Proteins circulating in the blood are critical for age-related disease processes; however, the serum proteome has remained largely unexplored. To this end, 4137 proteins covering most predicted ...extracellular proteins were measured in the serum of 5457 Icelanders over 65 years of age. Pairwise correlation between proteins as they varied across individuals revealed 27 different network modules of serum proteins, many of which were associated with cardiovascular and metabolic disease states, as well as overall survival. The protein modules were controlled by cis- and trans-acting genetic variants, which in many cases were also associated with complex disease. This revealed co-regulated groups of circulating proteins that incorporated regulatory control between tissues and demonstrated close relationships to past, current, and future disease states.
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.
Equations for estimating GFR with serum creatinine overestimate measured GFR in Blacks. The authors report new equations, without race as an inflation factor, using cystatin C and creatinine that ...reduced errors in estimation between Black participants and non-Black participants.
The nonlinear trimodal regression analysis (NTRA) method based on radiodensitometric CT distributions was recently developed and assessed for the quantification of lower extremity function and ...nutritional parameters in aging subjects. However, the use of the NTRA method for building predictive models of cardiovascular health was not explored; in this regard, the present study reports the use of NTRA parameters for classifying elderly subjects with coronary heart disease (CHD), cardiovascular disease (CVD), and chronic heart failure (CHF) using multivariate logistic regression and three tree-based machine learning (ML) algorithms. Results from each model were assembled as a typology of four classification metrics: total classification score, classification by tissue type, tissue-based feature importance, and classification by age. The predictive utility of this method was modelled using CHF incidence data. ML models employing the random forests algorithm yielded the highest classification performance for all analyses, and overall classification scores for all three conditions were excellent: CHD (AUCROC: 0.936); CVD (AUCROC: 0.914); CHF (AUCROC: 0.994). Longitudinal assessment for modelling the prediction of CHF incidence was likewise robust (AUCROC: 0.993). The present work introduces a substantial step forward in the construction of non-invasive, standardizable tools for associating adipose, loose connective, and lean tissue changes with cardiovascular health outcomes in elderly individuals.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Aortic stiffness increases with age and vascular risk factor exposure and is associated with increased risk for structural and functional abnormalities in the brain. High ambient flow and low ...impedance are thought to sensitize the cerebral microcirculation to harmful effects of excessive pressure and flow pulsatility. However, haemodynamic mechanisms contributing to structural brain lesions and cognitive impairment in the presence of high aortic stiffness remain unclear. We hypothesized that disproportionate stiffening of the proximal aorta as compared with the carotid arteries reduces wave reflection at this important interface and thereby facilitates transmission of excessive pulsatile energy into the cerebral microcirculation, leading to microvascular damage and impaired function. To assess this hypothesis, we evaluated carotid pressure and flow, carotid-femoral pulse wave velocity, brain magnetic resonance images and cognitive scores in participants in the community-based Age, Gene/Environment Susceptibility - Reykjavik study who had no history of stroke, transient ischaemic attack or dementia (n = 668, 378 females, 69-93 years of age). Aortic characteristic impedance was assessed in a random subset (n = 422) and the reflection coefficient at the aorta-carotid interface was computed. Carotid flow pulsatility index was negatively related to the aorta-carotid reflection coefficient (R = −0.66, P<0.001). Carotid pulse pressure, pulsatility index and carotid-femoral pulse wave velocity were each associated with increased risk for silent subcortical infarcts (hazard ratios of 1.62-1.71 per standard deviation, P<0.002). Carotid-femoral pulse wave velocity was associated with higher white matter hyperintensity volume (0.108 ± 0.045 SD/SD, P = 0.018). Pulsatility index was associated with lower whole brain (−0.127 ± 0.037 SD/SD, P<0.001), grey matter (−0.079 ± 0.038 SD/SD, P = 0.038) and white matter (−0.128 ± 0.039 SD/SD, P<0.001) volumes. Carotid-femoral pulse wave velocity (−0.095 ± 0.043 SD/SD, P = 0.028) and carotid pulse pressure (−0.114 ± 0.045 SD/SD, P = 0.013) were associated with lower memory scores. Pulsatility index was associated with lower memory scores (−0.165 ± 0.039 SD/SD, P<0.001), slower processing speed (−0.118 ± 0.033 SD/SD, P<0.001) and worse performance on tests assessing executive function (−0.155 ± 0.041 SD/SD, P<0.001). When magnetic resonance imaging measures (grey and white matter volumes, white matter hyperintensity volumes and prevalent subcortical infarcts) were included in cognitive models, haemodynamic associations were attenuated or no longer significant, consistent with the hypothesis that increased aortic stiffness and excessive flow pulsatility damage the microcirculation, leading to quantifiable tissue damage and reduced cognitive performance. Marked stiffening of the aorta is associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage and lower scores in various cognitive domains.
A large number of observational studies have reported harmful effects of low 25-hydroxyvitamin D (25OHD) levels on non-skeletal outcomes. We performed a systematic quantitative review on ...characteristics of randomized clinical trials (RCTs) included in meta-analyses (MAs) on non-skeletal effects of vitamin D supplementation.
We identified systematic reviews (SR) reporting summary data in terms of MAs of RCTs on selected non-skeletal outcomes. For each outcome, we summarized the results from available SRs and scrutinized included RCTs for a number of predefined characteristics. We identified 54 SRs including data from 210 RCTs. Most MAs as well as the individual RCTs reported null-findings on risk of cardiovascular diseases, type 2 diabetes, weight-loss, and malignant diseases. Beneficial effects of vitamin D supplementation was reported in 1 of 4 MAs on depression, 2 of 9 MAs on blood pressure, 3 of 7 MAs on respiratory tract infections, and 8 of 12 MAs on mortality. Most RCTs have primarily been performed to determine skeletal outcomes, whereas non-skeletal effects have been assessed as secondary outcomes. Only one-third of the RCTs had low level of 25OHD as a criterion for inclusion and a mean baseline 25OHD level below 50 nmol/L was only present in less than half of the analyses.
Published RCTs have mostly been performed in populations without low 25OHD levels. The fact that most MAs on results from RCTs did not show a beneficial effect does not disprove the hypothesis suggested by observational findings on adverse health outcomes of low 25OHD levels.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Interstitial lung abnormalities have been associated with lower 6-minute walk distance, diffusion capacity for carbon monoxide, and total lung capacity. However, to our knowledge, an ...association with mortality has not been previously investigated. OBJECTIVE: To investigate whether interstitial lung abnormalities are associated with increased mortality. DESIGN, SETTING, AND POPULATION: Prospective cohort studies of 2633 participants from the FHS (Framingham Heart Study; computed tomographic CT scans obtained September 2008-March 2011), 5320 from the AGES-Reykjavik Study (Age Gene/Environment Susceptibility; recruited January 2002-February 2006), 2068 from the COPDGene Study (Chronic Obstructive Pulmonary Disease; recruited November 2007-April 2010), and 1670 from ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints; between December 2005-December 2006). EXPOSURES: Interstitial lung abnormality status as determined by chest CT evaluation. MAIN OUTCOMES AND MEASURES: All-cause mortality over an approximate 3- to 9-year median follow-up time. Cause-of-death information was also examined in the AGES-Reykjavik cohort. RESULTS: Interstitial lung abnormalities were present in 177 (7%) of the 2633 participants from FHS, 378 (7%) of 5320 from AGES-Reykjavik, 156 (8%) of 2068 from COPDGene, and in 157 (9%) of 1670 from ECLIPSE. Over median follow-up times of approximately 3 to 9 years, there were more deaths (and a greater absolute rate of mortality) among participants with interstitial lung abnormalities when compared with those who did not have interstitial lung abnormalities in the following cohorts: 7% vs 1% in FHS (6% difference 95% CI, 2% to 10%), 56% vs 33% in AGES-Reykjavik (23% difference 95% CI, 18% to 28%), and 11% vs 5% in ECLIPSE (6% difference 95% CI, 1% to 11%). After adjustment for covariates, interstitial lung abnormalities were associated with a higher risk of death in the FHS (hazard ratio HR, 2.7 95% CI, 1.1 to 6.5; P = .03), AGES-Reykjavik (HR, 1.3 95% CI, 1.2 to 1.4; P < .001), COPDGene (HR, 1.8 95% CI, 1.1 to 2.8; P = .01), and ECLIPSE (HR, 1.4 95% CI, 1.1 to 2.0; P = .02) cohorts. In the AGES-Reykjavik cohort, the higher rate of mortality could be explained by a higher rate of death due to respiratory disease, specifically pulmonary fibrosis. CONCLUSIONS AND RELEVANCE: In 4 separate research cohorts, interstitial lung abnormalities were associated with a greater risk of all-cause mortality. The clinical implications of this association require further investigation.
Epigenetic studies are commonly conducted on DNA from tissue samples. However, tissues are ensembles of cells that may each have their own epigenetic profile, and therefore inter-individual cellular ...heterogeneity may compromise these studies. Here, we explore the potential for such confounding on DNA methylation measurement outcomes when using DNA from whole blood. DNA methylation was measured using pyrosequencing-based methodology in whole blood (n = 50-179) and in two white blood cell fractions (n = 20), isolated using density gradient centrifugation, in four CGIs (CpG Islands) located in genes HHEX (10 CpG sites assayed), KCNJ11 (8 CpGs), KCNQ1 (4 CpGs) and PM20D1 (7 CpGs). Cellular heterogeneity (variation in proportional white blood cell counts of neutrophils, lymphocytes, monocytes, eosinophils and basophils, counted by an automated cell counter) explained up to 40% (p<0.0001) of the inter-individual variation in whole blood DNA methylation levels in the HHEX CGI, but not a significant proportion of the variation in the other three CGIs tested. DNA methylation levels in the two cell fractions, polymorphonuclear and mononuclear cells, differed significantly in the HHEX CGI; specifically the average absolute difference ranged between 3.4-15.7 percentage points per CpG site. In the other three CGIs tested, methylation levels in the two fractions did not differ significantly, and/or the difference was more moderate. In the examined CGIs, methylation levels were highly correlated between cell fractions. In summary, our analysis detects region-specific differential DNA methylation between white blood cell subtypes, which can confound the outcome of whole blood DNA methylation measurements. Finally, by demonstrating the high correlation between methylation levels in cell fractions, our results suggest a possibility to use a proportional number of a single white blood cell type to correct for this confounding effect in analyses.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: With advancing age, an increased visibility of perivascular spaces (PVSs) on magnetic resonance imaging (MRI) is hypothesized to represent impaired drainage of interstitial fluid from the ...brain and may reflect underlying cerebral small vessel disease (SVD). However, whether large perivascular spaces (L-PVSs) (>3 mm in diameter) visible on MRI are associated with SVD and cognitive deterioration in older individuals is unknown. OBJECTIVE: To examine whether L-PVSs are associated with the progression of the established MRI markers of SVD, cognitive decline, and increased risk of dementia. DESIGN, SETTING, AND PARTICIPANTS: The prospective, population-based Age, Gene/Environment Susceptibility–Reykjavik Study assessed L-PVSs at baseline (September 1, 2002, through February 28, 2006) on MRI studies of the brain in 2612 participants. Participants returned for additional MRI from April 1, 2007, through September 30, 2011, and underwent neuropsychological testing at the 2 time points a mean (SD) of 5.2 (0.2) years apart. Data analysis was conducted from August 1, 2016, to May 4, 2017. EXPOSURES: The presence, number, and location of L-PVSs. MAIN OUTCOMES AND MEASURES: Incident subcortical infarcts, cerebral microbleeds, and progression of white matter hyperintensities detected on MRI; cognitive decline defined as composite score changes between baseline and follow-up in the domains of memory, information processing speed, and executive function; and adjudicated incident dementia cases diagnosed according to international guidelines. RESULTS: Of the 2612 study patients (mean SD age, 74.6 4.8 years; 1542 59.0% female), 424 had L-PVSs and 2188 did not. The prevalence of L-PVSs was 16.2% (median number of L-PVSs, 1; range, 1-17). After adjusting for age, sex, and interval between baseline and follow-up scanning, the presence of L-PVSs was significantly associated with an increased risk of incident subcortical infarcts (adjusted risk ratio, 2.54; 95% CI, 1.76-3.68) and microbleeds (adjusted risk ratio, 1.43; 95% CI, 1.18-1.72) and a greater 5-year progression of white matter hyperintensity volume. The presence of L-PVSs was also associated with a steeper decline in information processing speed and more than quadrupled the risk of vascular dementia. All associations persisted when further adjusted for genetic and cerebrovascular risk factors. The associations with cognitive outcomes were independent of educational level, depression, and other SVD MRI markers. CONCLUSIONS AND RELEVANCE: Large PVSs are an MRI marker of SVD and associated with the pathogenesis of vascular-related cognitive impairment in older individuals. Large PVSs should be included in assessments of vascular cognitive impairment in the older population and as potential targets for interventions.
OBJECTIVE:To assess the association of the number and anatomic location of cerebral microbleeds (CMBs), visible indicators of microvascular damage on MRI, with incident cognitive disease in the ...general population of older people.
METHODS:In the longitudinal population-based Age, Gene/Environment Susceptibility (AGES)–Reykjavik Study, 2,602 participants 66 to 93 years of age and free of prevalent dementia underwent brain MRI and cognitive testing of verbal memory, processing speed, and executive function at baseline and a mean of 5.2 years later. Adjudicated incident dementia cases were diagnosed according to international guidelines.
RESULTS:In the multiple linear regression models adjusted for demographic, genetic, cardiovascular risk, and other cerebrovascular MRI markers, the presence of CMBs located in deep or mixed (deep and lobar) areas was associated with a greater decline in all 3 cognitive domains. Mixed CMBs were the strongest correlate for decline in memory and speed. Compared to those with no CMBs, participants with ≥3 CMBs had a steeper decline in a composite measure of global cognitive function, memory, and speed. Among those with ≥3 deep or mixed CMBs, associations were strongest for memory; the association with speed was strongest in those having ≥3 strictly lobar CMBs. People with ≥3 CMBs, regardless of their locations, had a higher incidence of all-cause dementia and vascular dementia.
CONCLUSIONS:Mixed or a higher load of CMBs, with some specificity for location, is associated with accelerated cognitive decline in older people. These findings suggest a role for hypertensive vasculopathy and the combined effect of hypertensive and cerebral amyloid angiopathy in the pathogenesis of cognitive deterioration.
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