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Importance: Episodic memory and executive function are essential aspects of cognitive functioning that decline with aging. This decline may be ameliorable with lifestyle interventions. Objective: To determine whether mindfulness-based stress reduction (MBSR), exercise, or a combination of both improve cognitive function in older adults. Design, Setting, and Participants: This 2 × 2 factorial randomized clinical trial was conducted at 2 US sites (Washington University in St Louis and University of California, San Diego). A total of 585 older adults (aged 65-84 y) with subjective cognitive concerns, but not dementia, were randomized (enrollment from November 19, 2015, to January 23, 2019; final follow-up on March 16, 2020). Interventions: Participants were randomized to undergo the following interventions: MBSR with a target of 60 minutes daily of meditation (n = 150); exercise with aerobic, strength, and functional components with a target of at least 300 minutes weekly (n = 138); combined MBSR and exercise (n = 144); or a health education control group (n = 153). Interventions lasted 18 months and consisted of group-based classes and home practice. Main Outcomes and Measures: The 2 primary outcomes were composites of episodic memory and executive function (standardized to a mean [SD] of 0 [1]; higher composite scores indicate better cognitive performance) from neuropsychological testing; the primary end point was 6 months and the secondary end point was 18 months. There were 5 reported secondary outcomes: hippocampal volume and dorsolateral prefrontal cortex thickness and surface area from structural magnetic resonance imaging and functional cognitive capacity and self-reported cognitive concerns. Results: Among 585 randomized participants (mean age, 71.5 years; 424 [72.5%] women), 568 (97.1%) completed 6 months in the trial and 475 (81.2%) completed 18 months. At 6 months, there was no significant effect of mindfulness training or exercise on episodic memory (MBSR vs no MBSR: 0.44 vs 0.48; mean difference, -0.04 points [95% CI, -0.15 to 0.07]; P = .50; exercise vs no exercise: 0.49 vs 0.42; difference, 0.07 [95% CI, -0.04 to 0.17]; P = .23) or executive function (MBSR vs no MBSR: 0.39 vs 0.31; mean difference, 0.08 points [95% CI, -0.02 to 0.19]; P = .12; exercise vs no exercise: 0.39 vs 0.32; difference, 0.07 [95% CI, -0.03 to 0.18]; P = .17) and there were no intervention effects at the secondary end point of 18 months. There was no significant interaction between mindfulness training and exercise (P = .93 for memory and P = .29 for executive function) at 6 months. Of the 5 prespecified secondary outcomes, none showed a significant improvement with either intervention compared with those not receiving the intervention. Conclusions and Relevance: Among older adults with subjective cognitive concerns, mindfulness training, exercise, or both did not result in significant differences in improvement in episodic memory or executive function at 6 months. The findings do not support the use of these interventions for improving cognition in older adults with subjective cognitive concerns. Trial Registration: ClinicalTrials.gov Identifier: NCT02665481.
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Envelhecimento Cognitivo , Disfunção Cognitiva , Terapia por Exercício , Meditação , Atenção Plena , Idoso , Feminino , Humanos , Masculino , Cognição/fisiologia , Função Executiva/fisiologia , Exercício Físico/fisiologia , Exercício Físico/psicologia , Meditação/métodos , Meditação/psicologia , Atenção Plena/métodos , Memória Episódica , Terapia por Exercício/métodos , Terapia por Exercício/psicologia , Envelhecimento Cognitivo/fisiologia , Envelhecimento Cognitivo/psicologia , Estilo de Vida Saudável/fisiologia , Comportamentos Relacionados com a Saúde/fisiologia , Estresse Psicológico/fisiopatologia , Estresse Psicológico/prevenção & controle , Estresse Psicológico/terapia , Idoso de 80 Anos ou mais , Testes Neuropsicológicos , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Disfunção Cognitiva/terapia , Imageamento por Ressonância MagnéticaRESUMO
OBJECTIVE: This study aims to investigate whether a systemic molecular pattern associated with aging (senescent-associated secretory phenotype [SASP]) is elevated in adults with late-life depression (LLD), compared with never-depressed elderly comparison participants. DESIGN: Cross-sectional study. PARTICIPANTS: We included 111 older adults (80 with LLD and 31 comparison participants) in this study. MEASUREMENT: A panel of 22 SASP-related proteins was extracted from a previous multiplex protein panel performed in these participants. We conducted a principal component analysis to create the SASP index based on individual weights of each of protein. RESULTS: Participants with LLD showed a significantly increased SASP index compared with comparison participants, after controlling for age, depressive symptoms, medical comorbidity (CIRS-G) scores, sex, and cognitive performance (F(1,98) = 7.3, p = 0.008). Correlation analyses revealed that the SASP index was positively correlated with age (r = 0.2, p = 0.03) and CIRS score (r = 0.27, p = 0.005), and negatively correlated with information processing speed (r = -0.34, p = 0.001), executive function (r = -0.27, p = 0.004) and global cognitive performance (r = -0.28, p = 0.007). CONCLUSIONS: To the best of our knowledge, this is the first study to show that a set of proteins (i.e., SASP index) primarily associated with cellular aging is abnormally regulated and elevated in LLD. These results suggest that individuals with LLD display enhanced aging-related molecular patterns that are associated with higher medical comorbidity and worse cognitive function. Finally, we provide a set of proteins that can serve as potential therapeutic targets and biomarkers to monitor the effects of therapeutic or preventative interventions in LLD.
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Envelhecimento/metabolismo , Senescência Celular/fisiologia , Disfunção Cognitiva/fisiopatologia , Depressão/metabolismo , Substância Branca/diagnóstico por imagem , Estudos Transversais , Humanos , Imageamento por Ressonância Magnética , FenótipoRESUMO
OBJECTIVE: This study aimed to investigate the correlation between apolipoprotein E (APOE) ε4 and the mini-mental state examination (MMSE) dimension in an elderly population, using baseline data from the Bambui (Brazil) Cohort Study of Aging. DESIGN: We conducted a community-based cross-sectional study. SETTING: The study took place at Bambui city, Minas Gerais State, Southeast Brazil. PARTICIPANTS: A total of 1408 (87.7%) cohort participants had complete information on the MMSE and health measures. MEASUREMENTS: The association between each of five dimensions (concentration, language/praxis, orientation, attention, and memory) underlying the MMSE and APOE ε4 allele was assessed using multivariate linear regression models. Potential confounding variables included sociodemographic factors and selected biomarkers. RESULTS: The main finding is a strong negative association between the presence of APOE ε4 allele and memory dimension in the MMSE (fully adjusted ß coefficient = -0.14; 95% confidence interval: -0.27 to -0.04; p = 0.016). No other cognitive dimensions showed significant associations with the APOE ε4 allele. CONCLUSION: This study is the first to investigate the association between dimensions of the MMSE, obtained from principal component analysis and APOE ε4 carrier status in community-dwelling older adults taking into account a range of potential confounding factors. We found a strong negative association between the presence of APOE ε4 allele and scores on memory dimension of the MMSE, but no effect on other dimensions. Our results reinforce previous data on the literature that APOE ε4 allele has a significant effect on cognitive performance that can be detected even in screening tests, such as the MMSE.
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Envelhecimento/fisiologia , Envelhecimento/psicologia , Apolipoproteína E4/genética , Memória/fisiologia , Idoso , Idoso de 80 Anos ou mais , Alelos , Atenção/fisiologia , Brasil , Escalas de Graduação Psiquiátrica Breve , Cognição/fisiologia , Estudos de Coortes , Estudos Transversais , Feminino , Genótipo , Humanos , Masculino , Transtornos da Memória/genética , Testes Neuropsicológicos , Análise de RegressãoRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia, characterized by the accumulation of amyloid beta (Aß) peptides in the brain. Here, we present a simple, rapid, and affordable CRISPR-powered aptasensor for the quantitative detection of Aß40 and Aß42 biomarkers in cerebrospinal fluid (CSF) samples, enabling early and accurate diagnostics of AD patients. The aptasensor couples the high specificity of aptamers for Aß biomarkers with CRISPR-Cas12a-based fluorescence detection. The CRISPR-powered aptasensor enables us to detect Aß40 and Aß42 in CSF samples within 60 min, achieving a detection sensitivity of 1 pg/mL and 0.1 pg/mL, respectively. To validate its clinical utility, we quantitatively detected Aß40 and Aß42 biomarkers in clinical CSF samples. Furthermore, by combining CSF Aß42 levels with the c(Aß42)/c(Aß40) ratio, we achieved an accurate diagnostic classification of AD patients and healthy individuals, showing superior performance over the conventional ELISA method. We believe that our innovative aptasensor approach holds promise for the early diagnostic classification of AD patients.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Ensaio de Imunoadsorção Enzimática , Biomarcadores/líquido cefalorraquidianoRESUMO
Background: The cell cycle is a critical mechanism for proper cellular growth, development and viability. The p16INK4a and p21Waf1/Cip1 are important regulators of the cell cycle progression in response to internal and external stimuli (e.g., stress). Accumulating evidence indicates that the prefrontal cortex (PFC) is particularly vulnerable to stress, where stress induces, among others, molecular and morphological alterations, reflecting behavioral changes. Here, we investigated if the p16INK4a and p21Waf1/Cip1 expression are associated with behavioral outcomes. Methods: Prefrontal cortex mRNA and protein levels of p16INK4A and p21Waf1/Cip1 of mice (six independent groups of C57BL/6J, eight mice/group, 50% female) exposed from 0 to 35 days of chronic restraint stress (CRS) were quantified by qPCR and Western Blot, respectively. Correlation analyses were used to investigate the associations between cyclin-dependent kinase inhibitors (CKIs) expression and anxiety- and depression-like behaviors. Results: Our results showed that the PFC activated the cell cycle regulation pathways mediated by both CKIs p16INK4A and p21Waf1/Cip1 in mice exposed to CRS, with overall decreased mRNA expression and increased protein expression. Moreover, correlation analysis revealed that mRNA and protein levels are statistically significant correlated with anxiety and depressive-like behavior showing a greater effect in males than females. Conclusion: Our present study extends the existing literature providing evidence that PFC cells respond to chronic stress exposure by overexpressing CKIs. Furthermore, our findings indicated that abnormal expression of p16INK4A and p21Waf1/Cip1 may significantly contribute to non-adaptive behavioral responses.
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OBJECTIVE: To identify the CAMCOG sub-items that best contribute for the identification of patients with mild cognitive impairment (MCI) and incipient Alzheimer's disease (AD) in clinical practice. METHODS: Cross-sectional assessment of 272 older adults (98 MCI, 82 AD, and 92 controls) with a standardized neuropsychological battery and the CAMCOG schedule. Backward logistic regression analysis with diagnosis (MCI and controls) as dependent variable and the sub-items of the CAMCOG as independent variable was carried out to determine the CAMCOG sub-items that predicted the diagnosis of MCI. RESULTS: Lower scores on Language, Memory, Praxis, and Calculation CAMCOG sub-items were significantly associated with the diagnosis of MCI. A composite score obtained by the sum of these scores significantly discriminated MCI patients from comparison groups. This reduced version of the CAMCOG showed similar diagnostic accuracy than the original schedule for the identification of patients with MCI as compared to controls (AUC = 0.80 ± 0.03 for the reduced CAMCOG; AUC = 0.79 ± 0.03 for the original CAMCOG). CONCLUSION: This reduced version of the CAMCOG had similar diagnostic properties as the original CAMCOG and was faster and easier to administer, rendering it more suitable for the screening of subtle cognitive deficits in general clinical practice.
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Transtornos Cognitivos/diagnóstico , Demência/diagnóstico , Testes Neuropsicológicos , Atividades Cotidianas , Idoso , Análise de Variância , Área Sob a Curva , Estudos Transversais , Diagnóstico Precoce , Feminino , Humanos , Modelos Logísticos , Masculino , Programas de Rastreamento/instrumentação , Pessoa de Meia-Idade , Testes Neuropsicológicos/normas , Escalas de Graduação Psiquiátrica , Sensibilidade e EspecificidadeRESUMO
OBJECTIVES: Telomeres are structures at the extremity of chromosomes that prevents genomic instability, and its shortening seems to be a hallmark of cellular aging. Past studies have shown contradictory results of telomere length (TL) in major depression, and are a few studies in late-life depression (LLD). This explores the association between TL as a molecular marker of aging and diagnosis of LLD, the severity of depressive symptoms, and cognitive performance in older adults. METHODS/DESIGN: We included 78 older adults (45 with LLD and 33 nondepressed controls, according to DSM-V criteria), aged 60-90 years. TL was measured in leukocytes by a quantitative polymerase chain reaction, determining the relative ratio (T/S) between the telomere region copy number (T) and a single copy gene (S), using a relative standard curve. RESULTS: TL was significantly shorter in the LLD compared with control participants (p = .039). Comparing groups through the severity of depressive symptoms, we found a negative correlation with the severity of depressive symptoms (Hamilton Depression Rating Scale-21, r = -0.325, p = .004) and medical burden (r = -0.271, p = .038). There was no significant correlation between TL and cognitive performance (Mattis Dementia Rating Scale, r = 0.152, p = .21). CONCLUSIONS: We found that older adults with LLD have shorter telomere than healthy controls, especially those with a more severe depressive episode. Our findings suggest that shorter TL can be a marker of the severity of depressive episodes in older adults and indicate that these individuals may be at higher risk of age-associated adverse outcomes linked to depression.
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Transtorno Depressivo Maior , Encurtamento do Telômero , Idoso , Depressão/genética , Transtorno Depressivo Maior/genética , Humanos , Leucócitos , Telômero/genéticaRESUMO
The root cause of non-inherited Alzheimer's disease (AD) remains unknown despite hundreds of research studies performed to attempt to solve this problem. Since proper prophylaxis remains the best strategy, many scientists have studied the risk factors that may affect AD development. There is robust evidence supporting the hypothesis that cardiovascular diseases (CVD) may contribute to AD progression, as the diseases often coexist. Therefore, a lack of well-defined diagnostic criteria makes studying the relationship between AD and CVD complicated. Additionally, inflammation accompanies the pathogenesis of AD and CVD, and is not only a consequence but also implicated as a significant contributor to the course of the diseases. Of note, ÐÑоÐε4 is found to be one of the major risk factors affecting both the cardiovascular and nervous systems. According to genome wide association and epidemiological studies, numerous common risk factors have been associated with the development of AD-related pathology. Furthermore, the risk of developing AD and CVDs appears to be increased by a wide range of conditions and lifestyle factors: hypertension, dyslipidemia, hypercholesterolemia, hyperhomocysteinemia, gut/oral microbiota, physical activity, and diet. This review summarizes the literature and provides possible mechanistic links between CVDs and AD.
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Doença de Alzheimer , Doenças Cardiovasculares , Microbioma Gastrointestinal , Doença de Alzheimer/epidemiologia , Doenças Cardiovasculares/epidemiologia , Estudo de Associação Genômica Ampla , Humanos , InflamaçãoRESUMO
OBJECTIVE: To assess the serum levels of interleukin 1beta (IL-1beta) in elderly depressed patients in comparison with nondepressed healthy elderly subjects. DESIGN: Cross-sectional study. SETTING: Tertiary memory clinic. PARTICIPANTS: Twenty-three antidepressant-free elderly depressed patients and 44 nondepressed healthy elderly comparison group were enrolled to this study. MEASUREMENT: Serum IL-1beta levels were determined with highly sensitive colorimetric sandwich enzyme-linked immunosorbent assay. Severity of the depressive episode was determined by scores on the Hamilton Depression Scale-21 item and cognitive performance by the scores on the Cambridge Cognition Examination, Mini Mental State Examination clock drawing test, and verbal fluency. RESULTS: IL-1beta serum levels were increased in elderly patients versus nondepressed elderly (t = 2.21, df = 65, p = 0.04). After categorizing elderly depressed subjects into late onset (LOD) versus early onset (EOD), patients with EOD had the highest IL-1beta levels, when compared with nondepressed elderly patients and patients with LOD in analysis of variance (F = 4.9, df = 2, 64, p <0.01). CONCLUSIONS: Late-life depression is associated with higher IL-1beta levels suggesting that increased proinflammatory state may play a role in the physiopathology of depression in the elderly. The authors further show that this might be more prominent in those patients with EOD geriatric depression.
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Envelhecimento/sangue , Depressão/sangue , Interleucina-1beta/sangue , Idade de Início , Idoso , Cognição , Depressão/diagnóstico , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Desempenho Psicomotor , Índice de Gravidade de DoençaRESUMO
The magnitude of functional impairment that may indicate the threshold between MCI and incipient Alzheimer's disease (AD) has not been clearly defined. The objective was to examine the pattern of functional impairment in the continuum MCI-AD. Eighty-nine older adults (32 cognitively unimpaired, 31 MCI, and 26 AD patients) were examined with the Brazilian version of the Direct Assessment of Functional Status (DAFS-BR) at a university-based memory clinic. MCI patients were sub-divided according to the progression to AD upon follow-up, and had baseline cognitive, functional and biological variables analyzed. MCI patients displayed mild deficits in functional abilities, with intermediate scores as compared to controls and AD. The DAFS-BR items that differentiated MCI from controls involved the ability to deal with finances and shopping skills. At baseline, scores obtained by MCI patients who converted to AD were not significantly different from scores of nonconverters. The magnitude of functional deficits was associated with AD-like pathological findings in the CSF. In conclusion, MCI patients present with early functional changes in complex, instrumental abilities that require the integrity of memory and executive functions. The objective measurement of the functional state may help identify older adults with increased risk of developing dementia in the MCI-AD continuum.
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Transtornos Cognitivos/diagnóstico , Demência/diagnóstico , Testes Neuropsicológicos , Atividades Cotidianas , Idoso , Biomarcadores , Transtornos Cognitivos/líquido cefalorraquidiano , Transtornos Cognitivos/epidemiologia , Demência/líquido cefalorraquidiano , Demência/epidemiologia , Feminino , Humanos , Masculino , Índice de Gravidade de DoençaRESUMO
We aimed to examine the relationship between Apolipoprotein E ε4 (APOE*4) carriage on cognitive decline, and whether these associations were moderated by sex, baseline age, ethnicity, and vascular risk factors. Participants were 19,225 individuals aged 54-103 years from 15 longitudinal cohort studies with a mean follow-up duration ranging between 1.2 and 10.7 years. Two-step individual participant data meta-analysis was used to pool results of study-wise analyses predicting memory and general cognitive decline from carriage of one or two APOE*4 alleles, and moderation of these associations by age, sex, vascular risk factors, and ethnicity. Separate pooled estimates were calculated in both men and women who were younger (ie, 62 years) and older (ie, 80 years) at baseline. Results showed that APOE*4 carriage was related to faster general cognitive decline in women, and faster memory decline in men. A stronger dose-dependent effect was observed in older men, with faster general cognitive and memory decline in those carrying two versus one APOE*4 allele. Vascular risk factors were related to an increased effect of APOE*4 on memory decline in younger women, but a weaker effect of APOE*4 on general cognitive decline in older men. The relationship between APOE*4 carriage and memory decline was larger in older-aged Asians than Whites. In sum, APOE*4 is related to cognitive decline in men and women, although these effects are enhanced by age and carriage of two APOE*4 alleles in men, a higher numbers of vascular risk factors during the early stages of late adulthood in women, and Asian ethnicity.
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Envelhecimento/genética , Apolipoproteína E4/genética , Disfunção Cognitiva/genética , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Alelos , Disfunção Cognitiva/etnologia , Feminino , Genótipo , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores SexuaisRESUMO
BACKGROUND: We examined how the relationship between education and latelife cognitive impairment (defined as a Mini Mental State Examination score below 24) is influenced by age, sex, ethnicity, and Apolipoprotein E epsilon 4 (APOE*4). METHODS: Participants were 30,785 dementia-free individuals aged 55-103 years, from 18 longitudinal cohort studies, with an average follow-up ranging between 2 and 10 years. Pooled hazard ratios were obtained from multilevel parametric survival analyses predicting cognitive impairment (CI) from education and its interactions with baseline age, sex, APOE*4 and ethnicity. In separate models, education was treated as continuous (years) and categorical, with participants assigned to one of four education completion levels: Incomplete Elementary; Elementary; Middle; and High School. RESULTS: Compared to Elementary, Middle (HRâ¯=â¯0.645, Pâ¯=â¯0.004) and High School (HRâ¯=â¯0.472, Pâ¯<â¯0.001) education were related to reduced CI risk. The decreased risk of CI associated with Middle education weakened with older baseline age (HRâ¯=â¯1.029, Pâ¯=â¯0.056) and was stronger in women than men (HRâ¯=â¯1.309, Pâ¯=â¯0.001). The association between High School and lowered CI risk, however, was not moderated by sex or baseline age, but was stronger in Asians than Whites (HRâ¯=â¯1.047, Pâ¯=â¯0.044), and significant among Asian (HRâ¯=â¯0.34, Pâ¯<â¯0.001) and Black (HRâ¯=â¯0.382, Pâ¯=â¯0.016), but not White, APOE*4 carriers. CONCLUSION: High School completion may reduce risk of CI associated with advancing age and APOE*4. The observed ethnoregional differences in this effect are potentially due to variations in social, economic, and political outcomes associated with educational attainment, in combination with neurobiological and genetic differences, and warrant further study.
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Disfunção Cognitiva , Etnicidade , Idoso , Idoso de 80 Anos ou mais , Apolipoproteína E4/genética , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/genética , Escolaridade , Feminino , Humanos , Estudos Longitudinais , Masculino , Fatores de RiscoRESUMO
BACKGROUND/AIMS: The diagnostic stability of mild cognitive impairment (MCI) on short-term follow-up is a key issue in the characterization of this clinical syndrome. We aim to determine the cognitive outcome after 1 year of follow-up in a cohort of older adults. METHODS: Baseline clinical and neuropsychological assessments were carried out in older subjects recruited at a tertiary memory clinic. The subjects were reassessed after 1 year of follow-up with the same clinical and neuropsychological protocol. RESULTS: A total of 115 older adults, including MCI (n = 54) and controls (n = 61), underwent baseline and follow-up evaluation. Ten subjects classified as MCI at baseline (23%) resumed normal cognitive function and 13 controls (21%) progressed to MCI upon follow-up (chi(2) = 0.015, d.f. = 1, p = 0.90). The subjects diagnosed as having MCI on both assessments were older (p = 0.002) and had a worse global cognitive performance according to the Cambridge Cognitive Test (p = 0.014). CONCLUSION: The subjects who maintain the MCI status are older and have a worse baseline cognitive performance as well as multiple cognitive deficits.
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Transtornos Cognitivos/diagnóstico , Idoso , Transtornos Cognitivos/psicologia , Progressão da Doença , Feminino , Humanos , Masculino , Testes Neuropsicológicos , Valor Preditivo dos Testes , Estudos Prospectivos , Escalas de Graduação Psiquiátrica , Risco , Fatores SocioeconômicosRESUMO
BACKGROUND/AIMS: Abnormal inflammatory response has been associated to the pathogenesis of Alzheimer's disease (AD) and may be a marker of an ongoing neurodegenerative process. The aim of this study was to evaluate the serum levels of interleukin-1beta (IL-1beta) in patients with mild cognitive impairment (MCI) and AD. METHODS: One hundred and sixty-three older adults (58 with mild to moderate AD, 74 with MCI and 31 healthy controls) were recruited for this study. Serum IL-1beta levels were measured by ELISA. Patients with MCI were subcategorized in single-domain amnestic (aMCI), nonamnestic (naMCI), and multiple-domain (mdMCI) subtypes. RESULTS: Patients with AD and MCI (all subtypes) had a significant increase in serum IL-1beta levels as compared to controls (p = 0.03). Patients with mdMCI had serum IL-1beta levels comparable to those with AD, and significantly higher than those observed in aMCI and naMCI (p = 0.02). DISCUSSION: The present study provides evidence that inflammatory mechanisms, represented by elevated IL-1beta, are observed in patients with MCI, specifically in those with impairment in multiple cognitive domains. As these patients are at higher risk of conversion to dementia, we propose that an increased serum IL-1beta level is a stage marker of the ongoing brain neurodegeneration in the continuum between normal ageing and AD.
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Doença de Alzheimer/sangue , Transtornos Cognitivos/sangue , Interleucina-1beta/sangue , Idoso , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Brasil , Transtornos Cognitivos/genética , Função Executiva , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Fatores SocioeconômicosRESUMO
BACKGROUND: Individual randomized clinical trials (RCTs) with cholinesterase inhibitors (ChEIs) aiming to delay the progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) have not found significant benefit of their use for this purpose. The objective of this study is to meta-analyze the RCTs conducted with ChEIs in order to assess whether pooled analysis could show the benefit of these drugs in delaying the progression from MCI to AD. METHODS: We searched for references of published and unpublished studies on electronic databases (Medline, Embase, Web of Science, and Clinical Trial Database Registry, particularly the Clinicaltrials.gov--http://www.clinicaltrials.gov ). We retrieved 173 references, which yielded three references for data extraction. A total of 3.574 subjects from four RCTs were included in the meta-analysis. Among 1,784 subjects allocated in the ChEI-treatment group, 275 (15.4%) progressed to AD/dementia, as opposed to 366 (20.4%) out of 1,790 subjects in the placebo group. The relative risk (RR) for progression to AD/dementia in the ChEI-treated group was 0.75 [CI(95%) 0.66-0.87], z = -3.89, P < 0.001. The patients on the ChEI group had a significantly higher all-cause dropout risk than the patients on the placebo group (RR = 1.36 CI(95%) [1.24-1.49]; z = 6.59, P < 0.001). The RR for serious adverse events (SAE) in the ChEI-treated group showed no significantly statistical difference from the placebo group (RR = 0.95 [CI(95%) 0.83-1.09], z = -0.72, P = 0.47). The subjects in the ChEI-treated group had a marginally, non-significant, higher risk of death due to any cause than those in the placebo-treated group (RR = 1.04, CI(95%) 0.63-1.70, z = 0.16, P = 0.86). CONCLUSION: The long-term use of ChEIs in subjects with MCI may attenuate the risk of progression to AD/dementia. This finding may have a significant impact on public health and pharmaco-economic policies.
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Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/prevenção & controle , Inibidores da Colinesterase/uso terapêutico , Transtornos Cognitivos/tratamento farmacológico , Doença de Alzheimer/psicologia , Transtornos Cognitivos/psicologia , Progressão da Doença , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Risco , Resultado do TratamentoAssuntos
Transtorno Depressivo Maior/terapia , Estimulação Transcraniana por Corrente Contínua/métodos , Idoso de 80 Anos ou mais , Transtorno Depressivo Maior/psicologia , Eletrodos , Humanos , Masculino , Córtex Pré-Frontal/fisiologia , Estimulação Transcraniana por Corrente Contínua/normas , Resultado do TratamentoRESUMO
One of the most important scientific discoveries of recent years was the disclosure that the intestinal microflora takes part in bidirectional communication between the gut and the brain. Scientists suggest that human gut microflora may even act as the "second brain" and be responsible for neurodegenerative disorders like Alzheimer's disease (AD). Although human-associated microbial communities are generally stable, they can be altered by common human actions and experiences. Enteric bacteria, commensal, and pathogenic microorganisms, may have a major impact on immune system, brain development, and behavior, as they are able to produce several neurotransmitters and neuromodulators like serotonin, kynurenine, catecholamine, etc., as well as amyloids. However, brain destructive mechanisms, that can lead to dementia and AD, start with the intestinal microbiome dysbiosis, development of local and systemic inflammation, and dysregulation of the gut-brain axis. Increased permeability of the gut epithelial barrier results in invasion of different bacteria, viruses, and their neuroactive products that support neuroinflammatory reactions in the brain. It seems that, inflammatory-infectious hypothesis of AD, with the great role of the gut microbiome, starts to gently push into the shadow the amyloid cascade hypothesis that has dominated for decades. It is strongly postulated that AD may begin in the gut, and is closely related to the imbalance of gut microbiota. This is promising area for therapeutic intervention. Modulation of gut microbiota through personalized diet or beneficial microbiota intervention, alter microbial partners and their products including amyloid protein, will probably become a new treatment for AD.
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Doença de Alzheimer/microbiologia , Microbioma Gastrointestinal , Inflamação/microbiologia , Doença de Alzheimer/metabolismo , Animais , Encéfalo/metabolismo , Humanos , Inflamação/metabolismoRESUMO
Epidermal growth factor (EGF) and Fibroblast Growth Factor-2 (FGF-2) are growth factors involved neuronal growth and synaptic plasticity. These markers have been implicated in neuropsychiatric disorders, including major depression. However, no particular studies of EGF and FGF-2 have been conducted in older adults with major depressive disorder (MDD). In this study, we aim to investigate the plasma levels of EGF and FGF-2 in elderly with MDD. We included 89 older adults with MDD and 51 older (healthy control, HC) adults. The cognitive performance was evaluated by the Mattis Dementia Rating Scale (MDRS). The EGF and FGF-2 were measured by using multiplex assay for LUMINEX platform. There were also no significant differences between the patient group in terms of plasma levels of EGF and FGF-2 when compared to the HC group. There were not any significant correlations between plasma levels of EGF or FGF2 and MDRS total or individual scores in patient group and HC. There were significant correlations between plasma levels of EGF and FGF2 in both patient group and HC. Further study on plasma levels of EGF and FGF2 should be implemented in larger samples in elderly with MDD.
Assuntos
Transtorno Depressivo Maior/sangue , Fator de Crescimento Epidérmico/sangue , Fator 2 de Crescimento de Fibroblastos/sangue , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , MasculinoRESUMO
Changes in microRNAs (miRNAs) expression have been described in major depressive disorder in young and middle-aged adults. However, no study has evaluated miRNA expression in older adults with major depression (or late-life depression [LLD]). Our primary aim was to evaluate the expression of miRNAs in subjects with LLD. We first evaluated the miRNA expression using next-generation sequencing (NGS) and then we validated the miRNAs found in NGS in an independent sample of LLD patients, using RT-qPCR. Drosophila melanogaster model was used to evaluate the impact of changes in miRNA expression on behavior. NGS analysis showed that hsa-miR-184 (log2foldchangeâ¯=â¯-4.21, pâ¯=â¯1.2â¯×â¯10-03) and hsa-miR-1-3p (log2foldchangeâ¯=â¯-3.45, pâ¯=â¯1.3â¯×â¯10-02) were significantly downregulated in LLD compared to the control group. RT-qPCR validated the downregulation of hsa-miR-184 (pâ¯<â¯0.001), but not for the hsa-miR-1-3p. The knockout flies of the ortholog of hsa-miR-184 showed significantly reduced locomotor activity at 21-24â¯d.p.e (pâ¯=â¯0.04) and worse memory retention at 21-24â¯d.p.e (24h post-stimulus, pâ¯=â¯0.02) compared to control flies. Our results demonstrated that subjects with LLD have significant downregulation of hsa-miR-184. Moreover, the knockout of hsa-miR-184 in flies lead to depressive-like behaviors, being more pronounce in older flies.