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1.
Sci Rep ; 11(1): 19365, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34588469

RESUMO

Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

2.
Eur J Epidemiol ; 2021 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-34091768

RESUMO

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10-8) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10-13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

3.
J Alzheimers Dis ; 79(3): 1063-1074, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33427734

RESUMO

BACKGROUND: Air pollution has been consistently linked with dementia and cognitive decline. However, it is unclear whether risk is accumulated through long-term exposure or whether there are sensitive/critical periods. A key barrier to clarifying this relationship is the dearth of historical air pollution data. OBJECTIVE: To demonstrate the feasibility of modelling historical air pollution data and using them in epidemiologicalmodels. METHODS: Using the EMEP4UK atmospheric chemistry transport model, we modelled historical fine particulate matter (PM2.5) concentrations for the years 1935, 1950, 1970, 1980, and 1990 and combined these with contemporary modelled data from 2001 to estimate life course exposure in 572 participants in the Lothian Birth Cohort 1936 with lifetime residential history recorded. Linear regression and latent growth models were constructed using cognitive ability (IQ) measured by the Moray House Test at the ages of 11, 70, 76, and 79 years to explore the effects of historical air pollution exposure. Covariates included sex, IQ at age 11 years, social class, and smoking. RESULTS: Higher air pollution modelled for 1935 (when participants would have been in utero) was associated with worse change in IQ from age 11-70 years (ß = -0.006, SE = 0.002, p = 0.03) but not cognitive trajectories from age 70-79 years (p > 0.05). There was no support for other critical/sensitive periods of exposure or an accumulation of risk (all p > 0.05). CONCLUSION: The life course paradigm is essential in understanding cognitive decline and this is the first study to examine life course air pollution exposure in relation to cognitive health.


Assuntos
Poluição do Ar/efeitos adversos , Disfunção Cognitiva/induzido quimicamente , Adolescente , Adulto , Idoso , Poluição do Ar/história , Poluição do Ar/estatística & dados numéricos , Criança , Disfunção Cognitiva/epidemiologia , Exposição Ambiental/efeitos adversos , Exposição Ambiental/estatística & dados numéricos , Feminino , História do Século XX , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Material Particulado/efeitos adversos , Material Particulado/história , Escócia/epidemiologia , Adulto Jovem
4.
J Geriatr Psychiatry Neurol ; 34(5): 349-356, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32410488

RESUMO

Apathy is prevalent in dementia, such as behavioral variant frontotemporal dementia (bvFTD), primary progressive aphasia (PPA), and Alzheimer disease (AD). As a multidimensional construct, it can be assessed and subsumed under a Dimensional Apathy Framework. A consistent apathy profile in bvFTD and PPA has yet to be established. The aim was to explore apathy profiles and awareness in bvFTD, PPA, and AD. A total of 12 patients with bvFTD, 12 patients with PPA, 28 patients with AD, and 20 matched controls, as well as their informants/carers, were recruited. All participants completed the Dimensional Apathy Scale (DAS), assessing executive, emotional, and initiation apathy subtypes, a 1-dimensional apathy measure, depression measure, and functional and cognitive screens. Apathy subtype awareness was determined through DAS informant/carer and self-rating discrepancy. Apathy profile comparison showed patients with bvFTD had significantly higher emotional apathy than patients with AD (P < .01) and significantly higher apathy over all subtypes than patients with PPA (Ps < .05). Additionally, patients with bvFTD had significantly lower awareness for emotional apathy (P < .01) when compared to patients with AD and PPA. All patient groups had significant global apathy over all subtypes compared to controls. The emergent apathy profile for bvFTD seems to be emotional apathy (indifference or emotional/affective neutrality), with lower self-awareness in this subtype. Further, lower self-awareness for executive apathy (lack of motivation for planning, organization, or attention) differentiates bvFTD from PPA. Future research should investigate the cognitive and neural correlates as well as the practical impact of apathy subtypes.

5.
Aging (Albany NY) ; 12(14): 14092-14124, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32697766

RESUMO

DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to SERINC2, CHST12, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.


Assuntos
Metilação de DNA/genética , Valor Preditivo dos Testes , Adulto , Idoso , Envelhecimento , Causas de Morte , Mapeamento Cromossômico , Doença Crônica/epidemiologia , Estudos de Coortes , Epigênese Genética , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Locos de Características Quantitativas , Medição de Risco
6.
J Am Heart Assoc ; 9(8): e015299, 2020 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-32308120

RESUMO

Background Epigenome-wide association studies for cardiometabolic risk factors have discovered multiple loci associated with incident cardiovascular disease (CVD). However, few studies have sought to directly optimize a predictor of CVD risk. Furthermore, it is challenging to train multivariate models across multiple studies in the presence of study- or batch effects. Methods and Results Here, we analyzed existing DNA methylation data collected using the Illumina HumanMethylation450 microarray to create a predictor of CVD risk across 3 cohorts: Women's Health Initiative, Framingham Heart Study Offspring Cohort, and Lothian Birth Cohorts. We trained Cox proportional hazards-based elastic net regressions for incident CVD separately in each cohort and used a recently introduced cross-study learning approach to integrate these individual scores into an ensemble predictor. The methylation-based risk score was associated with CVD time-to-event in a held-out fraction of the Framingham data set (hazard ratio per SD=1.28, 95% CI, 1.10-1.50) and predicted myocardial infarction status in the independent REGICOR (Girona Heart Registry) data set (odds ratio per SD=2.14, 95% CI, 1.58-2.89). These associations remained after adjustment for traditional cardiovascular risk factors and were similar to those from elastic net models trained on a directly merged data set. Additionally, we investigated interactions between the methylation-based risk score and both genetic and biochemical CVD risk, showing preliminary evidence of an enhanced performance in those with less traditional risk factor elevation. Conclusions This investigation provides proof-of-concept for a genome-wide, CVD-specific epigenomic risk score and suggests that DNA methylation data may enable the discovery of high-risk individuals who would be missed by alternative risk metrics.


Assuntos
Doenças Cardiovasculares/genética , Metilação de DNA , Epigênese Genética , Epigenoma , Epigenômica , Idoso , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Feminino , Estudo de Associação Genômica Ampla , Fatores de Risco de Doenças Cardíacas , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/genética , Valor Preditivo dos Testes , Prevalência , Estudo de Prova de Conceito , Reprodutibilidade dos Testes , Medição de Risco
7.
BMC Psychiatry ; 20(1): 91, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111184

RESUMO

BACKGROUND: Previous studies have demonstrated an association between DNA methylation-based measures of accelerated ageing and age-related health outcomes and mortality. As a disease closely associated with advancing age, we hypothesized that DNA methylation-based measures of accelerated ageing might be associated with risk for dementia. This study therefore aimed to examine the association between four recognised measures of age acceleration and subsequent dementia. METHODS: Study subjects (n = 488) were members of the Lothian Birth Cohort 1921. Dementia case ascertainment used data from death certificates, electronic hospital records, and clinical reviews. Venous blood samples were taken at baseline, at age 79 years. DNA methylation and measures of epigenetic age were calculated in accordance with Horvath's epigenetic clock tutorial, using the online calculator (https://dnamage.genetics.ucla.edu/). From these values, four measures of accelerated ageing were calculated: extrinsic epigenetic age acceleration (EEAA), intrinsic epigenetic age acceleration (IEAA), AgeAccelPheno and AgeAccelGrim. Competing risk regression models - with death as a competing risk - were performed to examine the association between each measure of accelerated ageing and incident dementia. APOE ɛ4 status, sex, age, smoking status, history of cardiovascular disease, cerebrovascular disease, hypertension, and diabetes were included as covariates. RESULTS: None of the multivariate models revealed a positive association between increased epigenetic age acceleration and dementia risk. Across all included models, never-smoking increased risk for dementia (HR 1.69 [1.06, 2.71], p = 0.03), and having no APOE ɛ4 alleles reduced risk for dementia (HR 0.44 [0.29, 0.67], p < 0.001). CONCLUSIONS: The present study did not demonstrate any consistent association between DNA methylation-based measures of accelerated ageing and dementia in subjects aged over 79 years. Further, larger studies - including separate analyses of dementia subtypes - are required to further investigate the potential association between DNA methylation-based measures of accelerated ageing and dementia.


Assuntos
Metilação de DNA , Demência , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Metilação de DNA/genética , Demência/epidemiologia , Demência/genética , Epigênese Genética/genética , Epigenômica , Humanos
8.
Nat Commun ; 11(1): 800, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-32041957

RESUMO

Identifying biological correlates of late life cognitive function is important if we are to ascertain biomarkers for, and develop treatments to help reduce, age-related cognitive decline. Here, we investigated the associations between plasma levels of 90 neurology-related proteins (Olink® Proteomics) and general fluid cognitive ability in the Lothian Birth Cohort 1936 (LBC1936, N = 798), Lothian Birth Cohort 1921 (LBC1921, N = 165), and the INTERVAL BioResource (N = 4451). In the LBC1936, 22 of the proteins were significantly associated with general fluid cognitive ability (ß between -0.11 and -0.17). MRI-assessed total brain volume partially mediated the association between 10 of these proteins and general fluid cognitive ability. In an age-matched subsample of INTERVAL, effect sizes for the 22 proteins, although smaller, were all in the same direction as in LBC1936. Plasma levels of a number of neurology-related proteins are associated with general fluid cognitive ability in later life, mediated by brain volume in some cases.


Assuntos
Envelhecimento , Biomarcadores/sangue , Encéfalo/patologia , Cognição/fisiologia , Proteínas do Tecido Nervoso/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Proteínas do Tecido Nervoso/metabolismo , Proteômica
9.
Intelligence ; 78: 101407, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31983789

RESUMO

Fluctuating body asymmetry is theorized to indicate developmental instability, and to have small positive associations with low socioeconomic status (SES). Previous studies have reported small negative associations between fluctuating body asymmetry and cognitive functioning, but relationships between fluctuating brain asymmetry and cognitive functioning remain unclear. The present study investigated the association between general intelligence (a latent factor derived from a factor analysis on 13 cognitive tests) and the fluctuating asymmetry of four structural measures of brain hemispheric asymmetry: cortical surface area, cortical volume, cortical thickness, and white matter fractional anisotropy. The sample comprised members of the Lothian Birth Cohort 1936 (LBC1936, N = 636, mean age = 72.9 years). Two methods were used to calculate structural hemispheric asymmetry: in the first method, regions contributed equally to the overall asymmetry score; in the second method, regions contributed proportionally to their size. When regions contributed equally, cortical thickness asymmetry was negatively associated with general intelligence (ß = -0.18,p < .001). There was no association between cortical thickness asymmetry and childhood SES, suggesting that other mechanisms are involved in the thickness asymmetry-intelligence association. Across all cortical metrics, asymmetry of regions identified by the parieto-frontal integration theory (P-FIT) was not more strongly associated with general intelligence than non-P-FIT asymmetry. When regions contributed proportionally, there were no associations between general intelligence and any of the asymmetry measures. The implications of these findings, and of different methods of calculating structural hemispheric asymmetry, are discussed.

10.
Brain Commun ; 2(1): fcz049, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998866

RESUMO

Alzheimer's disease is a personally devastating neurodegenerative disorder and a major public health concern. There is an urgent need for medical imaging techniques that better characterize the early stages and monitor the progression of the disease. Magnetic resonance elastography (MRE) is a relatively new and highly sensitive MRI technique that can non-invasively assess tissue microstructural integrity via measurement of brain viscoelastic mechanical properties. For the first time, we use high-resolution MRE methods to conduct a voxel-wise MRE investigation and state-of-the-art post hoc region of interest analysis of the viscoelastic properties of the cerebral cortex in patients with Alzheimer's disease (N = 11) compared with cognitively healthy older adults (N = 12). We replicated previous findings that have reported significant volume and stiffness reductions at the whole-brain level. Significant reductions in volume were also observed in Alzheimer's disease when white matter, cortical grey matter and subcortical grey matter compartments were considered separately; lower stiffness was also observed in white matter and cortical grey matter, but not in subcortical grey matter. Voxel-based morphometry of both cortical and subcortical grey matter revealed localized reductions in volume due to Alzheimer's disease in the hippocampus, fusiform, middle, superior temporal gyri and precuneus. Similarly, voxel-based MRE identified lower stiffness in the middle and superior temporal gyri and precuneus, although the spatial distribution of these effects was not identical to the pattern of volume reduction. Notably, MRE additionally identified stiffness deficits in the operculum and precentral gyrus located within the frontal lobe; regions that did not undergo volume loss identified through voxel-based morphometry. Voxel-based-morphometry and voxel-based MRE results were confirmed by a complementary post hoc region-of-interest approach in native space where the viscoelastic changes remained significant even after statistically controlling for regional volumes. The pattern of reduction in cortical stiffness observed in Alzheimer's disease patients raises the possibility that MRE may provide unique insights regarding the neural mechanisms which underlie the development and progression of the disease. The measured mechanical property changes that we have observed warrant further exploration to investigate the diagnostic usefulness of MRE in cases of Alzheimer's disease and other dementias.

11.
Br J Psychiatry ; 216(1): 29-34, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-30868981

RESUMO

BACKGROUND: Environmental risk factors for dementia are poorly understood. Aluminium and fluorine in drinking water have been linked with dementia but uncertainties remain about this relationship. AIMS: In the largest longitudinal study in this context, we set out to explore the individual effect of aluminium and fluoride in drinking water on dementia risk and, as fluorine can increase absorption of aluminium, we also examine any synergistic influence on dementia. METHOD: We used Cox models to investigate the association between mean aluminium and fluoride levels in drinking water at their residential location (collected 2005-2012 by the Drinking Water Quality Regulator for Scotland) with dementia in members of the Scottish Mental Survey 1932 cohort who were alive in 2005. RESULTS: A total of 1972 out of 6990 individuals developed dementia by the linkage date in 2012. Dementia risk was raised with increasing mean aluminium levels in women (hazard ratio per s.d. increase 1.09, 95% CI 1.03-1.15, P < 0.001) and men (1.12, 95% CI 1.03-1.21, P = 0.004). A dose-response pattern of association was observed between mean fluoride levels and dementia in women (1.34, 95% CI 1.28-1.41, P < 0.001) and men (1.30, 95% CI 1.22-1.39, P < 0.001), with dementia risk more than doubled in the highest quartile compared with the lowest. There was no statistical interaction between aluminium and fluoride levels in relation with dementia. CONCLUSIONS: Higher levels of aluminium and fluoride were related to dementia risk in a population of men and women who consumed relatively low drinking-water levels of both.


Assuntos
Alumínio/efeitos adversos , Alumínio/análise , Demência/induzido quimicamente , Demência/epidemiologia , Água Potável/química , Fluoretos/efeitos adversos , Fluoretos/análise , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Medição de Risco , Escócia/epidemiologia
12.
Mol Psychiatry ; 25(10): 2584-2598, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-30760887

RESUMO

Polygenic scores can be used to distil the knowledge gained in genome-wide association studies for prediction of health, lifestyle, and psychological factors in independent samples. In this preregistered study, we used fourteen polygenic scores to predict variation in cognitive ability level at age 70, and cognitive change from age 70 to age 79, in the longitudinal Lothian Birth Cohort 1936 study. The polygenic scores were created for phenotypes that have been suggested as risk or protective factors for cognitive ageing. Cognitive abilities within older age were indexed using a latent general factor estimated from thirteen varied cognitive tests taken at four waves, each three years apart (initial n = 1091 age 70; final n = 550 age 79). The general factor indexed over two-thirds of the variance in longitudinal cognitive change. We ran additional analyses using an age-11 intelligence test to index cognitive change from age 11 to age 70. Several polygenic scores were associated with the level of cognitive ability at age-70 baseline (range of standardized ß-values = -0.178 to 0.302), and the polygenic score for education was associated with cognitive change from childhood to age 70 (standardized ß = 0.100). No polygenic scores were statistically significantly associated with variation in cognitive change between ages 70 and 79, and effect sizes were small. However, APOE e4 status made a significant prediction of the rate of cognitive decline from age 70 to 79 (standardized ß = -0.319 for carriers vs. non-carriers). The results suggest that the predictive validity for cognitive ageing of polygenic scores derived from genome-wide association study summary statistics is not yet on a par with APOE e4, a better-established predictor.


Assuntos
Cognição , Envelhecimento Cognitivo , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Idoso , Feminino , Humanos , Testes de Inteligência , Masculino , Testes Neuropsicológicos , Escócia
13.
Clin Neuropsychol ; 34(2): 423-435, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31154933

RESUMO

Objective: Apathy is a prominent syndrome across neurodegenerative diseases. The Dimensional Apathy Scale (DAS) assesses three apathy subtypes-executive, emotional, and initiation-and is sensitive and valid in amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease. This study describes the development of the brief DAS (b-DAS), which will enable apathy to be swiftly detected in the clinic.Method: 102 ALS and 102 AD patients' previously collected data were used. Mokken analyses were performed on item-level data of each informant/carer-rated DAS subscale (executive, emotional, and initiation) for the initial scale reduction. Item-total correlational analyses against standard apathy (convergent validity criteria) and depression (divergent validity criteria) measures and qualitative examination of items aided final item selection. Receiver operating curve analysis determined optimal cutoffs for the reduced subscales.Results: Mokken analyses suggested unidimensionality of each DAS subscale. Three items were removed that failed to satisfy monotone homogeneity model requirements, three items were removed due to validity criteria not being met, and six items were removed due to a combination of lower item scalability and item-total correlations. Item-theme examination further reduced the b-DAS to nine items, three per subscale, with a supplemental awareness deficit assessment being added. Sensitivity- and specificity-based optimal cutoffs were calculated for each b-DAS subscale.Conclusions: This study presents the b-DAS, an informant/carer-based robust yet short multidimensional apathy instrument with good convergent and divergent validity, with recommended clinical cutoffs. The b-DAS is appropriate for use in the clinic and for research to quickly and comprehensively screen for apathy subtype impairments.


Assuntos
Apatia/fisiologia , Testes Neuropsicológicos/normas , Escalas de Graduação Psiquiátrica/normas , Psicometria/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
14.
Brain Imaging Behav ; 14(5): 1865-1875, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31250262

RESUMO

Brain iron deposits (IDs) are indicative of microvessel dysfunction which may predispose to small vessel disease (SVD) brain damage and worsen cognition later in life. Visible perivascular spaces in the centrum semiovale (CSO-PVS) are SVD features linked with microvessel dysfunction. We examined possible associations of CSO-PVS volume and count with brain IDs and cognitive abilities in 700 community-dwelling individuals from the Lothian Birth Cohort 1936 who underwent detailed cognitive testing and multimodal brain MRI at mean age 72.7 years. Brain IDs were assessed automatically followed by manual editing. PVS were automatically assessed in the centrum semiovale and deep corona radiata supraventricular. General factors of overall cognitive function (g), processing speed (g-speed) and memory (g-memory) were used in the analyses. Median (IQR) volumes of IDs and CSO-PVS expressed as a percentage of intracranial volume were 0.0021 (0.011) and 0.22 (0.13)% respectively. Median count of CSO-PVS was 410 (IQR = 201). Total volumes of CSO-PVS and ID, adjusted for head size, were correlated (Spearman ρ = 0.13, p < 0.001). CSO-PVS volume, despite being correlated with all three cognitive measures, was only associated with g-memory (B = -114.5, SE = 48.35, p = 0.018) in general linear models, adjusting for age, sex, vascular risk factors, childhood intelligence and white matter hyperintensity volume. The interaction of CSO-PVS count with diabetes (B = -0.0019, SE = 0.00093, p = 0.041) and volume with age (B = 1.57, SE = 0.67, p = 0.019) were also associated with g-memory. Linear regression models did not replicate these associations. Therefore, it does not seem that CSO-PVS burden is directly associated with general cognitive ability in older age.


Assuntos
Cognição , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/metabolismo , Minerais/metabolismo , Idoso , Criança , Corpo Caloso/fisiologia , Feminino , Humanos , Inteligência , Imageamento por Ressonância Magnética , Masculino , Substância Branca/diagnóstico por imagem , Substância Branca/metabolismo , Substância Branca/fisiologia
15.
Brain Imaging Behav ; 14(1): 175-185, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30382528

RESUMO

Episodic memory is particularly sensitive to normative aging; however, studies investigating the structure-function relationships that support episodic memory have primarily been limited to gross volumetric measures of brain tissue health. Magnetic resonance elastography (MRE) is an emerging non-invasive, high-resolution imaging technique that uniquely quantifies brain viscoelasticity, and as such, provides a more specific measure of neural microstructural integrity. Recently, a significant double dissociation between orbitofrontal cortex-fluid intelligence and hippocampal-relational memory structure-function relationships was observed in young adults, highlighting the potential of sensitive MRE measures for studying brain health and its relation to cognitive function. However, the structure-function relationship observed by MRE has not yet been explored in healthy older adults. In this study, we examined the relationship between hippocampal (HC) viscoelasticity and episodic memory in cognitively healthy adults aged 66-73 years (N = 11), as measured with the verbal-paired associates (VPA) subtest from the Wechsler Memory Scale (WMS-R). Given the particular dependence of verbal memory tasks on the left HC, unilateral HC MRE measurements were considered for the first time. A significant negative correlation was found between left HC damping ratio, ξ and VPA recall score (rs = -0.77, p = 0.009), which is consistent with previous findings of a relationship between HC ξ and memory performance in young adults. Conversely, correlations between right HC ξ with VPA recall score were not significant. These results highlight the utility of MRE to study cognitive decline and brain aging and suggest its possible use as a sensitive imaging biomarker for memory-related impairments.


Assuntos
Técnicas de Imagem por Elasticidade/métodos , Hipocampo/fisiologia , Rememoração Mental/fisiologia , Idoso , Mapeamento Encefálico/métodos , Cognição/fisiologia , Feminino , Voluntários Saudáveis , Hipocampo/diagnóstico por imagem , Humanos , Inteligência , Imageamento por Ressonância Magnética/métodos , Masculino , Transtornos da Memória/patologia , Memória Episódica , Testes Neuropsicológicos , Relação Estrutura-Atividade
16.
J Epidemiol Community Health ; 74(2): 108-113, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31690586

RESUMO

BACKGROUND: Physical frailty is associated with many adverse outcomes including disability, chronic disease, hospitalisation, institutionalisation and death. It is unclear what impact it might have on the rate of normal cognitive ageing. We investigated whether physical frailty was related to initial level of, and change in, cognitive abilities from age 70 to 79 years. METHOD: Participants were 950 members of the Lothian Birth Cohort 1936. Physical frailty was assessed at age 70 years using the Fried criteria. Cognitive function was assessed at ages 70, 73, 76 and 79 years. We used linear regression to examine cross-sectional and prospective associations between physical frailty status at age 70 years and factor score estimates for baseline level of and change in four cognitive domains (visuospatial ability, memory, processing speed and crystallised ability) and in general cognitive ability. RESULTS: Physical frailty, but not prefrailty, was associated with lower baseline levels of visuospatial ability, memory, processing speed and general cognitive ability after control for age, sex, education, depressive symptoms, smoking and number of chronic illnesses. Physical frailty was associated with greater decline in each cognitive domain: age-adjusted and sex-adjusted standardised regression coefficients (95% CIs) were: -0.45 (-0.70 to -0.20) for visuospatial ability, -0.32 (-0.56 to -0.07) for memory, -0.47 (-0.72 to -0.22) for processing speed, -0.43 (-0.68 to -0.18) for crystallised ability and -0.45 (-0.70 to -0.21) for general cognitive ability. These associations were only slightly attenuated after additional control for other covariates. CONCLUSION: Physical frailty may be an important indicator of age-related decline across multiple cognitive domains.


Assuntos
Transtornos Cognitivos , Cognição/fisiologia , Idoso Fragilizado/psicologia , Fragilidade , Transtornos da Memória , Atividades Cotidianas , Idoso , Idoso de 80 Anos ou mais , Chicago/epidemiologia , Transtornos Cognitivos/epidemiologia , Comorbidade , Feminino , Humanos , Masculino , Transtornos da Memória/epidemiologia , Risco
17.
Wellcome Open Res ; 5: 111, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33728380

RESUMO

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 -8) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 -6). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV 1) (P=3.15x10 -15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV 1 more in males (untransformed FEV 1 ß=0.028 [SE 0.0022] litres) than females (ß=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10 -6), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.

18.
Transl Psychiatry ; 9(1): 248, 2019 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591380

RESUMO

Recent advances in genome-wide DNA methylation (DNAm) profiling for smoking behaviour have given rise to a new, molecular biomarker of smoking exposure. It is unclear whether a smoking-associated DNAm (epigenetic) score has predictive value for ageing-related health outcomes which is independent of contributions from self-reported (phenotypic) smoking measures. Blood DNA methylation levels were measured in 895 adults aged 70 years in the Lothian Birth Cohort 1936 (LBC1936) study using the Illumina 450K assay. A DNA methylation score based on 230 CpGs was used as a proxy for smoking exposure. Associations between smoking variables and health outcomes at age 70 were modelled using general linear modelling (ANCOVA) and logistic regression. Additional analyses of smoking with brain MRI measures at age 73 (n = 532) were performed. Smoking-DNAm scores were positively associated with self-reported smoking status (P < 0.001, eta-squared ɳ2 = 0.63) and smoking pack years (r = 0.69, P < 0.001). Higher smoking DNAm scores were associated with variables related to poorer cognitive function, structural brain integrity, physical health, and psychosocial health. Compared with phenotypic smoking, the methylation marker provided stronger associations with all of the cognitive function scores, especially visuospatial ability (P < 0.001, partial eta-squared ɳp2 = 0.022) and processing speed (P < 0.001, ɳp2 = 0.030); inflammatory markers (all P < 0.001, ranges from ɳp2 = 0.021 to 0.030); dietary patterns (healthy diet (P < 0.001, ɳp2 = 0.052) and traditional diet (P < 0.001, ɳp2 = 0.032); stroke (P = 0.006, OR 1.48, 95% CI 1.12, 1.96); mortality (P < 0.001, OR 1.59, 95% CI 1.42, 1.79), and at age 73; with MRI volumetric measures (all P < 0.001, ranges from ɳp2 = 0.030 to 0.052). Additionally, education was the most important life-course predictor of lifetime smoking tested. Our results suggest that a smoking-associated methylation biomarker typically explains a greater proportion of the variance in some smoking-related morbidities in older adults, than phenotypic measures of smoking exposure, with some of the accounted-for variance being independent of phenotypic smoking status.


Assuntos
Encéfalo/diagnóstico por imagem , Cognição , Metilação de DNA , Epigênese Genética , Aptidão Física , Fumar/genética , Idoso , Biomarcadores , Mapeamento Encefálico , Estudos de Coortes , Ilhas de CpG , Epigenômica , Feminino , Humanos , Modelos Lineares , Modelos Logísticos , Imageamento por Ressonância Magnética , Masculino , Fenótipo , Escócia , Autorrelato , Fumar/fisiopatologia
19.
Alzheimers Dement ; 15(12): 1546-1557, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31619348

RESUMO

INTRODUCTION: Prospective studies reporting associations between cognitive performance and subsequent incident dementia have been subject to attrition bias. Furthermore, the extent to which established risk factors account for such associations requires further elucidation. METHODS: We used UK Biobank baseline cognitive data (n ≤ 488,130) and electronically linked hospital inpatient and death records during three- to eight-year follow-up, to estimate risk of total dementia (n = 1051), Alzheimer's disease (n = 352), and vascular dementia (n = 169) according to four brief cognitive tasks, with/without adjustment for constitutional and modifiable risk factors. RESULTS: We found associations of cognitive task performance with all-cause and cause-specific dementia (P <  .01); these were not accounted for by established risk factors. Cognitive data added up to 5% to the discriminative accuracy of receiver operating characteristic curve models; areas under the curve ranged from 82% to 86%. DISCUSSION: This study offers robust evidence that brief cognitive testing could be a valuable addition to dementia prediction models.


Assuntos
Demência/diagnóstico , Demência/epidemiologia , Registros Eletrônicos de Saúde , Testes Neuropsicológicos/estatística & dados numéricos , Doença de Alzheimer/epidemiologia , Cognição , Demência/mortalidade , Demência Vascular/epidemiologia , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reino Unido
20.
Front Neurol ; 10: 784, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31404147

RESUMO

Background and Purpose: White matter hyperintensities (WMH) are commonly seen on structural MRI of older adults and are a manifestation of underlying and adjacent tissue damage. WMH may contribute to cortical disconnection and cognitive dysfunction, but it is unclear how WMH affect intersecting or nearby white matter tract integrity. This study investigated the effects of WMH on tract microstructure by determining the spatial distribution of water diffusion characteristics in white matter tract areas adjacent to both intersecting and nearby WMH. Methods: We used diffusion and structural MRI data from 52 representative participants from the Lothian Birth Cohort 1936 (72.2 ± 0.7 years) including a range of WMH burden. We segmented WMH, reconstructed 18 main white mater tracts using automated quantitative tractography and identified intersections between tracts and WMH. We measured mean diffusivity (MD) and fractional anisotropy (FA) in tract tissue at 2 mm incremental distances from tract-intersecting and non-intersecting (nearby) WMH. Results: We observed a spatial gradient of FA and MD abnormalities for most white matter tracts which diminished with a similar distance pattern for tract-intersecting and nearby WMH. Overall, FA was higher, while MD was lower around nearby WMH compared with tract-intersecting WMH. However, for some tracts, FA was lower in areas immediately surrounding nearby WMH, although with faster normalization than in FA values surrounding tract-intersecting WMH. Conclusion: WMH have similar effects on tract infrastructure, whether they be intersecting or nearby. However, the observed differences in tract water diffusion properties around WMH suggest that degenerative processes in small vessel disease may propagate further along the tract for intersecting WMH, while in some areas of the brain there is a larger and more localized accumulation of axonal damage in tract tissue nearby a non-connected WMH. Longitudinal studies should address differential effects of intersecting vs. nearby WMH progression and how they contribute to cognitive aging.

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