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1.
Yonsei Med J ; 62(3): 255-261, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33635016

RESUMO

PURPOSE: This study aimed to examine the inter-method reliability and volumetric differences between NeuroQuant (NQ) and Freesurfer (FS) using T1 volume imaging sequence with different slice thicknesses in patients with mild cognitive impairment (MCI). MATERIALS AND METHODS: This retrospective study enrolled 80 patients diagnosed with MCI at our memory clinic. NQ and FS were used for volumetric analysis of three-dimensional T1-weighted images with slice thickness of 1 and 1.2 mm. Inter-method reliability was measured with Pearson correlation coefficient (r), intraclass correlation coefficient (ICC), and effect size (ES). RESULTS: Overall, NQ volumes were larger than FS volumes in several locations: whole brain (0.78%), cortical gray matter (5.34%), and white matter (2.68%). Volume measures by NQ and FS showed good-to-excellent ICCs with both 1 and 1.2 mm slice thickness (ICC=0.75-0.97, ES=-1.0-0.73 vs. ICC=0.78-0.96, ES=-0.9-0.77, respectively), except for putamen, pallidum, thalamus, and total intracranial volumes. The ICCs in all locations, except the putamen and cerebellum, were slightly higher with a slice thickness of 1 mm compared to those of 1.2 mm. CONCLUSION: Inter-method reliability between NQ and FS was good-to-excellent in most regions with improvement with a 1-mm slice thickness. This finding indicates that the potential effects of slice thickness should be considered when performing volumetric measurements for cognitive impairment.


Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/patologia , Imagem por Ressonância Magnética , Idoso , Idoso de 80 Anos ou mais , Automação , Feminino , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Estudos Retrospectivos
2.
Neurology ; 96(11): e1501-e1511, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33504642

RESUMO

OBJECTIVE: To determine whether severe perivascular space (PVS) dilation is associated with longitudinal cognitive decline and incident dementia over 4 and 8 years, respectively, we analyzed data from a prospective cohort study. METHODS: A total of 414 community-dwelling older adults aged 72-92 years were assessed at baseline and biennially for up to 8 years, with cognitive assessments, consensus dementia diagnoses, and 3T MRI. The numbers of PVS in 2 representative slices in the basal ganglia (BG) and centrum semiovale (CSO) were counted and severe PVS pathology defined as the top quartile. The effects of severe PVS pathology in either region or both regions and those with severe BG PVS and severe CSO PVS were examined. White matter hyperintensity volume, cerebral microbleed number, and lacune number were calculated. RESULTS: Participants with severe PVS pathology in both regions or in the CSO alone had greater decline in global cognition over 4 years, even after adjustment for the presence of other small vessel disease neuroimaging markers. The presence of severe PVS pathology in both regions was an independent predictor of dementia across 8 years (odds ratio 2.91, 95% confidence interval 1.43-5.95, p = 0.003). The presence of severe PVS pathology in all groups examined was associated with greater dementia risk at either year 4 or 6. CONCLUSIONS: Severe PVS pathology is a marker for increased risk of cognitive decline and dementia, independent of other small vessel disease markers. The differential cognitive associations for BG and CSO PVS may represent differences in their underlying pathology.


Assuntos
Disfunção Cognitiva/patologia , Demência/patologia , Sistema Glinfático/patologia , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino
3.
JAMA Netw Open ; 4(1): e2031654, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33449094

RESUMO

Importance: Understanding mechanisms associated with prolonged cognitive health in combination with exceptional longevity might lead to approaches to enable successful aging. Objective: To investigate trajectories of cognitive functioning in centenarians across domains, and to examine the association of these trajectories with factors underlying cognitive reserve, physical health, and postmortem levels of Alzheimer disease (AD)-associated neuropathology. Design, Setting, and Participants: This cohort study used neuropsychological test data and postmortem neuropathological reports from Dutch centenarians who were drawn from the 100-plus Study between January 2013 and April 2019. Eligible participants self-reported being cognitively healthy, which was confirmed by a proxy. Data analysis was performed between June 2019 and June 2020. Exposures: Age, sex, APOE ε genotype, factors of cognitive reserve, physical health, and AD-associated neuropathology (ie, amyloid-ß, neurofibrillary tangles, and neuritic plaques). Main Outcomes and Measures: In annual visits (until death or until participation was no longer possible), centenarians underwent an extensive neuropsychological test battery, from which an mean z score of global cognition, memory, executive functions, verbal fluency, visuospatial functions, and attention/processing speed was calculated. Linear mixed models with a random intercept and time as independent variable were used to investigate cognitive trajectories, adjusted for sex, age, education, and vision and hearing capacities. In a second step, linear mixed models were used to associate cognitive trajectories with factors underlying cognitive reserve, physical health at baseline, and AD-associated neuropathology. Results: Of the 1023 centenarians approached, 340 were included in the study. We analyzed 330 centenarians for whom cognitive tests were available at baseline (239 [72.4%] women; median [interquartile range] age of 100.5 [100.2-101.7] years), with a mean (SD) follow-up duration of 1.6 (0.8) years. We observed no decline across investigated cognitive domains, with the exception of a slight decline in memory function (ß, -0.10 SD per year; 95% CI, -0.14 to -0.05 SD; P < .001). Cognitive performance was associated with factors of physical health (eg, higher Barthel index: ß, 0.37 SD per year; 95% CI, 0.24-0.49; P < .001) and cognitive reserve (eg, higher education: ß, 0.41 SD per year; 95% CI, 0.29-0.53; P < .001), but none of these factors were associated with the rate of decline. Neuropathological reports were available for 44 participants. While centenarian brains revealed varying loads of postmortem neuropathological hallmarks of AD, this was not associated with cognitive performance or rate of decline. Conclusions and Relevance: While we observed a slight vulnerability for decline in memory function, centenarians maintained high levels of performance in all other investigated cognitive domains for up to 4 years despite the presence of risk factors of cognitive decline. These findings suggest that mechanisms of resilience may underlie the prolongation of cognitive health until exceptional ages.


Assuntos
Encéfalo , Cognição/fisiologia , Disfunção Cognitiva , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Autopsia , Encéfalo/patologia , Encéfalo/fisiopatologia , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Masculino , Países Baixos , Testes Neuropsicológicos , Estudos Prospectivos , Fatores de Risco
4.
Int J Mol Sci ; 22(2)2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33430419

RESUMO

Obesity mediates most of its direct medical sequelae through the development of insulin resistance (IR). The cellular effects of insulin occur through two main postreceptor pathways that are the phosphatidylinositol 3-kinase (PI3-K) and the mitogen-activated protein kinase (MAP-K) pathways. Obesity-related IR implicates the PI3-K pathway that confers the metabolic effects of insulin. Numerous and complex pathogenic pathways link obesity with the development of IR, including chronic inflammation, mitochondrial dysfunction (with the associated production of reactive oxygen species and endoplasmic reticulum stress), gut microbiota dysbiosis and adipose extracellular matrix remodelling. IR itself plays a key role in the development of metabolic dysfunction, including hypertension, dyslipidaemia and dysglycaemia. Furthermore, IR promotes weight gain related to secondary hyperinsulinaemia, with a resulting vicious cycle of worsening IR and its metabolic sequelae. Ultimately, IR underlies obesity-related conditions such as type 2 diabetes mellitus (T2D) and polycystic ovary syndrome (PCOS). IR also underlies many obesity-related malignancies, through the effects of compensatory hyperinsulinaemia on the relatively intact MAP-K insulin pathway, which controls cellular growth processes and mitoses. Furthermore, the emergent data over recent decades support an important role of obesity- and T2D-related central IR in the development of cognitive dysfunction, including effects on hippocampal synaptic plasticity. Importantly, IR is largely reversible through the optimisation of lifestyle factors that include regular engagement in physical activity with the avoidance of sedentariness, improved diet including increased fibre intake and sleep sufficiency. IR lies at the key crossroad between obesity and both metabolic and cognitive dysfunction. Given the importance of IR in the pathogenesis of many 21st century chronic diseases and its eminent reversibility, it is important that we all embrace and facilitate optimised lifestyles to improve the future health and wellbeing of the populace.


Assuntos
Disfunção Cognitiva/genética , Diabetes Mellitus Tipo 2/genética , Resistência à Insulina/genética , Obesidade/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Insulina/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Obesidade/metabolismo , Obesidade/patologia , Fosfatidilinositol 3-Quinase/genética
5.
BMC Neurol ; 21(1): 16, 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33430806

RESUMO

BACKGROUND: Parkinson's disease (PD), frequently accompanied by cognitive impairments, is associated with systemic oxidative stress and abnormal structural changes on brain images. We aimed to identify the correlation between systemic oxidative stress and cognitive function in PD patients with different periventricular white matter hyperintensities (PWMH) and deep white matter hyperintensities (DWMH). METHODS: A total of 146 participants with idiopathic PD underwent brain MRI, which revealed PWMH and DWMH. The number of lesions were evaluated using the Fazekas criteria. Systemic oxidative stress was determined as early or late phase changes in leukocyte apoptosis and its subsets by flow cytometry. Cognitive functions, including attention, executive function, memory, language, and visual space, were assessed. RESULTS: For different DWMH, the leukocyte apoptosis and its subsets were significantly different.. However, there were no significant differences in oxidative stress biomarkers in PD patients with different PWMH. Attention and memory were significantly decreased in patients with more advanced DWMH injuries. Attention, memory, and language were significantly impaired in patients with worse PWMH lesions. CONCLUSION: Significant oxidative stress biomarker alternations in PD patients with DWMH, but not PWMH, might be associated with white matter injury. Systemic inflammatory responses may contribute to deep white matter damage in PD. Further, more cognitive deficits were seen in PD patients with worse deep white matter lesions, especially in moderate to severe periventricular white matter injury. TRIAL REGISTRATION: Retrospective study.


Assuntos
Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Estresse Oxidativo/fisiologia , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Idoso , Feminino , Humanos , Leucoaraiose/etiologia , Leucoaraiose/patologia , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neuroimagem/métodos , Estudos Retrospectivos , Substância Branca/patologia
6.
Int J Mol Sci ; 22(1)2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33466498

RESUMO

Hepatic encephalopathy (HE) is one of the main consequences of liver disease and is observed in severe liver failure and cirrhosis. Recent studies have provided significant evidence that HE shows several neurological symptoms including depressive mood, cognitive dysfunction, impaired circadian rhythm, and attention deficits as well as motor disturbance. Liver disease is also a risk factor for the development of diabetes mellitus. Diabetic encephalopathy (DE) is characterized by cognitive dysfunction and motor impairment. Recent research investigated the relationship between metabolic changes and the pathogenesis of neurological disease, indicating the importance between metabolic organs and the brain. Given that a diverse number of metabolites and changes in the brain contribute to neurologic dysfunction, HE and DE are emerging types of neurologic disease. Here, we review significant evidence of the association between HE and DE, and summarise the common risk factors. This review may provide promising therapeutic information and help to design a future metabolic organ-related study in relation to HE and DE.


Assuntos
Encéfalo/patologia , Diabetes Mellitus/patologia , Encefalopatia Hepática/patologia , Fígado/patologia , Animais , Disfunção Cognitiva/patologia , Humanos
7.
Neuroimage ; 227: 117676, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33359337

RESUMO

OBJECTIVE: Estimate the time-course of the spread of key pathological markers and the onset of cognitive dysfunction in Alzheimer's disease. METHODS: In a cohort of 335 older adults, ranging in cognitive functioning, we estimated the time of initial changes of Aß, tau, and decreases in cognition with respect to the time of Aß-positivity. RESULTS: Small effect sizes of change in CSF Aß42 and regional Aß PET were estimated to occur several decades before Aß-positivity. Increases in CSF tau occurred 7-8 years before Aß-positivity. Temporoparietal tau PET showed increases 4-5 years before Aß-positivity. Subtle cognitive dysfunction was observed 4-6 years before Aß-positivity. CONCLUSIONS: Increases in tau and cognitive dysfunction occur years before commonly used thresholds for Aß-positivity. Explicit estimates of the time for these events provide a clearer picture of the time-course of the amyloid cascade and identify potential windows for specific treatments.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Progressão da Doença , Proteínas tau/metabolismo , Idoso , Doença de Alzheimer/complicações , Doença de Alzheimer/metabolismo , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Feminino , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Fatores de Tempo
8.
Biomed Pharmacother ; 133: 111088, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33378982

RESUMO

Alzheimer's disease (AD) is a neurodegenerative condition mostly communal in people of advanced years accompanying various dysfunctionalities especially cognitive impairments. A number of cellular damages, such as amyloid-beta aggregation, tau protein hyperphosphorylation, some neurotransmitter imbalances, apoptosis, oxidative stress, and inflammatory responses are responsible for AD incidence. As a reason for inadequate efficacy, side effects, and pharmacokinetic problems of conventional drugs used for AD, the discovery of novel therapeutic agents with multi-targeted potential is desirable. Protective properties of phytochemicals combat numerous diseases and their vast acceptance and demand in human beings encouraged scientists to assess their effective activities. Zingiber officinale, gingerol, shogaol, and borneol were evaluated against memory impairments. Online databases including; Web of Science, Scopus, Embase, Pubmed, ProQuest, ScienceDirect, and Cochrane Library were searched until 3th February 2020. In vitro, in vivo, and clinical studies are included after screening their eligibility. Mostly interventive mechanisms such as; oxidative stress, neuroinflammation, and apoptosis are described. Correlation between the pathogenesis of AD and signaling pathways is explicated. Results and scores of cognition measurements are clarified due to in vivo studies and clinical trials. Some traditional aspects of consuming ginger in AD are also mentioned in the present review. In accumulation ginger and its components possess great potency for improving and abrogating memory dysfunctions but conducting further studies to evaluate their pharmacological and pharmaceutical aspects is required.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/tratamento farmacológico , Gengibre , Memória/efeitos dos fármacos , Nootrópicos/uso terapêutico , Extratos Vegetais/uso terapêutico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Animais , Apoptose/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Gengibre/química , Humanos , Mediadores da Inflamação/metabolismo , Nootrópicos/isolamento & purificação , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação
9.
Zhonghua Yi Xue Za Zhi ; 100(43): 3397-3401, 2020 Nov 24.
Artigo em Chinês | MEDLINE | ID: mdl-33238668

RESUMO

Objective: To investigate the association of age-related white matter hyperintensity (WMH) with brain atrophy and cognitive impairment in patients with Parkinson's disease (PD). Methods: Consecutive samples of a prospective PD cohort with complete 3-dimensional magnetic resonance imaging in the Department of Movement Disorders in Beijing Tiantan Hospital, Capital Medical University, from October 2018 to August 2019 was retrospectively analyzed. Cognition was evaluated by Mini-Mental State Scale (MMSE) and Montreal Cognitive Assessment (MoCA). The severity of WMH was semi-quantitatively measured by Fazekas scale (0-6 points), and the mean cortical thickness and thalamus volume were calculated by FreeSurfer software. The demographic and disease characteristics, the severity of WMH, the mean cortical thickness and thalamus volume were respectively compared between PD patients with and without dementia. Moreover, univariate and multivariate generalized linear models were used to analyze the correlation of the severity of WMH with brain atrophy and MoCA. Results: A total of 225 patients with PD were included in the study, with a median age of 66 years old. Comparisons between groups suggested that patients with dementia were with severer WMH, older, and had lower levels of serum cholesterol and low-density lipoprotein and more reduced mean cortical thickness than those without dementia (all P<0.05), but no significant difference in the thalamus volume was found between the two groups. The generalized linear model showed that the cognitive impairment of PD patients was significantly correlated with WMH (ß=-0.021, 95%CI:-0.040--0.002, P=0.032), but independent of age, cortical thickness, and levels of serum cholesterol and low-density lipoprotein. Conclusion: WMH may worsen PD cognitive impairment independent of brain atrophy. Clinical prevention and treatment of cerebral small vessel disease may have protective effects on cognitive function in patients with PD.


Assuntos
Disfunção Cognitiva , Doença de Parkinson , Substância Branca , Idoso , Atrofia/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Humanos , Imagem por Ressonância Magnética , Testes Neuropsicológicos , Doença de Parkinson/complicações , Doença de Parkinson/patologia , Estudos Prospectivos , Estudos Retrospectivos , Substância Branca/patologia
10.
Nat Commun ; 11(1): 5522, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33139698

RESUMO

Tauopathies including Alzheimer's disease (AD) are marked by the accumulation of aberrantly modified tau proteins. Acetylated tau, in particular, has recently been implicated in neurodegeneration and cognitive decline. HDAC6 reversibly regulates tau acetylation, but its role in tauopathy progression remains unclear. Here, we identified an HDAC6-chaperone complex that targets aberrantly modified tau. HDAC6 not only deacetylates tau but also suppresses tau hyperphosphorylation within the microtubule-binding region. In neurons and human AD brain, HDAC6 becomes co-aggregated within focal tau swellings and human AD neuritic plaques. Using mass spectrometry, we identify a novel HDAC6-regulated tau acetylation site as a disease specific marker for 3R/4R and 3R tauopathies, supporting uniquely modified tau species in different neurodegenerative disorders. Tau transgenic mice lacking HDAC6 show reduced survival characterized by accelerated tau pathology and cognitive decline. We propose that a HDAC6-dependent surveillance mechanism suppresses toxic tau accumulation, which may protect against the progression of AD and related tauopathies.


Assuntos
Disfunção Cognitiva/patologia , Desacetilase 6 de Histona/metabolismo , Tauopatias/patologia , Proteínas tau/metabolismo , Acetilação , Idoso , Idoso de 80 Anos ou mais , Animais , Encéfalo/patologia , Disfunção Cognitiva/genética , Modelos Animais de Doenças , Progressão da Doença , Feminino , Desacetilase 6 de Histona/genética , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Fosforilação , Processamento de Proteína Pós-Traducional , Tauopatias/genética , Proteínas tau/genética
11.
Phys Rev Lett ; 125(12): 128102, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-33016724

RESUMO

Neurodegenerative diseases, such as Alzheimer's or Parkinson's disease, show characteristic degradation of structural brain networks. This degradation eventually leads to changes in the network dynamics and degradation of cognitive functions. Here, we model the progression in terms of coupled physical processes: The accumulation of toxic proteins, given by a nonlinear reaction-diffusion transport process, yields an evolving brain connectome characterized by weighted edges on which a neuronal-mass model evolves. The progression of the brain functions can be tested by simulating the resting-state activity on the evolving brain network. We show that while the evolution of edge weights plays a minor role in the overall progression of the disease, dynamic biomarkers predict a transition over a period of 10 years associated with strong cognitive decline.


Assuntos
Demência/patologia , Modelos Neurológicos , Doenças Neurodegenerativas/patologia , Animais , Relógios Biológicos , Encéfalo/patologia , Encéfalo/fisiopatologia , Morte Celular/fisiologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/fisiopatologia , Conectoma/métodos , Demência/fisiopatologia , Humanos , Camundongos , Doenças Neurodegenerativas/fisiopatologia , Neurônios/patologia
12.
PLoS One ; 15(9): e0239484, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32956392

RESUMO

OBJECTIVE: To assess and compare the involvement of choroidal thickness (CT) in patients with mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD) defined by amyloid PET and healthy controls (HC). METHODS: Sixty-three eyes from 34 AD patients [12 eyes (19.0%) with dementia and 51 eyes (80.9%) with MCI], positive to 11C-labelled Pittsburgh Compound-B with positron emission tomography (11C-PiB PET/CT), and the same number of sex- and age-paired HC were recruited. All participants underwent enhanced depth imaging optical coherence tomography (EDI-OCT) assessing CT at 14 measurements from 2 B-scans. Paired Student t-test was used to compare CT measurements between MCI, dementia and sex- and age-paired HC. A univariate generalized estimating equations model (GEE) test was performed to compare MCI and dementia individually with all HC included. RESULTS: Compared with HC, eyes from patients with positive 11C-PiB PET/CT showed a significant CT thinning in 5 selected locations (in foveal thickness in vertical scan, in temporal scan at 1500µm, in superior scan at 500µm and in inferior scan at 1000µm and 1500µm, p = 0.020-0.045) whilst few significant CT reduction data was reported in MCI or dementia individually versus HC. However, the GEE test identified significant CT thinning in AD compared with all HC included (p = 0.015-0.046). CONCLUSIONS: To our knowledge, the present study is the first measuring CT in eyes from MCI and dementia eyes positive to 11C-PiB PET/CT reporting a significant trend towards CT thinning in MCI patients which became more pronounced in dementia stage. We support further investigation involving larger and prospective OCT studies in AD population characterized with available biomarkers to describe whether choroidal vascular damage occurs specifically in prodromal stages of AD.


Assuntos
Doença de Alzheimer/patologia , Amiloide/análise , Corioide/ultraestrutura , Disfunção Cognitiva/patologia , Sintomas Prodrômicos , Tomografia de Coerência Óptica , Idoso , Doença de Alzheimer/diagnóstico por imagem , Compostos de Anilina , Antropometria , Área Sob a Curva , Radioisótopos de Carbono , Estudos de Casos e Controles , Disfunção Cognitiva/diagnóstico por imagem , Estudos Transversais , Progressão da Doença , Diagnóstico Precoce , Feminino , Humanos , Masculino , Neuroimagem , Variações Dependentes do Observador , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Tiazóis
13.
PLoS One ; 15(9): e0236868, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976486

RESUMO

Detection and diagnosis of early and subclinical stages of Alzheimer's Disease (AD) play an essential role in the implementation of intervention and prevention strategies. Neuroimaging techniques predominantly provide insight into anatomic structure changes associated with AD. Deep learning methods have been extensively applied towards creating and evaluating models capable of differentiating between cognitively unimpaired, patients with Mild Cognitive Impairment (MCI) and AD dementia. Several published approaches apply information fusion techniques, providing ways of combining several input sources in the medical domain, which contributes to knowledge of broader and enriched quality. The aim of this paper is to fuse sociodemographic data such as age, marital status, education and gender, and genetic data (presence of an apolipoprotein E (APOE)-ε4 allele) with Magnetic Resonance Imaging (MRI) scans. This enables enriched multi-modal features, that adequately represent the MRI scan visually and is adopted for creating and modeling classification systems capable of detecting amnestic MCI (aMCI). To fully utilize the potential of deep convolutional neural networks, two extra color layers denoting contrast intensified and blurred image adaptations are virtually augmented to each MRI scan, completing the Red-Green-Blue (RGB) color channels. Deep convolutional activation features (DeCAF) are extracted from the average pooling layer of the deep learning system Inception_v3. These features from the fused MRI scans are used as visual representation for the Long Short-Term Memory (LSTM) based Recurrent Neural Network (RNN) classification model. The proposed approach is evaluated on a sub-study containing 120 participants (aMCI = 61 and cognitively unimpaired = 59) of the Heinz Nixdorf Recall (HNR) Study with a baseline model accuracy of 76%. Further evaluation was conducted on the ADNI Phase 1 dataset with 624 participants (aMCI = 397 and cognitively unimpaired = 227) with a baseline model accuracy of 66.27%. Experimental results show that the proposed approach achieves 90% accuracy and 0.90 F1-Score at classification of aMCI vs. cognitively unimpaired participants on the HNR Study dataset, and 77% accuracy and 0.83 F1-Score on the ADNI dataset.


Assuntos
Apolipoproteínas E/genética , Disfunção Cognitiva/diagnóstico , Imagem por Ressonância Magnética , Neuroimagem , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/patologia , Conjuntos de Dados como Assunto , Aprendizado Profundo , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Socioeconômicos
14.
Neurology ; 95(14): e1918-e1931, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32887784

RESUMO

OBJECTIVE: To characterize lesion evolution and neurodegeneration in retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) using multimodal MRI. METHODS: We prospectively performed MRI and cognitive testing in RVCL-S and healthy control cohorts. Gray and white matter volume and disruption of white matter microstructure were quantified. Asymmetric spin echo acquisition permitted voxel-wise oxygen extraction fraction (OEF) calculation as an in vivo marker of microvascular ischemia. The RVCL-S cohort was included in a longitudinal analysis of lesion subtypes in which hyperintense lesions on fluid-attenuated inversion recovery (FLAIR), T1-postgadolinium, and diffusion-weighted imaging were delineated and quantified volumetrically. RESULTS: Twenty individuals with RVCL-S and 26 controls were enrolled. White matter volume and microstructure declined faster in those with RVCL-S compared to controls. White matter atrophy in RVCL-S was highly linear (ρ = -0.908, p < 0.0001). Normalized OEF was elevated in RVCL-S and increased with disease duration. Multiple cognitive domains, specifically those measuring working memory and processing speed, were impaired in RVCL-S. Lesion volumes, regardless of subtype, progressed/regressed with high variability as a function of age, while FLAIR lesion burden increased near time to death (p < 0.001). CONCLUSION: RVCL-S is a monogenic microvasculopathy affecting predominantly the white matter with regard to atrophy and cognitive impairment. White matter volumes in RVCL-S declined linearly, providing a potential metric against which to test the efficacy of future therapies. Progressive elevation of white matter OEF suggests that microvascular ischemia may underlie neurodegeneration in RVCL-S.


Assuntos
Disfunção Cognitiva/patologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Degeneração Neural/patologia , Doenças Retinianas/patologia , Doenças Vasculares/patologia , Substância Branca/patologia , Adulto , Disfunção Cognitiva/diagnóstico por imagem , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Degeneração Neural/diagnóstico por imagem , Neuroimagem/métodos , Doenças Retinianas/diagnóstico por imagem , Doenças Vasculares/diagnóstico por imagem , Substância Branca/diagnóstico por imagem
15.
Int J Mol Sci ; 21(17)2020 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-32824985

RESUMO

The aim of this study is to examine the use of an inflammasome competitor as a preventative agent. Coronaviruses have zoonotic potential due to the adaptability of their S protein to bind receptors of other species, most notably demonstrated by SARS-CoV. The binding of SARS-CoV-2 to TLR (Toll-like receptor) causes the release of pro-IL-1ß, which is cleaved by caspase-1, followed by the formation and activation of the inflammasome, which is a mediator of lung inflammation, fever, and fibrosis. The NLRP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome is implicated in a variety of human diseases including Alzheimer's disease (AD), prion diseases, type 2 diabetes, and numerous infectious diseases. By examining the use of 4,4'-diaminodiphenyl sulfone (DDS) in the treatment of patients with Hansen's disease, also diagnosed as Alzheimer's disease, this study demonstrates the diverse mechanisms involved in the activation of inflammasomes. TLRs, due to genetic polymorphisms, can alter the immune response to a wide variety of microbial ligands, including viruses. In particular, TLR2Arg677Trp was reported to be exclusively present in Korean patients with lepromatous leprosy (LL). Previously, mutation of the intracellular domain of TLR2 has demonstrated its role in determining the susceptibility to LL, though LL was successfully treated using a combination of DDS with rifampicin and clofazimine. Of the three tested antibiotics, DDS was effective in the molecular regulation of NLRP3 inflammasome activators that are important in mild cognitive impairment (MCI), Parkinson's disease (PD), and AD. The specific targeting of NLRP3 itself or up-/downstream factors of the NLRP3 inflammasome by DDS may be responsible for its observed preventive effects, functioning as a competitor.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Dapsona/farmacologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Pneumonia Viral/tratamento farmacológico , Doença de Alzheimer/patologia , Clofazimina/farmacologia , Disfunção Cognitiva/patologia , Humanos , Interleucina-1beta/metabolismo , Hanseníase/tratamento farmacológico , Hanseníase/genética , Pandemias , Transtornos Parkinsonianos/patologia , Rifampina/farmacologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Receptor 2 Toll-Like/genética
16.
Biomolecules ; 10(8)2020 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-32784855

RESUMO

Zinc therapy is normally utilized for treatment of Wilson disease (WD), an inherited condition that is characterized by increased levels of non-ceruloplasmin bound ('free') copper in serum and urine. A subset of patients with Alzheimer's disease (AD) or its prodromal form, known as Mild Cognitive Impairment (MCI), fail to maintain a normal copper metabolic balance and exhibit higher than normal values of non-ceruloplasmin copper. Zinc's action mechanism involves the induction of intestinal cell metallothionein, which blocks copper absorption from the intestinal tract, thus restoring physiological levels of non-ceruloplasmin copper in the body. On this basis, it is employed in WD. Zinc therapy has shown potential beneficial effects in preliminary AD clinical trials, even though the studies have missed their primary endpoints, since they have study design and other important weaknesses. Nevertheless, in the studied AD patients, zinc effectively decreased non-ceruloplasmin copper levels and showed potential for improved cognitive performances with no major side effects. This review discusses zinc therapy safety and the potential therapeutic effects that might be expected on a subset of individuals showing both cognitive complaints and signs of copper imbalance.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Cobre/metabolismo , Zinco/uso terapêutico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Ceruloplasmina/metabolismo , Disfunção Cognitiva/enzimologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Humanos , Zinco/administração & dosagem , Zinco/efeitos adversos , Zinco/metabolismo
17.
Neurology ; 95(14): e1951-e1962, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32753441

RESUMO

OBJECTIVE: To examine the impact of 3 pathologic groups, pure limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy (LATE) neuropathologic changes (NC), pure Alzheimer disease neuropathologic change (ADNC), and mixed ADNC with LATE-NC, on late-life cognitive decline. METHODS: Data came from 1,356 community-based older persons who completed detailed annual cognitive testing and systematic neuropathologic examination at autopsy to identify LATE-NC, ADNC, and other age-related pathologies. Persons were categorized into (0) a group without a pathologic diagnosis of LATE or ADNC (n = 378), (1) LATE-NC without ADNC (n = 91), (2) ADNC without LATE-NC (n = 535), and (3) mixed ADNC with LATE-NC (n = 352). We used mixed-effect models to examine the group associations with rate of decline in global cognition and 5 cognitive domains and then examined whether age modified associations. RESULTS: Compared to those without LATE-NC or ADNC, those with pure LATE-NC had a faster decline in global cognition (p = 0.025) and episodic memory (p = 0.002); however, compared to persons with pure ADNC, those with pure LATE-NC showed a slower decline. Those with mixed ADNC with LATE-NC showed the fastest decline compared to those with either pathology alone. Persons ≥90 years of age with mixed ADNC with LATE-NC had slower cognitive decline compared to those ≤89 years of age. CONCLUSION: Persons with pure LATE-NC follow a slower trajectory compared to those with pure ADNC. Those with mixed LATE/ADNC have a steeper decline than individuals with either pathology alone. In addition, age may modify the effect of pathology on cognitive decline. These findings have important implications for the development of biomarkers and prognosis for late-life cognitive decline. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that LATE-NC and Alzheimer disease pathologic changes are associated with different trajectories of late-life cognitive decline.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Disfunção Cognitiva/patologia , Proteinopatias TDP-43/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/complicações , Disfunção Cognitiva/etiologia , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Proteinopatias TDP-43/complicações
19.
PLoS One ; 15(7): e0236453, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726329

RESUMO

OBJECTIVES: To assess the potential value of some miRNAs as diagnostic biomarkers for mild cognitive impairment (MCI) among patients with type2 diabetes mellitus (T2DM) and to identify other risk factors for MCI among them. METHODS: This study enrolled 163 adults with T2DM using face to face interview. Cognitive function with its domains was assessed using Adenbrooke's Cognitive Examination III (ACE III). Lipid profile, glycated hemoglobin, and miR-128, miR-132, miR- 874, miR-134, miR-323, and miR-382 expressions, using quantitative real-time PCR, were assessed. RESULTS: MCI was detected among 59/163 (36.2%) patients with T2DM. Plasma expression of miR-132 was significantly higher in T2DM patients with MCI compared to those without MCI and to normal cognitive healthy individuals (median = 2, 1.1 and 1.2 respectively, P < 0.05. Logistic regression analysis showed that higher miR-132 expression with adjusted odds ratio (AOR): 1.2 (95% CI 1.0-1.3), female gender (AOR:2.1; 95%CI 1.0-4.3), education below postgraduate (secondary and university education with AOR: 9.5 & 19.4 respectively) were the significant predicting factors for MCI among T2DM patients. Using ROC curve, miR-132 was the only assayed miRNA that significantly differentiates T2DM patients with MCI from those with normal cognition with 72.3% sensitivity, 56.2% specificity, and 63.8% accuracy (P < 0.05). Other studied miRNAs showed lower sensitivity and specificity for detecting MCI among studied T2DM participants. CONCLUSION: MCI affects nearly one-third of adult patients with T2DM. A significantly over expression of miR-132 was detected among T2DM with MCI compared to those with normal cognition.


Assuntos
Biomarcadores/sangue , Disfunção Cognitiva/sangue , Diabetes Mellitus Tipo 2/sangue , MicroRNAs/sangue , Adulto , Cognição/fisiologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Feminino , Hemoglobina A Glicada/genética , Humanos , Lipídeos/sangue , Masculino , MicroRNAs/classificação , MicroRNAs/genética , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fatores de Risco
20.
PLoS One ; 15(7): e0235974, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32658926

RESUMO

OBJECTIVE: To investigate the relationship between food patterns and mild cognitive impairment (MCI) among Chinese elderly to provide evidence for risk prevention and control of MCI among elderly population. METHODS: Between February 2017 to October 2018, a stratified multistage cluster sampling method was used to select participants from 760 communities of six districts in Xi'an, China, for 49-item food frequency questionnaire survey. A total of 2311 participants aged 60 to 88 years were included in the study with 444 (19.2%) participants of MCI among Chinese community-dwelling elderly adults. Food patterns associated with risk of dementia were assessed by using a reduced rank regression (RRR) analysis, and the multivariate linear regression was used to test trends of risk factors across scores for the food pattern. RESULTS: Four dietary patterns were extracted which explained 88.65% of the total variation in food intakes. Furthermore, the food pattern 1 (FP1) accounted for 60.25% of the total variation of all responsible variables and as a target dietary pattern in the study, which was related with high intake of legumes, vegetables, fruits, milk and dairy products, nuts and a low intake of noodles and cereals (p<0.05). Multivariate linear regression analysis showed that participants with a high score for FP1 had higher direction, memory and language function and FP1 can improve the ability of cognitive function (p<0.05). CONCLUSION: The FP1 of Chinese dietary patterns was significantly correlated with higher cognitive function which can reduce the risk of MCI among Chinese elderly.


Assuntos
Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Disfunção Cognitiva/etiologia , Dieta/efeitos adversos , Comportamento Alimentar/psicologia , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/patologia , Disfunção Cognitiva/psicologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Inquéritos e Questionários
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