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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.
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Sordera , Pérdida Auditiva , Animales , Cóclea , Estudio de Asociación del Genoma Completo , Pérdida Auditiva/genética , Humanos , Ratones , Estría VascularRESUMEN
The plasma proteome can mediate associations between periodontal disease (Pd) and brain white matter integrity (WMI). We screened 5089 UK Biobank participants aged 40-70 years for poor oral health problems (POHP). We examined the association between POHP and WMI (fractional anisotropy (FA), mean diffusivity (MD), Intracellular Volume Fraction (ICVF), Isotropic Volume Fraction (ISOVF) and Orientation Diffusion (OD)), decomposing the total effect through the plasma proteome of 1463 proteins into pure mediation, pure interaction, neither, while adjusting for socio-demographic and cardiovascular health factors. Similarly, structural equations modeling (SEM) was conducted. POHP was more prevalent among men (12.3% vs. 9.6%), and was associated with lower WMI on most metrics, in a sex-specific manner. Of 15 proteins strongly associated with POHP, growth differentiation factor 15 (GDF15) and WAP four-disulfide core domain 2 (WFDC2; also known as human epididymis protein 4; HE4) were consistent mediators. Both proteins mediated 7-8% of total POHP effect on FAmean. SEM yielded significant total effects for FAmean, MDmean and ISOVFmean in full models, with %mediated by common latent factor (GDF15 and WFDC2) ranging between 13% (FAmean) and 19% (ISOVFmean). For FA, mediation by this common factor was found for 16 of 49 tract-specific and global mean metrics. Protein metabolism, immune system, and signal transduction were the most common pathways for mediational effects. POHP was associated with poorer WMI, which was partially mediated by GDF15 and WFDC2.
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We examined associations of an Alzheimer's disease (AD) Genetic Risk Score (AD-GRS) and midlife cognitive and neuroimaging outcomes in 1,252 middle-aged participants (311 with brain MRI). A higher AD-GRS based on 25 previously identified loci (excluding apolipoprotein E [APOE]) was associated with worse Montreal Cognitive Assessment (-0.14 standard deviation [SD] [95% confidence interval {CI}: -0.26, -0.02]), older machine learning predicted brain age (2.35 years[95%CI: 0.01, 4.69]), and white matter hyperintensity volume (0.35 SD [95% CI: 0.00, 0.71]), but not with a composite cognitive outcome, total brain, or hippocampal volume. APOE ε4 allele was not associated with any outcomes. AD risk genes beyond APOE may contribute to subclinical differences in cognition and brain health in midlife. ANN NEUROL 2023;93:629-634.
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Enfermedad de Alzheimer , Persona de Mediana Edad , Humanos , Preescolar , Enfermedad de Alzheimer/genética , Encéfalo , Envejecimiento/genética , Cognición , Apolipoproteínas E , Apolipoproteína E4/genéticaRESUMEN
BACKGROUND: The study examined how plasma proteome indicators may explain the link between poor cardiovascular health (CVH) and dementia risk. METHODS: The present study involved 28,974 UK Biobank participants aged 50-74y at baseline (2006-2010) who were followed-up for ≤ 15 y for incidence of dementia. CVH was calculated using Life's Essential 8 (LE8) total scores. The scores were standardized and reverse coded to reflect poor CVH (LE8z_rev). OLINK proteomics was available on this sample (k = 1,463 plasma proteins). The study primarily tested the mediating effects of the plasma proteome in LE8z_rev-dementia effect. The total effect was decomposed into "mediation only" or pure indirect effect (PIE), "interaction only" or interaction referent (INTREF), "neither mediation nor interaction" or controlled direct effect (CDE), and "both mediation and interaction" or mediated interaction (INTMED). RESULTS: The study found poorer CVH assessed by LE8z_rev increased the risk of all-cause dementia by 11 % [per 1 SD, hazard ratio, (HR) = 1.11, 95 % CI: 1.03-1.20, p = 0.005). The study identified 11 plasma proteins with strong mediating effects, with GDF15 having the strongest association with dementia risk (per 1 SD, HR = 1.24, 95 % CI: 1.16, 1.33, P < 0.001 when LE8z_rev is set at its mean value) and the largest proportion mediated combining PIE and INTMED (62.6 %; 48 % of TE is PIE), followed by adrenomedullin or ADM. A first principal component with 10 top mediators (TNFRSF1A, GDF15, FSTL3, COL6A3, PLAUR, ADM, GFRAL, ACVRL1, TNFRSF6B, TGFA) mediated 53.6 % of the LE8z_rev-dementia effect. Using all the significant PIE (k = 526) proteins, we used OLINK Insight pathway analysis to identify key pathways, which revealed the involvement of the immune system, signal transduction, metabolism, disease, protein metabolism, hemostasis, membrane trafficking, extracellular matrix organization, developmental biology, and gene expression among others. STRING analysis revealed that five top consistent proteomic mediators were represented in two larger clusters reflecting numerous interconnected biological gene ontology pathways, most notably cytokine-mediated signaling pathway for GDF15 cluster (GO:0019221) and regulation of peptidyl-tyrosine phosphorylation for the ADM cluster (GO:0050730). CONCLUSION: Dementia is linked to poor CVH mediated by GDF15 and ADM among several key proteomic markers which collectively explained â¼ 54 % of the total effect.
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Bancos de Muestras Biológicas , Biomarcadores , Enfermedades Cardiovasculares , Demencia , Proteómica , Humanos , Masculino , Anciano , Femenino , Reino Unido/epidemiología , Demencia/sangre , Demencia/epidemiología , Persona de Mediana Edad , Proteómica/métodos , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/epidemiología , Proteoma/metabolismo , Incidencia , Factores de Riesgo , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/análisis , Biobanco del Reino UnidoRESUMEN
BACKGROUND: Infection burden (IB), although linked to neurodegeneration, including Alzheimer's Disease (AD), has not been examined against neurite orientation, dispersion, and density imaging (NODDI) measures. METHODS: Among 38,803 UK Biobank adults (Age:40-70 years), we tested associations of total IB (IBtotal, 47.5 %) and hospital-treated IB (IBhosp, 9.7 %) with NODDI measures (5-15 years later), including volume fraction of Gaussian isotropic diffusion (ISOVF), intra-cellular volume fraction (ICVF) and orientation dispersion (OD) indices, using multiple linear regression models. RESULTS: Total and hospital-treated infection burdens (IBtotal and IBhosp) were associated with increased ISOVF, indicating increased free-water component. IBtotal was positively associated with OD, indicating that at higher IBtotal there was greater fanning of neurites. This was more evident in the lower cardiovascular health group. IBhosp was associated with higher OD, and lower ICVF at higher AD polygenic risk. Together, these findings indicate that both total and hospital-treated infections have effects on NODDI outcomes in the direction of poor brain health. These effects were largely homogeneous across cardiovascular health and AD polygenic risk groups, with some effects shown to be stronger at poor cardiovascular health and/or higher AD risk. CONCLUSIONS: Total and hospital-treated infections were associated with poorer white matter microstructure (higher ISOVF or OD or lower ICVF), with some heterogeneity across cardiovascular health and AD risk. Longitudinal studies with multiple repeats on neuroimaging markers in comparable samples are needed.
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Imagen de Difusión Tensora , Sustancia Blanca , Imagen de Difusión Tensora/métodos , Neuritas , Bancos de Muestras Biológicas , Encéfalo , Sustancia Blanca/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética/métodosRESUMEN
Cerebral white matter hyperintensities on MRI are markers of cerebral small vessel disease, a major risk factor for dementia and stroke. Despite the successful identification of multiple genetic variants associated with this highly heritable condition, its genetic architecture remains incompletely understood. More specifically, the role of DNA methylation has received little attention. We investigated the association between white matter hyperintensity burden and DNA methylation in blood at â¼450 000 cytosine-phosphate-guanine (CpG) sites in 9732 middle-aged to older adults from 14 community-based studies. Single CpG and region-based association analyses were carried out. Functional annotation and integrative cross-omics analyses were performed to identify novel genes underlying the relationship between DNA methylation and white matter hyperintensities. We identified 12 single CpG and 46 region-based DNA methylation associations with white matter hyperintensity burden. Our top discovery single CpG, cg24202936 (P = 7.6 × 10-8), was associated with F2 expression in blood (P = 6.4 × 10-5) and co-localized with FOLH1 expression in brain (posterior probability = 0.75). Our top differentially methylated regions were in PRMT1 and in CCDC144NL-AS1, which were also represented in single CpG associations (cg17417856 and cg06809326, respectively). Through Mendelian randomization analyses cg06809326 was putatively associated with white matter hyperintensity burden (P = 0.03) and expression of CCDC144NL-AS1 possibly mediated this association. Differentially methylated region analysis, joint epigenetic association analysis and multi-omics co-localization analysis consistently identified a role of DNA methylation near SH3PXD2A, a locus previously identified in genome-wide association studies of white matter hyperintensities. Gene set enrichment analyses revealed functions of the identified DNA methylation loci in the blood-brain barrier and in the immune response. Integrative cross-omics analysis identified 19 key regulatory genes in two networks related to extracellular matrix organization, and lipid and lipoprotein metabolism. A drug-repositioning analysis indicated antihyperlipidaemic agents, more specifically peroxisome proliferator-activated receptor-alpha, as possible target drugs for white matter hyperintensities. Our epigenome-wide association study and integrative cross-omics analyses implicate novel genes influencing white matter hyperintensity burden, which converged on pathways related to the immune response and to a compromised blood-brain barrier possibly due to disrupted cell-cell and cell-extracellular matrix interactions. The results also suggest that antihyperlipidaemic therapy may contribute to lowering risk for white matter hyperintensities possibly through protection against blood-brain barrier disruption.
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Sustancia Blanca , Persona de Mediana Edad , Humanos , Anciano , Sustancia Blanca/diagnóstico por imagen , Estudio de Asociación del Genoma Completo/métodos , Encéfalo/diagnóstico por imagen , Metilación de ADN/genética , Imagen por Resonancia Magnética , Epigénesis Genética , Proteína-Arginina N-Metiltransferasas , Proteínas RepresorasRESUMEN
The mixed evidence of the association between high levels of cardiovascular risk factors (CVRF) and the risk for cognitive impairment may be due to confounding of age across studies. We pooled and harmonized individual-level data (30,967 persons, age range 42-96 years) from five prospective cohorts to investigate by 1 year age increments to investigate whether or not there is change in slope describing the association of CVRF to a cognitive outcome (Digit Symbol Substitution Test; DSST). The CVRF included: systolic and diastolic blood pressure, total cholesterol, fasting glucose and body mass index. Linear and quadratic piecewise regression models were fit to the trajectory patterns of these slopes (betas). The pattern of yearly slope changes showed higher CVRF were associated with lower DSST, but associations attenuated toward zero as age increased for all but DBP where 1 year slopes for DBP changed direction from negative to positive from mid- to late-age. Age is not only a driver of cognitive decline-age also modifies the direction and strength of the association of cognitive function to CVRF and cohort age may be one reason why the evidence for CVRF-CD association is mixed.
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Cognición , Disfunción Cognitiva , Humanos , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Estudios Prospectivos , Factores de Riesgo , Disfunción Cognitiva/epidemiología , Índice de Masa CorporalRESUMEN
Midlife blood pressure is associated with structural brain changes, cognitive decline, and dementia in late life. However, the relationship between early adulthood blood pressure exposure, brain structure and function, and cognitive performance in midlife is not known. A better understanding of these relationships in the preclinical stage may advance our mechanistic understanding of vascular contributions to late-life cognitive decline and dementia and may provide early therapeutic targets. To identify resting-state functional connectivity of executive control networks (ECNs), a group independent components analysis was performed of functional MRI scans of 600 individuals from the Coronary Artery Risk Development in Young Adults longitudinal cohort study, with cumulative systolic blood pressure (cSBP) measured at nine visits over the preceding 30 y. Dual regression analysis investigated performance-related connectivity of ECNs in 578 individuals (mean age 55.5 ± 3.6 y, 323 female, 243 Black) with data from the Stroop color-word task of executive function. Greater connectivity of a left ECN to the bilateral anterior gyrus rectus, right posterior orbitofrontal cortex, and nucleus accumbens was associated with better executive control performance on the Stroop. Mediation analyses showed that while the relationship between cSBP and Stroop performance was mediated by white matter hyperintensities (WMH), resting-state connectivity of the ECN mediated the relationship between WMH and executive function. Increased connectivity of the left ECN to regions involved in reward processing appears to compensate for the deleterious effects of WMH on executive function in individuals across the burden of cumulative systolic blood pressure exposure in midlife.
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Presión Sanguínea , Encéfalo/fisiopatología , Disfunción Cognitiva/epidemiología , Demencia/epidemiología , Función Ejecutiva/fisiología , Vías Nerviosas , Sustancia Blanca/fisiopatología , Adolescente , Adulto , Mapeo Encefálico , Disfunción Cognitiva/patología , Demencia/patología , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.
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Apolipoproteínas E/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Obesidad/genética , Alanina Transaminasa , Alelos , Enfermedad de Alzheimer/genética , Apolipoproteínas E/metabolismo , Bases de Datos Genéticas , Exoma/genética , Frecuencia de los Genes/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Hígado , Cirrosis Hepática/genética , Infarto del Miocardio/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/metabolismo , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Pronóstico , Factores de Riesgo , TriglicéridosRESUMEN
BACKGROUND: Gut microbiota may influence metabolic pathways related to chronic health conditions. Evidence for physical activity and diet influences on gut microbial composition exists, but data from diverse population-based cohort studies are limited. OBJECTIVES: We hypothesized that gut microbial diversity and genera are associated with physical activity and diet quality. METHODS: Data were from 537 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a prospective cohort, who attended the year 30 follow-up examination (2015-2016; aged 47-61 y; 45% Black race/55% White race; 45% men/55% women). The 16S ribosomal RNA marker gene was sequenced from stool DNA, and genus-level taxonomy was assigned. Within-person microbial diversity (α-diversity) was assessed with Shannon diversity index and richness scores; between-person diversity (ß-diversity) measures were generated with principal coordinates analysis (PCoA). Current and long-term physical activity and diet quality measures were derived from data collected over 30 y of follow-up. Multivariable-adjusted regression analysis controlled for: sociodemographic variables (age, race, sex, education, and field center), other health behaviors (smoking, alcohol consumption, and medication use), and adjusted for multiple comparisons with the false discovery rate (<0.20). RESULTS: Based on PCoA ß-diversity, participants' microbial community compositions differed significantly (P < 0.001), with respect to both current and long-term physical activity and diet quality. α-Diversity was associated only with current physical activity (positively) in multivariable-adjusted analysis. Multiple genera (n = 45) were associated with physical activity and fewer with diet (n = 5), including positive associations with Lachnospiraceae UCG-001 and Ruminococcaceae IncertaeSedis with both behaviors. CONCLUSIONS: Physical activity and diet quality were associated with gut microbial composition among 537 participants in the CARDIA study. Multiple genera were associated with physical activity. Physical activity and diet quality were associated with genera consistent with pathways related to inflammation and short-chain fatty acid production.
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Microbioma Gastrointestinal , Masculino , Humanos , Femenino , Adulto Joven , Vasos Coronarios , Estudios Prospectivos , Dieta , Ejercicio Físico , ARN Ribosómico 16S , HecesRESUMEN
BACKGROUND: Bidirectional longitudinal relationships between depression and diabetes have been observed, but the dominant direction of their temporal relationships remains controversial. METHODS: The random-intercept cross-lagged panel model decomposes observed variables into a latent intercept representing the traits, and occasion-specific latent 'state' variables. This permits correlations to be assessed between the traits, while longitudinal 'cross-lagged' associations and cross-sectional correlations can be assessed between occasion-specific latent variables. We examined dynamic relationships between depressive symptoms and insulin resistance across five visits over 20 years of adulthood in the population-based Coronary Artery Risk Development in Young Adults (CARDIA) study. Possible differences based on population group (Black v. White participants), sex and years of education were tested. Depressive symptoms and insulin resistance were quantified using the Center for Epidemiologic Studies Depression (CES-D) scale and the homeostatic model assessment for insulin resistance (HOMA-IR), respectively. RESULTS: Among 4044 participants (baseline mean age 34.9 ± 3.7 years, 53% women, 51% Black participants), HOMA-IR and CES-D traits were weakly correlated (r = 0.081, p = 0.002). Some occasion-specific correlations, but no cross-lagged associations were observed overall. Longitudinal dynamics of these relationships differed by population groups such that HOMA-IR at age 50 was associated with CES-D score at age 55 (ß = 0.076, p = 0.038) in White participants only. Longitudinal dynamics were consistent between sexes and based on education. CONCLUSIONS: The relationship between depressive symptoms and insulin resistance was best characterized by weak correlations between occasion-specific states and enduring traits, with weak evidence that insulin resistance might be temporally associated with subsequent depressive symptoms among White participants later in adulthood.
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Diabetes Mellitus , Resistencia a la Insulina , Adulto Joven , Humanos , Femenino , Adulto , Persona de Mediana Edad , Masculino , Depresión/epidemiología , Estudios Transversales , Factores de Riesgo , Estudios LongitudinalesRESUMEN
BACKGROUND: Cardiovascular health is associated with brain magnetic resonance imaging (MRI) markers of pathology and infections may modulate this association. METHODS: Using data from 38,803 adults (aged 40-70 years) and followed-up for 5-15 years, we tested associations of prevalent total (47.5%) and hospital-treated infection burden (9.7%) with brain structural and diffusion-weighted MRI (i.e., sMRI and dMRI, respectively) common in dementia phenome. Poor white matter tissue integrity was operationalized with lower global and tract-specific fractional anisotropy (FA) and higher mean diffusivity (MD). Volumetric sMRI outcomes included total, gray matter (GM), white matter (WM), frontal bilateral GM, white matter hyperintensity (WMH), and selected based on previous associations with dementia. Cardiovascular health was measured with Life's Essential 8 score (LE8) converted to tertiles. Multiple linear regression models were used, adjusting for intracranial volumes (ICV) for subcortical structures, and for demographic, socio-economic, and the Alzheimer's Disease polygenic risk score for all outcomes, among potential confounders. RESULTS: In fully adjusted models, hospital-treated infections were inversely related to GM (ß ± SE: -1042 ± 379, p = 0.006) and directly related to WMH as percent of ICV (Loge transformed) (ß ± SE:+0.026 ± 0.007, p < 0.001). Both total and hospital-treated infections were associated with poor WMI, while the latter was inversely related to FA within the lowest LE8 tertile (ß ± SE:-0.0011 ± 0.0003, p < 0.001, PLE8×IB < 0.05), a pattern detected for GM, Right Frontal GM, left accumbens and left hippocampus volumes. Within the uppermost LE8 tertile, total infection burden was linked to smaller right amygdala while being associated with larger left frontal GM and right putamen volumes, in the overall sample. Within that uppermost tertile of LE8, caudate volumes were also positively associated with hospital-treated infections. CONCLUSIONS: Hospital-treated infections had more consistent deleterious effects on volumetric and white matter integrity brain neuroimaging outcomes compared with total infectious burden, particularly in poorer cardiovascular health groups. Further studies are needed in comparable populations, including longitudinal studies with multiple repeats on neuroimaging markers.
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Demencia , Sustancia Blanca , Adulto , Humanos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Imagen de Difusión Tensora/métodos , Bancos de Muestras Biológicas , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Reino UnidoRESUMEN
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 = 41â326), whole-exome sequencing (n = 15â965), or exome chip (n = 5249) data contributed 13â776 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.
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Isquemia Encefálica , Enfermedades de los Pequeños Vasos Cerebrales , Accidente Cerebrovascular , Animales , Isquemia Encefálica/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/complicaciones , Enfermedades de los Pequeños Vasos Cerebrales/diagnóstico por imagen , Enfermedades de los Pequeños Vasos Cerebrales/genética , Células Endoteliales/patología , Estudio de Asociación del Genoma Completo , Ratones , Accidente Cerebrovascular/complicacionesRESUMEN
Rationale: Knowledge on biomarkers of interstitial lung disease is incomplete. Interstitial lung abnormalities (ILAs) are radiologic changes that may present in its early stages. Objectives: To uncover blood proteins associated with ILAs using large-scale proteomics methods. Methods: Data from two prospective cohort studies, the AGES-Reykjavik (Age, Gene/Environment Susceptibility-Reykjavik) study (N = 5,259) for biomarker discovery and the COPDGene (Genetic Epidemiology of COPD) study (N = 4,899) for replication, were used. Blood proteins were measured using DNA aptamers, targeting more than 4,700 protein analytes. The association of proteins with ILAs and ILA progression was assessed with regression modeling, as were associations with genetic risk factors. Adaptive Least Absolute Shrinkage and Selection Operator models were applied to bootstrap data samples to discover sets of proteins predictive of ILAs and their progression. Measurements and Main Results: Of 287 associations, SFTPB (surfactant protein B) (odds ratio [OR], 3.71 [95% confidence interval (CI), 3.20-4.30]; P = 4.28 × 10-67), SCGB3A1 (Secretoglobin family 3A member 1) (OR, 2.43 [95% CI, 2.13-2.77]; P = 8.01 × 10-40), and WFDC2 (WAP four-disulfide core domain protein 2) (OR, 2.42 [95% CI, 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, concentrations of SFTPB were associated with the rs35705950 MUC5B (mucin 5B) promoter polymorphism, and SFTPB and WFDC2 had the strongest associations with ILA progression. Multivariate models of ILAs in AGES-Reykjavik, ILAs 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 favorable predictive potential. Several proteins are revealed as potential markers of early fibrotic lung disease.
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Enfermedades Pulmonares Intersticiales , Anomalías del Sistema Respiratorio , Predisposición Genética a la Enfermedad , Humanos , Pulmón , Enfermedades Pulmonares Intersticiales/epidemiología , Enfermedades Pulmonares Intersticiales/genética , Estudios Prospectivos , Proteómica , Tomografía Computarizada por Rayos XRESUMEN
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.
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Enfermedades Pulmonares Intersticiales , Anomalías del Sistema Respiratorio , Adulto , Humanos , Pulmón/diagnóstico por imagen , Monocitos , Tomografía Computarizada por Rayos XRESUMEN
BACKGROUND: Early identification of dementia is crucial for prompt intervention for high-risk individuals in the general population. External validation studies on prognostic models for dementia have highlighted the need for updated models. The use of machine learning in dementia prediction is in its infancy and may improve predictive performance. The current study aimed to explore the difference in performance of machine learning algorithms compared to traditional statistical techniques, such as logistic and Cox regression, for prediction of all-cause dementia. Our secondary aim was to assess the feasibility of only using clinically accessible predictors rather than MRI predictors. METHODS: Data are from 4,793 participants in the population-based AGES-Reykjavik Study without dementia or mild cognitive impairment at baseline (mean age: 76 years, % female: 59%). Cognitive, biometric, and MRI assessments (total: 59 variables) were collected at baseline, with follow-up of incident dementia diagnoses for a maximum of 12 years. Machine learning algorithms included elastic net regression, random forest, support vector machine, and elastic net Cox regression. Traditional statistical methods for comparison were logistic and Cox regression. Model 1 was fit using all variables and model 2 was after feature selection using the Boruta package. A third model explored performance when leaving out neuroimaging markers (clinically accessible model). Ten-fold cross-validation, repeated ten times, was implemented during training. Upsampling was used to account for imbalanced data. Tuning parameters were optimized for recalibration automatically using the caret package in R. RESULTS: 19% of participants developed all-cause dementia. Machine learning algorithms were comparable in performance to logistic regression in all three models. However, a slight added performance was observed in the elastic net Cox regression in the third model (c = 0.78, 95% CI: 0.78-0.78) compared to the traditional Cox regression (c = 0.75, 95% CI: 0.74-0.77). CONCLUSIONS: Supervised machine learning only showed added benefit when using survival techniques. Removing MRI markers did not significantly worsen our model's performance. Further, we presented the use of a nomogram using machine learning methods, showing transportability for the use of machine learning models in clinical practice. External validation is needed to assess the use of this model in other populations. Identifying high-risk individuals will amplify prevention efforts and selection for clinical trials.
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Demencia , Aprendizaje Automático , Humanos , Femenino , Anciano , Masculino , Prueba de Estudio Conceptual , Aprendizaje Automático Supervisado , Algoritmos , Demencia/diagnóstico , Demencia/epidemiologíaRESUMEN
INTRODUCTION: Dementia prediction models are necessary to inform the development of dementia risk reduction strategies. Here, we examine the utility of neuropathological-based risk scores to predict clinical dementia. METHODS: Models were developed for predicting Alzheimer's disease (AD) and non-AD neuropathologies using the Honolulu Asia Aging neuropathological sub-study (HAAS; n = 852). Model accuracy for predicting clinical dementia, over 30 years, was tested in the non-autopsied HAAS sample (n = 2960) and the Age, Gene/Environment Susceptibility-Reykjavik Study (n = 4614). RESULTS: Different models were identified for predicting neurodegenerative and vascular neuropathology (c-statistic range: 0.62 to 0.72). These typically included age, APOE, and a blood pressure-related measure. The neurofibrillary tangle and micro-vascular lesion models showed good accuracy for predicting clinical vascular dementia. DISCUSSION: There may be shared risk factors across dementia-related lesions, suggesting common pathways. Strategies targeting these models may reduce risk or postpone clinical symptoms of dementia as well as reduce neuropathological burden associated with AD and vascular lesions.
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Enfermedad de Alzheimer , Demencia Vascular , Demencia , Humanos , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Demencia Vascular/epidemiología , Demencia Vascular/patología , Demencia/patología , Encéfalo/patología , Envejecimiento/patología , Factores de Riesgo , Ovillos Neurofibrilares/patologíaRESUMEN
INTRODUCTION: We aimed to investigate the association between white matter hyperintensity (WMH) shape and volume and the long-term dementia risk in community-dwelling older adults. METHODS: Three thousand seventy-seven participants (mean age: 75.6 ± 5.2 years) of the Age Gene/Environment Susceptibility (AGES)-Reykjavik study underwent baseline 1.5T brain magnetic resonance imaging and were followed up for dementia (mean follow-up: 9.9 ± 2.6 years). RESULTS: More irregular shape of periventricular/confluent WMH (lower solidity (hazard ratio (95% confidence interval) 1.34 (1.17 to 1.52), p < .001) and convexity 1.38 (1.28 to 1.49), p < .001); higher concavity index 1.43 (1.32 to 1.54), p < .001) and fractal dimension 1.45 (1.32 to 1.58), p < .001)), higher total WMH volume (1.68 (1.54 to 1.87), p < .001), higher periventricular/confluent WMH volume (1.71 (1.55 to 1.89), p < .001), and higher deep WMH volume (1.17 (1.08 to 1.27), p < .001) were associated with an increased long-term dementia risk. DISCUSSION: WMH shape markers may in the future be useful in determining patient prognosis and may aid in patient selection for future preventive treatments in community-dwelling older adults.
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Demencia , Sustancia Blanca , Humanos , Anciano , Anciano de 80 o más Años , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Pronóstico , Modelos de Riesgos Proporcionales , Demencia/diagnóstico por imagen , Demencia/epidemiología , Demencia/patología , Imagen por Resonancia MagnéticaRESUMEN
INTRODUCTION: Among older adults, total and hospitalized infection may be associated with incidence of all-cause and Alzheimer's disease (AD) dementias, with variation by cardiovascular health (CVH). METHODS: We used Cox proportional hazards (PH) models to examine the relationships between International Classification of Diseases-10th revision (ICD-10)-specific viral and bacterial infectious agents and incident all-cause and AD dementia among 355,046 UK Biobank participants ≥50 years at baseline. Life's Essential 8 (LE8) index reflected CVH. RESULTS: In both sexes, total infection burden (yes vs. no) was associated with all-cause dementia, with significant interactions by LE8 tertiles, whereby this relationship was significant only in the lowest LE8 tertile. Hospital-treated infection burden (yes vs no) was significantly related to all-cause and AD dementia, with no significant interaction with LE8 tertile. Age group patterns were detected. DISCUSSION: AD and all-cause dementia were related to hospital-treated infections, while CVH modified the relationship of total infection burden with all-cause dementia. Highlights Secondary analysis on >355,000 UK Biobank participants ≥50 years at baseline. Alzheimer's disease and all-cause dementia are both related to hospital-treated infection. Cardiovascular health modifies association of infection burden with all-cause dementia.
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Enfermedad de Alzheimer , Enfermedades Cardiovasculares , Femenino , Masculino , Humanos , Anciano , Enfermedad de Alzheimer/epidemiología , Bancos de Muestras Biológicas , Reino Unido/epidemiología , Factores de Riesgo , Enfermedades Cardiovasculares/epidemiologíaRESUMEN
INTRODUCTION: We evaluated whether better cardiovascular health at midlife and improvement of cardiovascular health within midlife were associated with dementia risk. METHODS: Two longitudinal population-based studies were used: Atherosclerosis Risk in Communities (ARIC) (n = 11,460/visits at ages 54 and 60), and Age, Gene/Environment Susceptibility (AGES)-Reykjavik (n = 3907/visit at age 51). A cardiovascular health score (range 0-12/0-14, depending on diet availability) including six/seven items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Cardiovascular health was defined as low (score 0-4/0-5), intermediate (5-7/6-9), or high (8-12/10-14). Incident dementia was ascertained through linkage to health records and with neuropsychological examinations. RESULTS: Midlife high compared to low cardiovascular health (hazard ratios [HRs]: for ARIC: 0.60 [95% confidence interval: 0.52, 0.69]); for AGES-Reykjavik: 0.83 [0.66, 0.99] and improvement of cardiovascular health score within midlife (HR per one-point increase: ARIC: 0.94 [0.92, 0.96]) were associated with lower dementia risk. DISCUSSION: Better cardiovascular health at midlife and improvement of cardiovascular health within midlife are associated with lower dementia risk. HIGHLIGHTS: Cardiovascular health and dementia were studied in two large cohort studies. Better cardiovascular health at midlife relates to lower dementia risk. Improvement of cardiovascular health within midlife relates to lower dementia risk. Promotion of cardiovascular health at midlife can help to reduce dementia risk.