Association analysis between an epigenetic risk score and blood pressure.

Background: Epigenome-wide association studies have revealed multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. Results: We generated an alcohol consumption epigenetic risk score (ERS) based on previously reported 144 alcohol-associated CpGs and examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. We found an association of alcohol intake with the ERS in the meta-analysis with 0.09 units higher ERS per drink consumed per day (p < 0.0001). Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with blood pressure levels, i.e., a one-unit increase in ERS was associated with 0.74 (p = 0.002) and 0.50 (p = 0.0006) mm Hg higher SBP and DBP, but could not confirm the association with hypertension. Longitudinal analyses in FHS (n = 3,260) and five independent external cohorts (n = 4,021) showed that the baseline ERS was not associated with a change in blood pressure over time or with incident HTN. Conclusions: Our findings provide proof-of-concept that utilizing an ERS is a useful approach to capture the recent health consequences of lifestyle behaviors such as alcohol consumption.

Association analysis between an epigenetic alcohol risk score and blood pressure.

Background: Epigenome-wide association studies have revealed multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. Results: We generated an alcohol consumption epigenetic risk score (ERS) based on previously reported 144 alcohol-associated CpGs and examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. We found an association of alcohol intake with the ERS in the meta-analysis with 0.09 units higher ERS per drink consumed per day (p < 0.0001). Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with blood pressure levels, i.e., a one-unit increase in ERS was associated with 0.74 (p = 0.002) and 0.50 (p = 0.0006) mm Hg higher SBP and DBP, but could not confirm the association with hypertension. Longitudinal analyses in FHS (n = 3,260) and five independent external cohorts (n = 4,021) showed that the baseline ERS was not associated with a change in blood pressure over time or with incident HTN. Conclusions: Our findings provide proof-of-concept that utilizing an ERS is a useful approach to capture the recent health consequences of lifestyle behaviors such as alcohol consumption.

Associations of measured and genetically predicted leukocyte telomere length with vascular phenotypes: a population-based study.

Shorter leukocyte telomere length (LTL) is associated with cardiovascular dysfunction. Whether this association differs between measured and genetically predicted LTL is still unclear. Moreover, the molecular processes underlying the association remain largely unknown. We used baseline data of the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany [56.2% women, age: 55.5 ± 14.0 years (range 30 - 95 years)]. We calculated genetically predicted LTL in 4180 participants and measured LTL in a subset of 1828 participants with qPCR. Using multivariable regression, we examined the association of measured and genetically predicted LTL, and the difference between measured and genetically predicted LTL (ΔLTL), with four vascular functional domains and the overall vascular health. Moreover, we performed epigenome-wide association studies of three LTL measures. Longer measured LTL was associated with better microvascular and cardiac function. Longer predicted LTL was associated with better cardiac function. Larger ΔLTL was associated with better microvascular and cardiac function and overall vascular health, independent of genetically predicted LTL. Several CpGs were associated (p < 1e-05) with measured LTL (n = 5), genetically predicted LTL (n = 8), and ΔLTL (n = 27). Genes whose methylation status was associated with ΔLTL were enriched in vascular endothelial signaling pathways and have been linked to environmental exposures, cardiovascular diseases, and mortality. Our findings suggest that non-genetic causes of LTL contribute to microvascular and cardiac function and overall vascular health, through an effect on the vascular endothelial signaling pathway. Interventions that counteract LTL may thus improve vascular function.

Identification of circulating proteins associated with general cognitive function among middle-aged and older adults.

Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p < 4.9E-5, n up to 7289). Of these, 45 were replicated using SomaScan data, and three were replicated using Olink data at Bonferroni-corrected significance. Enrichment analysis linked the proteins associated with general cognitive function to cell signaling pathways and synapse architecture. Mendelian randomization analysis implicated higher levels of NECTIN2, a protein mediating viral entry into neuronal cells, with higher Alzheimer's disease (AD) risk (p = 2.5E-26). Levels of 14 other protein measures were implicated as consequences of AD susceptibility (p < 2.0E-4). Proteins implicated as causes or consequences of AD susceptibility may provide new insight into the potential relationship between immunity and AD susceptibility as well as potential therapeutic targets.

Over- and Undertreatment With Levothyroxine.

BACKGROUND: Levothyroxine is a very commonly prescribed drug, and treatment with it is often insufficient or excessive. Nonetheless, there have been only a few reports on the determinants of inadequate levothyroxine treatment. METHODS: Data from 2938 participants in the population-based Rhineland Study were analyzed. Putative determinants of inadequate levothyroxine treatment (overtreatment, thyrotropin level <0.56 mU/L; undertreatment, thyrotropin level >4.27 mU/L) were studied with logistic regression. The determinants of the levothyroxine dose were assessed with linear regression. RESULTS: Overall, 23% of the participants (n = 662) stated that they were taking levothyroxine. Among these participants, 18% were overtreated and 4% were undertreated. Individuals over 70 years of age and above were four times as likely to be overtreated (OR = 4.05, 95% CI [1.20; 13.72]). Each rise in the levothyroxine dose by 25 µg was associated with an increased risk of overtreatment (OR = 1.02, 95% CI [1.02; 1.03]) and of undertreatment (OR = 1.02, 95% CI [1.00; 1.03]). Well-controlled participants (normal thyrotropin levels 0.56-4.27 mU/L) received a lower levothyroxine dose (1.04 ± 0.5 µg/kg/d) than overtreated (1.40 ±0.5 µg/kg/d) or undertreated (1.37 ±0.5 µg/kg/d) participants. No association was found between sociodemographic factors or comorbidities and the levothyroxine dose. Iodine supplementation was associated with a lower daily dose (ß = -0.19, 95% CI [-0.28; -0.10]), while three years or more of levothyroxine exposure was associated with a higher daily dose (ß = 0.24, 95% CI [0.07; 0.41]). CONCLUSION: Levothyroxine intake was high in our sample, and suboptimal despite monitoring. Our findings underscore the need for careful dosing and for due consideration of deintensification of treatment where appropriate.

The lipidomic correlates of epigenetic aging across the adult lifespan: A population-based study.

Lipid signaling is involved in longevity regulation, but which specific lipid molecular species affect human biological aging remains largely unknown. We investigated the relation between complex lipids and DNA methylation-based metrics of biological aging among 4181 participants (mean age 55.1 years (range 30.0-95.0)) from the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany. The absolute concentration of 14 lipid classes, covering 964 molecular species and 267 fatty acid composites, was measured by Metabolon Complex Lipid Panel. DNA methylation-based metrics of biological aging (AgeAccelPheno and AgeAccelGrim) were calculated based on published algorithms. Epigenome-wide association analyses (EWAS) of biological aging-associated lipids and pathway analysis were performed to gain biological insights into the mechanisms underlying the effects of lipidomics on biological aging. We found that higher levels of molecular species belonging to neutral lipids, phosphatidylethanolamines, phosphatidylinositols, and dihydroceramides were associated with faster biological aging, whereas higher levels of lysophosphatidylcholine, hexosylceramide, and lactosylceramide species were associated with slower biological aging. Ceramide, phosphatidylcholine, and lysophosphatidylethanolamine species with odd-numbered fatty acid tail lengths were associated with slower biological aging, whereas those with even-numbered chain lengths were associated with faster biological aging. EWAS combined with functional pathway analysis revealed several complex lipids associated with biological aging as important regulators of known longevity and aging-related pathways.

Quantifying MR head motion in the Rhineland Study - A robust method for population cohorts.

Head motion during MR acquisition reduces image quality and has been shown to bias neuromorphometric analysis. The quantification of head motion, therefore, has both neuroscientific as well as clinical applications, for example, to control for motion in statistical analyses of brain morphology, or as a variable of interest in neurological studies. The accuracy of markerless optical head tracking, however, is largely unexplored. Furthermore, no quantitative analysis of head motion in a general, mostly healthy population cohort exists thus far. In this work, we present a robust registration method for the alignment of depth camera data that sensitively estimates even small head movements of compliant participants. Our method outperforms the vendor-supplied method in three validation experiments: 1. similarity to fMRI motion traces as a low-frequency reference, 2. recovery of the independently acquired breathing signal as a high-frequency reference, and 3. correlation with image-based quality metrics in structural T1-weighted MRI. In addition to the core algorithm, we establish an analysis pipeline that computes average motion scores per time interval or per sequence for inclusion in downstream analyses. We apply the pipeline in the Rhineland Study, a large population cohort study, where we replicate age and body mass index (BMI) as motion correlates and show that head motion significantly increases over the duration of the scan session. We observe weak, yet significant interactions between this within-session increase and age, BMI, and sex. High correlations between fMRI and camera-based motion scores of proceeding sequences further suggest that fMRI motion estimates can be used as a surrogate score in the absence of better measures to control for motion in statistical analyses.

Physical activity is associated with slower epigenetic ageing-Findings from the Rhineland study.

Epigenetic ageing, i.e., age-associated changes in DNA methylation patterns, is a sensitive marker of biological ageing, a major determinant of morbidity and functional decline. We examined the association of physical activity with epigenetic ageing and the role of immune function and cardiovascular risk factors in mediating this relation. Moreover, we aimed to identify novel molecular processes underlying the association between physical activity and epigenetic ageing. We analysed cross-sectional data from 3567 eligible participants (mean age: 55.5 years, range: 30-94 years, 54.8% women) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Physical activity components (metabolic equivalent (MET)-Hours, step counts, sedentary, light-intensity and moderate-to-vigorous intensity activities) were recorded with accelerometers. DNA methylation was measured with the Illumina HumanMethylationEPIC BeadChip. Epigenetic age acceleration (Hannum's age, Horvath's age, PhenoAge and GrimAge) was calculated based on published algorithms. The relation between physical activity and epigenetic ageing was examined with multivariable regression, while structural equation modeling was used for mediation analysis. Moreover, we conducted an epigenome-wide association study of physical activity across 850,000 CpG sites. After adjustment for age, sex, season, education, smoking, cell proportions and batch effects, physical activity (step counts, MET-Hours and %time spend in moderate-to-vigorous activities) was non-linearly associated with slower epigenetic ageing, in part through its beneficial effects on immune function and cardiovascular health. Additionally, we identified 12 and 7 CpGs associated with MET-Hours and %time spent in moderate-to-vigorous activities, respectively (p < 1 × 10-5 ). Our findings suggest that regular physical activity slows epigenetic ageing by counteracting immunosenescence and lowering cardiovascular risk.

25-hydroxyvitamin D level is associated with greater grip strength across adult life span: a population-based cohort study.

Objective: Maintaining muscle function throughout life is critical for healthy ageing. Although in vitro studies consistently indicate beneficial effects of 25-hydroxyvitamin D (25-OHD) on muscle function, findings from population-based studies remain inconclusive. We therefore aimed to examine the association between 25-OHD concentration and handgrip strength across a wide age range and assess potential modifying effects of age, sex and season. Methods: We analysed cross-sectional baseline data of 2576 eligible participants out of the first 3000 participants (recruited from March 2016 to March 2019) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Multivariate linear regression models were used to assess the relation between 25-OHD levels and grip strength while adjusting for age, sex, education, smoking, season, body mass index, physical activity levels, osteoporosis and vitamin D supplementation. Results: Compared to participants with deficient 25-OHD levels (<30 nmol/L), grip strength was higher in those with inadequate (30 to <50 nmol/L) and adequate (≥50 to ≤125 nmol/L) levels (ßinadequate = 1.222, 95% CI: 0.377; 2.067, P = 0.005; ßadequate = 1.228, 95% CI: 0.437; 2.019, P = 0.002). Modelling on a continuous scale revealed grip strength to increase with higher 25-OHD levels up to ~100 nmol/L, after which the direction reversed (ßlinear = 0.505, 95% CI: 0.179; 0.830, P = 0.002; ßquadratic = -0.153, 95% CI: -0.269; -0.038, P = 0.009). Older adults showed weaker effects of 25-OHD levels on grip strength than younger adults (ß25OHDxAge = -0.309, 95% CI: -0.594; -0.024, P = 0.033). Conclusions: Our findings highlight the importance of sufficient 25-OHD levels for optimal muscle function across the adult life span. However, vitamin D supplementation should be closely monitored to avoid detrimental effects.

Cardiovascular correlates of epigenetic aging across the adult lifespan: a population-based study.

Individuals with a similar chronological age can exhibit marked differences in cardiovascular risk profiles, but it is unknown whether this variation is related to different rates of biological aging. Therefore, we investigated the relation between nine domains of cardiovascular function and four epigenetic age acceleration estimators (i.e., AgeAccel.Horvath, AgeAccel.Hannum, AgeAccelPheno, and AgeAccelGrim), derived from DNA methylation profiles. Among 4194 participants (mean age 54.2 years (range 30.0-95.0)) from the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany, epigenetic age acceleration increased by 0.19-1.84 years per standard deviation (SD) increase in cardiovascular risk across multiple domains, including measures of kidney function, adiposity, and a composite cardiovascular risk score. Measures of inflammation and glucose homeostasis were associated with AgeAccel.Hannum, AgeAccelPheno, and AgeAccelGrim, but not with AgeAccel.Horvath. Moreover, effect sizes were larger for AgeAccelPheno and AgeAccelGrim than for AgeAccel.Horvath and AgeAccel.Hannum. Similarly, epigenetic age acceleration increased by 0.15-0.81 years per SD increase in markers of vascular function (blood pressure, arterial stiffness, and hemodynamic measures), whereas better endothelial function was only associated with lower AgeAccelGrim. Most effects on epigenetic age acceleration were independent, which suggests they independently contribute to different rates of biological aging.

Visual impairment and retinal and brain neurodegeneration: A population-based study.

Visual impairment and retinal neurodegeneration are intrinsically connected and both have been associated with cognitive impairment and brain atrophy, but the underlying mechanisms remain unclear. To investigate whether transneuronal degeneration is implicated, we systematically assessed the relation between visual function and retinal, visual pathway, hippocampal and brain degeneration. We analyzed baseline data from 3316 eligible Rhineland Study participants with visual acuity (VA), optical coherence tomography (OCT), and magnetic resonance imaging (MRI) data available. Regional volumes, cortical volume, and fractional anisotropy (FA) were derived from T1-weighted and diffusion-weighted 3 T MRI scans. Statistical analyses were performed using multivariable linear regression and structural equation modeling. VA and ganglion cell layer (GCL) thinning were both associated with global brain atrophy (SD effect size [95% CI] -0.090 [-0.118 to -0.062] and 0.066 [0.053-0.080], respectively), and hippocampal atrophy (-0.029 [-0.055 to -0.003] and 0.114 [0.087-0.141], respectively). The effect of VA on whole brain and hippocampal volume was partly mediated by retinal neurodegeneration. Similarly, the effect of retinal neurodegeneration on brain and hippocampal atrophy was mediated through intermediate visual tracts, accounting for 5.2%-23.9% of the effect. Visual impairment and retinal neurodegeneration were robustly associated with worse brain atrophy, FA, and hippocampal atrophy, partly mediated through disintegration of intermediate visual tracts. Our findings support the use of OCT-derived retinal measures as markers of neurodegeneration, and indicate that both general and transneuronal neurodegeneration along the visual pathway, partly reflecting visual impairment, account for the association between retinal neurodegeneration and brain atrophy.

Epigenetic and integrative cross-omics analyses of cerebral white matter hyperintensities on MRI.

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 ∼450 000 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.

Polygenic risk scores for schizophrenia are associated with oculomotor endophenotypes.

BACKGROUND: Schizophrenia is a heterogeneous disorder with substantial heritability. The use of endophenotypes may help clarify its aetiology. Measures from the smooth pursuit and antisaccade eye movement tasks have been identified as endophenotypes for schizophrenia in twin and family studies. However, the genetic basis of the overlap between schizophrenia and these oculomotor markers is largely unknown. Here, we tested whether schizophrenia polygenic risk scores (PRS) were associated with oculomotor performance in the general population. METHODS: Analyses were based on the data of 2956 participants (aged 30-95) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Genotyping was performed on Omni-2.5 exome arrays. Using summary statistics from a recent meta-analysis based on the two largest schizophrenia genome-wide association studies to date, we quantified genetic risk for schizophrenia by creating PRS at different p value thresholds for genetic markers. We examined associations between PRS and oculomotor performance using multivariable regression models. RESULTS: Higher PRS were associated with higher antisaccade error rate and latency, and lower antisaccade amplitude gain. PRS showed inconsistent patterns of association with smooth pursuit velocity gain and were not associated with saccade rate during smooth pursuit or performance on a prosaccade control task. CONCLUSIONS: There is an overlap between genetic determinants of schizophrenia and oculomotor endophenotypes. Our findings suggest that the mechanisms that underlie schizophrenia also affect oculomotor function in the general population.

Deep phenotyping and lifetime trajectories reveal limited effects of longevity regulators on the aging process in C57BL/6J mice.

Current concepts regarding the biology of aging are primarily based on studies aimed at identifying factors regulating lifespan. However, lifespan as a sole proxy measure for aging can be of limited value because it may be restricted by specific pathologies. Here, we employ large-scale phenotyping to analyze hundreds of markers in aging male C57BL/6J mice. For each phenotype, we establish lifetime profiles to determine when age-dependent change is first detectable relative to the young adult baseline. We examine key lifespan regulators (putative anti-aging interventions; PAAIs) for a possible countering of aging. Importantly, unlike most previous studies, we include in our study design young treated groups of animals, subjected to PAAIs prior to the onset of detectable age-dependent phenotypic change. Many PAAI effects influence phenotypes long before the onset of detectable age-dependent change, but, importantly, do not alter the rate of phenotypic change. Hence, these PAAIs have limited effects on aging.

Associations of genetic liability for Alzheimer's disease with cognition and eye movements in a large, population-based cohort study.

To identify cognitive measures that may be particularly sensitive to early cognitive decline in preclinical Alzheimer's disease (AD), we investigated the relation between genetic risk for AD and cognitive task performance in a large population-based cohort study. We measured performance on memory, processing speed, executive function, crystallized intelligence and eye movement tasks in 5182 participants of the Rhineland Study, aged 30 to 95 years. We quantified genetic risk for AD by creating three weighted polygenic risk scores (PRS) based on the genome-wide significant single-nucleotide polymorphisms coming from three different genetic association studies. We assessed the relation of AD PRS with cognitive performance using generalized linear models. Three PRS were associated with lower performance on the Corsi forward task, and two PRS were associated with a lower probability of correcting antisaccade errors, but none of these associations remained significant after correction for multiple testing. Associations between age and trail-making test A (TMT-A) performance were modified by AD genetic risk, with individuals at high genetic risk showing the strongest association. We conclude that no single measure of our cognitive test battery robustly captures genetic liability for AD as quantified by current PRS. However, Corsi forward performance and the probability of correcting antisaccade errors may represent promising candidates whose ability to capture genetic liability for AD should be investigated further. Additionally, our finding on TMT-A performance suggests that processing speed represents a sensitive marker of AD genetic risk in old age and supports the processing speed theory of age-related cognitive decline.

Association Between Accelerometer-Derived Physical Activity Measurements and Brain Structure: A Population-Based Cohort Study.

BACKGROUND AND OBJECTIVES: While there is growing evidence that physical activity promotes neuronal health, studies examining the relation between physical activity and brain morphology remain inconclusive. We therefore examined whether objectively quantified physical activity is related to brain volume, cortical thickness, and gray matter density in a large cohort study. In addition, we assessed molecular pathways that may underlie the effects of physical activity on brain morphology. METHODS: We used cross-sectional baseline data from 2,550 eligible participants (57.6% women; mean age: 54.7 years, range: 30-94 years) of a prospective cohort study. Physical activity dose (metabolic equivalent hours and step counts) and intensity (sedentary and light-intensity and moderate-to-vigorous intensity activities) were recorded with accelerometers. Brain volumetric, gray matter density, and cortical thickness measures were obtained from 3T MRI scans using FreeSurfer and Statistical Parametric Mapping. The relation of physical activity (independent variable) and brain structure (outcome) was examined with polynomial multivariable regression, while adjusting for age, sex, intracranial volume, education, and smoking. Using gene expression profiles from the Allen Brain Atlas, we extracted molecular signatures associated with the effects of physical activity on brain morphology. RESULTS: Physical activity dose and intensity were independently associated with larger brain volumes, gray matter density, and cortical thickness of several brain regions. The effects of physical activity on brain volume were most pronounced at low physical activity quantities and differed between men and women and across age. For example, more time spent in moderate-to-vigorous intensity activities was associated with greater total gray matter volume, but the relation leveled off with more activity (standardized ß [95% CIs]: 1.37 [0.35-2.39] and -0.70 [-1.25 to -0.15] for the linear and quadratic terms, respectively). The strongest effects of physical activity were observed in motor regions and cortical regions enriched for genes involved in mitochondrial respiration. DISCUSSION: Our findings suggest that physical activity benefits brain health, with the strongest effects in motor regions and regions with a high oxidative demand. While young adults may particularly profit from additional high-intensity activities, older adults may already benefit from light-intensity activities. Physical activity and reduced sedentary time may be critical in the prevention of age-associated brain atrophy and neurodegenerative diseases.

Genome-wide associations of aortic distensibility suggest causality for aortic aneurysms and brain white matter hyperintensities.

Aortic dimensions and distensibility are key risk factors for aortic aneurysms and dissections, as well as for other cardiovascular and cerebrovascular diseases. We present genome-wide associations of ascending and descending aortic distensibility and area derived from cardiac magnetic resonance imaging (MRI) data of up to 32,590 Caucasian individuals in UK Biobank. We identify 102 loci (including 27 novel associations) tagging genes related to cardiovascular development, extracellular matrix production, smooth muscle cell contraction and heritable aortic diseases. Functional analyses highlight four signalling pathways associated with aortic distensibility (TGF-ß, IGF, VEGF and PDGF). We identify distinct sex-specific associations with aortic traits. We develop co-expression networks associated with aortic traits and apply phenome-wide Mendelian randomization (MR-PheWAS), generating evidence for a causal role for aortic distensibility in development of aortic aneurysms. Multivariable MR suggests a causal relationship between aortic distensibility and cerebral white matter hyperintensities, mechanistically linking aortic traits and brain small vessel disease.

Regional seropositivity for Borrelia burgdorferi and associated risk factors: findings from the Rhineland Study, Germany.

BACKGROUND: Lyme borreliosis is the most prevalent vector-borne disease in Europe, and numbers might increase due to climate change. However, borreliosis is not notifiable in North Rhine-Westphalia (NRW), Germany. Hence, little is known about the current human seroprevalence in NRW. However, the proportion of Borrelia burgdorferi sensu lato-infected ticks has increased in a NRW nature reserve. The literature suggests increasing age and male sex as risk factors for seropositivity, whereas the influence of socioeconomic status is controversial. Thus, we aimed to determine regional seropositivity for Borrelia burgdorferi sensu lato (B. burgdorferi s.l.) and its risk factors in the Rhineland Study population in Bonn, NRW, and to compare it with previous surveys to evaluate potential effects of climate change. METHODS: We assessed seropositivity in 2865 Rhineland Study participants by determining immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies for B. burgdorferi s.l. using a two-step algorithm combining enzyme-linked immunosorbent assay tests and line immunoblots. We calculated the odds of being classified as IgG or IgM positive as a function of age, sex, and educational level using binomial logistic regression models. We applied varying seropositivity classifications and weights considering age, sex and education to compensate for differences between the sample and regional population characteristics. RESULTS: IgG antibodies for B. burgdorferi s.l. were present in 2.4% and IgM antibodies in 0.6% of the participants (weighted: 2.2% [IgG], 0.6% [IgM]). The likelihood of IgG seropositivity increased by 3.0% (95% confidence interval [CI] 1.5-5.2%) per 1 year increase in age. Men had 1.65 times the odds for IgG seropositivity as women (95% CI 1.01-2.73), and highly educated participants had 1.83 times the odds (95% CI 1.10-3.14) as participants with an intermediate level of education. We found no statistically significant link between age, sex, or education and IgM seropositivity. Our weighted and age-standardized IgG seroprevalence was comparable to the preceding serosurvey German Health Interview and Examination Survey for Adults (DEGS) for NRW. CONCLUSIONS: We confirmed that increasing age and male sex are associated with increased odds for IgG seropositivity and provide evidence for increased seropositivity in the highly educated group. B. burgdorferi s.l. seropositivity remained constant over the past decade in this regional German population.

Relation Between Sex, Menopause, and White Matter Hyperintensities: The Rhineland Study.

BACKGROUND AND OBJECTIVES: Mounting evidence implies that there are sex differences in white matter hyperintensity (WMH) burden in older people. Questions remain regarding possible differences in WMH burden between men and women of younger age, sex-specific age trajectories and effects of (un)controlled hypertension, and the effect of menopause on WMH. Therefore, our aim was to investigate these sex differences and age dependencies in WMH load across the adult life span and to examine the effect of menopause. METHODS: This cross-sectional analysis was based on participants of the population-based Rhineland Study (30-95 years) who underwent brain MRI. We automatically quantified WMH using T1-weighted, T2-weighted, and fluid-attenuated inversion recovery images. Menopausal status was self-reported. We examined associations of sex and menopause with WMH load (logit-transformed and z-standardized) using linear regression models while adjusting for age, age-squared, and vascular risk factors. We checked for an age × sex and (un)controlled hypertension × sex interaction and stratified for menopausal status comparing men with premenopausal women (persons aged 59 years or younger), men with postmenopausal women (persons aged 45 years or older), and premenopausal with postmenopausal women (age range 45-59 years). RESULTS: Of 3,410 participants with a mean age of 54.3 years (SD = 13.7), 1,973 (57.9%) were women, of which 1,167 (59.1%) were postmenopausal. We found that the increase in WMH load accelerates with age and in a sex-dependent way. Premenopausal women and men of similar age did not differ in WMH burden. WMH burden was higher and accelerated faster in postmenopausal women compared with men of similar age. In addition, we observed changes related to menopause, in that postmenopausal women had more WMH than premenopausal women of similar age. Women with uncontrolled hypertension had a higher WMH burden compared with men, which was unrelated to menopausal status. DISCUSSION: After menopause, women displayed a higher burden of WMH than contemporary premenopausal women and men and an accelerated increase in WMH. Sex-specific effects of uncontrolled hypertension on WMH were not related to menopause. Further studies are warranted to investigate menopause-related physiologic changes that may inform on causal mechanisms involved in cerebral small vessel disease progression.