Blood-Based Oxidative Stress Markers and Cognitive Performance in Early Old Age: The HAPIEE Study.

BACKGROUND/AIMS: Oxidative stress is involved in Alzheimer disease pathology, but its impact on cognitive function in community-dwelling older adults remains unknown. We estimated associations between serum oxidative stress markers and cognitive function in early old age. METHODS: Subjects aged 45-69 years recruited in urban centers in Central and Eastern Europe had memory, verbal fluency, and processing speed assessed at baseline (2002-2005) and 3 years later. Derivatives of reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP), and total thiol levels (TTLs) were measured at baseline in a subsample. Linear regression was used to estimate associations of biomarkers with cognitive test scores cross-sectionally (n = 4,304) and prospectively (n = 2,882). RESULTS: Increased d-ROM levels were inversely associated with global cognition and verbal fluency cross-sectionally and in prospective analysis; observed effects corresponded to 3-4 years' higher age. TTL was inconsistently associated with memory. BAP was not related to cognitive function. CONCLUSION: This study found modest evidence for a relationship between serum d-ROMs and cognitive function in a population sample of older adults

HbA1c levels in non-diabetic older adults - No J-shaped associations with primary cardiovascular events, cardiovascular and all-cause mortality after adjustment for confounders in a meta-analysis of individual participant data from six cohort studies

Background:To determine the shape of the associations of HbA1c with mortality and cardiovascular outcomes in non-diabetic individuals and explore potential explanations. Methods: The associations of HbA1c with all-cause mortality, cardiovascular mortality and primary cardiovascular events (myocardial infarction or stroke) were assessed in non-diabetic subjects ≥50 years from six population-based cohort studies from Europe and the USA and meta-analyzed. Very low, low, intermediate and increased HbA1c were defined as <5.0, 5.0 to <5.5, 5.5 to <6.0 and 6.0 to <6.5 % (equals <31, 31 to <37, 37 to <42 and 42 to <48 mmol/mol), respectively, and low HbA1c was used as reference in Cox proportional hazards models. Results:Overall, 6,769 of 28,681 study participants died during a mean follow-up of 10.7 years, of whom 2,648 died of cardiovascular disease. Furthermore, 2,493 experienced a primary cardiovascular event. A linear association with primary cardiovascular events was observed. Adjustment for cardiovascular risk factors explained about 50 % of the excess risk and attenuated hazard ratios (95 % confidence interval) for increased HbA1c to 1.14 (1.03–1.27), 1.17 (1.00–1.37) and 1.19 (1.04–1.37) for all-cause mortality, cardiovascular mortality and cardiovascular events, respectively. The six cohorts yielded inconsistent results for the association of very low HbA1c levels with the mortality outcomes and the pooled effect estimates were not statistically significant. In one cohort with a pronounced J-shaped association of HbA1c levels with all-cause and cardiovascular mortality (NHANES), the following confounders of the association of very low HbA1c levels with mortality outcomes were identified: race/ethnicity; alcohol consumption; BMI; as well as biomarkers of iron deficiency anemia and liver function. Associations for very low HbA1c levels lost statistical significance in this cohort after adjusting for these confounders.Conclusions: A linear association of HbA1c levels with primary cardiovascular events was observed. For cardiovascular and all-cause mortality, the observed small effect sizes at both the lower and upper end of HbA1c distribution do not support the notion of a J-shaped association of HbA1c levels because a certain degree of residual confounding needs to be considered in the interpretation of the results. Keywords: Glycated hemoglobin, Cardiovascular disease, Myocardial infarction, Stroke, Mortality, Cohort study, Meta-analysi

High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality

Aims High-density lipoprotein (HDL) cholesterol is a strong predictor of cardiovascular mortality. This work aimed to investigate whether the presence of coronary artery disease (CAD) impacts on its predictive value. Methods and results We studied 3141 participants (2191 males, 950 females) of the LUdwigshafen RIsk and Cardiovascular health (LURIC) study. They had a mean ± standard deviation age of 62.6 ± 10.6 years, body mass index of 27.5 ± 4.1 kg/m², and HDL cholesterol of 38.9 ± 10.8 mg/dL. The cohort consisted of 699 people without CAD, 1515 patients with stable CAD, and 927 patients with unstable CAD. The participants were prospectively followed for cardiovascular mortality over a median (inter-quartile range) period of 9.9 (8.7-10.7) years. A total of 590 participants died from cardiovascular diseases. High-density lipoprotein cholesterol by tertiles was inversely related to cardiovascular mortality in the entire cohort (P = 0.009). There was significant interaction between HDL cholesterol and CAD in predicting the outcome (P = 0.007). In stratified analyses, HDL cholesterol was strongly associated with cardiovascular mortality in people without CAD [3rd vs. 1st tertile: HR (95% CI) = 0.37 (0.18-0.74), P = 0.005], but not in patients with stable [3rd vs. 1st tertile: HR (95% CI) = 0.81 (0.61-1.09), P = 0.159] and unstable [3rd vs. 1st tertile: HR (95% CI) = 0.91 (0.59-1.41), P = 0.675] CAD. These results were replicated by analyses in 3413 participants of the AtheroGene cohort and 5738 participants of the ESTHER cohort, and by a meta-analysis comprising all three cohorts. Conclusion The inverse relationship of HDL cholesterol with cardiovascular mortality is weakened in patients with CAD. The usefulness of considering HDL cholesterol for cardiovascular risk stratification seems limited in such patient

Alcoholic Beverage Preference and Dietary Habits in Elderly across Europe: Analyses within the Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES) Project

Introduction: The differential associations of beer, wine, and spirit consumption on cardiovascular risk found in observational studies may be confounded by diet. We described and compared dietary intake and diet quality according to alcoholic beverage preference in European elderly. Methods: From the Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES), seven European cohorts were included, i.e. four sub-cohorts from EPIC-Elderly, the SENECA Study, the Zutphen Elderly Study, and the Rotterdam Study. Harmonized data of 29,423 elderly participants from 14 European countries were analyzed. Baseline data on consumption of beer, wine, and spirits, and dietary intake were collected with questionnaires. Diet quality was assessed using the Healthy Diet Indicator (HDI). Intakes and scores across categories of alcoholic beverage preference (beer, wine, spirit, no preference, non-consumers) were adjusted for age, sex, socio-economic status, self-reported prevalent diseases, and lifestyle factors. Cohort-specific mean intakes and scores were calculated as well as weighted means combining all cohorts. Results: In 5 of 7 cohorts, persons with a wine preference formed the largest group. After multivariate adjustment, persons with a wine preference tended to have a higher HDI score and intake of healthy foods in most cohorts, but differences were small. The weighted estimates of all cohorts combined revealed that non-consumers had the highest fruit and vegetable intake, followed by wine consumers. Non-consumers and persons with no specific preference had a higher HDI score, spirit consumers the lowest. However, overall diet quality as measured by HDI did not differ greatly across alcoholic beverage preference categories. Discussion: This study using harmonized data from ~30,000 elderly from 14 European countries showed that, after multivariate adjustment, dietary habits and diet quality did not differ greatly according to alcoholic beverage preference

Vitamin D and subsequent all-age and premature mortality: a systematic review

&lt;br&gt;Background: All-cause mortality in the population &#60; 65 years is 30% higher in Glasgow than in equally deprived Liverpool and Manchester. We investigated a hypothesis that low vitamin D in this population may be associated with premature mortality via a systematic review and meta-analysis.&lt;/br&gt; &lt;br&gt;Methods: Medline, EMBASE, Web of Science, the Cochrane Library and grey literature sources were searched until February 2012 for relevant studies. Summary statistics were combined in an age-stratified meta-analysis.&lt;/br&gt; &lt;br&gt;Results: Nine studies were included in the meta-analysis, representing 24,297 participants, 5,324 of whom died during follow-up. The pooled hazard ratio for low compared to high vitamin D demonstrated a significant inverse association (HR 1.19, 95% CI 1.12-1.27) between vitamin D levels and all-cause mortality after adjustment for available confounders. In an age-stratified meta-analysis, the hazard ratio for older participants was 1.25 (95% CI 1.14-1.36) and for younger participants 1.12 (95% CI 1.01-1.24).&lt;/br&gt; &lt;br&gt;Conclusions: Low vitamin D status is inversely associated with all-cause mortality but the risk is higher amongst older individuals and the relationship is prone to residual confounding. Further studies investigating the association between vitamin D deficiency and all-cause mortality in younger adults with adjustment for all important confounders (or using randomised trials of supplementation) are required to clarify this relationship.&lt;/br&gt

High cholesterol levels change the association of biomarkers of neurodegenerative diseases with dementia risk: findings from a population‐based cohort

Introduction This study assessed whether in a population with comorbidity of neurodegenerative and cerebrovascular disease (mixed pathology) the association of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau181 (p-tau181) with dementia risk varied depending on levels of total cholesterol and apolipoprotein E (APOE) ε4 genotype. Methods Plasma biomarkers were measured using Simoa technology in 768 participants of a nested case-control study embedded within an ongoing population-based cohort. Logistic and spline regression models, and receiver operating characteristic curves were calculated. Results The strength of the association between GFAP and NfL with risk of a clinical diagnosis of dementia changed depending on cholesterol levels and on APOE ε4 genotype. No significant association was seen with p-tau181. Discussion In individuals with mixed pathology blood GFAP and NfL are better predictors of dementia risk than p-tau181, and their associations with dementia risk are amplified by hypercholesterolemia, also depending on APOE ε4 genotype. HIGHLIGHTS Cholesterol levels changed the association of blood biomarkers with dementia risk. Blood biomarkers seem to perform differently in community- and clinic-based cohorts. Neurofilament light chain might be a biomarker candidate for dementia risk after stroke

Vitamin D in the general population of young adults with autism in the Faroe Islands

Vitamin D deficiency has been proposed as a possible risk factor for developing autism spectrum disorder (ASD). 25-Hydroxyvitamin D3 (25(OH)D3) levels were examined in a cross-sectional population-based study in the Faroe Islands. The case group consisting of a total population cohort of 40 individuals with ASD (aged 15–24 years) had significantly lower 25(OH)D3 than their 62 typically-developing siblings and their 77 parents, and also significantly lower than 40 healthy age and gender matched comparisons. There was a trend for males having lower 25(OH)D3 than females. Effects of age, month/season of birth, IQ, various subcategories of ASD and Autism Diagnostic Observation Schedule score were also investigated, however, no association was found. The very low 25(OH)D3 in the ASD group suggests some underlying pathogenic mechanism

Burden of hip fracture using disability-adjusted life-years: a pooled analysis of prospective cohorts in the CHANCES consortium

Background No studies have estimated disability-adjusted life-years (DALYs) lost due to hip fractures using real-life follow-up cohort data. We aimed to quantify the burden of disease due to incident hip fracture using DALYs in prospective cohorts in the CHANCES consortium, and to calculate population attributable fractions based on DALYs for specific risk factors. Methods We used data from six cohorts of participants aged 50 years or older at recruitment to calculate DALYs. We applied disability weights proposed by the National Osteoporosis Foundation and did a series of sensitivity analyses to examine the robustness of DALY estimates. We calculated population attributable fractions for smoking, body-mass index (BMI), physical activity, alcohol intake, type 2 diabetes and parity, use of hormone replacement therapy, and oral contraceptives in women. We calculated summary risk estimates across cohorts with pooled analysis and randomeffects meta-analysis methods. Findings 223 880 men and women were followed up for a mean of 13 years (SD 6). 7724 (3·5%) participants developed an incident hip fracture, of whom 413 (5·3%) died as a result. 5964 DALYs (27 per 1000 individuals) were lost due to hip fractures, 1230 (20·6%) of which were in the group aged 75–79 years. 4150 (69·6%) DALYs were attributed to disability. Current smoking was the risk factor responsible for the greatest hip fracture burden (7·5%, 95% CI 5·2–9·7) followed by physical inactivity (5·5%, 2·1–8·5), history of diabetes (2·8%, 2·1–4·0), and low to average BMI (2·0%, 1·4–2·7), whereas low alcohol consumption (0·01–2·5 g per day) and high BMI had a protective effect. Interpretation Hip fracture can lead to a substantial loss of healthy life-years in elderly people. National public health policies should be strengthened to reduce hip fracture incidence and mortality. Primary prevention measures should be strengthened to prevent falls, and reduce smoking and a sedentary lifestyle

Subjective cognitive complaints and blood biomarkers of neurodegenerative diseases: a longitudinal cohort study

Background Subjective cognitive complaints (SCC) have been mostly studied in the context of Alzheimer’s disease in memory clinic settings. The potential of combining SCC with genetic information and blood biomarkers of neurodegenerative diseases for risk assessment of dementia and depression in the absence of dementia among community-dwelling older adults has so far not been explored. Methods Data were based on a population-based cohort of 6357 participants with a 17-year follow-up (ESTHER study) and a clinic-based cohort of 422 patients. Participants of both cohorts were grouped according to the diagnosis of dementia (yes/no) and the diagnosis of depression in the absence of dementia (yes/no). Participants without dementia included both cognitively unimpaired participants and cognitively impaired participants. Genetic information (APOE ε4 genotype) and blood-based biomarkers of neurodegenerative diseases (glial fibrillary acidic protein; GFAP, neurofilament light chain; NfL, phosphorylated tau181; p-tau181) were available in the ESTHER study and were determined with Simoa Technology in a nested case–control design. Logistic regression models adjusted for relevant confounders were run for the outcomes of all-cause dementia and depression in the absence of dementia. Results The results showed that persistent SCC were associated both with increased risk of all-cause dementia and of depression without dementia, independently of the diagnostic setting. However, the results for the ESTHER study also showed that the combination of subjective complaints with APOE ε4 and with increased GFAP concentrations in the blood yielded a substantially increased risk of all-cause dementia (OR 5.35; 95%CI 3.25–8.81, p-value < 0.0001 and OR 7.52; 95%CI 2.79–20.29, p-value < 0.0001, respectively) but not of depression. Associations of NfL and p-tau181 with risk of all-cause dementia and depression were not statistically significant, either alone or in combination with SCC, but increased concentrations of p-tau181 seemed to be associated with an increased risk for depression. Conclusion In community and clinical settings, SCC predict both dementia and depression in the absence of dementia. The addition of GFAP could differentiate between the risk of all-cause dementia and the risk of depression among individuals without dementia

Application of non-HDL cholesterol for population-based cardiovascular risk stratification: results from the Multinational Cardiovascular Risk Consortium.

BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524 444 individuals in the 44 cohorts in the Consortium database, we identified 398 846 individuals belonging to 38 cohorts (184 055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199 415 individuals were included in the derivation cohort (91 786 [48·4%] women) and 199 431 (92 269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54 542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research