SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the rapidly unfolding coronavirus disease 2019 (COVID-19) pandemic1,2. Clinical manifestations of COVID-19 vary, ranging from asymptomatic infection to respiratory failure. The mechanisms that determine such variable outcomes remain unresolved. Here we investigated CD4+ T cells that are reactive against the spike glycoprotein of SARS-CoV-2 in the peripheral blood of patients with COVID-19 and SARS-CoV-2-unexposed healthy donors. We detected spike-reactive CD4+ T cells not only in 83% of patients with COVID-19 but also in 35% of healthy donors. Spike-reactive CD4+ T cells in healthy donors were primarily active against C-terminal epitopes in the spike protein, which show a higher homology to spike glycoproteins of human endemic coronaviruses, compared with N-terminal epitopes. Spike-protein-reactive T cell lines generated from SARS-CoV-2-naive healthy donors responded similarly to the C-terminal region of the spike proteins of the human endemic coronaviruses 229E and OC43, as well as that of SARS-CoV-2. This results indicate that spike-protein cross-reactive T cells are present, which were probably generated during previous encounters with endemic coronaviruses. The effect of pre-existing SARS-CoV-2 cross-reactive T cells on clinical outcomes remains to be determined in larger cohorts. However, the presence of spike-protein cross-reactive T cells in a considerable fraction of the general population may affect the dynamics of the current pandemic, and has important implications for the design and analysis of upcoming trials investigating COVID-19 vaccines.

Is Short Sleep Bad for the Brain? Brain Structure and Cognitive Function in Short Sleepers.

Many sleep less than recommended without experiencing daytime sleepiness. According to prevailing views, short sleep increases risk of lower brain health and cognitive function. Chronic mild sleep deprivation could cause undetected sleep debt, negatively affecting cognitive function and brain health. However, it is possible that some have less sleep need and are more resistant to negative effects of sleep loss. We investigated this using a cross-sectional and longitudinal sample of 47,029 participants of both sexes (20-89 years) from the Lifebrain consortium, Human Connectome project (HCP) and UK Biobank (UKB), with measures of self-reported sleep, including 51,295 MRIs of the brain and cognitive tests. A total of 740 participants who reported to sleep <6 h did not experience daytime sleepiness or sleep problems/disturbances interfering with falling or staying asleep. These short sleepers showed significantly larger regional brain volumes than both short sleepers with daytime sleepiness and sleep problems (n = 1742) and participants sleeping the recommended 7-8 h (n = 3886). However, both groups of short sleepers showed slightly lower general cognitive function (GCA), 0.16 and 0.19 SDs, respectively. Analyses using accelerometer-estimated sleep duration confirmed the findings, and the associations remained after controlling for body mass index, depression symptoms, income, and education. The results suggest that some people can cope with less sleep without obvious negative associations with brain morphometry and that sleepiness and sleep problems may be more related to brain structural differences than duration. However, the slightly lower performance on tests of general cognitive abilities warrants closer examination in natural settings.SIGNIFICANCE STATEMENT Short habitual sleep is prevalent, with unknown consequences for brain health and cognitive performance. Here, we show that daytime sleepiness and sleep problems are more strongly related to regional brain volumes than sleep duration. However, participants sleeping ≤6 h had slightly lower scores on tests of general cognitive function (GCA). This indicates that sleep need is individual and that sleep duration per se is very weakly if at all related brain health, while daytime sleepiness and sleep problems may show somewhat stronger associations. The association between habitual short sleep and lower scores on tests of general cognitive abilities must be further scrutinized in natural settings.

Sex differences in the age-related decrease of spontaneous baroreflex function in healthy individuals.

The baroreflex is a powerful physiological mechanism for rapidly adjusting heart rate in response to changes in blood pressure. Spontaneous baroreflex sensitivity (BRS) has been shown to decrease with age. However, studies of sex differences in these age-related changes are rare. Here we investigated several markers of spontaneous baroreflex function in a large sample of healthy individuals. Cardiovascular signals were recorded in the supine position under carefully controlled resting conditions. After quality control, n = 980 subjects were divided into five age groups [age < 30 yr (n = 612), 30-39 yr (n = 140), 40-49 yr (n = 95), 50-59 yr (n = 61), and >60 yr (n = 72)]. Spontaneous baroreflex function was assessed in the time domain (bradycardic and tachycardic slope) and in the frequency domain in the low- and high-frequency band (LF-α, HF-α) applying the transfer function. General linear models showed a significant effect of factor age (P < 0.001) and an age × sex interaction effect (P < 0.05) on each indicator of the baroreflex function. Simple main effects showed a significantly higher BRS as indicated by tachycardic slope, LF-α and HF-α in middle-aged women compared with men (30-39 yr) and higher LF-α, bradycardic and tachycardic slope in men compared with women of the oldest age group (>60 yr). Changes in BRS over the lifespan suggest that baroreflex function declines more slowly but earlier in life in men than in women. Our findings could be linked to age-related changes in major sex hormone levels, suggesting significant implications for diverse cardiovascular outcomes and the implementation of targeted preventive strategies.NEW & NOTEWORTHY In this study, we demonstrate that the age-related decrease of spontaneous baroreflex sensitivity is different in men and women by analyzing resting state cardiovascular data of a large sample of healthy individuals.

Cutting Edge: Serum but Not Mucosal Antibody Responses Are Associated with Pre-Existing SARS-CoV-2 Spike Cross-Reactive CD4+ T Cells following BNT162b2 Vaccination in the Elderly.

Advanced age is a main risk factor for severe COVID-19. However, low vaccination efficacy and accelerated waning immunity have been reported in this age group. To elucidate age-related differences in immunogenicity, we analyzed human cellular, serological, and salivary SARS-CoV-2 spike glycoprotein-specific immune responses to the BNT162b2 COVID-19 vaccine in old (69-92 y) and middle-aged (24-57 y) vaccinees compared with natural infection (COVID-19 convalescents, 21-55 y of age). Serological humoral responses to vaccination excee-ded those of convalescents, but salivary anti-spike subunit 1 (S1) IgA and neutralizing capacity were less durable in vaccinees. In old vaccinees, we observed that pre-existing spike-specific CD4+ T cells are associated with efficient induction of anti-S1 IgG and neutralizing capacity in serum but not saliva. Our results suggest pre-existing SARS-CoV-2 cross-reactive CD4+ T cells as a predictor of an efficient COVID-19 vaccine-induced humoral immune response in old individuals.

Atlas of gut microbe-derived products from aromatic amino acids and risk of cardiovascular morbidity and mortality.

AIMS: Precision microbiome modulation as a novel treatment strategy is a rapidly evolving and sought goal. The aim of this study is to determine relationships among systemic gut microbial metabolite levels and incident cardiovascular disease risks to identify gut microbial pathways as possible targets for personalized therapeutic interventions. METHODS AND RESULTS: Stable isotope dilution mass spectrometry methods to quantitatively measure aromatic amino acids and their metabolites were used to examine sequential subjects undergoing elective diagnostic cardiac evaluation in two independent cohorts with longitudinal outcome data [US (n = 4000) and EU (n = 833) cohorts]. It was also used in plasma from humans and mice before vs. after a cocktail of poorly absorbed antibiotics to suppress gut microbiota. Multiple aromatic amino acid-derived metabolites that originate, at least in part, from gut bacteria are associated with incident (3-year) major adverse cardiovascular event (MACE) risks (myocardial infarction, stroke, or death) and all-cause mortality independent of traditional risk factors. Key gut microbiota-derived metabolites associated with incident MACE and poorer survival risks include: (i) phenylacetyl glutamine and phenylacetyl glycine (from phenylalanine); (ii) p-cresol (from tyrosine) yielding p-cresol sulfate and p-cresol glucuronide; (iii) 4-OH-phenyllactic acid (from tyrosine) yielding 4-OH-benzoic acid and 4-OH-hippuric acid; (iv) indole (from tryptophan) yielding indole glucuronide and indoxyl sulfate; (v) indole-3-pyruvic acid (from tryptophan) yielding indole-3-lactic acid and indole-3-acetyl-glutamine, and (vi) 5-OH-indole-3-acetic acid (from tryptophan). CONCLUSION: Key gut microbiota-generated metabolites derived from aromatic amino acids independently associated with incident adverse cardiovascular outcomes are identified, and thus will help focus future studies on gut-microbial metabolic outputs relevant to host cardiovascular health.

Today's Older Adults Are Cognitively Fitter Than Older Adults Were 20 Years Ago, but When and How They Decline Is No Different Than in the Past.

History-graded increases in older adults' levels of cognitive performance are well documented, but little is known about historical shifts in within-person change: cognitive decline and onset of decline. We combined harmonized perceptual-motor speed data from independent samples recruited in 1990 and 2010 to obtain 2,008 age-matched longitudinal observations (M = 78 years, 50% women) from 228 participants in the Berlin Aging Study (BASE) and 583 participants in the Berlin Aging Study II (BASE-II). We used nonlinear growth models that orthogonalized within- and between-person age effects and controlled for retest effects. At age 78, the later-born BASE-II cohort substantially outperformed the earlier-born BASE cohort (d = 1.20; 25 years of age difference). Age trajectories, however, were parallel, and there was no evidence of cohort differences in the amount or rate of decline and the onset of decline. Cognitive functioning has shifted to higher levels, but cognitive decline in old age appears to proceed similarly as it did two decades ago.

Diabetes type 2 in the Berlin Aging Study II: Cross-sectional and longitudinal data on prevalence, incidence and severity over on average seven years of follow-up.

AIMS: Aim of the current study was to describe the prevalence, incidence, and severity of diabetes mellitus type 2 (T2D) in a cohort of older men and women aged 60 years and above over the course of on average 7 years, since longitudinal data on this topic are scarce for this age group in Germany. METHODS: Baseline data of 1671 participants of the Berlin Aging Study II (BASE-II; 68.8 ± 3.7 years) and follow-up data assessed 7.4 ± 1.5 years later were analysed. The BASE-II is an exploratory, observational study on cross-sectional and longitudinal data of an older population. T2D was diagnosed based on self-report, antidiabetic medication use and laboratory parameters. T2D severity was determined by the diabetes complications severity index (DCSI). Prognostic capacity of laboratory parameters was evaluated. RESULTS: The proportion of participants with T2D increased from 12.9% (37.3% women) at baseline to 17.1% (41.1% women) with 74 incident cases and 22.2% not being aware of the disease at follow-up. The incidence rate is 10.7 new T2D diagnoses per 1000 person-years. More than half of the 41 newly identified incident T2D cases were diagnosed solely by the 2 h-plasma glucose test (OGTT) and diagnosis based on OGTT as the only criterion among incident cases was found more frequently in women (p = 0.028). T2D severity expressed by the DCSI significantly increased from baseline to follow-up (mean DCSI 1.1 ± 1.2 vs. 2.0 ± 1.8; range 0-5 vs. 0-6). Cardiovascular complications had the highest impact (43.2% at baseline and 67.6% at follow-up). CONCLUSIONS: A comprehensive picture of T2D with respect to prevalence, incidence, and severity in older people of the Berlin Aging Study II is provided.

High-Sensitivity Cardiac Troponin T and Cognitive Decline in Older Adults: Results of the Berlin Aging Study II.

INTRODUCTION: There is evidence of an association between markers of cardiac injury and cognition in patients with cardiovascular disease. We hypothesized that levels of high-sensitivity cardiac troponin T (hs-cTnT) are associated with cognitive performance and cognitive decline in a population of predominantly healthy older adults. METHODS: We included 1,226 predominantly healthy adults ≥60 years from the Berlin Aging Study II. Participants were recruited from the general population of the Berlin metropolitan area from 2009 to 2014. At baseline, participants underwent measurement of hs-cTnT and cognitive testing using the extended Consortium to Establish a Registry for Alzheimer's Disease (CERAD-Plus) battery. In addition, the Digit Symbol Substitution Test (DSST) was performed at baseline and at follow-up (7.3 ± 1.4 years after the baseline visit). The CERAD test results were summarized into four cognitive domains (processing speed, executive function, visuo-construction, and memory). After summing-up the respective raw scores, we calculated standardized z scores. We performed unadjusted and adjusted linear regression models to assess links between hs-cTnT and cognitive domains. We used linear mixed models to analyze associations between hs-cTnT and cognitive decline according to changes in DSST scores over time. RESULTS: The mean age of study participants at baseline was 68.5 (±3.6) years, 49% were female, and median hs-cTnT levels were 6 ng/L (IQR 4-8 ng/L). We detected no significant association between hs-cTnT and different cognitive domains at baseline after adjustment for age, sex, education, and cardiovascular risk factors. Hs-cTnT was associated with cognitive decline, which remained statistically significant after full adjustment (adjusted beta-coefficient -0.82 (-1.28 to -0.36), p = 0.001). After stratification for sex, the association with hs-cTnT remained statistically significant in men but not in women. CONCLUSION: Higher hs-cTnT levels in older men are associated with cognitive decline measured with the DSST.

Differentiating Sex and Gender Among Older Men and Women.

OBJECTIVE: This study aimed to paradigmatically show the development of a gender score that can be used as either an adjustment or a matching variable to separate the effects of gender versus biological sex in a sample of older adults. METHODS: Our sample comprised 1100 participants from the Berlin Aging Study II (52% women, mean [standard deviation] age = 75.6 [3.8] years). The gender score included a multitude of gender-related variables and was constructed via logistic regression. In models of health outcomes, it was used as an adjustment variable in regression analyses as well as a matching variable to match older men and women according to their gender. RESULTS: Matching by gender substantially reduced sample size to n = 340. Analyses (either adjusting for gender or matching men and women according to gender) revealed that female sex was independently associated with lower grip strength (B = -14.47, 95% confidence interval [CI] = -15.51 to -13.44), better cognitive performance (B = 3.47, 95% CI = 1.94 to 5.0), higher pulse wave velocity (B = 0.19, 95% CI = 0.06 to 0.31), lower body mass index (B = -0.97, 95% CI = -1.74 to -0.21), and lower rates of metabolic syndrome (odds ratio = 0.53, 95% CI = 0.37 to 0.77). In addition, both sex and gender were independently associated with cognitive performance and depression. CONCLUSIONS: Calculating a gender score allows for the inclusion of a large number of variables, creating parsimonious models that are adaptable to different data sets and alternative gender definitions. Depending on the research question and the sample properties, the gender score can be used as either an adjustment or a matching variable.Trial Registration: DRKS-Deutsches Register Klinischer Studien (Study ID: DRKS00016157).

Potential of prevention strategies for the modifiable risk factor type 2 diabetes with relation to the future number of dementia patients in Germany- a multi-state projection through 2040.

BACKGROUND: We assess the impact of prevention strategies regarding type 2 diabetes as a modifiable risk factor for dementia and its consequences for the future number of dementia patients in Germany. METHODS: We used a random sample of health claims data (N = 250,000) of insured persons aged 50+ drawn in 2014, and data on population size and death rates in 2015 from the Human Mortality Database. Using exponential hazard models, we calculated age- and sex-specific transition probabilities and death rates between the states (no diabetes/no dementia, diabetes/no dementia, no diabetes/dementia, diabetes/dementia). In multi-state projections, we estimated the future number of dementia cases aged 75+ through 2040 depending on the development of the incidence of diabetes among persons without diabetes and without dementia, and the dementia incidence among persons with and without diabetes. RESULTS: In 2015 there were 1.53 million people with dementia aged 75+ in Germany. A relative annual reduction in death rates of 2.5% and in dementia incidence in persons without diabetes of 1% will increase this number to 3.38 million by 2040. A relative reduction of diabetes incidence by 1% annually would decrease dementia cases by around 30,000, while a reduction of dementia incidence among people with diabetes by 1% would result in 220,000 fewer dementia cases. Both prevention strategies combined would prevent 240,000 dementia cases in 2040. CONCLUSIONS: The increase in life expectancy is decisive for the future number of people with dementia. Strategies of better diabetes treatment have the potential to lower the increase in the number of dementia patients in the coming decades.

Poor Self-Reported Sleep is Related to Regional Cortical Thinning in Aging but not Memory Decline-Results From the Lifebrain Consortium.

We examined whether sleep quality and quantity are associated with cortical and memory changes in cognitively healthy participants across the adult lifespan. Associations between self-reported sleep parameters (Pittsburgh Sleep Quality Index, PSQI) and longitudinal cortical change were tested using five samples from the Lifebrain consortium (n = 2205, 4363 MRIs, 18-92 years). In additional analyses, we tested coherence with cell-specific gene expression maps from the Allen Human Brain Atlas, and relations to changes in memory performance. "PSQI # 1 Subjective sleep quality" and "PSQI #5 Sleep disturbances" were related to thinning of the right lateral temporal cortex, with lower quality and more disturbances being associated with faster thinning. The association with "PSQI #5 Sleep disturbances" emerged after 60 years, especially in regions with high expression of genes related to oligodendrocytes and S1 pyramidal neurons. None of the sleep scales were related to a longitudinal change in episodic memory function, suggesting that sleep-related cortical changes were independent of cognitive decline. The relationship to cortical brain change suggests that self-reported sleep parameters are relevant in lifespan studies, but small effect sizes indicate that self-reported sleep is not a good biomarker of general cortical degeneration in healthy older adults.

Diabetes duration and the risk of dementia: a cohort study based on German health claims data.

OBJECTIVE: Diabetes is a risk factor for dementia but little is known about the impact of diabetes duration on the risk of dementia. We investigated the effect of type 2 diabetes duration on the risk of dementia. DESIGN: Prospective cohort study using health claims data representative for the older German population. The data contain information about diagnoses and medical prescriptions from the in- and outpatient sector. METHODS: We performed piecewise exponential models with a linear and a quadratic term for time since first type 2 diabetes diagnosis to predict the dementia risk in a sample of 13,761 subjects (2,558 dementia cases) older than 65 years. We controlled for severity of diabetes using the Adopted Diabetes Complications Severity Index. RESULTS: We found a U-shaped dementia risk over time. After type 2 diabetes diagnosis the dementia risk decreased (26% after 1 year) and reached a minimum at 4.75 years, followed by an increase through the end of follow-up. The pattern was consistent over different treatment groups, with the strongest U-shape for insulin treatment and for those with diabetes complications at the time of diabetes diagnosis. CONCLUSIONS: We identified a non-linear association of type 2 diabetes duration and the risk of dementia. Physicians should closely monitor cognitive function in diabetic patients beyond the first few years after diagnosis, because the later increase in dementia occurred in all treatment groups.

Sex Differences in Characteristics Associated with Potentially Inappropriate Medication Use and Associations with Functional Capacity in Older Participants of the Berlin Aging Study II.

INTRODUCTION: Medication safety is a vital aim in older adults' pharmacotherapy. Increased morbidity and vulnerability require particularly careful prescribing. Beneath avoiding unnecessary polypharmacy and prescribing omissions, physicians have to be aware of potentially inappropriate medications (PIMs) and related outcomes to optimize older adults' drug therapy, and to reduce adverse drug events. OBJECTIVE: The aim of this study was to identify participants characteristics associated with PIM use and associations of PIM use with functional capacity with a focus on sex differences. METHODS: Multivariable logistic regression analyses of cross-sectional Berlin Aging Study II (BASE-II) data (N = 1,382, median age 69 years, interquartile range 67-71, 51.3% women) were performed with PIM classification according to the EU(7)-PIM list. RESULTS: In the overall study population, higher education was associated with lower odds of PIM use (odds ratio [OR] 0.93, confidence interval [CI] 95% 0.87-0.99, p = 0.017). Falls (OR 1.53, CI 95% 1.08-2.17, p = 0.016), frailty/prefrailty (OR 1.68, 1.17-2.41, p = 0.005), and depression (OR 2.12, CI 95% 1.32-3.41, p = 0.002) were associated with increased odds of PIM use. A better nutritional status was associated with lower odds of PIM use (OR 0.88, CI 95% 0.81-0.97, p = 0.008). In the sex-stratified analysis, higher education was associated with lower odds of PIM use in men (OR 0.90, CI 95% 0.82-0.99, p = 0.032). Frailty/prefrailty was associated with increased odds of PIM use in men (OR 2.04, CI 95% 1.18-3.54, p = 0.011) and a better nutritional status was associated with lower odds of PIM use in men (OR 0.83, CI 95% 0.72-0.96, p = 0.011). Falls in the past 12 months were related to an increased prevalence of PIM use in women (OR 1.74, CI 95% 1.10-2.75, p = 0.019). Depression was associated with a higher prevalence of PIM use in both men (OR 2.74, CI 95% 1.20-6.24, p = 0.016) and women (OR 2.06, CI 95% 1.14-3.71, p = 0.017). We did not detect sex differences regarding the overall use of drugs with anticholinergic effects, but more men than women used PIMs referring to the cardiovascular system (p = 0.036), while more women than men used PIMs referring to the genitourinary system and sex hormones (p < 0.001). CONCLUSION: We found similarities, but also differences between men and women as to the associations between PIM use and participants' characteristics and functional capacity assessments. The association of lower education with PIM use may suggest that physicians' prescribing behavior is modified by patient education, a relationship that could evolve from more critical attitudes of educated patients towards medication use. We conclude that sex differences in associations of PIM use with functional capacities might be partly attributable to sex differences in drug classes used, but not with regard to anticholinergics, as these are used to a similar extent in men and women in the cohort studied here.

Muscle Mass and Inflammation in Older Adults: Impact of the Metabolic Syndrome.

BACKGROUND: Inflammatory processes are a cause of accelerated loss of muscle mass. Metabolic syndrome (MetS) is a highly prevalent age-related condition, which may promote and be promoted by inflammation. However, whether inflammation in MetS (metaflammation) is associated with lower muscle mass is still unclear. METHODS: Complete cross-sectional data on body composition, MetS, and the inflammatory markers interleukin (IL)-1ß, IL-6, IL-10, tumor necrosis factor (TNF), and C-reactive protein (CRP) were available for 1,377 BASE-II participants (51.1% women; 68 ± 4 years old). Appendicular lean mass (ALM) was assessed by dual-energy X-ray absorptiometry. Low muscle mass (low ALM-to-BMI ratio [ALMBMI]) was defined according to the Foundation for the National Institutes of Health (FNIH) Sarcopenia Project. Regression models, adjusted for an increasing number of confounders (sex, age, physical activity, morbidities, diabetes mellitus type II, TSH, albumin, HbA1c, smoking habits, alcohol intake, education, and energy intake/day), were used to calculate the association between low ALMBMI and high inflammation (tertile 3) according to MetS. RESULTS: MetS was present in 36.2% of the study population, and 9% had low ALMBMI. In the whole study population, high CRP (odds ratio [OR]: 2.7 [95% CI: 1.6-4.7; p = 0.001]) and high IL-6 (OR: 2.1 [95% CI: 1.2-1.9; p = 0.005]) were associated with low ALMBMI. In contrast, no significant association was found between TNF, IL-10, or IL-1ß with low ALMBMI. When participants were stratified by MetS, results for IL-6 remained significant only in participants with MetS. CONCLUSIONS: Among BASE-II participants, low ALMBMI was associated with inflammation. Low-grade inflammation triggered by disease state, especially in the context of MetS, might favor loss of muscle mass, so a better control of MetS might help to prevent sarcopenia. Intervention studies to test whether strategies to prevent MetS might also prevent loss of muscle mass seem to be promising.

Location, Location, Location: The Role of Objective Neighborhood Characteristics for Perceptions of Control.

INTRODUCTION: Control beliefs can protect against age-related declines in functioning. It is unclear whether neighborhood characteristics shape how much control people perceive over their life. This article studies associations of neighborhood characteristics with control beliefs of residents of a diverse metropolitan area (Berlin, Germany). METHODS: We combine self-report data about perceptions of control obtained from participants in the Berlin Aging Study II (N = 507, 60-87 years, 51% women) with multisource geo-referenced indicators of neighborhood characteristics using linear regression models. RESULTS: Findings indicate that objective neighborhood characteristics (i.e., unemployment rate) are indeed tied to perceptions of control, in particular, how much control participants feel others have over their lives. Including neighborhood characteristics in part doubled the amount of explained variance compared with a reference model covarying for demographic characteristics only (from R2 = 0.017 to R2 = 0.030 for internal control beliefs; R2 = 0.056 to R2 = 0.102 for external control beliefs in chance; R2 = 0.006 to R2 = 0.030 for external control beliefs in powerful others). DISCUSSION/CONCLUSION: Findings highlight the importance of access to neighborhood resources for control beliefs across old age and can inform interventions to build up neighborhood characteristics which might be especially helpful in residential areas with high unemployment.

Low-density lipoprotein cholesterol goal attainment in patients with clinical evidence of familial hypercholesterolemia and elevated Lp(a).

BACKGROUND: Although potent lipid-lowering therapies are available, patients commonly fall short of recommended low-density lipoprotein cholesterol (LDL-C) levels. The aim of this study was to examine the relationship between familial hypercholesterolemia (FH) and elevated lipoprotein(a) [Lp(a)] and LDL-C goal attainment, as well as the prevalence and severity of coronary artery disease (CAD). Moreover, we characterized patients failing to meet recommended LDL-C goals. METHODS: We performed a cross-sectional analysis in a cohort of patients undergoing cardiac catheterization. Clinical FH was determined by the Dutch Clinical Lipid Network Score, and Lp(a) ≥ 50 mg/dL (≈ 107 nmol/L) was considered elevated. RESULTS: A total of 838 participants were included. Overall, the prevalence of CAD was 72%, and 62% received lipid-lowering treatment. The prevalence of clinical FH (probable and definite FH) was 4%, and 19% had elevated Lp(a) levels. With 35%, LDL-C goal attainment was generally poor. Among the participants with clinical FH, none reached their LDL-C target. Among patients with elevated Lp(a), LDL-C target achievement was only 28%. The prevalence and severity of CAD were higher in participants with clinical FH (86% prevalence) and elevated Lp(a) (80% prevalence). CONCLUSION: Most participants failed to meet their individual LDL-C goals according to the ESC 2016 and 2019 guidelines. In particular, high-risk patients with clinical FH or elevated Lp(a) rarely met their target for LDL-C. The identification of these patients and more intense treatment approaches are crucial for the improvement of CAD primary and secondary prevention.

A common polymorphism in the dopamine transporter gene predicts working memory performance and in vivo dopamine integrity in aging.

Dopamine (DA) integrity is suggested as a potential cause of individual differences in working memory (WM) performance among older adults. Still, the principal dopaminergic mechanisms giving rise to WM differences remain unspecified. Here, 61 single-nucleotide polymorphisms, located in or adjacent to various dopamine-related genes, were assessed for their links to WM performance in a sample of 1313 adults aged 61-80 years from the Berlin Aging Study II. Least Absolute Shrinkage and Selection Operator (LASSO) regression was conducted to estimate associations between polymorphisms and WM. Rs40184 in the DA transporter gene, SLC6A3, showed allelic group differences in WM, with T-carriers performing better than C homozygotes (p<0.01). This finding was replicated in an independent sample from the Cognition, Brain, and Aging study (COBRA; baseline: n = 181, ages: 64-68 years; 5-year follow up: n = 129). In COBRA, in vivo DA integrity was measured with 11C-raclopride and positron emission tomography. Notably, WM as well as in vivo DA integrity was higher for rs40184 T-carriers at baseline (p<0.05 for WM and caudate and hippocampal D2-receptor availability) and at the 5-year follow-up (p<0.05 for WM and hippocampal D2 availability). Our findings indicate that individual differences in DA transporter function contribute to differences in WM performance in old age, presumably by regulating DA availability.

Vitamin D insufficiency is associated with metabolic syndrome independent of insulin resistance and obesity in young adults - The Berlin Aging Study II.

PURPOSE: Age-related changes affect vitamin D absorption and metabolism. Low 25-hydroxyvitamin D concentrations have been reported as risk factor for the development of metabolic syndrome (MetS). However, recent evaluations suggest this association might be explained by obesity or insulin resistance (IR) in subjects with MetS. Our aim was to analyze associations between vitamin D insufficiency and MetS in a young cohort without diabetes and two senior cohorts with and without diabetes. METHODS: Four hundred sixteen young and 1357 older BASE-II participants were analyzed. Type 2 diabetes (T2D) was defined according to European Society of Cardiology (ESC) guidelines, MetS as suggested by International Diabetes Federation/American Heart Association/National Heart, Lung and Blood Institute (IDF/AHA/NHLBI 2009). Vitamin D insufficiency was defined as 25-hydroxyvitamin D concentrations <50 nmol/L. Among other confounders, BMI and IR were taken into account. RESULTS: MetS was prevalent in 7.7% of the young and in 35.6% of the older BASE-II participants and T2D occurred in 12.7% of the older participants. In young subjects without diabetes, vitamin D insufficiency was associated with an independent 3.2-fold increased odds of having MetS (OR: 3.2 CI: 1.0-8.7; p = 0.042). However, in the older participants, this association was lost once BMI was taken into account among those with diabetes, and once IR was taken into account among those without diabetes. CONCLUSION: Independent associations between vitamin D insufficiency and MetS were only found among young subjects without diabetes. In the older adults, BMI annihilated these associations among subjects without diabetes as did HOMA-IR among subjects with diabetes.

Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia.

Autosomal-dominant familial hypercholesterolemia (FH) is characterized by increased plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and a substantial risk to develop cardiovascular disease. Causative mutations in three major genes are known: the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB) and the proprotein convertase subtilisin/kexin 9 gene (PCSK9). We clinically characterized 336 patients suspected to have FH and screened them for disease causing mutations in LDLR, APOB, and PCSK9. We genotyped six single nucleotide polymorphisms (SNPs) to calculate a polygenic risk score for the patients and 1985 controls. The 117 patients had a causative variant in one of the analyzed genes. Most variants were found in the LDLR gene (84.9%) with 11 novel mutations. The mean polygenic risk score was significantly higher in FH mutation negative subjects than in FH mutation positive patients (P < .05) and healthy controls (P < .001), whereas the score of the two latter groups did not differ significantly. However, the score explained only about 3% of the baseline LDL-C variance. We verified the previously described clinical and genetic variability of FH for German hypercholesterolemic patients. Evaluation of a six-SNP polygenic score recently proposed for clinical use suggests that it is not a reliable tool to classify hypercholesterolemic patients.

T cell phenotypes associated with insulin resistance: results from the Berlin Aging Study II.

BACKGROUND: Obesity is associated with chronic low-grade inflammation leading to metabolic and cardiovascular diseases, but a subset of obese individuals is considered insulin sensitive (IS). The underlying pathophysiologic mechanisms remain elusive and clinical studies on the relationship between inflammatory markers and metabolically healthy obesity (MHO) are scarce. METHODS: In this cross-sectional analysis, we included a sample of 437 older participants (60-84 years) from the Berlin Aging Study II (BASE-II). Peripheral blood mononuclear cells were isolated, immune cell subsets were analyzed with multiparameter flow cytometry and systemic cytokine levels were measured. Immune cell parameters were correlated with metabolic measures and multiple linear regression analysis was conducted and adjusted for various demographic and clinical factors. RESULTS: We found that frequencies of naïve and memory CD4+ and CD8+ T cells inversely correlated with measures for insulin sensitivity in the older population. Moreover, the percentages of naïve CD4+ and CD8+ T cells were significantly higher, whereas activated T cells and IL-6 levels were lower in IS compared to insulin resistant (IR) obese individuals. The percentages of naïve CD4+ and CD8+ T cells were predictive for impaired insulin sensitivity (ß = 0.16, p = 0.01 and ß = 0.11, p = 0.04), and the association of naïve CD4+ T cells with insulin sensitivity persisted after multivariate adjustment (ß = 0.14, p = 0.02). CONCLUSIONS: These findings support the hypothesis that parameters of systemic inflammation can differentiate IS from IR obese individuals that are at higher risk for cardiometabolic diseases and may have clinical implications with regard to obesity treatment stratification. TRIAL REGISTRATION: DRKS00009277 . Registered 31 August 2015 - Retrospectively registered.