Individual bioenergetic capacity as a potential source of resilience to Alzheimer's disease.

Impaired glucose uptake in the brain is one of the earliest presymptomatic manifestations of Alzheimer's disease (AD). The absence of symptoms for extended periods of time suggests that compensatory metabolic mechanisms can provide resilience. Here, we introduce the concept of a systemic 'bioenergetic capacity' as the innate ability to maintain energy homeostasis under pathological conditions, potentially serving as such a compensatory mechanism. We argue that fasting blood acylcarnitine profiles provide an approximate peripheral measure for this capacity that mirrors bioenergetic dysregulation in the brain. Using unsupervised subgroup identification, we show that fasting serum acylcarnitine profiles of participants from the AD Neuroimaging Initiative yields bioenergetically distinct subgroups with significant differences in AD biomarker profiles and cognitive function. To assess the potential clinical relevance of this finding, we examined factors that may offer diagnostic and therapeutic opportunities. First, we identified a genotype affecting the bioenergetic capacity which was linked to succinylcarnitine metabolism and significantly modulated the rate of future cognitive decline. Second, a potentially modifiable influence of beta-oxidation efficiency seemed to decelerate bioenergetic aging and disease progression. Our findings, which are supported by data from more than 9,000 individuals, suggest that interventions tailored to enhance energetic health and to slow bioenergetic aging could mitigate the risk of symptomatic AD, especially in individuals with specific mitochondrial genotypes.

Strong Association of Depression and Anxiety With the Presence of Back Pain While Impact of Spinal Imaging Findings is Limited: Analysis of an MRI Cohort Study.

Development of back pain is multifactorial, and it is not well understood which factors are the main drivers of the disease. We therefore applied a machine-learning approach to an existing large cohort study data set and sought to identify and rank the most important contributors to the presence of back pain amongst the documented parameters of the cohort. Data from 399 participants in the KORA-MRI (Cooperative health research in the region Augsburg-magnetic resonance imaging) (Cooperative Health Research in the Region Augsburg) study was analyzed. The data set included MRI images of the whole body, including the spine, metabolic, sociodemographic, anthropometric, and cardiovascular data. The presence of back pain was one of the documented items in this data set. Applying a machine-learning approach to this preexisting data set, we sought to identify the variables that were most strongly associated with back pain. Mediation analysis was performed to evaluate the underlying mechanisms of the identified associations. We found that depression and anxiety were the 2 most selected predictors for back pain in our model. Additionally, body mass index, spinal canal width and disc generation, medium and heavy physical work as well as cardiovascular factors were among the top 10 most selected predictors. Using mediation analysis, we found that the effects of anxiety and depression on the presence of back pain were mainly direct effects that were not mediated by spinal imaging. In summary, we found that psychological factors were the most important predictors of back pain in our cohort. This supports the notion that back pain should be treated in a personalized multidimensional framework. PERSPECTIVE: This article presents a wholistic approach to the problem of back pain. We found that depression and anxiety were the top predictors of back pain in our cohort. This strengthens the case for a multidimensional treatment approach to back pain, possibly with a special emphasis on psychological factors.

Dietary and supplemental intake of vitamins C and E is associated with altered DNA methylation in an epigenome-wide association study meta-analysis.

BACKGROUND: Dietary intake of antioxidants such as vitamins C and E protect against oxidative stress, and may also be associated with altered DNA methylation patterns. METHODS: We meta-analysed epigenome-wide association study (EWAS) results from 11,866 participants across eight population-based cohorts to evaluate the association between self-reported dietary and supplemental intake of vitamins C and E with DNA methylation. EWAS were adjusted for age, sex, BMI, caloric intake, blood cell type proportion, smoking status, alcohol consumption, and technical covariates. Significant results of the meta-analysis were subsequently evaluated in gene set enrichment analysis (GSEA) and expression quantitative trait methylation (eQTM) analysis. RESULTS: In meta-analysis, methylation at 4,656 CpG sites was significantly associated with vitamin C intake at FDR ≤ 0.05. The most significant CpG sites associated with vitamin C (at FDR ≤ 0.01) were enriched for pathways associated with systems development and cell signalling in GSEA, and were associated with downstream expression of genes enriched in the immune response in eQTM analysis. Furthermore, methylation at 160 CpG sites was significantly associated with vitamin E intake at FDR ≤ 0.05, but GSEA and eQTM analysis of the top most significant CpG sites associated with vitamin E did not identify significant enrichment of any biological pathways investigated. CONCLUSIONS: We identified significant associations of many CpG sites with vitamin C and E intake, and our results suggest that vitamin C intake may be associated with systems development and the immune response.

Pooled analysis of epigenome-wide association studies of food consumption in KORA, TwinsUK and LLS.

PURPOSE: Examining epigenetic patterns is a crucial step in identifying molecular changes of disease pathophysiology, with DNA methylation as the most accessible epigenetic measure. Diet is suggested to affect metabolism and health via epigenetic modifications. Thus, our aim was to explore the association between food consumption and DNA methylation. METHODS: Epigenome-wide association studies were conducted in three cohorts: KORA FF4, TwinsUK, and Leiden Longevity Study, and 37 dietary exposures were evaluated. Food group definition was harmonized across the three cohorts. DNA methylation was measured using Infinium MethylationEPIC BeadChip in KORA and Infinium HumanMethylation450 BeadChip in the Leiden study and the TwinsUK study. Overall, data from 2293 middle-aged men and women were included. A fixed-effects meta-analysis pooled study-specific estimates. The significance threshold was set at 0.05 for false-discovery rate-adjusted p values per food group. RESULTS: We identified significant associations between the methylation level of CpG sites and the consumption of onions and garlic (2), nuts and seeds (18), milk (1), cream (11), plant oils (4), butter (13), and alcoholic beverages (27). The signals targeted genes of metabolic health relevance, for example, GLI1, RPTOR, and DIO1, among others. CONCLUSION: This EWAS is unique with its focus on food groups that are part of a Western diet. Significant findings were mostly related to food groups with a high-fat content.

Setting the European environment and health research agenda -under-researched areas and solution-oriented research.

BACKGROUND: The aim of the EU-funded HERA (health and environment research agenda) project is to set priorities for the future European research agenda in the environment, climate and health nexus. We report results from a European researcher's perspective and identify research areas that have been inadequately investigated to date. METHODS: An online survey was completed by European researchers to assess, evaluate and visualise research gaps. These research gaps were identified for 21 predefined areas within 3 main categories: i) classical environment and health paradigm; ii) problem or sector-based research areas and approaches and iii) holistic research areas and concepts. All research gaps were then evaluated by expert groups with the pre-defined criteria and systematically summarized. For areas identified within the survey as under-reported, additional input was sought from a range of key selected experts. The EU project database Cordis was utilized to verify that these areas were under-researched. RESULTS: Between May and July 2019, 318 respondents from 38 countries reported 624 research gaps. The main areas for attention identified were: urban environments; chemicals; and climate change, (combined n = 313 gaps). Biodiversity loss and health; transport, mobility, sustainable solutions and health; energy transition and health; waste and the circular economy and health; ethics and philosophy and health were areas that were acknowledged as under-researched (combined n = 27 gaps). These under-researched areas were identified as having certain commonalities, they: i) mostly fell in the category "problem or sector based approaches"; ii) they are essential for developing and implementing solutions; and iii) require trans-disciplinary and cross-sectoral collaboration. CONCLUSIONS: Currently attention is given to topical and highly researched areas in environmental health. In contrast, this paper identifies key topics and approaches that are under-researched, yet, are critical for the implementation of the EU Green Deal, related strategies and action plans, and require further investigation and investment. The findings reveal the imperative to foster solutions-oriented, trans-disciplinary and participatory research and its implementation through changes in research funding and research structures.

Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption.

Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10-7), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10-6). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.

Significant Impact of Coffee Consumption on MR-Based Measures of Cardiac Function in a Population-Based Cohort Study without Manifest Cardiovascular Disease.

Subclinical effects of coffee consumption (CC) with regard to metabolic, cardiac, and neurological complications were evaluated using a whole-body magnetic resonance imaging (MRI) protocol. A blended approach was used to estimate habitual CC in a population-based study cohort without a history of cardiovascular disease. Associations of CC with MRI markers of gray matter volume, white matter hyperintensities, cerebral microhemorrhages, total and visceral adipose tissue (VAT), hepatic proton density fat fraction, early/late diastolic filling rate, end-diastolic/-systolic and stroke volume, ejection fraction, peak ejection rate, and myocardial mass were evaluated by linear regression. In our analysis with 132 women and 168 men, CC was positively associated with MR-based cardiac function parameters including late diastolic filling rate, stroke volume (p < 0.01 each), and ejection fraction (p < 0.05) when adjusting for age, sex, smoking, hypertension, diabetes, Low-density lipoprotein (LDL), triglycerides, cholesterol, and alcohol consumption. CC was inversely associated with VAT independent of demographic variables and cardiovascular risk factors (p < 0.05), but this association did not remain significant after additional adjustment for alcohol consumption. CC was not significantly associated with potential neurodegeneration. We found a significant positive and independent association between CC and MRI-based systolic and diastolic cardiac function. CC was also inversely associated with VAT but not independent of alcohol consumption.

Mortality and Morbidity Effects of Long-Term Exposure to Low-Level PM2.5, BC, NO2, and O3: An Analysis of European Cohorts in the ELAPSE Project.

INTRODUCTION: Epidemiological cohort studies have consistently found associations between long-term exposure to outdoor air pollution and a range of morbidity and mortality endpoints. Recent evaluations by the World Health Organization and the Global Burden of Disease study have suggested that these associations may be nonlinear and may persist at very low concentrations. Studies conducted in North America in particular have suggested that associations with mortality persisted at concentrations of particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5) well below current air quality standards and guidelines. The uncertainty about the shape of the concentration-response function at the low end of the concentration distribution, related to the scarcity of observations in the lowest range, was the basis of the current project. Previous studies have focused on PM2.5, but increasingly associations with nitrogen dioxide (NO2) are being reported, particularly in studies that accounted for the fine spatial scale variation of NO2. Very few studies have evaluated the effects of long-term exposure to low concentrations of ozone (O3). Health effects of black carbon (BC), representing primary combustion particles, have not been studied in most large cohort studies of PM2.5. Cohort studies assessing health effects of particle composition, including elements from nontailpipe traffic emissions (iron, copper, and zinc) and secondary aerosol (sulfur) have been few in number and reported inconsistent results. The overall objective of our study was to investigate the shape of the relationship between long-term exposure to four pollutants (PM2.5, NO2, BC, and O3) and four broad health effect categories using a number of different methods to characterize the concentration-response function (i.e., linear, nonlinear, or threshold). The four health effect categories were (1) natural- and cause-specific mortality including cardiovascular and nonmalignant as well as malignant respiratory and diabetes mortality; and morbidity measured as (2) coronary and cerebrovascular events; (3) lung cancer incidence; and (4) asthma and chronic obstructive pulmonary disease (COPD) incidence. We additionally assessed health effects of PM2.5 composition, specifically the copper, iron, zinc, and sulfur content of PM2,5. METHODS: We focused on analyses of health effects of air pollutants at low concentrations, defined as less than current European Union (EU) Limit Values, U.S. Environmental Protection Agency (U.S. EPA), National Ambient Air Quality Standards (NAAQS), and/or World Health Organization (WHO) Air Quality Guideline values for PM2.5, NO2, and O3. We address the health effects at low air pollution levels by performing new analyses within selected cohorts of the ESCAPE study (European Study of Cohorts for Air Pollution Effects; Beelen et al. 2014a) and within seven very large European administrative cohorts. By combining well-characterized ESCAPE cohorts and large administrative cohorts in one study the strengths and weaknesses of each approach can be addressed. The large administrative cohorts are more representative of national or citywide populations, have higher statistical power, and can efficiently control for area-level confounders, but have fewer possibilities to control for individual-level confounders. The ESCAPE cohorts have detailed information on individual confounders, as well as country-specific information on area-level confounding. The data from the seven included ESCAPE cohorts and one additional non-ESCAPE cohort have been pooled and analyzed centrally. More than 300,000 adults were included in the pooled cohort from existing cohorts in Sweden, Denmark, Germany, the Netherlands, Austria, France, and Italy. Data from the administrative cohorts have been analyzed locally, without transfer to a central database. Privacy regulations prevented transfer of data from administrative cohorts to a central database. More than 28 million adults were included from national administrative cohorts in Belgium, Denmark, England, the Netherlands, Norway, and Switzerland as well as an administrative cohort in Rome, Italy. We developed central exposure assessment using Europewide hybrid land use regression (LUR) models, which incorporated European routine monitoring data for PM2.5, NO2, and O3, and ESCAPE monitoring data for BC and PM2.5 composition, land use, and traffic data supplemented with satellite observations and chemical transport model estimates. For all pollutants, we assessed exposure at a fine spatial scale, 100 × 100 m grids. These models have been applied to individual addresses of all cohorts including the administrative cohorts. In sensitivity analyses, we applied the PM2.5 models developed within the companion HEI-funded Canadian MAPLE study (Brauer et al. 2019) and O3 exposures on a larger spatial scale for comparison with previous studies. Identification of outcomes included linkage with mortality, cancer incidence, hospital discharge registries, and physician-based adjudication of cases. We analyzed natural-cause, cardiovascular, ischemic heart disease, stroke, diabetes, cardiometabolic, respiratory, and COPD mortality. We also analyzed lung cancer incidence, incidence of coronary and cerebrovascular events, and incidence of asthma and COPD (pooled cohort only). We applied the Cox proportional hazard model with increasing control for individual- and area-level covariates to analyze the associations between air pollution and mortality and/or morbidity for both the pooled cohort and the individual administrative cohorts. Age was used as the timescale because of evidence that this results in better adjustment for potential confounding by age. Censoring occurred at the time of the event of interest, death from other causes, emigration, loss to follow-up for other reasons, or at the end of follow-up, whichever came first. A priori we specified three confounder models, following the modeling methods of the ESCAPE study. Model 1 included only age (time axis), sex (as strata), and calendar year of enrollment. Model 2 added individual-level variables that were consistently available in the cohorts contributing to the pooled cohort or all variables available in the administrative cohorts, respectively. Model 3 further added area-level socioeconomic status (SES) variables. A priori model 3 was selected as the main model. All analyses in the pooled cohort were stratified by subcohort. All analyses in the administrative cohorts accounted for clustering of the data in neighborhoods by adjusting the variance of the effect estimates. The main exposure variable we analyzed was derived from the Europewide hybrid models based on 2010 monitoring data. Sensitivity analyses were conducted using earlier time periods, time-varying exposure analyses, local exposure models, and the PM2.5 models from the Canadian MAPLE project. We first specified linear single-pollutant models. Two-pollutant models were specified for all combinations of the four main pollutants. Two-pollutant models for particle composition were analyzed with PM2.5 and NO2 as the second pollutant. We then investigated the shape of the concentration-response function using natural splines with two, three, and four degrees of freedom; penalized splines with the degrees of freedom determined by the algorithm and shape-constrained health impact functions (SCHIF) using confounder model 3. Additionally, we specified linear models in subsets of the concentration range, defined by removing concentrations above a certain value from the analysis, such as for PM2.5 25 µg/m3 (EU limit value), 20, 15, 12 µg/m3 (U.S. EPA National Ambient Air Quality Standard), and 10 µg/m3 (WHO Air Quality Guideline value). Finally, threshold models were evaluated to investigate whether the associations persisted below specific concentration values. For PM2.5, we evaluated 10, 7.5, and 5 µg/m3 as potential thresholds. Performance of threshold models versus the corresponding no-threshold linear model were evaluated using the Akaike information criterion (AIC). RESULTS: In the pooled cohort, virtually all subjects in 2010 had PM2.5 and NO2 annual average exposures below the EU limit values (25 µg/m3 and 40 µg/m3, respectively). More than 50,000 had a residential PM2.5 exposure below the U.S. EPA NAAQS (12 µg/m3). More than 25,000 subjects had a residential PM2.5 exposure below the WHO guideline (10 µg/m3). We found significant positive associations between PM2.5, NO2, and BC and natural-cause, respiratory, cardiovascular, and diabetes mortality. In our main model, the hazard ratios (HRs) (95% [confidence interval] CI) were 1.13 (CI = 1.11, 1.16) for an increase of 5 µg/m3 PM2.5, 1.09 (CI = 1.07, 1.10) for an increase of 10 µg/m3 NO2, and 1.08 (CI = 1.06, 1.10) for an increase of 0.5 × 10-5/m BC for natural-cause mortality. The highest HRs were found for diabetes mortality. Associations with O3 were negative, both in the fine spatial scale of the main ELAPSE model and in large spatial scale exposure models. For PM2.5, NO2, and BC, we generally observed a supralinear association with steeper slopes at low exposures and no evidence of a concentration below which no association was found. Subset analyses further confirmed that these associations remained at low levels: below 10 µg/m3 for PM2.5 and 20 µg/m3 for NO2. HRs were similar to the full cohort HRs for subjects with exposures below the EU limit values for PM2.5 and NO2, the U.S. NAAQS values for PM2.5, and the WHO guidelines for PM2.5 and NO2. The mortality associations were robust to alternative specifications of exposure, including different time periods, PM2.5 from the MAPLE project, and estimates from the local ESCAPE model. Time-varying exposure natural spline analyses confirmed associations at low pollution levels. HRs in two-pollutant models were attenuated but remained elevated and statistically significant for PM2.5 and NO2. In two-pollutant models of PM2.5 and NO2 HRs for natural-cause mortality were 1.08 (CI = 1.05, 1.11) for PM2.5 and 1.05 (CI = 1.03, 1.07) for NO2. Associations with O3 were attenuated but remained negative in two-pollutant models with NO2, BC, and PM2.5. We found significant positive associations between PM2.5, NO2, and BC and incidence of stroke and asthma and COPD hospital admissions. Furthermore, NO2 was significantly related to acute coronary heart disease and PM2.5 was significantly related to lung cancer incidence. We generally observed linear to supralinear associations with no evidence of a threshold, with the exception of the association between NO2 and acute coronary heart disease, which was sublinear. Subset analyses documented that associations remained even with PM2.5 below 20 µg/m3 and possibly 12 µg/m3. Associations remained even when NO2 was below 30 µg/m3 and in some cases 20 µg/m3. In two-pollutant models, NO2 was most consistently associated with acute coronary heart disease, stroke, asthma, and COPD hospital admissions. PM2.5 was not associated with these outcomes in two-pollutant models with NO2. PM2.5 was the only pollutant that was associated with lung cancer incidence in two-pollutant models. Associations with O3 were negative though generally not statistically significant. In the administrative cohorts, virtually all subjects in 2010 had PM2.5 and NO2 annual average exposures below the EU limit values. More than 3.9 million subjects had a residential PM2.5 exposure below the U.S. EPA NAAQS (12 µg/m3) and more than 1.9 million had residential PM2.5 exposures below the WHO guideline (10 µg/m3). We found significant positive associations between PM2.5, NO2, and BC and natural-cause, respiratory, cardiovascular, and lung cancer mortality, with moderate to high heterogeneity between cohorts. We found positive but statistically nonsignificant associations with diabetes mortality. In our main model meta-analysis, the HRs (95% CI) for natural-cause mortality were 1.05 (CI = 1.02, 1.09) for an increase of 5 µg/m3 PM2.5, 1.04 (CI = 1.02, 1.07) for an increase of 10 µg/m3 NO2, and 1.04 (CI = 1.02, 1.06) for an increase of 0.5 × 10-5/m BC, and 0.95 (CI = 0.93, 0.98) for an increase of 10 µg/m3 O3. The shape of the concentration-response functions differed between cohorts, though the associations were generally linear to supralinear, with no indication of a level below which no associations were found. Subset analyses documented that these associations remained at low levels: below 10 µg/m3 for PM2.5 and 20 µg/m3 for NO2. BC and NO2 remained significantly associated with mortality in two-pollutant models with PM2.5 and O3. The PM2.5 HR attenuated to unity in a two-pollutant model with NO2. The negative O3 association was attenuated to unity and became nonsignificant. The mortality associations were robust to alternative specifications of exposure, including time-varying exposure analyses. Time-varying exposure natural spline analyses confirmed associations at low pollution levels. Effect estimates in the youngest participants (<65 years at baseline) were much larger than in the elderly (>65 years at baseline). Effect estimates obtained with the ELAPSE PM2.5 model did not differ from the MAPLE PM2.5 model on average, but in individual cohorts, substantial differences were found. CONCLUSIONS: Long-term exposure to PM2.5, NO2, and BC was positively associated with natural-cause and cause-specific mortality in the pooled cohort and the administrative cohorts. Associations were found well below current limit values and guidelines for PM2.5 and NO2. Associations tended to be supralinear, with steeper slopes at low exposures with no indication of a threshold. Two-pollutant models documented the importance of characterizing the ambient mixture with both NO2 and PM2.5. We mostly found negative associations with O3. In two-pollutant models with NO2, the negative associations with O3 were attenuated to essentially unity in the mortality analysis of the administrative cohorts and the incidence analyses in the pooled cohort. In the mortality analysis of the pooled cohort, significant negative associations with O3 remained in two-pollutant models. Long-term exposure to PM2.5, NO2, and BC was also positively associated with morbidity outcomes in the pooled cohort. For stroke, asthma, and COPD, positive associations were found for PM2.5, NO2, and BC. For acute coronary heart disease, an increased HR was observed for NO2. For lung cancer, an increased HR was found only for PM2.5. Associations mostly showed steeper slopes at low exposures with no indication of a threshold.

A call for urgent action to safeguard our planet and our health in line with the helsinki declaration.

In 2015, the Rockefeller Foundation-Lancet Commission launched a report introducing a novel approach called Planetary Health and proposed a concept, a strategy and a course of action. To discuss the concept of Planetary Health in the context of Europe, a conference entitled: "Europe That Protects: Safeguarding Our Planet, Safeguarding Our Health" was held in Helsinki in December 2019. The conference participants concluded with a need for action to support Planetary Health during the 2020s. The Helsinki Declaration emphasizes the urgency to act as scientific evidence shows that human activities are causing climate change, biodiversity loss, land degradation, overuse of natural resources and pollution. They threaten the health and safety of human kind. Global, regional, national, local and individual initiatives are called for and multidisciplinary and multisectorial actions and measures are needed. A framework for an action plan is suggested that can be modified for local needs. Accordingly, a shift from fragmented approaches to policy and practice towards systematic actions will promote human health and health of the planet. Systems thinking will feed into conserving nature and biodiversity, and into halting climate change. The Planetary Health paradigm ‒ the health of human civilization and the state of natural systems on which it depends ‒ must become the driver for all policies.

[Mental health research opportunities in the MONICA-KORA study]. / Seelische Gesundheit als Forschungsgegenstand in der MONICA-KORA-Studie.

Mental health research opportunities in the MONICA-KORA study Goal: Initially, part of the worldwide MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Project of the World Health Organization (WHO), the project was pursued 1996 as KORA (Cooperative Health Research in the Region Augsburg) Study, which now substantially expands the former focus on cardiovascular medicine. Major research questions within the mental health focus emphasize the prognostic impact of psychosocial stress on the incidence of somatic endpoints and the gender-driven crosstalk of psycho-neuro- immunological conditions with somatic diseases. Methods: Three independent representative population-based MONICA/KORA surveys (S1 to S3) starting in 1984/85 and performed in 5-years intervals, constitute the backbone of the psychosocial MONICA sub study. An extensive set of psychosocial baseline data captured in the S1 to S3 surveys are available for a total of approximately 13000 participants in the age range of 25 to 75 years. Here, data allow estimates of work-stress conditions, social isolation, social network, life satisfaction and the Type A Behavior Pattern. The Follow-up studies (F3, F4, FFF4) allow for prospective, time-dependent analyses. In the follow-up (F) surveys, psychosomatic research was strengthened with the inclusion of standardized assessments of depression, anxiety, Type D personality and (in F4) for Posttraumatic Stress Disorder (PTSD), psychosocial stress and life satisfaction. Combined analyses with genetic, epigenetic and metabolomic datasets are feasible. Results: The initial S1 to S3 surveys provided psychosocial baseline data for approximately 13000 participants in the age range of 25 to75 years. The Follow-up studies (F3, F4, FFF4) each included approximately 3000 participants with validated datasets with a median of 9 to 15 years of follow-up period from baseline. An increasing number of co-operations dealing with sophisticated basic research tools are currently ongoing. Conclusions: Prospective assessments of psychosocial stress conditions on the onset of somatic disease conditions and research on the interaction with autonomic, endocrine and inflammatory pathways result in new insights of established disease conditions and may contribute as a game-changer in the current disease understanding.

Prevalence and Predictors of Subclinical Micronutrient Deficiency in German Older Adults: Results from the Population-Based KORA-Age Study.

Subclinical micronutrient deficiency in older adults is associated with chronic age-related diseases and adverse functional outcomes. In Germany, the older population is at risk of insufficient micronutrient intake, but representative studies on micronutrient status in old and very old adults are scarce. This study's objectives were to estimate the prevalence of subclinical vitamin D, folate, vitamin B12 and iron deficiencies among older adults, aged 65 to 93, from the KORA-Age study in Augsburg, Germany (n = 1079), and to examine associated predictors, using multiple logistic regression. Serum concentrations of 25-hydroxyvitamin D (25OHD), folate, vitamin B12, and iron were analyzed. The prevalence of subclinical vitamin D and vitamin B12 deficiencies were high, with 52.0% and 27.3% of individuals having low 25OHD (<50 nmol/L) and low vitamin B12 concentrations (<221 pmol/L), respectively. Furthermore, 11.0% had low iron (men <11.6 µmol/L, women <9.0 µmol/L) and 8.7% had low folate levels (<13.6 nmol/L). Common predictors associated with subclinical micronutrient deficiency included very old age, physical inactivity, frailty and no/irregular use of supplements. Subclinical micronutrient deficiency is a public health concern among KORA-Age participants, especially for vitamins D and B12. The predictors identified provide further rationale for screening high-risk subgroups and developing targeted public health interventions to tackle prevailing micronutrient inadequacies among older adults.

Intake of Vitamin and Mineral Supplements and Longitudinal Association with HbA1c Levels in the General Non-Diabetic Population--Results from the MONICA/KORA S3/F3 Study.

BACKGROUND: Lower levels of hemoglobin A1c (HbA1c) are associated with a decreased risk of cardiovascular complications in diabetic and non-diabetic individuals. The aim of the study was to longitudinally investigate the association between the use of 11 vitamins and minerals (vitamins E, C, D, B1, folic acid, carotenoids, calcium, magnesium, zinc, iron, and selenium) and change in HbA1c levels over 10 years in non-diabetic individuals drawn from the general population. METHODS: Baseline data were available from 4447 subjects included in the population-based "Monitoring of Trends and Determinants in Cardiovascular Diseases" (MONICA) Augsburg S3 survey (1994/95). Follow-up data were derived from 2774 participants in the follow-up survey named "Cooperative Health Research in the Region of Augsburg" (KORA) F3 (2004/05). Vitamin/mineral intake from supplements and medications was assessed in a personal interview, where participants were asked to bring product packages of preparations that had been ingested during the last 7 days prior to the examination. Associations between regular vitamin/mineral intake amounts and HbA1c levels measured at baseline and follow-up were investigated using generalized estimating equation models. For carotenoids, analyses were stratified by smoking status. RESULTS: None of the investigated nutrients except for carotenoids was significantly associated with changes in HbA1c levels after 10 years. Regular intake of carotenoids from supplements and medications in amounts > 6.8 mg/d (upper tertile) was associated with an absolute -0.26% (95% CI: -0.43 to -0.08) lower increase in HbA1c levels compared with no intake of carotenoids. An inverse association was observed in those who never smoked but not in (former) smokers. CONCLUSION: Larger prospective and intervention studies in non-diabetic/non-smoking individuals are needed to confirm the results and to assess whether the observed associations between carotenoid intake and change in HbA1c levels are causal. If our results are confirmed, high carotenoid intake could be one strategy for the prevention of cardiovascular complications in non-diabetic people.

Associations between calcium and vitamin D supplement use as well as their serum concentrations and subclinical cardiovascular disease phenotypes.

BACKGROUND: Supplementation of calcium (Ca) and vitamin D for the prevention of osteoporosis is frequently found in Western countries. Recent re-analyses of clinical trials observed a higher risk of myocardial infarction and stroke in subjects taking Ca (+vitamin D) supplements, although the underlying mechanisms are not clear. OBJECTIVE: Thus, we analyzed the associations between Ca and vitamin D supplementation as well as serum concentrations of Ca and 25-hydroxyvitamin D (25(OH)D) and subclinical cardiovascular disease (CVD) phenotypes, namely intima-media thickness, ankle-brachial-index (ABI), intermittent claudication, and atrial fibrillation (AF). DESIGN: Data of 1601 participants aged 50-81 years of the population-based cross-sectional Cooperative Health Research in the Region of Augsburg (KORA) F4 study in Germany were analyzed. Logistic and linear regression models were used to estimate odds ratios (OR) (95% confidence intervals (CI)) and ß-estimates (p-values), respectively. RESULTS: Regular Ca supplementation showed a significant positive association with the presence of AF after multivariable adjustment (OR = 3.89; 95% CI 1.28-11.81). Higher serum 25(OH)D concentrations were independently associated with a lower prevalence of asymptomatic peripheral arterial disease as assessed by ABI measurements (ß = 0.007; p = 0.01). No other significant associations between supplementation or serum concentrations of Ca or vitamin D and CVD phenotypes were identified. CONCLUSIONS: Although based on few cases the finding of a significant higher prevalence of AF in Ca supplement users hints at one possible mechanism that may contribute to an increased risk of myocardial infarction and stroke. The observed association between serum 25(OH)D and ABI supports results from other studies.

Vitamin E supplementation is associated with lower levels of C-reactive protein only in higher dosages and combined with other antioxidants: The Cooperative Health Research in the Region of Augsburg (KORA) F4 study.

The aim of the present study was to examine the association between intake of five common antioxidative nutrients from supplements and medications (vitamin E, vitamin C, carotenoids, Se, and Zn) and levels of high-sensitivity C-reactive protein (hs-CRP) in the general population. For this purpose, a total of 2924 participants of the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4 study (2006-8) were investigated cross-sectionally. Intake of dietary supplements and medication during the last 7 d was recorded in a personal interview, when participants were asked to show product packages of ingested preparations. Linear regression models were calculated; first, the exposure to regular nutrient intake was treated with a binary response (yes/no); then regularly ingested amounts were divided into quartiles to examine dose-response relationships. Effect of single v. combined supplementation of antioxidants was assessed through the inclusion of interaction terms into the models. Regular intake of any of the five investigated antioxidants per se was not associated with hs-CRP levels. However, dose-response analyses revealed that participants who regularly ingested more than 78 mg vitamin E/d, which corresponds to the upper quartile, had 22% lower hs-CRP levels (95% CI 0·63, 0·97) compared to those of persons who were not exposed to any vitamin E supplementation. Stratified analyses showed that this association was found only in persons who took vitamin E in combination with other antioxidants. The combined supplementation of vitamin E with other antioxidants could thus be a promising strategy for the prevention of inflammation-related diseases in the general population, if further studies could confirm that the proposed association is causal.

Prevalence of use and level of awareness of CAM in older people - results from the KORA-Age study.

BACKGROUND: Despite the growing proportion of older adults in Europe there is only limited knowledge of CAM use among the elderly. This analysis aims to provide estimates for the prevalence of CAM use in persons with an age of ≥65, and to investigate correlations of CAM use with demographic characteristics. METHODS: Based on participants of the MONICA/KORA studies S1-S4 who were born before 1944, a random sample of 1,079 was selected for comprehensive medical examinations. Questions were presented in structured face-to-face interviews conducted from February to November 2009. RESULTS: Data on CAM use were available for 1,026 subjects with a mean age of 76 years, ranging from 65 to 93 years. 14% of the participants were unaware of CAM. The overall prevalence of CAM use was estimated 37% with minor differences between age groups, but clear differences between male (29%) and female (44%) participants. 1-year prevalence of CAM use was 22% (16% males, 28% females). 1-year of CAM use was associated with a higher level of education in both men and women; with higher income in men; and with more actual diseases in women. CONCLUSION: Findings indicate that awareness of CAM is high even among people ≥65 years. Estimates for the prevalence of CAM use confirm the relevance of this treatment sector in the healthcare system for the elderly.

Influence of external, intrinsic and individual behaviour variables on serum 25(OH)D in a German survey.

The objective of the present study was to identify external, intrinsic or behavioural factors that significantly influenced serum 25-hydroxyvitamin D (25(OH)D) concentrations in a German survey. Data from 3061 participants in the Cooperative Health Research in the Region of Augsburg, Germany (KORA) F4 survey were used to relate potential determinants to measured mean serum 25(OH)D concentrations using multivariable regression models. The factors significantly associated with hypovitaminosis D (defined as 25(OH)D<25 nmolL(-1)) were season (winter, spring and autumn), urban environment and high body mass index. In contrast, times spent in sunny regions, hours per day spent outdoors in the summer as well as additional oral intake were associated with higher 25(OH)D concentrations. These results suggest that mainly ambient UV exposure but also individual behaviour are the most important determinants for personal 25(OH)D concentrations. The analyses further showed that in winter 43% of subjects were vitamin D deficient and 42% insufficient. Even in summer over half the population has insufficient vitamin D status with 8% deficient and 47% insufficient. Therefore measures to mitigate widespread vitamin D insufficiency such as regular short-term sun exposure and/or improved dietary intake/supplementation recommendations by public health bodies need to be considered.

Low levels of serum 25-hydroxyvitamin D are associated with increased risk of myocardial infarction, especially in women: results from the MONICA/KORA Augsburg case-cohort study.

CONTEXT AND OBJECTIVE: A growing body of evidence suggests that vitamin D deficiency may adversely affect the cardiovascular system. Therefore, we thought to prospectively assess the association between serum 25-hydroxyvitamin D, the most commonly used index of vitamin D status, and incident coronary heart disease. DESIGN, SETTING, AND PATIENTS: We measured serum levels of 25[OH]D in 1783 healthy middle-aged subjects (964 men, 819 women) in the population-based Monitoring of Trends and Determinants in Cardiovascular Disease/Cooperative Health Research in the Region of Augsburg studies. A total of 298 coronary heart disease cases were identified over a mean follow-up period of 11 yr. RESULTS: After adjustment for age, survey, and season of blood sampling, the hazard ratio (HR) and 95% confidence interval comparing tertile extremes of serum levels of 25[OH]D was 0.32 (0.16-0.65) (P for trend = 0.001) in women and 0.56 (0.38-0.82) (P for trend = 0.005) in men. Further adjustment for traditional cardiovascular risk factors slightly attenuated the association in women [HR 0.39 (0.18-0.84); P for trend = 0.013], whereas it became nonsignificant in men [HR 0.76 (0.49-1.17); P for trend = 0.215]. After additional adjustment for C-reactive protein, IL-6, soluble intercellular adhesion molecule-1, and interferon-γ-inducible protein-10, the association still remained significant in women [HR 0.42 (0.19-0.93); P for trend = 0.028], and it was further reduced in men [HR 0.84 (0.52-1.35); P for trend = 0.461]. CONCLUSION: Our findings suggest that higher vitamin D levels are associated with decreased risk of coronary heart disease. This effect is more pronounced in women than in men. Further clinical and experimental studies are needed to investigate the sex differences and whether vitamin D supplementation could contribute to the prevention of coronary heart disease.