Idoso de 80 Anos ou mais , Disfunção Cognitiva/fisiopatologia , Estudos de Coortes , Demência/fisiopatologia , Humanos , Estimativa de Kaplan-Meier , Síndrome Metabólica/diagnóstico , Taiwan
14.
Medicine (Baltimore) ; 100(23): e26281, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115028

RESUMO

BACKGROUND AND OBJECTIVE: Previous studies have shown that the default-mode network (DMN) has a substantial role in patients with major depressive disorder (MDD). However, there is a shortage of information regarding variations in the functional connectivity (FC) of the DMN of treatment-naive patients with first-episode MDD. The present study aims to explore the FC of the DMN in such patients. METHODS: The study population consisted of 33 patients and 35 controls, paired regarding age, gender, education level, and health condition. Depression severity was assessed through the Hamilton Depression Scale (HAM-D), and subjects underwent evaluation during the resting-state through functional magnetic resonance imaging (rs-fMRI). To assess the result, we used FC and ICA. We used Spearman's correlation test to detect potential correlations between anomalous FC and severity of HAM-D scores. RESULTS: We have found a decreased FC in the left medial orbitofrontal gyrus (MOFG) and right marginal gyrus (SMG) in depressive patients compared to controls. There was a negative correlation between abnormal FC in the right SMG and HAM-D scores. We have not found any increase in FC of the DMN in treatment-naive, first-episode of MDD patients. CONCLUSIONS: Our study provided evidence of a negative correlation between abnormal FC in the DMN and severity of depression symptoms measured by HAM-D in treatment-naive MDD patients. This finding could shed some light on the relevance of DMN for understanding the pathophysiology of cognitive impairment in MDD.


Assuntos
Mapeamento Encefálico/métodos , Rede de Modo Padrão/fisiopatologia , Transtorno Depressivo Maior , Imageamento por Ressonância Magnética/métodos , Córtex Pré-Frontal , Adulto , Cognição/fisiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Conectoma/métodos , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/psicologia , Feminino , Humanos , Masculino , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Escalas de Graduação Psiquiátrica
15.
J Alzheimers Dis ; 82(3): 883-898, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34092646

RESUMO

Cognitive impairment following SARS-CoV-2 infection is being increasingly recognized as an acute and possibly also long-term sequela of the disease. Direct viral entry as well as systemic mechanisms such as cytokine storm are thought to contribute to neuroinflammation in these patients. Biomarkers of COVID-19-induced cognitive impairment are currently lacking, but there is some limited evidence that SARS-CoV-2 could preferentially target the frontal lobes, as suggested by behavioral and dysexecutive symptoms, fronto-temporal hypoperfusion on MRI, EEG slowing in frontal regions, and frontal hypometabolism on 18F-FDG-PET. Possible confounders include cognitive impairment due to hypoxia and mechanical ventilation and post-traumatic stress disorder. Conversely, patients already suffering from dementia, as well as their caregivers, have been greatly impacted by the disruption of their care caused by COVID-19. Patients with dementia have experienced worsening of cognitive, behavioral, and psychological symptoms, and the rate of COVID-19-related deaths is disproportionately high among cognitively impaired people. Multiple factors, such as difficulties in remembering and executing safeguarding procedures, age, comorbidities, residing in care homes, and poorer access to hospital standard of care play a role in the increased morbidity and mortality. Non-pharmacological interventions and new technologies have shown a potential for the management of patients with dementia, and for the support of their caregivers.


Assuntos
Doença de Alzheimer , Encéfalo , COVID-19/complicações , Disfunção Cognitiva , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Biomarcadores/análise , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Encéfalo/virologia , COVID-19/imunologia , COVID-19/psicologia , COVID-19/terapia , Disfunção Cognitiva/imunologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/virologia , Comorbidade , Humanos , Neuroimagem/métodos , Neuroimunomodulação/imunologia , Assistência ao Paciente , SARS-CoV-2
16.
J Stroke Cerebrovasc Dis ; 30(8): 105887, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34102554

RESUMO

OBJECTIVES: Atrial fibrillation (AF) is associated with high risk of dementia and brain atrophy in stroke-free patients, but the mechanisms underlying this association remain unclear. We aimed to examine the brain volume and connectivity of paramount cognitive brain networks in stroke-free patients with AF without dementia. MATERIALS AND METHODS: Twenty-six stroke-free patients with AF and 26 age and sex-matched subjects without AF were submitted to a 3-tesla brain structural and functional MRI. An extensive clinical evaluation excluded stroke, dementia, low cardiac output, carotid stenosis and metabolic diseases without optimal therapy. We used CHA2DS2-VASc score to classify the cardiovascular risk factor burden and a broad neuropsychological battery to assess the cognitive performance. Voxel based morphometry analysis of. structural MRI defined whole-brain gray and white matter volumes. Finally, we used eco-plannar MRI images to compare the differences of functional connectivity of 7 large-scale resting-state networks between AF patients and controls. RESULTS: Taking into account the history of hypertension and heart failure, AF was associated to volume decrease of the right basal frontal lobe and right inferior cerebellum. Decreased connectivity of the ventral Default Mode Network (vDMN) was observed in the AF group. No disruption of connectivity was observed in the executive, visuospatial and salience networks. CONCLUSION: Individuals with AF without stroke or dementia have subtle reduction of gray and white matter, restricted to frontal areas and cerebellum. These patients show decreased vDMN connectivity, without other large-scale brain network disruption.


Assuntos
Fibrilação Atrial/complicações , Encéfalo/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Neuroimagem Funcional , Imageamento por Ressonância Magnética , Rede Nervosa/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/diagnóstico , Fibrilação Atrial/fisiopatologia , Atrofia , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Cognição , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Feminino , Humanos , Masculino , Testes de Estado Mental e Demência , Pessoa de Meia-Idade , Rede Nervosa/fisiopatologia , Testes Neuropsicológicos , Valor Preditivo dos Testes
17.
Int J Mol Sci ; 22(10)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34069523

RESUMO

Cognitive dysfunction is one of the core symptoms in schizophrenia, and it is predictive of functional outcomes and therefore useful for treatment targets. Rather than improving cognitive deficits, currently available antipsychotics mainly focus on positive symptoms, targeting dopaminergic/serotoninergic neurons and receptors in the brain. Apart from investigating the neural mechanisms underlying schizophrenia, emerging evidence indicates the importance of glial cells in brain structure development and their involvement in cognitive functions. Although the etiopathology of astrocytes in schizophrenia remains unclear, accumulated evidence reveals that alterations in gene expression and astrocyte products have been reported in schizophrenic patients. To further investigate the role of astrocytes in schizophrenia, we highlighted recent progress in the investigation of the effect of astrocytes on abnormalities in glutamate transmission and impairments in the blood-brain barrier. Recent advances in animal models and behavioral methods were introduced to examine schizophrenia-related cognitive deficits and negative symptoms. We also highlighted several experimental tools that further elucidate the role of astrocytes. Instead of focusing on schizophrenia as a neuron-specific disorder, an additional astrocytic perspective provides novel and promising insight into its causal mechanisms and treatment. The involvement of astrocytes in the pathogenesis of schizophrenia and other brain disorders is worth further investigation.


Assuntos
Astrócitos/fisiologia , Disfunção Cognitiva/fisiopatologia , Esquizofrenia/fisiopatologia , Animais , Astrócitos/metabolismo , Encéfalo/metabolismo , Cognição , Transtornos Cognitivos/metabolismo , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Neuroglia/metabolismo , Neurônios/metabolismo , Esquizofrenia/metabolismo
18.
Top Antivir Med ; 29(2): 334-343, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34107203

RESUMO

The 2021 Conference on Retroviruses and Opportunistic Infections (CROI) featured a timely review of the neurologic complications of COVID-19 as well as new research findings on mechanisms by which SARS-CoV-2 may affect the brain. CROI included new and important findings about the neurologic complications of HIV-1, human polyomavirus 2 (also known as JC Virus), and cryptococcus. New long-term analyses of cognition in people with HIV-1 identified that cognitive decline over time is associated with multimorbidity, particularly diabetes, chronic lung disease, and vascular disease risk conditions. These conditions are associated with aging, and the question of whether people with HIV are at risk for premature aging was addressed by several reports. New findings from large analyses of resting state networks also provided valuable information on the structural and functional networks that are affected by HIV-1 infection and cognitive impairment. Several reports addressed changes after initiating or switching antiretroviral therapy (ART). Findings that will improve understanding of the biologic mechanisms of brain injury in people with HIV were also presented and included evidence that host (eg, myeloid activation, inflammation, and endothelial activation) and viral (eg, transcriptional activity and compartmentalization) factors adversely affect brain health. Other research focused on adjunctive therapies to treat HIV-1 and its complications in the central nervous system. This summary will review these and other findings in greater detail and identify key gaps and opportunities for researchers and clinicians.


Assuntos
COVID-19/complicações , Infecções por HIV/complicações , HIV-1 , Doenças do Sistema Nervoso , Neuroimagem , Infecções por Retroviridae , Envelhecimento/fisiologia , Antirretrovirais/uso terapêutico , Encéfalo/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Cryptococcus/isolamento & purificação , Infecções por HIV/tratamento farmacológico , Humanos , Vírus JC/isolamento & purificação , Doenças do Sistema Nervoso/epidemiologia , Doenças do Sistema Nervoso/patologia , Estados Unidos
19.
Aging (Albany NY) ; 13(10): 13430-13442, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34038387

RESUMO

The cause of cognitive dedifferentiation has been suggested as specific to late-life abnormal cognitive decline rather than a general feature of aging. This hypothesis was tested in two large cohorts with different characteristics. Individuals (n = 2710) were identified in the Alzheimer's Disease Neuroimaging Initiative (ADNI) research database (n = 1282) in North America, and in the naturalistic multi-site MemClin Project database (n = 1223), the latter recruiting from 9 out of 10 memory clinics in the greater Stockholm catchment area in Sweden. Comprehensive neuropsychological testing informed diagnosis of dementia, mild cognitive impairment (MCI), or subjective cognitive impairment (SCI). Diagnosis was further collapsed into cognitive impairment (CI: MCI or dementia) vs no cognitive impairment (NCI). After matching, loadings on the first principal component were higher in the CI vs NCI group in both ADNI (53.1% versus 38.3%) and MemClin (33.3% vs 30.8%). Correlations of all paired combinations of individual tests by diagnostic group were also stronger in the CI group in both ADNI (mean inter-test r = 0.51 vs r = 0.33, p < 0.001) and MemClin (r = 0.31 vs r = 0.27, p = 0.042). Dedifferentiation was explained by cognitive impairment when controlling for age, sex, and education. This finding replicated across two separate, large cohorts of older individuals. Knowledge that the structure of human cognition becomes less diversified and more dependent on general intelligence as a function of cognitive impairment should inform clinical assessment and care for these patients as their neurodegeneration progresses.


Assuntos
Doença de Alzheimer/fisiopatologia , Cognição/fisiologia , Disfunção Cognitiva/fisiopatologia , Memória/fisiologia , Neuroimagem , Idoso , Doença de Alzheimer/diagnóstico por imagem , Estudos de Coortes , Feminino , Humanos , Masculino , Análise de Componente Principal
20.
Eur J Vasc Endovasc Surg ; 61(6): 888-899, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33966986

RESUMO

OBJECTIVE: The aim was to evaluate the relationship between asymptomatic carotid stenosis (ACS) of any severity and cognitive impairment and to determine whether there is evidence supporting an aetiological role for ACS in the pathophysiology of cognitive impairment. DATA SOURCES: PubMed/Medline, Embase, Scopus, and the Cochrane library. REVIEW METHODS: This was a systematic review (35 cross sectional or longitudinal studies) RESULTS: Study heterogeneity confounded data interpretation, largely because of no standardisation regarding cognitive testing. In the 30 cross sectional and six longitudinal studies (one included both), 33/35 (94%) reported an association between any degree of ACS and one or more tests of impaired cognitive function (20 reported one to three tests with poorer cognition; 11 reported four to six tests with poorer cognition, while three studies reported seven or more tests with poorer cognition). There was no evidence that ACS caused cognitive impairment via silent cortical infarction, or via involvement in the pathophysiology of lacunar infarction or white matter hyperintensities. However, nine of 10 studies evaluating cerebral vascular reserve (CVR) reported that ACS patients with impaired CVR were significantly more likely to have cognitive impairment and that impaired CVR was associated with worsening cognition over time. Patients with severe ACS but normal CVR had cognitive scores similar to controls. CONCLUSION: Notwithstanding significant heterogeneity within the constituent studies, which compromised overall interpretation, 94% of studies reported an association between ACS and one or more tests of cognitive impairment. However, "significant association" does not automatically imply an aetiological relationship. At present, there is no clear evidence that ACS causes cognitive impairment via silent cortical infarction (but very few studies have addressed this question) and no evidence of ACS involvement in the pathophysiology of white matter hyperintensities or lacunar infarction. There is, however, better evidence that patients with severe ACS and impaired CVR are more likely to have cognitive impairment and to suffer further cognitive decline with time.


Assuntos
Encéfalo/irrigação sanguínea , Estenose das Carótidas , Cognição/fisiologia , Disfunção Cognitiva/fisiopatologia , Doenças Assintomáticas , Estenose das Carótidas/diagnóstico , Estenose das Carótidas/psicologia , Estudos Transversais , Humanos , Estudos Longitudinais
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