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1.
Life Sci ; 241: 117170, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31838137

RESUMO

AIMS: In this study, we investigate the effect and underlying mechanism of hyperbaric oxygen (HBO) treatment on a model of repeated cerebral ischemia-reperfusion injury (IR). MAIN METHODS: Eighty rats were randomly separated into sham, vehicle, hyperbaric air (HBA; 0.25 MPa, 60 min), and HBO (0.25 MPa, 60 min) groups. Repeated cerebral IR was induced by ligating the right and left bilateral common carotid arteries for 10 min and then allowing reperfusion for 10 min. This pattern was repeated three times. The neuroprotective effects of HBO were assessed by animal behavior, neuron morphology, inflammatory markers, intracellular calcium ion content, and autophagy-related protein and gene expression. KEY FINDINGS: Our result showed that HBO improved learning and memory in the navigation trail and probe trail of the Morris water maze, and these findings were supported by the observation data from 2,3,5-Triphenyltet-razolium chloride staining, Nissl staining, and electron microscopic. Importantly, we found that HBO reduced excessive autophagy in the prefrontal cortex, which was evidenced by activating of the mammalian target of the rapamycin (mTOR) and 4E-BP1, as well as suppression of LC3II and ATG5. Moreover, HBO significantly inhibited the cerebral IR-induced inflammatory reaction. Furthermore, HBO treatment modulated autophagy pathway-related factors, including producing a decrease in the intracellular calcium ion concentration and p53 level; meanwhile, the levels of BDNF and p-Akt were increased. SIGNIFICANCE: Our results indicated that HBO protected against IR-induced neuron injury by attenuating autophagy, inflammation, and calcium overload. These results provide a new mechanism and laboratory evidence for clinical treatment of VD.


Assuntos
Autofagia , Isquemia Encefálica/complicações , Disfunção Cognitiva/prevenção & controle , Modelos Animais de Doenças , Oxigenação Hiperbárica/métodos , Fármacos Neuroprotetores , Traumatismo por Reperfusão/complicações , Animais , Comportamento Animal , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Feminino , Masculino , Camundongos , Ratos , Ratos Sprague-Dawley
2.
Neurology ; 93(23): e2144-e2156, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31666352

RESUMO

OBJECTIVE: To investigate predictors of performance on a range of cognitive measures including the Preclinical Alzheimer Cognitive Composite (PACC) and test for associations between cognition and dementia biomarkers in Insight 46, a substudy of the Medical Research Council National Survey of Health and Development. METHODS: A total of 502 individuals born in the same week in 1946 underwent cognitive assessment at age 69-71 years, including an adapted version of the PACC and a test of nonverbal reasoning. Performance was characterized with respect to sex, childhood cognitive ability, education, and socioeconomic position (SEP). In a subsample of 406 cognitively normal participants, associations were investigated between cognition and ß-amyloid (Aß) positivity (determined from Aß-PET imaging), whole brain volumes, white matter hyperintensity volumes (WMHV), and APOE ε4. RESULTS: Childhood cognitive ability was strongly associated with cognitive scores including the PACC more than 60 years later, and there were independent effects of education and SEP. Sex differences were observed on every PACC subtest. In cognitively normal participants, Aß positivity and WMHV were independently associated with lower PACC scores, and Aß positivity was associated with poorer nonverbal reasoning. Aß positivity and WMHV were not associated with sex, childhood cognitive ability, education, or SEP. Normative data for 339 cognitively normal Aß-negative participants are provided. CONCLUSIONS: This study adds to emerging evidence that subtle cognitive differences associated with Aß deposition are detectable in older adults, at an age when dementia prevalence is very low. The independent associations of childhood cognitive ability, education, and SEP with cognitive performance at age 70 have implications for interpretation of cognitive data in later life.


Assuntos
Encéfalo/patologia , Cognição/fisiologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/patologia , Idoso , Peptídeos beta-Amiloides/metabolismo , Encéfalo/fisiopatologia , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes Neuropsicológicos
3.
Ophthalmic Surg Lasers Imaging Retina ; 50(11): 709-718, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31755970

RESUMO

BACKGROUD AND OBJECTIVE: To evaluate the relationship between retinal microvascular parameters on optical coherence tomography angiography (OCTA) and neurodegenerative changes assessed by measurement of brain volume on volumetric magnetic resonance imaging (MRI) in Alzheimer's disease (AD) and mild cognitive impairment (MCI). PATIENTS AND METHODS: Sixteen subjects with AD and MCI underwent OCTA imaging (3 mm × 3 mm and 6 mm × 6 mm scans) and volumetric brain MRI imaging with automated volumetric segmentation and quantification. Spearman's correlation (ρ) was performed between forebrain parenchyma, cortical gray matter, inferolateral ventricle (ILV), lateral ventricle (LV), and hippocampus (HP) MRI volumes and vessel density (VD), along with perfusion density (PD) for the 6-mm circle, 6-mm ring, 3-mm circle, and 3-mm ring Early Treatment Diabetic Retinopathy Study regions of the superficial capillary plexus. RESULTS: Thirty eyes of 16 patients (seven MCI and nine AD) with good-quality OCTA images were analyzed. ILV volume inversely correlated with the VD in the 6-mm circle (ρ = -0 .565, P = .028) and 3-mm ring (ρ = -0.569, P = .027) and PD in the 3-mm ring (ρ = -0.605, P = .0169). Forebrain, cortical gray matter, LV, and HP volumes did not significantly correlate with either VD or PD (P > .05). CONCLUSIONS: In this pilot investigation, the authors found a significant correlation between reduction in the superficial capillary plexus VD and PD on OCTA and expansion of the ILV in MCI and AD. This relationship between the retinal microvasculature and cerebral volumetric changes deserves further investigation. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:709-718.].


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Disfunção Cognitiva/patologia , Vasos Retinianos/patologia , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Feminino , Angiofluoresceinografia/métodos , Humanos , Imagem por Ressonância Magnética , Masculino , Microvasos/patologia , Pessoa de Meia-Idade , Projetos Piloto , Fluxo Sanguíneo Regional , Tomografia de Coerência Óptica/métodos
4.
Nat Med ; 25(11): 1680-1683, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31686034

RESUMO

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease.


Assuntos
Doença de Alzheimer/genética , Apolipoproteína E3/genética , Doenças Neurodegenerativas/genética , Presenilina-1/genética , Idoso , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Amiloide/genética , Amiloide/metabolismo , Apolipoproteína E2/genética , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Feminino , Homozigoto , Humanos , Masculino , Mutação/genética , Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Linhagem
5.
Medicine (Baltimore) ; 98(40): e17127, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577703

RESUMO

To investigate the functional connectome alterations in cerebral small-vessel disease (CSVD) patients with thalamus lacunes and its relation to cognitive impairment.This case-control study was approved by the local research ethics committee, and all participants provided informed consent. There were 14 CSVD patients with thalamus lacunes (CSVDw.), 27 without (CSVDwo.), and 34 healthy controls (HC) recruited matched for age, sex, and education to undergo a 3T resting-state functional MR examination. The whole-brain functional connectome was constructed by thresholding the Pearson correlation matrices of 90 brain regions, and the topologic properties were analyzed by using graph theory approaches. Networks were compared between CSVD patients and HC, and associations between network measures and cognitive function were tested.Compared with HC, the functional connectome in CSVDw. patients showed abnormalities at the global level and at the nodal level (P < .05, false discovery rate corrected). The network-based statistics method identified a significantly altered network consisting 6 nodes and 13 connections. Among all the 13 connections, only two connections had significant correlation with episodic memory (EM) and processing speed (PS) respectively (P < .05). The CSVDwo. patients showed no significant network alterations relative to controls (P > .05).The configurations of brain functional connectome in CSVDw. patients were perturbed but not obvious for those without, and correlated with the mild cognitive impairment, especially for EM and PS. This study suggested that lacunes on thalamus played a vital role in mediating the neural functional changes of CSVD patients.


Assuntos
Doenças de Pequenos Vasos Cerebrais/patologia , Disfunção Cognitiva/patologia , Conectoma , Leucoencefalopatias/patologia , Tálamo/patologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Estudos Transversais , Escolaridade , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Leucoencefalopatias/complicações , Masculino , Pessoa de Meia-Idade , Avaliação Nutricional , Índice de Gravidade de Doença , Fatores Sexuais , Tálamo/diagnóstico por imagem
6.
Int J Mol Sci ; 20(18)2019 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505809

RESUMO

Many neurodegenerative disorders have lysosomal impediments, and the list of proposed treatments targeting lysosomes is growing. We investigated the role of lysosomes in Alzheimer's disease (AD) and other age-related disorders, as well as in a strategy to compensate for lysosomal disturbances. Comprehensive immunostaining was used to analyze brains from wild-type mice vs. amyloid precursor protein/presenilin-1 (APP/PS1) mice that express mutant proteins linked to familial AD. Also, lysosomal modulation was evaluated for inducing synaptic and behavioral improvements in transgenic models of AD and Parkinson's disease, and in models of mild cognitive impairment (MCI). Amyloid plaques were surrounded by swollen organelles positive for the lysosome-associated membrane protein 1 (LAMP1) in the APP/PS1 cortex and hippocampus, regions with robust synaptic deterioration. Within neurons, lysosomes contain the amyloid ß 42 (Aß42) degradation product Aß38, and this indicator of Aß42 detoxification was augmented by Z-Phe-Ala-diazomethylketone (PADK; also known as ZFAD) as it enhanced the lysosomal hydrolase cathepsin B (CatB). PADK promoted Aß42 colocalization with CatB in lysosomes that formed clusters in neurons, while reducing Aß deposits as well. PADK also reduced amyloidogenic peptides and α-synuclein in correspondence with restored synaptic markers, and both synaptic and cognitive measures were improved in the APP/PS1 and MCI models. These findings indicate that lysosomal perturbation contributes to synaptic and cognitive decay, whereas safely enhancing protein clearance through modulated CatB ameliorates the compromised synapses and cognition, thus supporting early CatB upregulation as a disease-modifying therapy that may also slow the MCI to dementia continuum.


Assuntos
Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Lisossomos/metabolismo , Doença de Parkinson/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/patologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Humanos , Glicoproteínas de Membrana Associadas ao Lisossomo/genética , Glicoproteínas de Membrana Associadas ao Lisossomo/metabolismo , Lisossomos/genética , Lisossomos/patologia , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/patologia , Doença de Parkinson/genética , Doença de Parkinson/patologia , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo , Sinapses/metabolismo , Sinapses/patologia
8.
Neurology ; 93(16): e1514-e1525, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31511349

RESUMO

OBJECTIVE: To examine the effects of baseline Alzheimer disease and cerebrovascular disease markers on longitudinal default mode network (DMN) and executive control network (ECN) functional connectivity (FC) changes in mild cognitive impairment (MCI). METHODS: We studied 30 patients with amnestic MCI (aMCI) and 55 patients with subcortical vascular MCI (svMCI) with baseline Pittsburgh Compound B (PiB)-PET scans and longitudinal MRI scans. Participants were followed up clinically with annual MRI for up to 4 years (aMCI: 26 with 2 timepoints, 4 with 3 timepoints; svMCI: 13 with 2 timepoints, 16 with 3 timepoints, 26 with 4 timepoints). RESULTS: ß-Amyloid (Aß) burden was associated with longitudinal DMN FC declines, while cerebrovascular burden was associated with longitudinal ECN FC changes. When patients were divided into PiB+ and PiB- groups, PiB+ patients showed longitudinal DMN FC declines, while patients with svMCI showed longitudinal ECN FC increases. Direct comparisons between the 2 groups without mixed pathology (aMCI PiB+ and svMCI PiB-) recapitulated this divergent pattern: aMCI PiB+ patients showed steeper longitudinal DMN FC declines, while svMCI PiB- patients showed steeper longitudinal ECN FC increases. Finally, using baseline PiB uptake and lacune numbers as continuous variables, baseline PiB uptake showed inverse U-shape associations with longitudinal DMN FC changes in both MCI subtypes, while baseline lacune numbers showed mainly inverse U-shape relationships with longitudinal ECN FC changes in patients with svMCI. CONCLUSIONS: Our findings underscore the divergent effects of Aß and cerebrovascular burden on longitudinal FC changes in the DMN and ECN in the predementia stage, which reflect the underlying pathology and may be used to track early changes in Alzheimer disease and cerebrovascular disease.


Assuntos
Doença de Alzheimer/patologia , Amiloide/metabolismo , Encéfalo/patologia , Rede Nervosa/patologia , Idoso , Doença de Alzheimer/metabolismo , Proteínas Amiloidogênicas/metabolismo , Amiloidose/metabolismo , Amiloidose/patologia , Encéfalo/metabolismo , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Rede Nervosa/metabolismo , Testes Neuropsicológicos
9.
Life Sci ; 236: 116867, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31520598

RESUMO

AIM: Cyclophosphamide (CP) is a potent anticancer and immunosuppressant drug. Studies have shown significant oxidative stress and cognitive impairment but neuroinflammatory and histological aberrations with its administration is underexplored. Nerolidol (NER) is a lipophilic bioactive molecule with antioxidant and anti-inflammatory properties but it has not been explored for neuroprotective potential in CP-induced neurotoxic manifestations. Therefore, in the present study, we aimed to evaluate the neuroprotective potential of NER in CP-induced neuroinflammation and associated comorbid conditions like depression and cognitive dysfunctions. MATERIALS AND METHOD: In-silico study using Schrödinger software was used to assess the binding affinity of NER with Nrf2. In the In vivo study, NER 200 and 400 mg/kg p.o. were given from 1st day to 14th day. CP 200 mg/kg, i.p., was administered on the 7th day. After 24 h of the last dosing, neurobehavioral tests like spontaneous body alternation, passive avoidance and forced swim test were performed. On completion of study, mice were sacrificed, hippocampus and cortex were removed for biochemical estimations, histopathology and immunohistochemistry of p65 NF- κB and Nrf2. KEY FINDINGS: In-silico study showed significant binding of NER into the pocket domain of Nrf2. In-vivo study showed protective effect of NER against CP-induced neuroinflammation, oxidative stress, cognitive impairment and structural abnormalities in the hippocampus and cortex regions. SIGNIFICANCE: Findings of the study suggested that NER is a potential therapeutic molecule which can mitigate CP-induced neurotoxic manifestations via Nrf2 and NF-κB pathway. However, more detailed studies are needed to explicate the mechanism underlying its neuroprotective effect.


Assuntos
Disfunção Cognitiva/prevenção & controle , Ciclofosfamida/toxicidade , Inflamação/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Síndromes Neurotóxicas/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Sesquiterpenos/farmacologia , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Regulação da Expressão Gênica , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imunossupressores/toxicidade , Inflamação/induzido quimicamente , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/genética , NF-kappa B/genética , Fármacos Neuroprotetores , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Transdução de Sinais
10.
Yonsei Med J ; 60(10): 935-943, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31538428

RESUMO

PURPOSE: This study aimed to identify the neural basis of executive function (EF) in amnestic mild cognitive impairment (aMCI) according to beta-amyloid (Aß) positivity. Furthermore, we explored if the identified brain areas could serve as predictors for clinical progression. MATERIALS AND METHODS: We included individuals with aMCI using data from [18F]-florbetapir-positron emission tomography (PET), fluorodeoxyglucose-PET, and EF scores, as well as follow-up clinical severity scores at 1 and 5 years from baseline from the Alzheimer's Disease Neuroimaging Initiative database. The correlations between EF score and regional cerebral glucose metabolism (rCMglc) were analyzed separately for aMCI with low Aß burden (aMCI Aß-, n=230) and aMCI with high Aß burden (aMCI Aß+, n=268). Multiple linear regression analysis was conducted to investigate the associations between rCMglc and clinical progression. RESULTS: Longitudinal courses differed between aMCI Aß- and aMCI Aß+ groups. On average, aMCI Aß- subjects maintained their level of clinical severity, whereas aMCI Aß+ subjects showed progression. EF impairment in aMCI Aß- was related to the anterior cingulate cortex (ACC), whereas that in aMCI Aß+ was related to Alzheimer's Disease-vulnerable brain regions. ACC and the posterior cingulate cortex were associated with clinical progression in aMCI Aß- and aMCI Aß+, respectively. CONCLUSION: Our findings suggest that although MCI subjects showed similar behavioral phenotypes at the time of diagnosis, EF and further progression were associated with different brain regions according to Aß burden. Clarification of the etiologies and nature of EF impairment in aMCI are critical for disease prognosis and management.


Assuntos
Amiloide/metabolismo , Encéfalo/fisiopatologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Progressão da Doença , Função Executiva/fisiologia , Idoso , Peptídeos beta-Amiloides/metabolismo , Feminino , Seguimentos , Glucose/metabolismo , Humanos , Modelos Lineares , Masculino , Tomografia por Emissão de Pósitrons
11.
Life Sci ; 235: 116822, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31476310

RESUMO

AIMS: To investigate the effects of malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) on cognitive dysfunction, the expression of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß and amyloid ß peptide (Aß) in the hippocampus, as well as dendritic pathology in the hippocampal CA1 region in sepsis-associated encephalopathy (SAE) rats. MAIN METHODS: The rats were randomly divided into four groups: 1) control group (subjected to sham surgery), 2) control plus Mfhas1 siRNA group (rats received intracerebroventricular injection of Mfhas1 siRNA after sham surgery), 3) CLP plus control siRNA group (rats received intracerebroventricular injection of control siRNA after cecal ligation and puncture (CLP)), 4) CLP plus Mfhas1 siRNA group (rats received intracerebroventricular injection of Mfhas1 siRNA after CLP). The learning and memory capabilities of the rats were examined by means of fear conditioning and Barnes maze test. The concentration of TNF-α and IL-1ß was determined by enzyme-linked immunosorbent assay. The efficiency of siRNA transfection, MFHAS1 and Aß expression were detected by Western blotting. Total branch lengths of pyramidal dendrites of the CA1 basilar trees and spine density were determined by Golgi staining. KEY FINDINGS: We observed that MFHAS1 knock-down by Mfhas1 siRNA intracerebroventricular injection could improve cognitive impairment, reduce the expression of TNF-α, IL-1ß and Aß in the hippocampus induced by CLP, and alleviate the dendritic spinal loss of the pyramidal neurons, as well as increase the dendritic branching of the CA1 basilar trees of septic rats. SIGNIFICANCE: MFHAS1 knock-down can alleviate cognitive impairment, neuroinflammation and dendritic spinal loss in SAE rats.


Assuntos
Disfunção Cognitiva/prevenção & controle , Dendritos/efeitos dos fármacos , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Proteínas Oncogênicas/antagonistas & inibidores , RNA Interferente Pequeno/administração & dosagem , Encefalopatia Associada a Sepse/complicações , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Dendritos/metabolismo , Dendritos/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Proteínas Oncogênicas/genética , Proteínas Oncogênicas/metabolismo , RNA Interferente Pequeno/genética , Ratos , Ratos Wistar
12.
Neurology ; 93(15): e1474-e1484, 2019 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-31492718

RESUMO

OBJECTIVE: Ladostigil reduces oxidative stress and microglial activation in aging rats. We assessed its safety and potential efficacy in a 3-year, randomized, double-blind, placebo-controlled phase 2 clinical trial in patients with mild cognitive impairment (MCI) and medial temporal lobe atrophy. METHODS: Patients 55 to 85 years of age with MCI, Clinical Dementia Rating (CDR) score of 0.5, Mini-Mental State Examination (MMSE) score >24, Wechsler Memory Scale-Revised Verbal Paired Associates I score ≤18, and Medial Temporal Lobe Atrophy Scale score >1 were stratified by APOE ε4 genotype and randomly assigned (1:1) to ladostigil 10 mg/d or placebo. Primary outcomes were safety and onset of Alzheimer disease dementia. Secondary endpoints were Neuropsychological Test Battery (NTB) composite, Disability Assessment in Dementia (DAD), and Geriatric Depression Scale (GDS) scores. Exploratory outcomes were NTB component, CDR, and MMSE scores. Biomarkers included MRI-derived whole-brain, hippocampus, and entorhinal cortex volumes. RESULTS: Two hundred ten patients from 15 sites in Austria, Germany, and Israel were randomly allocated to placebo (107 patients) or ladostigil (103 patients). After 36 months, 21 of 103 patients on placebo and 14 of 99 patients receiving ladostigil progressed to Alzheimer disease (log-rank test p = 0.162). There were no significant effects on the NTB composite, DAD, or GDS score. Whole-brain and hippocampus volumes decreased more in the placebo than in the ladostigil group (whole brain, p = 0.025, Cohen d = 0.43; hippocampus, p = 0.043, d = 0.43). Serious adverse events were reported by 28 of 107 patients treated with placebo and 26 of 103 with ladostigil. CONCLUSION: Ladostigil was safe and well tolerated but did not delay progression to dementia. Its association with reduced brain and hippocampus volume loss suggests a potential effect on atrophy. CLINICALTRIALSGOV IDENTIFIER: NCT01429623. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with MCI and medial temporal lobe atrophy, ladostigil did not significantly decrease the risk of the development of Alzheimer disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Indanos/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Animais , Atrofia/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Disfunção Cognitiva/patologia , Progressão da Doença , Método Duplo-Cego , Feminino , Humanos , Indanos/administração & dosagem , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Ratos
13.
Life Sci ; 233: 116707, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31374234

RESUMO

The epidemiological investigations and animal model experiments have confirmed the impact of obesity on the brain, behavior, and cognition. However, the mechanism by which obesity affects cognitive function is not fully understood. With the development of an aging society, there is an increase in the economic and social burden caused by the decline in cognitive function. This manuscript reviews the effects of inflammation and endoplasmic reticulum stress (ERS) on the hypothalamus, hippocampus, and the possible impact on cognitive impairment. These findings provide new insights into the pathophysiological mechanisms that lead to the development of cognitive impairment in the context of obesity.


Assuntos
Disfunção Cognitiva/etiologia , Estresse do Retículo Endoplasmático , Inflamação/fisiopatologia , Obesidade/complicações , Animais , Disfunção Cognitiva/patologia , Humanos
14.
Mol Med Rep ; 20(4): 3085-3094, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31432123

RESUMO

The present study was aimed to observe the protective effect of rapamycin on cognitive dysfunction induced by sevoflurane in aged rats and its effect on autophagy­related proteins, and to investigate the regulatory mechanism of the Toll­like receptor 4/myeloid differentiation primary response 88/nuclear factor­κB (TLR4/MyD88/NF­κB) signaling pathway. Fifty Sprague­Dawley rats were randomly assigned to a control group, a sevoflurane group, a rapamycin pretreatment group, a TLR4 inhibitor group and a 3MA autophagy inhibitor group. A water maze test was used to evaluate the cognition and memory of rats. Hematoxylin and eosin (H&E) staining was performed to observe pathological changes of brain tissue. A TUNEL assay was used to detect the apoptosis of brain tissue. ELISA was used to assess changes in brain injury markers and inflammatory factors. A western blot assay or quantitative reverse transcription PCR (RT­qPCR) were performed to determine the expression of autophagy­related proteins and the TLR4/MyD88/NF­κB signaling pathway in brain tissue. The results revealed that rapamycin could improve cognitive dysfunction of aged rats induced by sevoflurane. Rapamycin was identified to play a therapeutic role, including mitigating brain tissue damage, inhibiting apoptosis, and activating autophagy in a sevoflurane­treated aged rat model. This function of rapamycin was demonstrated to depend on the TLR4/MyD88/NF­κB signaling pathway.


Assuntos
Envelhecimento , Disfunção Cognitiva/tratamento farmacológico , Fator 88 de Diferenciação Mieloide/metabolismo , NF-kappa B/metabolismo , Sevoflurano/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Sirolimo/farmacologia , Receptor 4 Toll-Like/metabolismo , Animais , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Sevoflurano/farmacologia
16.
Biol Pharm Bull ; 42(8): 1384-1393, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366873

RESUMO

We previously demonstrated that Bacopa monnier (L.) WETTST. extract (BME) ameliorated cognitive dysfunction in animal models of dementia by enhancing synaptic plasticity-related signaling in the hippocampus and protecting cholinergic neurons in the medial septum. To further clarify the pharmacological features and availability of BME as a novel anti-dementia agent, we investigated whether BME affects neuronal repair using a mouse model of trimethyltin (TMT)-induced neuronal loss/self-repair in the hippocampus. Mice pretreated with TMT (2.8 mg/kg, intraperitoneally (i.p.)) on day 0 were given BME (50 mg/kg, per os (p.o.)) once daily for 15-30 d. Cognitive performance of the animals was elucidated twice by the object location test and modified Y maze test on days 17-20 (Phase I) and days 32-35 (Phase II) or by the passive avoidance test on Phase II. TMT impaired hippocampus-dependent spatial working memory and amygdala-dependent fear-motivated memory. The administration of BME significantly prevented TMT-induced cognitive deficits. The protective effects of BME on the spatial memory deficits were confirmed by Nissl staining of hippocampal tissues and propidium iodide staining of organotypic hippocampal slice cultures. Immunohistochemical studies conducted on days 17 and 32 revealed that thirty days of treatment with BME increased the number of 5-bromo-2'-deoxyuridine (BrdU)-immunopositive cells in the dentate gyrus region of TMT-treated mice, whereas fifteen days of treatment with BME had no effect. These results suggest that BME ameliorates TMT-induced cognition dysfunction mainly via protecting the hippocampal neurons from TMT-induced hippocampal lesions and partly via promoting neuroregeneration in the dentate gyrus regions.


Assuntos
Bacopa , Disfunção Cognitiva/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Animais , Disfunção Cognitiva/patologia , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Transtornos da Memória/patologia , Camundongos , Regeneração Nervosa/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Síndromes Neurotóxicas/patologia , Compostos de Trimetilestanho
17.
Nat Med ; 25(9): 1364-1369, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31451782

RESUMO

The exact etiology of dementia is still unclear, but both genetic and lifestyle factors are thought to be key drivers of this complex disease. The recognition of familial patterns of dementia has led to the discovery of genetic factors that have a role in the pathogenesis of dementia, including the apolipoprotein E (APOE) genotype and a large and still-growing number of genetic variants1,2. Beyond genetic architecture, several modifiable risk factors have been implicated in the development of dementia3. Prevention trials of measures to halt or delay cognitive decline are increasingly recruiting older individuals who are genetically predisposed to dementia. However, it remains unclear whether targeted health and lifestyle interventions can attenuate or even offset increased genetic risk. Here, we leverage long-term data on both genetic and modifiable risk factors from 6,352 individuals aged 55 years and older in the population-based Rotterdam Study. In this study, we demonstrate that, in individuals at low and intermediate genetic risk, favorable modifiable-risk profiles are related to a lower risk of dementia compared to unfavorable profiles. In contrast, these protective associations were not found in those at high genetic risk.


Assuntos
Apolipoproteínas E/genética , Disfunção Cognitiva/genética , Demência/genética , Predisposição Genética para Doença , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos como Assunto , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/patologia , Demência/epidemiologia , Demência/patologia , Feminino , Genótipo , Humanos , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Fatores de Risco
18.
J Neurol ; 266(10): 2535-2545, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31267207

RESUMO

OBJECTIVE: The aim of this study is to assess the impact of age at onset on the prognostic value of Alzheimer's biomarkers in a large sample of patients with mild cognitive impairment (MCI). METHODS: We measured Aß42, t-tau, hippocampal volume on magnetic resonance imaging (MRI) and cortical metabolism on fluorodeoxyglucose-positron emission tomography (FDG-PET) in 188 MCI patients followed for at least 1 year. We categorised patients into earlier and later onset (EO/LO). Receiver operating characteristic curves and corresponding areas under the curve (AUCs) were performed to assess and compar the biomarker prognostic performances in EO and LO groups. Linear Model was adopted for estimating the time-to-progression in relation with earlier/later onset MCI groups and biomarkers. RESULTS: In earlier onset patients, all the assessed biomarkers were able to predict cognitive decline (p < 0.05), with FDG-PET showing the best performance. In later onset patients, all biomarkers but t-tau predicted cognitive decline (p < 0.05). Moreover, FDG-PET alone in earlier onset patients showed a higher prognostic value than the one resulting from the combination of all the biomarkers in later onset patients (earlier onset AUC 0.935 vs later onset AUC 0.753, p < 0.001). Finally, FDG-PET showed a different prognostic value between earlier and later onset patients (p = 0.040) in time-to-progression allowing an estimate of the time free from disease. DISCUSSION: FDG-PET may represent the most universal tool for the establishment of a prognosis in MCI patients and may be used for obtaining an onset-related estimate of the time free from disease.


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/metabolismo , Córtex Cerebral , Disfunção Cognitiva/diagnóstico , Progressão da Doença , Imagem por Ressonância Magnética/normas , Fragmentos de Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons/normas , Proteínas tau/metabolismo , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Biomarcadores/metabolismo , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Conjuntos de Dados como Assunto , Feminino , Fluordesoxiglucose F18 , Seguimentos , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico
19.
J Neuroinflammation ; 16(1): 143, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291963

RESUMO

BACKGROUND: Alzheimer's disease (AD) is a neuropathology strongly associated with the activation of inflammatory pathways. Accordingly, inflammation resulting from obesity exacerbates learning and memory deficits in humans and in animal models of AD. Consequently, the long-term use of non-steroidal anti-inflammatory agents diminishes the risk for developing AD, but the side effects produced by these drugs limit their prophylactic use. Thus, plants natural products have become an excellent option for modern therapeutics. Malva parviflora is a plant well known for its anti-inflammatory properties. METHODS: The present study was aimed to determine the anti-inflammatory potential of M. parviflora leaf hydroalcoholic extract (MpHE) on AD pathology in lean and obese transgenic 5XFAD mice, a model of familial AD. The inflammatory response and Amyloid ß (Aß) plaque load in lean and obese 5XFAD mice untreated or treated with MpHE was evaluated by immunolocalization (Iba-1 and GFAP) and RT-qPCR (TNF) assays and thioflavin-S staining, respectively. Spatial learning memory was assessed by the Morris Water Maze behavioral test. Microglia phagocytosis capacity was analyzed in vivo and by ex vivo and in vitro assays, and its activation by morphological changes (phalloidin staining) and expression of CD86, Mgl1, and TREM-2 by RT-qPCR. The mechanism triggered by the MpHE was characterized in microglia primary cultures and ex vivo assays by immunoblot (PPAR-γ) and RT-qPCR (CD36) and in vivo by flow cytometry, using GW9662 (PPAR-γ inhibitor) and pioglitazone (PPAR-γ agonist). The presence of bioactive compounds in the MpHE was determined by HPLC. RESULTS: MpHE efficiently reduced astrogliosis, the presence of insoluble Aß peptides in the hippocampus and spatial learning impairments, of both, lean, and obese 5XFAD mice. This was accompanied by microglial cells accumulation around Aß plaques in the cortex and the hippocampus and decreased expression of M1 inflammatory markers. Consistent with the fact that the MpHE rescued microglia phagocytic capacity via a PPAR-γ/CD36-dependent mechanism, the MpHE possess oleanolic acid and scopoletin as active phytochemicals. CONCLUSIONS: M. parviflora suppresses neuroinflammation by inhibiting microglia pro-inflammatory M1 phenotype and promoting microglia phagocytosis. Therefore, M. parviflora phytochemicals represent an alternative to prevent cognitive impairment associated with a metabolic disorder as well as an effective prophylactic candidate for AD progression.


Assuntos
Doença de Alzheimer , Encéfalo/efeitos dos fármacos , Disfunção Cognitiva/patologia , Microglia/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Encéfalo/patologia , Disfunção Cognitiva/etiologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Malva , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , PPAR gama/metabolismo , Fagocitose/efeitos dos fármacos , Folhas de Planta
20.
J Clin Neurosci ; 68: 168-173, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31324472

RESUMO

The aim of this study was to compare brain volume reduction in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) with age-related changes in age- and gender-matched healthy individuals. Sixty-six patients were divided in three groups based on medical history, neurological and neurocognitive assessment: 26 patients with AD, 20 patients with aMCI and 20 healthy controls. All participants underwent high-resolution magnetic resonance (MR) imaging on 3 T unit. MR volumetry of cerebral cortex, white matter and lateral ventricles volumes, as well as volumes of subcortical nuclei (hippocampus, amygdala, thalamus) was performed. Global cerebral and grey matter volumes were lower in AD patients compared to aMCI (p = 0.023 and p = 0.001, respectively) and controls (p < 0.001 and p < 0.001, respectively). Volume of lateral ventricles was significantly higher in AD patients compared to controls (right p = 0.007, left p = 0.007). Volumes of thalamus were lower in AD patients (right p < 0.001, left p < 0.001), and in aMCI patients (right p = 0.004, left p = 0.015), compared to controls. Hippocampal volume was lower in AD patients compared to both aMCI patients (right p = 0.047, left p = 0.003) and controls (right p < 0.001, left p < 0.001). In aMCI patients, hippocampal volume was lower than in controls (right p = 0.004, left p = 0.007). Volumes of amygdala were lower in AD patients compared to controls (righ p = 0.003, left p = 0.001). Our results show that thalamic volume loss could be an early sign associated with poorercognitiveperformance in aMCI, preceeding the atrophy of amygdala, global grey and white matter volume loss, and cerebrospinal fluid spaces dilatation.


Assuntos
Doença de Alzheimer/patologia , Disfunção Cognitiva/patologia , Tálamo/patologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade
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