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1.
Nat Commun ; 13(1): 3401, 2022 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-35697682

RESUMO

Age-related macular degeneration (AMD) is one of the most common causes of visual impairment in the elderly, with a complex and still poorly understood etiology. Whole-genome association studies have discovered 34 genomic regions associated with AMD. However, the genes and cognate proteins that mediate the risk, are largely unknown. In the current study, we integrate levels of 4782 human serum proteins with all genetic risk loci for AMD in a large population-based study of the elderly, revealing many proteins and pathways linked to the disease. Serum proteins are also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study identifies several proteins that are causally related to the disease and are directionally consistent with the observational estimates. In this work, we present a robust and unique framework for elucidating the pathobiology of AMD.


Assuntos
Degeneração Macular , Proteogenômica , Idoso , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Degeneração Macular/genética , Degeneração Macular/metabolismo , Análise da Randomização Mendeliana , Fatores de Risco
2.
Am J Hum Genet ; 109(6): 1077-1091, 2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35580588

RESUMO

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss.


Assuntos
Surdez , Perda Auditiva , Animais , Cóclea , Estudo de Associação Genômica Ampla , Perda Auditiva/genética , Humanos , Camundongos , Estria Vascular
3.
Brain ; 2022 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-35511193

RESUMO

Cerebral small vessel disease is a leading cause of stroke and a major contributor to cognitive decline and dementia, but our understanding of specific genes underlying the cause of sporadic cerebral small vessel disease is limited. We report a genome-wide association study and a whole-exome association study on a composite extreme phenotype of cerebral small vessel disease derived from its most common MRI features: white matter hyperintensities and lacunes. Seventeen population-based cohorts of older persons with MRI measurements and genome-wide genotyping (n = 41 326), whole-exome sequencing (n = 15 965), or exome chip (n = 5249) data contributed 13 776 and 7079 extreme small vessel disease samples for the genome-wide association study and whole-exome association study, respectively. The genome-wide association study identified significant association of common variants in 11 loci with extreme small vessel disease, of which the chr12q24.11 locus was not previously reported to be associated with any MRI marker of cerebral small vessel disease. The whole-exome association study identified significant associations of extreme small vessel disease with common variants in the 5' UTR region of EFEMP1 (chr2p16.1) and one probably damaging common missense variant in TRIM47 (chr17q25.1). Mendelian randomization supports the causal association of extensive small vessel disease severity with increased risk of stroke and Alzheimer's disease. Combined evidence from summary-based Mendelian randomization studies and profiling of human loss-of-function allele carriers showed an inverse relation between TRIM47 expression in the brain and blood vessels and extensive small vessel disease severity. We observed significant enrichment of Trim47 in isolated brain vessel preparations compared to total brain fraction in mice, in line with the literature showing Trim47 enrichment in brain endothelial cells at single cell level. Functional evaluation of TRIM47 by small interfering RNAs-mediated knockdown in human brain endothelial cells showed increased endothelial permeability, an important hallmark of cerebral small vessel disease pathology. Overall, our comprehensive gene-mapping study and preliminary functional evaluation suggests a putative role of TRIM47 in the pathophysiology of cerebral small vessel disease, making it an important candidate for extensive in vivo explorations and future translational work.

4.
Alzheimers Dement (N Y) ; 8(1): e12254, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35441085

RESUMO

Introduction: Multidomain intervention approaches have emerged as a potential strategy to reduce dementia risk. We sought to describe the baseline assessment approaches, health conditions, and risk profiles for brain aging of participants in the randomized controlled Multimodal INterventions to delay Dementia and disability in rural China (MIND-China). Methods: MIND-China engaged residents who were ≥60 years of age and living in rural communities in the western Shandong province. In March to September 2018, all participants underwent the core module assessments via face-to-face interviews, clinical examinations, neuropsychological testings, and laboratory tests. Specific modules of examination were performed for sub-samples, including brain magnetic resonance imaging scans, genetic and blood biochemical markers, actigraphy testing, cardiopulmonary coupling analysis for sleep quality and disturbances, audiometric testing, and optical coherence tomography examination. We performed descriptive analysis. Results: In total, 5765 participants (74.9% of all eligible residents) undertook the baseline assessments. The mean age was 70.9 years (standard deviation, 5.9), 57.2% were women, 40.6% were illiterate, and 88.3% were farmers. The overall prevalence of common chronic diseases was 67.2% for hypertension, 23.4% for dyslipidemia, 23.5% for heart disease, 14.4% for diabetes mellitus, and 5.4% for dementia. The prevalence rates of hypertension, diabetes mellitus, dyslipidemia, obesity, heart disease, depressive symptoms, and dementia were higher in women than in men (P < .05). Overall, 87.1% of the participants had at least two of the 15 chronic diseases (89.3% in women vs 84.2% in men, P < .001). Participants examined for the specific modules were younger, more likely to be women, and more educated than those not examined. Discussion: Comprehensive baseline assessments of participants in MIND-China provide extremely valuable data sources for interdisciplinary research into the complex relationships of aging, health, brain aging, and functional consequences among older adults living in the rural communities. Highlights: MIND-China is a multimodal intervention study among rural residents ≥60 years of age.At baseline, 5765 participants undertook the interdisciplinary assessments.The baseline assessments consisted of core module and specific modules.Specific modules included brain magnetic resonance imaging (MRI), blood biomarkers, ActiGraph, cardiopulmonary coupling (CPC), pure-tone audiometry (PTA), and optical coherence tomography (OCT).

5.
Hum Brain Mapp ; 2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35429100

RESUMO

White matter hyperintensities (WMHs) are emblematic of cerebral small vessel disease, yet effects on the brain have not been well characterized at midlife. Here, we investigated whether WMH volume is associated with brain network alterations in midlife adults. Two hundred and fifty-four participants from the Coronary Artery Risk Development in Young Adults study were selected and stratified by WMH burden into Lo-WMH (mean age = 50 ± 3.5 years) and Hi-WMH (mean age = 51 ± 3.7 years) groups of equal size. We constructed group-level covariance networks based on cerebral blood flow (CBF) and gray matter volume (GMV) maps across 74 gray matter regions. Through consensus clustering, we found that both CBF and GMV covariance networks partitioned into modules that were largely consistent between groups. Next, CBF and GMV covariance network topologies were compared between Lo- and Hi-WMH groups at global (clustering coefficient, characteristic path length, global efficiency) and regional (degree, betweenness centrality, local efficiency) levels. At the global level, there were no between-group differences in either CBF or GMV covariance networks. In contrast, we found between-group differences in the regional degree, betweenness centrality, and local efficiency of several brain regions in both CBF and GMV covariance networks. Overall, CBF and GMV covariance analyses provide evidence that WMH-related network alterations are present at midlife.

6.
Artigo em Inglês | MEDLINE | ID: mdl-35438610

RESUMO

Rationale Knowledge on biomarkers of interstitial lung disease is incomplete. Interstitial lung abnormalities (ILA) are radiologic changes that may present in its early stages. Objectives To uncover blood proteins associated with ILA using large-scale proteomics methods. Methods Data from two prospective cohort studies, the AGES-Reykjavik study (n=5,259) for biomarker discovery and the Genetic Epidemiology of COPD (COPDGene) study (n=4,899) for replication, were used. Blood proteins were measured using DNA aptamers, targeting over 4,700 protein analytes. The association of proteins with ILA and ILA progression was assessed with regression modelling, as were associations with genetic risk factors. Adaptive LASSO models were applied to bootstrap data samples to discover sets of proteins predictive of ILA and their progression. Measurements and Main Results Of 287 associations, SFTPB (OR 3.71 [95% CI 3.20-4.30], P 4.28×10-67), SCG3AB1 (OR 2.43 [2.13-2.77], P 8.01×10-40) and WFDC2 (OR 2.42 [2.11-2.78], P 4.01×10-36) were most significantly associated with ILA in AGES-Reykjavik and were replicated in COPDGene. In AGES-Reykjavik, levels of SFTPB were associated with the rs35705950 MUC5B promoter polymorphism and SFTPB and WFDC2 had the strongest associations with ILA progression. Multivariate models of ILA in AGES-Reykjavik, ILA in COPDGene and ILA progression in AGES-Reykjavik, had validated areas under the receiver operating characteristic curve of 0.880, 0.826 and 0.824, respectively. Conclusions Novel, replicated associations of ILA, its progression and genetic risk factors with numerous blood proteins are demonstrated as well as machine-learning based models with favourable predictive potential. Several proteins are revealed as potential markers of early fibrotic lung disease.

7.
Brain Behav ; 12(5): e2525, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35362209

RESUMO

BACKGROUND: Hypertension is a well-established risk factor for cognitive impairment, brain atrophy, and dementia. However, the relationship of other types of hypertensions, such as isolated hypertension on brain health and its comparison to systolic-diastolic hypertension (where systolic and diastolic measures are high), is still relatively unknown. Due to its increased prevalence, it is important to investigate the impact of isolated hypertension to help understand its potential impact on cognitive decline and future dementia risk. In this study, we compared a variety of global brain measures between participants with isolated hypertension to those with normal blood pressure (BP) or systolic-diastolic hypertension using the largest cohort of healthy individuals. METHODS: Using the UK Biobank cohort, we carried out a cross-sectional study using 29,775 participants (mean age 63 years, 53% female) with BP measurements and brain magnetic resonance imaging (MRI) data. We used linear regression models adjusted for multiple confounders to compare a variety of global, subcortical, and white matter brain measures. We compared participants with either isolated systolic or diastolic hypertension with normotensives and then with participants with systolic-diastolic hypertension. RESULTS: The results showed that participants with isolated systolic or diastolic hypertension taking BP medications had smaller gray matter but larger white matter microstructures and macrostructures compared to normotensives. Isolated systolic hypertensives had larger total gray matter and smaller white matter traits when comparing these regions with participants with systolic-diastolic hypertension. CONCLUSIONS: These results provide support to investigate possible preventative strategies that target isolated hypertension as well as systolic-diastolic hypertension to maintain brain health and/or reduce dementia risk earlier in life particularly in white matter regions.


Assuntos
Demência , Hipertensão , Bancos de Espécimes Biológicos , Pressão Sanguínea/fisiologia , Encéfalo , Estudos Transversais , Demência/diagnóstico por imagem , Demência/epidemiologia , Feminino , Humanos , Hipertensão/diagnóstico por imagem , Hipertensão/epidemiologia , Hipertensão/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Reino Unido/epidemiologia
8.
Commun Biol ; 5(1): 336, 2022 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-35396452

RESUMO

Circulating total-tau levels can be used as an endophenotype to identify genetic risk factors for tauopathies and related neurological disorders. Here, we confirmed and better characterized the association of the 17q21 MAPT locus with circulating total-tau in 14,721 European participants and identified three novel loci in 953 African American participants (4q31, 5p13, and 6q25) at P < 5 × 10-8. We additionally detected 14 novel loci at P < 5 × 10-7, specific to either Europeans or African Americans. Using whole-exome sequence data in 2,279 European participants, we identified ten genes associated with circulating total-tau when aggregating rare variants. Our genetic study sheds light on genes reported to be associated with neurological diseases including stroke, Alzheimer's, and Parkinson's (F5, MAP1B, and BCAS3), with Alzheimer's pathological hallmarks (ADAMTS12, IL15, and FHIT), or with an important function in the brain (PARD3, ELFN2, UBASH3B, SLIT3, and NSD3), and suggests that the genetic architecture of circulating total-tau may differ according to ancestry.


Assuntos
Doença de Alzheimer , Tauopatias , Afro-Americanos/genética , Doença de Alzheimer/genética , Exoma , Estudo de Associação Genômica Ampla , Humanos
10.
JAMA Netw Open ; 5(3): e221175, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35267035

RESUMO

Importance: Midlife elevated blood pressure (BP) is an important risk factor associated with brain structure and function. Little is known about trajectories of BP that modulate this risk. Objective: To identify BP trajectory patterns from young adulthood to midlife that are associated with brain structure in midlife. Design, Setting, and Participants: This cohort study used data of US adults from Coronary Artery Risk Development in Young Adults (CARDIA), a prospective longitudinal study of Black and White men and women (baseline age 18 to 30 years) examined up to 8 times over 30 years (1985-1986 to 2015-2016). There were 885 participants who underwent brain magnetic resonance imaging (MRI) in the 25th or 30th year examinations. Analyses were conducted November 2019 to December 2020. Exposures: Using group-based trajectory modeling, 5 25-year BP trajectories for 3 BP traits were identified in the total CARDIA cohort of participants with 3 or more BP measures, which were then applied to analyses of the subset of 853 participants in the Brain MRI substudy. Mean arterial pressure (MAP) was examined as an integrative measure of systolic and diastolic BP. With linear regression, the associations of the BP trajectories with brain structures were examined, adjusting sequentially for demographics, cardiovascular risk factors, and antihypertensive medication use. Main Outcomes and Measures: Brain MRI outcomes include total brain, total gray matter, normal-looking and abnormal white matter volumes, gray matter cerebral blood flow, and white matter fractional anisotropy. Results: Brain MRI analyses were conducted on 853 participants (mean [SD] age, 50.3 [3.6] years; 399 [46.8%] men; 354 [41.5%] Black and 499 [58.5%] White individuals). The MAP trajectory distribution was 187 individuals (21.1%) with low-stable, 385 (43.5%) with moderate-gradual, 71 (8.0%) with moderate-increasing, 204 (23.1%) with elevated-stable, and 38 (4.3%) with elevated-increasing. Compared with the MAP low-stable trajectory group, individuals in the moderate-increasing and elevated-increasing groups were more likely to have higher abnormal white matter volume (moderate: ß, 0.52; 95% CI, 0.23 to 0.82; elevated: ß, 0.57; 95% CI, 0.19 to 0.95). Those in the MAP elevated-increasing group had lower gray matter cerebral blood flow (ß, -0.42; 95% CI, -0.79 to -0.05) after adjusting for sociodemographics and cardiovascular risk factors. After adjustment for antihypertensive medication use, the difference was consistent for abnormal white matter volume, but results were no longer significant for gray matter cerebral blood flow. Conclusions and Relevance: Among young adults with moderate to high levels of BP, a gradual increase in BP to middle-age may increase the risk in diffuse small vessel disease and lower brain perfusion.


Assuntos
Anti-Hipertensivos , Doenças do Sistema Nervoso , Adolescente , Adulto , Pressão Sanguínea/fisiologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Estudos de Coortes , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem
11.
JAMA Neurol ; 79(4): 380-389, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35254390

RESUMO

IMPORTANCE: Antihypertensive treatments benefit cerebrovascular health and cognitive function in patients with hypertension, but it is uncertain whether an intensive blood pressure target leads to potentially harmful cerebral hypoperfusion. OBJECTIVE: To investigate the association of intensive systolic blood pressure (SBP) control vs standard control with whole-brain cerebral blood flow (CBF). DESIGN, SETTING, AND PARTICIPANTS: This substudy of the Systolic Blood Pressure Intervention Trial (SPRINT) randomized clinical trial compared the efficacy of 2 different blood pressure-lowering strategies with longitudinal brain magnetic resonance imaging (MRI) including arterial spin labeled perfusion imaging to quantify CBF. A total of 1267 adults 50 years or older with hypertension and increased cardiovascular risk but free of diabetes or dementia were screened for the SPRINT substudy from 6 sites in the US. Randomization began in November 2010 with final follow-up MRI in July 2016. Analyses were performed from September 2020 through December 2021. INTERVENTIONS: Study participants with baseline CBF measures were randomized to an intensive SBP target less than 120 mm Hg or standard SBP target less than 140 mm Hg. MAIN OUTCOMES AND MEASURES: The primary outcome was change in whole-brain CBF from baseline. Secondary outcomes were change in gray matter, white matter, and periventricular white matter CBF. RESULTS: Among 547 participants with CBF measured at baseline, the mean (SD) age was 67.5 (8.1) years and 219 (40.0%) were women; 315 completed follow-up MRI at a median (IQR) of 4.0 (3.7-4.1) years after randomization. Mean whole-brain CBF increased from 38.90 to 40.36 (difference, 1.46 [95% CI, 0.08-2.83]) mL/100 g/min in the intensive treatment group, with no mean increase in the standard treatment group (37.96 to 37.12; difference, -0.84 [95% CI, -2.30 to 0.61] mL/100 g/min; between-group difference, 2.30 [95% CI, 0.30-4.30; P = .02]). Gray, white, and periventricular white matter CBF showed similar changes. The association of intensive vs standard treatment with CBF was generally similar across subgroups defined by age, sex, race, chronic kidney disease, SBP, orthostatic hypotension, and frailty, with the exception of an indication of larger mean increases in CBF associated with intensive treatment among participants with a history of cardiovascular disease (interaction P = .05). CONCLUSIONS AND RELEVANCE: Intensive vs standard antihypertensive treatment was associated with increased, rather than decreased, cerebral perfusion, most notably in participants with a history of cardiovascular disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01206062.


Assuntos
Doenças Cardiovasculares , Hipertensão , Idoso , Anti-Hipertensivos/farmacologia , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/fisiologia , Circulação Cerebrovascular , Feminino , Humanos , Hipertensão/complicações , Hipertensão/diagnóstico por imagem , Hipertensão/tratamento farmacológico
12.
JAMA Netw Open ; 5(2): e2143941, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35133436

RESUMO

Importance: Animal experiments and small clinical studies support a role for the gut microbiota in cognitive functioning. Few studies have investigated gut microbiota and cognition in large community samples. Objective: To examine associations of gut microbial composition with measures of cognition in an established population-based study of middle-aged adults. Design, Setting, and Participants: This cross-sectional study analyzed data from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) cohort in 4 US metropolitan centers between 2015 and 2016. Data were analyzed in 2019 and 2020. Exposures: Stool DNA were sequenced, and the following gut microbial measures were gathered: (1) ß-diversity (between-person) derived with multivariate principal coordinates analysis; (2) α-diversity (within-person), defined as richness (genera count) and the Shannon index (integrative measure of genera richness and evenness); and (3) taxonomy (107 genera, after filtering). Main Outcomes and Measures: Cognitive status was assessed using 6 clinic-administered cognitive tests: Montreal Cognitive Assessment (MoCA), Digit Symbol Substitution Test (DSST), Rey-Auditory Verbal Learning Test (RAVLT), Stroop, category fluency, and letter fluency. A global score measure derived using principal components analysis was also assessed; the first principal component explained 56% of variability. Results: Microbiome data were available on 597 CARDIA participants; mean (SD) age was 55.2 (3.5) years, 268 participants (44.7%) were men, and 270 (45.2%) were Black. In multivariable-adjusted principal coordinates analysis, permutational multivariate analysis of variance tests for ß-diversity were statistically significant for all cognition measures (principal component analysis, P = .001; MoCA, P = .001; DSST, P = .001; RAVLT, P = .001; Stroop, P = .007; category fluency, P = .001) with the exception of letter fluency (P = .07). After adjusting for sociodemographic variables (age, race, sex, education), health behaviors (physical activity, diet, smoking, medication use), and clinical covariates (body mass index, diabetes, hypertension), Barnesiella was positively associated with the first principal component (ß, 0.16; 95% CI, 0.08-0.24), DSST (ß, 1.18; 95% CI, 0.35-2.00), and category fluency (ß, 0.59; 95% CI, 0.31-0.87); Lachnospiraceae FCS020 group was positively associated with DSST (ß, 2.67; 95% CI, 1.10-4.23), and Sutterella was negatively associated with MoCA (ß, -0.27; 95% CI, -0.44 to -0.11). Conclusions and Relevance: In this cross-sectional study, microbial community composition, based on ß-diversity, was associated with all cognitive measures in multivariable-adjusted analysis. These data contribute to a growing body of literature suggesting that the gut microbiota may be associated with cognitive aging, but must be replicated in larger samples and further researched to identify relevant pathways.


Assuntos
Afro-Americanos/estatística & dados numéricos , Envelhecimento/patologia , Cognição/fisiologia , Microbioma Gastrointestinal/fisiologia , /estatística & dados numéricos , Fatores Etários , Alabama , California , Chicago , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Minnesota , Estudos Prospectivos , Fatores Raciais , Fatores de Risco , Fatores Socioeconômicos
13.
Nat Commun ; 13(1): 480, 2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35078996

RESUMO

With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein's genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease.


Assuntos
Proteínas Sanguíneas/genética , Doença/genética , Predisposição Genética para Doença , Genoma Humano , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Doença/classificação , Feminino , Humanos , Islândia , Masculino
14.
Nat Commun ; 13(1): 481, 2022 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-35079000

RESUMO

Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. In the current study, 54,469 low-frequency and common exome-array variants were compared to 4782 protein measurements in the serum of 5343 individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that 2021 independent exome array variants are associated with serum levels of 1942 proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins' emerging role as biomarkers and potential causative agents of a wide range of diseases.


Assuntos
Proteínas Sanguíneas/genética , Doença/genética , Exoma/genética , Predisposição Genética para Doença , Genótipo , Polimorfismo de Nucleotídeo Único , Proteoma/metabolismo , Idoso , Doença/classificação , Feminino , Humanos , Islândia , Masculino
15.
Stroke ; 53(4): 1199-1206, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-34809439

RESUMO

BACKGROUND: Studies on the association of cerebrovascular risk factors to magnetic resonance imaging detected brain infarcts have been inconsistent, partly reflecting limits of assessment to infarcts anywhere in the brain, as opposed to specific brain regions. We hypothesized that risk-factors may differ depending on where the infarct is located in subcortical-, cortical-, and cerebellar regions. METHODS: Participants (n=2662, mean age 74.6±4.8) from the longitudinal population-based AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study underwent brain magnetic resonance imaging at baseline and on average 5.2 years later. We assessed the number and location of brain infarcts (prevalent versus incident). We estimated the risk-ratios of prevalent (PRR) and incident (IRR) infarcts by baseline cerebrovascular risk-factors using Poisson regression. RESULTS: Thirty-one percent of the study participants had prevalent brain infarcts and 21% developed new infarcts over 5 years. Prevalent subcortical infarcts were associated with hypertension (PRR, 2.7 [95% CI, 1.1-6.8]), systolic blood pressure (PRR, 1.2 [95% CI, 1.1-1.4]), and diabetes (PRR, 2.8 [95% CI, 1.9-4.1]); incident subcortical infarcts were associated with systolic (IRR, 1.2 [95% CI, 1.0-1.4]) and diastolic (IRR, 1.3 [95% CI, 1.0-1.6]) blood pressure. Prevalent and incident cortical infarcts were associated with carotid plaques (PRR, 1.8 [95% CI, 1.3-2.5] and IRR, 1.9 [95% CI, 1.3-2.9], respectively), and atrial fibrillation was significantly associated with prevalent cortical infarcts (PRR, 1.8 [95% CI, 1.2-2.7]). Risk-factors for prevalent cerebellar infarcts included hypertension (PRR, 2.45 [95% CI, 1.5-4.0]), carotid plaques (PRR, 1.45 [95% CI, 1.2-1.8]), and migraine with aura (PRR, 1.6 [95% CI, 1.1-2.2]). Incident cerebellar infarcts were only associated with any migraine (IRR, 1.4 [95% CI, 1.0-2.0]). CONCLUSIONS: The risk for subcortical infarcts tends to increase with small vessel disease risk-factors such as hypertension and diabetes. Risk for cortical infarcts tends to increase with atherosclerotic/coronary processes and risk for cerebellar infarcts with a more mixed profile of factors. Assessment of risk-factors by location of asymptomatic infarcts found on magnetic resonance imaging may improve the ability to target and optimize preventive therapeutic approaches to prevent stroke.


Assuntos
Hipertensão , Transtornos de Enxaqueca , Idoso , Encéfalo/diagnóstico por imagem , Infarto Encefálico/diagnóstico por imagem , Infarto Encefálico/epidemiologia , Infarto Cerebral/diagnóstico por imagem , Infarto Cerebral/epidemiologia , Humanos , Hipertensão/epidemiologia , Imageamento por Ressonância Magnética , Fatores de Risco
16.
Brain Imaging Behav ; 16(2): 637-644, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34487279

RESUMO

The purpose of this study was to investigate whether long-term television viewing patterns, a common sedentary behavior, in early to mid-adulthood is associated with gray matter brain volume in midlife and if this is independent of physical activity. We evaluated 599 participants (51% female, 44% black, mean age 30.3 ± 3.5 at baseline and 50.2 ± 3.5 years at follow-up and MRI) from the prospective Coronary Artery Risk Development in Young Adults (CARDIA) study. We assessed television patterns with repeated interviewer-administered questionnaire spanning 20 years. Structural MRI (3T) measures of frontal cortex, entorhinal cortex, hippocampal, and total gray matter volumes were assessed at midlife. Over the 20 years, participants reported viewing an average of 2.5 ± 1.7 h of television per day (range: 0-10 h). After multivariable adjustment, greater television viewing was negatively associated with gray matter volume in the frontal (ß = - 0.77; p = 0.01) and entorhinal cortex (ß = - 23.83; p = 0.05) as well as total gray matter (ß = - 2.09; p = 0.003) but not hippocampus. These results remained unchanged after additional adjustment for physical activity. For each one standard deviation increase in television viewing, the difference in gray matter volume z-score was approximately 0.06 less for each of the three regions (p < 0.05). Among middle-aged adults, greater television viewing in early to mid-adulthood was associated with lower gray matter volume. Sedentariness or other facets of television viewing may be important for brain aging even in middle age.


Assuntos
Substância Cinzenta , Imageamento por Ressonância Magnética , Adulto , Encéfalo/diagnóstico por imagem , Feminino , Substância Cinzenta/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Televisão , Adulto Jovem
17.
Alzheimers Dement ; 2022 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-35142033

RESUMO

OBJECTIVE: To examine longitudinal race and sex differences in mid-life brain health and to evaluate whether cardiovascular health (CVH) or apolipoprotein E (APOE) ε4 explain differences. METHODS: The study included 478 Black and White participants (mean age: 50 years). Total (TBV), gray (GMV), white (WMV), and white matter hyperintensity (WMH) volumes and GM-cerebral blood flow (CBF) were acquired with 3T-magnetic resonance imaging at baseline and 5-year follow-up. Analyses were based on general linear models. RESULTS: There were race x sex interactions for GMV (P-interaction = .004) and CBF (P-interaction = .01) such that men showed more decline than women, and this was most evident in Blacks. Blacks compared to Whites had a significantly greater increase in WMH (P = .002). All sex-race differences in change were marginally attenuated by CVH and APOE ε4. CONCLUSION: Race-sex differences in brain health emerge by mid-life. Identifying new environmental factors beyond CVH is needed to develop early interventions to maintain brain health.

18.
Neurobiol Aging ; 111: 14-23, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34923217

RESUMO

Late-life depression (LLD) increases risk for dementia and brain pathology, but possibly this is only true for one or more symptom profiles of LLD. In 4354 participants (76 ± 5 years; 58% female) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, we identified five LLD symptom profiles, based on the Geriatric Depression Scale-15 (no LLD (57%); apathy (31%); apathy with emptiness (2%), mild LLD (8%) and severe LLD (2%)). Cox regression analyses showed that severe LLD, mild LLD and apathy increased risk of dementia up to 12 years, compared to no LLD. Additionally, hippocampal volume loss and white matter lesion increase, were assessed on 1.5 T MR images, at baseline and after 5 years follow-up. Only severe LLD showed increased WML volume over time, but not on hippocampal volume loss. WML increase over time mediated partially the relation between mild LLD and dementia but not for the other symptom profiles. It appears that hippocampal atrophy and LLD are independent predictors for dementia incidence, whereas for mild LLD the risk for dementia is partially mediated by WML changes.


Assuntos
Envelhecimento/patologia , Demência/etiologia , Demência/patologia , Depressão/complicações , Depressão/patologia , Hipocampo/patologia , Substância Branca/patologia , Idoso , Idoso de 80 Anos ou mais , Apatia , Demência/genética , Depressão/psicologia , Feminino , Previsões , Interação Gene-Ambiente , Humanos , Masculino , Tamanho do Órgão , Gravidade do Paciente
19.
J Alzheimers Dis ; 85(4): 1677-1687, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34958034

RESUMO

BACKGROUND: Late-life depression (LLD) is related to an increased risk of developing dementia; however, the biological mechanisms explaining this relationship remain unclear. OBJECTIVE: To determine whether the relationship between LLD and dementia can be best explained by the glucocorticoid cascade or vascular hypothesis. METHODS: Data are from 4,354 persons (mean age 76±5 years) without dementia at baseline from the AGES-Reykjavik Study. LLD was assessed with the MINI diagnostic interview (current and remitted major depressive disorder [MDD]) and the Geriatric Depression Scale-15. Morning and evening salivary cortisol were collected (glucocorticoid cascade hypothesis). White matter hyperintensities (WMH; vascular hypothesis) volume was assessed using 1.5T brain MRI. Using Cox proportional hazard models, we estimated the associations of LLD, cortisol levels, and WMH volume with incident all-cause dementia, AD, and non-AD dementia. RESULTS: During 8.8±3.2 years of follow-up, 843 persons developed dementia, including 397 with AD. Current MDD was associated with an increased risk of developing all-cause dementia (HR = 2.17; 95% CI 1.66-2.67), with risks similar for AD and non-AD, while remitted MDD was not (HR = 1.02; 95% CI 0.55-1.49). Depressive symptoms were also associated with increased risk of dementia, in particular non-AD dementias. Higher levels of evening cortisol increased risk of dementia, but this was independent of MDD. WMH partially explained the relation between current MDD and dementia risk but remained increased (HR = 1.71; 95% CI 1.34-2.08). CONCLUSION: The current study highlights the importance of LLD in developing dementia. However, neither the glucocorticoid cascade nor the vascular hypotheses fully explained the relation between depression and dementia.


Assuntos
Encéfalo/patologia , Demência/diagnóstico , Transtorno Depressivo Maior/epidemiologia , Hidrocortisona/análise , Substância Branca/patologia , Idoso , Feminino , Humanos , Islândia , Entrevistas como Assunto , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Fatores de Risco
20.
Am J Respir Crit Care Med ; 205(7): 795-805, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-34929108

RESUMO

Rationale: Higher blood monocyte counts are associated with worse survival in adults with clinically diagnosed pulmonary fibrosis. Their association with the development and progression of interstitial lung abnormalities (ILA) in humans is unknown. Objectives: We evaluated the associations of blood monocyte count, and other immune cell types, with ILA, high-attenuation areas, and FVC in four independent cohorts. Methods: We included participants with measured monocyte counts and computed tomographic (CT) imaging enrolled in MESA (Multi-Ethnic Study of Atherosclerosis, n = 484), AGES-Reykjavik (Age/Gene Environment Susceptibility Study, n = 3,547), COPDGene (Genetic Epidemiology of COPD, n = 2,719), and the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points, n = 646). Measurements and Main Results: After adjustment for covariates, a 1-SD increment in blood monocyte count was associated with ILA in MESA (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.0-1.8), AGES-Reykjavik (OR, 1.2; 95% CI, 1.1-1.3), COPDGene (OR, 1.3; 95% CI, 1.2-1.4), and ECLIPSE (OR, 1.2; 95% CI, 1.0-1.4). A higher monocyte count was associated with ILA progression over 5 years in AGES-Reykjavik (OR, 1.2; 95% CI, 1.0-1.3). Compared with participants without ILA, there was a higher percentage of activated monocytes among those with ILA in MESA. Higher monocyte count was associated with greater high-attenuation areas in MESA and lower FVC in MESA and COPDGene. Associations of other immune cell types were less consistent. Conclusions: Higher blood monocyte counts were associated with the presence and progression of interstitial lung abnormalities and lower FVC.


Assuntos
Doenças Pulmonares Intersticiais , Anormalidades do Sistema Respiratório , Adulto , Humanos , Pulmão/diagnóstico por imagem , Monócitos , Tomografia Computadorizada por Raios X
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