Social Health and Cognitive Change in Old Age: Role of Brain Reserve.

OBJECTIVE: Individual aspects of social health (SH; eg, network, engagement, support) have been linked to cognitive health. However, their combined effect and the role of the structural properties of the brain (brain reserve [BR]) remain unclear. We investigated the interplay of SH and BR on cognitive change in older adults. METHODS: Within the Swedish National Study on Aging and Care-Kungsholmen, 368 dementia-free adults aged ≥60 years with baseline brain magnetic resonance imaging were followed over 12 years to assess cognitive change. A measure of global cognition was computed at each of the 5 waves of assessment by averaging domain-specific Z scores for episodic memory, perceptual speed, semantic memory, and letter and category fluency. An SH composite score was computed at baseline by combining leisure activities and social network. BR was proxied by total brain tissue volume (TBTV). Linear mixed models (adjusted for sociodemographic, vascular, and genetic factors) were used to estimate cognitive trajectories in relation to SH and TBTV. Interaction analysis and stratification were used to examine the interplay between SH and TBTV. RESULTS: Moderate-good SH (n = 245; vs poor, ß-slope = 0.01, 95% confidence interval [CI] = 0.002-0.02, p = 0.018) and moderate-to-large TBTV (n = 245; vs small, ß-slope = 0.03, 95% CI = 0.02-0.04, p < 0.001) were separately associated with slower cognitive decline. In stratified analysis, moderate-good SH was associated with higher cognitive levels (but not change) only in participants with moderate-to-large TBTV (ß-intercept = 0.21, 95% CI = 0.06-0.37, p < 0.01; interaction SH * TBTV, p < 0.05). INTERPRETATION: Our findings highlight the interplay between SH and BR that likely unfolds throughout the entire life course to shape old-age cognitive outcomes. ANN NEUROL 2023;93:844-855.

Social Health and Change in Cognitive Capability among Older Adults: Findings from Four European Longitudinal Studies.

INTRODUCTION: In this study, we examine whether social health markers measured at baseline are associated with differences in cognitive capability and the rate of cognitive decline over an 11-to-18-year period among older adults and compare results across studies. METHODS: We applied an integrated data analysis approach to 16,858 participants (mean age 65 years; 56% female) from the National Survey for Health and Development (NSHD), the English Longitudinal Study of Aging (ELSA), the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), and the Rotterdam Study. We used multilevel models to examine social health in relation to cognitive capability and the rate of cognitive decline. RESULTS: Pooled estimates show distinct relationships between markers of social health and cognitive domains, e.g., a large network size (≥6 people vs. none) was associated with higher executive function (0.17 standard deviation [SD] [95% CI: 0.00, 0.34], I2 = 27%) but not with memory (0.08 SD [95% CI: -0.02, 0.18], I2 = 19%). We also observed pooled associations between being married or cohabiting, having a large network size, and participating in social activities with slower decline in cognitive capability. However, estimates were close to zero, e.g., 0.01 SD/year (95% CI: 0.01, 0.02) I2 = 19% for marital status and executive function. There were clear study-specific differences: results for average processing speed were the most homogenous, and results for average memory were the most heterogeneous. CONCLUSION: Overall, markers of good social health have a positive association with cognitive capability. However, we found differential associations between specific markers of social health and cognitive domains and differences between studies. These findings highlight the importance of examining between-study differences and considering the context specificity of findings in developing and deploying interventions.

The UK Coronavirus Job Retention Scheme and diet, physical activity, and sleep during the COVID-19 pandemic: evidence from eight longitudinal population surveys.

BACKGROUND: In March 2020, the UK implemented the Coronavirus Job Retention Scheme (furlough) to minimise job losses. Our aim was to investigate associations between furlough and diet, physical activity, and sleep during the early stages of the COVID-19 pandemic. METHODS: We analysed data on 25,092 participants aged 16-66 years from eight UK longitudinal studies. Changes in employment, including being furloughed, were based on employment status before and during the first lockdown. Health behaviours included fruit and vegetable consumption, physical activity, and sleep. Study-specific estimates obtained using modified Poisson regression, adjusting for socio-demographic characteristics and pre-pandemic health and health behaviours, were statistically pooled using random effects meta-analysis. Associations were also stratified by sex, age, and education. RESULTS: Across studies, between 8 and 25% of participants were furloughed. Compared to those who remained working, furloughed workers were slightly less likely to be physically inactive (RR = 0.85; [95% CI 0.75-0.97]; I 2 = 59%) and did not differ overall with respect to low fruit and vegetable consumption or atypical sleep, although findings for sleep were heterogenous (I 2 = 85%). In stratified analyses, furlough was associated with lower fruit and vegetable consumption among males (RR = 1.11; [1.01-1.22]; I 2 = 0%) but not females (RR = 0.84; [0.68-1.04]; I 2 = 65%). Considering changes in quantity, furloughed workers were more likely than those who remained working to report increases in fruit and vegetable consumption, exercise, and hours of sleep. CONCLUSIONS: Those furloughed exhibited similar health behaviours to those who remained in employment during the initial stages of the pandemic. There was little evidence to suggest that adoption of such social protection policies in the post-pandemic recovery period and during future economic crises had adverse effects on population health behaviours.

The UK Coronavirus Job Retention Scheme and smoking, alcohol consumption and vaping during the COVID-19 pandemic: evidence from eight longitudinal population surveys.

BACKGROUND: Employment disruptions can impact smoking and alcohol consumption. During the COVID-19 pandemic, many countries implemented furlough schemes to prevent job loss. We examine how furlough was associated with smoking, vaping and alcohol consumption in the UK. METHODS: Data from 27,841 participants in eight UK adult longitudinal surveys were analysed. Participants self-reported employment status and current smoking, current vaping and alcohol consumption (>4 days/week or 5+ drinks per typical occasion) both before and during the early stages of the pandemic (April-July 2020). Risk ratios were estimated within each study using modified Poisson regression, adjusting for a range of potential confounders, including pre-pandemic behaviour. Findings were synthesised using random effects meta-analysis. RESULTS: Compared to stable employment and after adjustment for pre-pandemic characteristics, furlough was not associated with smoking (ARR = 1.05; 95% CI: 0.95-1.16; I2: 10%), vaping (ARR = 0.89; 95% CI: 0.74-1.08; I2: 0%) or drinking (ARR = 1.03; 95% CI: 0.94-1.13; I2: 48%). There were similar findings for no longer being employed, and stable unemployment, though this varied by sex: stable unemployment was associated with smoking for women (ARR = 1.35; 95% CI: 1.00-1.82; I2: 47%) but not men (0.84; 95% CI: 0.67-1.05; I2: 0%). No longer being employed was associated with vaping among women (ARR = 2.74; 95% CI: 1.59-4.72; I2: 0%) but not men (ARR = 1.25; 95% CI: 0.83-1.87; I2: 0%). CONCLUSIONS: We found no clear evidence of furlough or unemployment having adverse impacts on smoking, vaping or drinking behaviours during the early stages of the COVID-19 pandemic in the UK. Differences in risk compared to those who remained employed were largely explained by pre-pandemic characteristics.

Pre-pandemic mental health and disruptions to healthcare, economic and housing outcomes during the COVID-19 pandemic: evidence from 12 UK longitudinal studies.

BACKGROUND: The COVID-19 pandemic has disrupted lives and livelihoods, and people already experiencing mental ill health may have been especially vulnerable. AIMS: Quantify mental health inequalities in disruptions to healthcare, economic activity and housing. METHOD: We examined data from 59 482 participants in 12 UK longitudinal studies with data collected before and during the COVID-19 pandemic. Within each study, we estimated the association between psychological distress assessed pre-pandemic and disruptions since the start of the pandemic to healthcare (medication access, procedures or appointments), economic activity (employment, income or working hours) and housing (change of address or household composition). Estimates were pooled across studies. RESULTS: Across the analysed data-sets, 28% to 77% of participants experienced at least one disruption, with 2.3-33.2% experiencing disruptions in two or more domains. We found 1 s.d. higher pre-pandemic psychological distress was associated with (a) increased odds of any healthcare disruptions (odds ratio (OR) 1.30, 95% CI 1.20-1.40), with fully adjusted odds ratios ranging from 1.24 (95% CI 1.09-1.41) for disruption to procedures to 1.33 (95% CI 1.20-1.49) for disruptions to prescriptions or medication access; (b) loss of employment (odds ratio 1.13, 95% CI 1.06-1.21) and income (OR 1.12, 95% CI 1.06 -1.19), and reductions in working hours/furlough (odds ratio 1.05, 95% CI 1.00-1.09) and (c) increased likelihood of experiencing a disruption in at least two domains (OR 1.25, 95% CI 1.18-1.32) or in one domain (OR 1.11, 95% CI 1.07-1.16), relative to no disruption. There were no associations with housing disruptions (OR 1.00, 95% CI 0.97-1.03). CONCLUSIONS: People experiencing psychological distress pre-pandemic were more likely to experience healthcare and economic disruptions, and clusters of disruptions across multiple domains during the pandemic. Failing to address these disruptions risks further widening mental health inequalities.

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

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

Diet quality in late midlife is associated with faster walking speed in later life in women, but not men: findings from a prospective British birth cohort.

Healthy diet has been linked to better age-related functioning, but evidence on the relationship of diet quality in late midlife and measures of physical capability in later life is limited. Research on potential sex differences in this relationship is scarce. The aim was to investigate the prospective association between overall diet quality, as assessed by the Healthy Eating Index-2015 (HEI-2015) at 60-64 years and measures of walking speed 7 years later, among men and women from the Insight 46, a neuroscience sub-study of the Medical Research Council National Survey of Health and Development. Diet was assessed at 60-64 years using 5-d food diaries, from which total HEI-2015 was calculated. At 69-71 years, walking speed was estimated during four 10-m walks at self-selected pace, using inertial measurement units. Multivariable linear regression models with sex as a modifier, controlling for age, follow-up, lifestyle, health/social variables and physical performance, were used. The final sample consists of 164 women and 167 men (n 331). Women had higher HEI-2015 and slower walking speed than men. A 10-point increase in HEI-2015 was associated with faster walking speed among women (B 0·024, 95 % CI 0·006, 0·043), but not men. The association remained significant in the multivariable model (B 0·021, 95 % CI 0·003, 0·040). In women, higher diet quality in late midlife is associated with faster walking speed. A healthy diet in late midlife is likely to contribute towards better age-related physical capability, and sex differences are likely to affect this relationship.

Adherence to a Dietary Approaches to Stop Hypertension (DASH)-type diet over the life course and associated vascular function: a study based on the MRC 1946 British birth cohort.

Little is known about long-term associations between the Dietary Approaches to Stop Hypertension (DASH) diet and conventional cardiovascular (CV)-risk factors as well as novel measures of vascular function. This study aimed to examine whether long-term adherence to a DASH-type diet in a British birth cohort is associated with conventional CV-risk factors and two vascular function markers, carotid intima-media thickness (cIMT) and pulse wave velocity (PWV). Data came from 1409 participants of the Medical Research Council (MRC) National Survey of Health and Development. Dietary intake was assessed at 36, 43, 53 and 60-64 years using 5-d estimated food diaries. The DASH-type diet score was calculated using the Fung index. Conventional CV-risk factors (blood pressure (BP) and lipids), cIMT in the right and/or left common carotid artery and PWV was measured when participants were 60-64 years. Associations between the DASH-type diet score and outcomes were assessed using multiple regression models adjusted for socioeconomic position, BMI, smoking and physical activity. Participants in higher sex-specific quintiles (Q) of the long-term DASH-type diet had lower BP (P≤0·08), higher HDL-cholesterol (P<0·001) and lower TAG (P<0·001) compared with people in Q1. Participants in Q5 of the long-term DASH-type diet had lower PWV (-0·28 sd; 95 % CI -0·50, -0·07, P trend=0·01) and cIMT (-0·24 sd; 95 % CI -0·44, -0·04, P trend=0·02) compared with participants in the Q1. This association was independent of the conventional CV-risk factors. Greater adherence to a DASH diet over the life course is associated with conventional CV-risk factors and independently associated with cIMT and PWV.

25-Hydroxyvitamin D and cognitive performance in mid-life.

Hypovitaminosis D has been linked with poor cognitive function, particularly in older adults, but studies lack a lifespan approach; hence, the effects of reverse causality remain unknown. In the present study, we aimed to assess the relationship between 25-hydroxyvitamin D (25(OH)D) concentrations and subsequent cognitive performance in mid-adulthood and the influence of earlier life factors, including childhood cognitive ability, on this association. Information for the present study was obtained from the members of the 1958 British birth cohort (n 6496). Serum 25(OH)D concentration, indicating vitamin D status, was measured at age 45 years. Verbal memory (immediate and delayed word recall), verbal fluency (animal naming) and speed of processing were tested at age 50 years. Information on childhood cognitive ability, educational attainment, vitamin D-related behaviours and other covariates was collected prospectively from participants throughout their life. Childhood cognitive ability and educational attainment by age 42 years were strongly correlated with cognitive performance at age 50 years and with several vitamin D-related behaviours in mid-adulthood, but not with 25(OH)D concentrations at age 45 years. Participants with both low (<25 nmol/l) and high (≥75 nmol/l) 25(OH)D concentrations at age 45 years performed significantly worse on immediate word recall. The associations attenuated after adjustment for childhood cognitive ability, education, and socio-economic position; however, for the immediate word recall test, there was a non-linear association with 25(OH)D after further adjustment for obesity, menopausal status, smoking, alcohol consumption, physical activity and depressive symptoms at age 45 years (P(curvature)=0·01). The present study demonstrated that 25(OH)D concentrations were non-linearly associated with immediate word recall in mid-life. A clarification of the level of 25(OH)D concentrations that is most beneficial for predicting better cognitive performance in mid-life is required.

Proximity to high streets, social isolation and social support in British adolescents: A longitudinal analysis of sociospatial influences on social connectedness using geospatial data.

High streets have been shown to be central to socio-economic activity, given their diverse residential, leisure, and commercial activities. This study explores the link between adolescent social isolation and proximity to, and land use mix in, high streets. Hypothesising that greater distance from high streets might increase social isolation, measured via social activities, friend contact frequency, and social support, we used multilevel modelling with data from the Millennium Cohort Study. We did not observe a relationship between proximity to high streets and these social isolation indicators, suggesting that high streets may either not significantly influence adolescent social engagement or that young people are willing to travel greater distances.

Examining the Interrelationships Between Social Isolation and Loneliness and Their Correlates Among Older British Adults Before and During the COVID-19 Lockdown: Evidence From Four British Longitudinal Studies.

Background and Objectives: Unprecedented social restrictions during the coronavirus disease 2019 (COVID-19) pandemic have provided a new lens for considering the interrelationship between social isolation and loneliness in later life. We present these interrelationships before and during the COVID-19 restrictions and investigate to what extent demographic, socioeconomic, and health factors associated with such experiences differed during the pandemic. Research Design and Methods: We used data from four British longitudinal population-based studies (1946 NSHD, 1958 NCDS, 1970 BCS, and ELSA, N = 12,129). Rates, co-occurrences, and correlates of social isolation and loneliness are presented prior to and during the early stage of the COVID-19 pandemic and the interrelationships between these experiences are elucidated in both periods. Results: Across the Four studies, prepandemic proportions reporting social isolation ranged from 15% to 54%, with higher rates in older ages (e.g., 32% of individuals aged 70-79 years and 54% of those more than 80). During the pandemic, the percentage of older people reporting both social isolation and loneliness and isolation only slightly increased. The interrelationship between social isolation and loneliness did not change. Associations between sociodemographic and health characteristics and social isolation and loneliness also remained consistent, with greater burden among those with higher economic precarity (females, nonhomeowners, unemployed, illness, and greater financial stress). Discussion and Implications: There were already large inequalities in experiences of social isolation and loneliness and the pandemic had a small impact on worsening extent and inequalities in these. The concepts of loneliness and social isolation are not interchangeable, and clarity is needed in how they are conceptualized, operationalized, and interpreted. Given many older adults experience high levels of social isolation, there should be greater emphasis on reducing social isolation and the inequalities observed in who experiences greater isolation and loneliness.

Social health and subsequent cognitive functioning in people aged 50 years and older: examining the mediating roles of depressive symptoms and inflammatory biomarkers in two European longitudinal studies.

BACKGROUND: Social health markers, including marital status, contact frequency, network size, and social support, have been shown to be associated with cognition. However, the mechanisms underlying these associations remain poorly understood. We investigated whether depressive symptoms and inflammation mediated associations between social health and subsequent cognition. METHODS: In the English Longitudinal Study of Ageing (ELSA), a nationally representative longitudinal study in England, UK, we sampled 7136 individuals aged 50 years or older living in private households without dementia at baseline or at the intermediate mediator assessment timepoint, who had recorded information on at least one social health marker and potential mediator. We used four-way decomposition to examine to what extent depressive symptoms, C-reactive protein, and fibrinogen mediated associations between social health and subsequent standardised cognition (verbal fluency and delayed and immediate recall), including cognitive change, with slopes derived from multilevel models (12-year slope). We examined whether findings were replicated in the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a population-based longitudinal study in Sweden, in a sample of 2604 individuals aged 60 years or older living at home or in institutions in Kungsholmen (central Stockholm) without dementia at baseline or at the intermediate mediator assessment timepoint (6-year slope). Social health exposures were assessed at baseline, potential mediators were assessed at an intermediate timepoint (wave 2 in ELSA and 6-year follow-up in SNAC-K); cognitive outcomes were assessed at a single timepoint (wave 3 in ELSA and 12-year follow-up in SNAC-K), and cognitive change (between waves 3 and 9 in ELSA and between 6-year and 12-year follow-ups in SNAC-K). FINDINGS: The study sample included 7136 participants from ELSA, of whom 3962 (55·5%) were women and 6934 (97·2%) were White; the mean baseline age was 63·8 years (SD 9·4). Replication analyses included 2604 participants from SNAC-K, of whom 1604 (61·6%) were women (SNAC-K did not collect ethnicity data); the mean baseline age was 72·3 years (SD 10·1). In ELSA, we found indirect effects via depressive symptoms of network size, positive support, and less negative support on subsequent verbal fluency, and of positive support on subsequent immediate recall (pure indirect effect [PIE] 0·002 [95% CI 0·001-0·003]). Depressive symptoms also partially mediated associations between less negative support and slower decline in immediate recall (PIE 0·001 [0·000-0·002]) and in delayed recall (PIE 0·001 [0·000-0·002]), and between positive support and slower decline in immediate recall (PIE 0·001 [0·000-0·001]). We did not observe mediation by inflammatory biomarkers. Findings of mediation by depressive symptoms in the association between positive support and verbal fluency and between positive support and change in immediate recall were replicated in SNAC-K. INTERPRETATION: The findings of this study provide new insights into mechanisms linking social health with cognition, suggesting that associations between interactional aspects of social health, especially social support, and cognition are partly underpinned by depressive symptoms. FUNDING: EU Joint Programme-Neurodegenerative Disease Research (JPND) and Alzheimer's Society. TRANSLATION: For the Swedish translation of the abstract see Supplementary Materials section.

Genetic variants influencing biomarkers of nutrition are not associated with cognitive capability in middle-aged and older adults.

Several investigations have observed positive associations between good nutritional status, as indicated by micronutrients, and cognitive measures; however, these associations may not be causal. Genetic polymorphisms that affect nutritional biomarkers may be useful for providing evidence for associations between micronutrients and cognitive measures. As part of the Healthy Ageing across the Life Course (HALCyon) program, men and women aged between 44 and 90 y from 6 UK cohorts were genotyped for polymorphisms associated with circulating concentrations of iron [rs4820268 transmembrane protease, serine 6 (TMPRSS6) and rs1800562 hemochromatosis (HFE)], vitamin B-12 [(rs492602 fucosyltransferase 2 (FUT2)], vitamin D ([rs2282679 group-specific component (GC)] and ß-carotene ([rs6564851 beta-carotene 15,15'-monooxygenase 1 (BCMO1)]. Meta-analysis was used to pool within-study effects of the associations between these polymorphisms and the following measures of cognitive capability: word recall, phonemic fluency, semantic fluency, and search speed. Among the several statistical tests conducted, we found little evidence for associations. We found the minor allele of rs1800562 was associated with poorer word recall scores [pooled ß on Z-score for carriers vs. noncarriers: -0.05 (95% CI: -0.09, -0.004); P = 0.03, n = 14,105] and poorer word recall scores for the vitamin D-raising allele of rs2282679 [pooled ß per T allele: -0.03 (95% CI: -0.05, -0.003); P = 0.03, n = 16,527]. However, there was no evidence for other associations. Our findings provide little evidence to support associations between these genotypes and cognitive capability in older adults. Further investigations are required to elucidate whether the previous positive associations from observational studies between circulating measures of these micronutrients and cognitive performance are due to confounding and reverse causality.

Subjective and objective indicators of neighbourhood safety and physical activity among UK adolescents.

BACKGROUND: The health benefits of regular physical activity in adolescence are well-documented and many health-related behaviours are established in adolescence. The neighbourhood environment is a key setting for physical activity for adolescents and feeling unsafe in their neighbourhood may be a potential barrier to physical activity. AIM: This study aimed to examine associations between neighbourhood safety and physical activity using objective and subjective measures for both. METHODS: Participants (n = 10,913) came from the Millennium Cohort Study, a nationally representative UK longitudinal birth cohort. Linear regression and Zero Inflated Poisson models were used to examine associations between subjective and objective indicators of safety (self-reported safety, Index of Multiple Deprivation crime, Reported Crime Incidence) and physical activity (self-reported weekly and device-measured physical activity). RESULTS: Adolescents who feel unsafe in their neighbourhood, or who live in areas with high IMD crime or violent crime rates report 0.29 (95% CI -0.49, -0.09) 0.32 (95% CI -0.47, -0.16) and 0.20 (95% CI -0.39, -0.20) fewer days of physical activity, respectively. No associations were found between Reported Crime Incidence and either objective or subjective measures of physical activity. CONCLUSIONS: This study demonstrates varying associations between subjective safety and objective crime with physical activity levels in adolescence, highlighting the complexities around subjective and objective measurements and their associations with health outcomes.

Genetic impacts on DNA methylation help elucidate regulatory genomic processes.

BACKGROUND: Pinpointing genetic impacts on DNA methylation can improve our understanding of pathways that underlie gene regulation and disease risk. RESULTS: We report heritability and methylation quantitative trait locus (meQTL) analysis at 724,499 CpGs profiled with the Illumina Infinium MethylationEPIC array in 2358 blood samples from three UK cohorts. Methylation levels at 34.2% of CpGs are affected by SNPs, and 98% of effects are cis-acting or within 1 Mbp of the tested CpG. Our results are consistent with meQTL analyses based on the former Illumina Infinium HumanMethylation450 array. Both SNPs and CpGs with meQTLs are overrepresented in enhancers, which have improved coverage on this platform compared to previous approaches. Co-localisation analyses across genetic effects on DNA methylation and 56 human traits identify 1520 co-localisations across 1325 unique CpGs and 34 phenotypes, including in disease-relevant genes, such as USP1 and DOCK7 (total cholesterol levels), and ICOSLG (inflammatory bowel disease). Enrichment analysis of meQTLs and integration with expression QTLs give insights into mechanisms underlying cis-meQTLs (e.g. through disruption of transcription factor binding sites for CTCF and SMC3) and trans-meQTLs (e.g. through regulating the expression of ACD and SENP7 which can modulate DNA methylation at distal sites). CONCLUSIONS: Our findings improve the characterisation of the mechanisms underlying DNA methylation variability and are informative for prioritisation of GWAS variants for functional follow-ups. The MeQTL EPIC Database and viewer are available online at https://epicmeqtl.kcl.ac.uk .

Accelerated DNA methylation age plays a role in the impact of cardiovascular risk factors on the human heart.

BACKGROUND: DNA methylation (DNAm) age acceleration (AgeAccel) and cardiac age by 12-lead advanced electrocardiography (A-ECG) are promising biomarkers of biological and cardiac aging, respectively. We aimed to explore the relationships between DNAm age and A-ECG heart age and to understand the extent to which DNAm AgeAccel relates to cardiovascular (CV) risk factors in a British birth cohort from 1946. RESULTS: We studied four DNAm ages (AgeHannum, AgeHorvath, PhenoAge, and GrimAge) and their corresponding AgeAccel. Outcomes were the results from two publicly available ECG-based cardiac age scores: the Bayesian A-ECG-based heart age score of Lindow et al. 2022 and the deep neural network (DNN) ECG-based heart age score of Ribeiro et al. 2020. DNAm AgeAccel was also studied relative to results from two logistic regression-based A-ECG disease scores, one for left ventricular (LV) systolic dysfunction (LVSD), and one for LV electrical remodeling (LVER). Generalized linear models were used to explore the extent to which any associations between biological cardiometabolic risk factors (body mass index, hypertension, diabetes, high cholesterol, previous cardiovascular disease [CVD], and any CV risk factor) and the ECG-based outcomes are mediated by DNAm AgeAccel. We derived the total effects, average causal mediation effects (ACMEs), average direct effects (ADEs), and the proportion mediated [PM] with their 95% confidence intervals [CIs]. 498 participants (all 60-64 years) were included, with the youngest ECG heart age being 27 and the oldest 90. When exploring the associations between cardiometabolic risk factors and Bayesian A-ECG cardiac age, AgeAccelPheno appears to be a partial mediator, as ACME was 0.23 years [0.01, 0.52] p = 0.028 (i.e., PM≈18%) for diabetes, 0.34 [0.03, 0.74] p = 0.024 (i.e., PM≈15%) for high cholesterol, and 0.34 [0.03, 0.74] p = 0.024 (PM≈15%) for any CV risk factor. Similarly, AgeAccelGrim mediates ≈30% of the relationship between diabetes or high cholesterol and the DNN ECG-based heart age. When exploring the link between cardiometabolic risk factors and the A-ECG-based LVSD and LVER scores, it appears that AgeAccelPheno or AgeAccelGrim mediate 10-40% of these associations. CONCLUSION: By the age of 60, participants with accelerated DNA methylation appear to have older, weaker, and more electrically impaired hearts. We show that the harmful effects of CV risk factors on cardiac age and health, appear to be partially mediated by DNAm AgeAccelPheno and AgeAccelGrim. This highlights the need to further investigate the potential cardioprotective effects of selective DNA methyltransferases modulators.

Living alone and mental health: parallel analyses in UK longitudinal population surveys and electronic health records prior to and during the COVID-19 pandemic.

BACKGROUND: People who live alone experience greater levels of mental illness; however, it is unclear whether the COVID-19 pandemic had a disproportionately negative impact on this demographic. OBJECTIVE: To describe the mental health gap between those who live alone and with others in the UK prior to and during the COVID-19 pandemic. METHODS: Self-reported psychological distress and life satisfaction in 10 prospective longitudinal population surveys (LPSs) assessed in the nearest pre-pandemic sweep and three periods during the pandemic. Recorded diagnosis of common and severe mental illnesses between March 2018 and January 2022 in electronic healthcare records (EHRs) within the OpenSAFELY-TPP. FINDINGS: In 37 544 LPS participants, pooled models showed greater psychological distress (standardised mean difference (SMD): 0.09 (95% CI: 0.04; 0.14); relative risk: 1.25 (95% CI: 1.12; 1.39)) and lower life satisfaction (SMD: -0.22 (95% CI: -0.30; -0.15)) for those living alone pre-pandemic. This gap did not change during the pandemic. In the EHR analysis of c.16 million records, mental health conditions were more common in those who lived alone (eg, depression 26 (95% CI: 18 to 33) and severe mental illness 58 (95% CI: 54 to 62) more cases more per 100 000). For common mental health disorders, the gap in recorded cases in EHRs narrowed during the pandemic. CONCLUSIONS: People living alone have poorer mental health and lower life satisfaction. During the pandemic, this gap in self-reported distress remained; however, there was a narrowing of the gap in service use. CLINICAL IMPLICATIONS: Greater mental health need and potentially greater barriers to mental healthcare access for those who live alone need to be considered in healthcare planning.

Metabolic correlates of late midlife cognitive outcomes: findings from the 1946 British Birth Cohort.

Investigating associations between metabolites and late midlife cognitive function could reveal potential markers and mechanisms relevant to early dementia. Here, we systematically explored the metabolic correlates of cognitive outcomes measured across the seventh decade of life, while untangling influencing life course factors. Using levels of 1019 metabolites profiled by liquid chromatography-mass spectrometry (age 60-64), we evaluated relationships between metabolites and cognitive outcomes in the British 1946 Birth Cohort (N = 1740). We additionally conducted pathway and network analyses to allow for greater insight into potential mechanisms, and sequentially adjusted for life course factors across four models, including sex and blood collection (Model 1), Model 1 + body mass index and lipid medication (Model 2), Model 2 + social factors and childhood cognition (Model 3) and Model 3 + lifestyle influences (Model 4). After adjusting for multiple tests, 155 metabolites, 10 pathways and 5 network modules were associated with cognitive outcomes. Of the 155, 35 metabolites were highly connected in their network module (termed 'hub' metabolites), presenting as promising marker candidates. Notably, we report relationships between a module comprised of acylcarnitines and processing speed which remained robust to life course adjustment, revealing palmitoylcarnitine (C16) as a hub (Model 4: ß = -0.10, 95% confidence interval = -0.15 to -0.052, P = 5.99 × 10-5). Most associations were sensitive to adjustment for social factors and childhood cognition; in the final model, four metabolites remained after multiple testing correction, and 80 at P < 0.05. Two modules demonstrated associations that were partly or largely attenuated by life course factors: one enriched in modified nucleosides and amino acids (overall attenuation = 39.2-55.5%), and another in vitamin A and C metabolites (overall attenuation = 68.6-92.6%). Our other findings, including a module enriched in sphingolipid pathways, were entirely explained by life course factors, particularly childhood cognition and education. Using a large birth cohort study with information across the life course, we highlighted potential metabolic mechanisms associated with cognitive function in late midlife, suggesting marker candidates and life course relationships for further study.

Investigating change across time in prevalence or association: the challenges of cross-study comparative research and possible solutions.

Cross-study research initiatives to understand change across time are an increasingly prominent component of social and health sciences, yet they present considerable practical, analytical and conceptual challenges. First, we discuss the key challenges to comparative research as a basis for detecting societal change, as well as possible solutions. We focus on studies which investigate changes across time in outcome occurrence or the magnitude and/or direction of associations. We discuss the use and importance of such research, study inclusion, sources of bias and mitigation, and interpretation. Second, we propose a structured framework (a checklist) that is intended to provide guidance for future authors and reviewers. Third, we outline a new open-access teaching resource that offers detailed instruction and reusable analytical syntax to guide newcomers on techniques for conducting comparative analysis and data visualisation (in both R and Stata formats). Supplementary Information: The online version contains supplementary material available at 10.1007/s44155-022-00021-1.