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Although the common pathology of Alzheimer’s disease (AD) and white matter hyperintensities (WMH) is disputed, the gene TREML2 has been implicated in both conditions: its whole-blood gene expression was associated with WMH volume and its missense variant rs3747742 with AD risk. We re-examined those associations within one comprehensive dataset of the general population, additionally searched for cross-relations and illuminated the role of the apolipoprotein E (APOE) ε4 status in the associations. For our linear regression and linear mixed effect models, we used 1949 participants from the Study of Health in Pomerania (Germany). AD was assessed using a continuous pre-symptomatic MRI-based score evaluating a participant’s AD-related brain atrophy. In our study, increased whole-blood TREML2 gene expression was significantly associated with reduced WMH volume but not with the AD score. Conversely, rs3747742-C was significantly associated with a reduced AD score but not with WMH volume. The APOE status did not influence the associations. In sum, TREML2 robustly associated with WMH volume and AD-related brain atrophy on different molecular levels. Our results thus underpin TREML2’s role in neurodegeneration, might point to its involvement in AD and WMH via different biological mechanisms, and highlight TREML2 as a worthwhile target for disentangling the two pathologies.
A New Laboratory Workflow Integrating the Free Light Chains Kappa Quotient into Routine CSF Analysis
(2022)
We performed this cohort study to test whether further analysis of intrathecal inflammation can be omitted if the free light chain kappa (FLCκ) quotient is within the reference range in the corresponding quotient diagram. FLCκ concentrations were measured in serum and cerebrospinal fluid (CSF) samples. The intrathecal fraction (IF) of FLCκ was calculated in relation to the hyperbolic reference range. 679 patient samples were used as a discovery cohort (DC). The sensitivity and negative predictive value (NPV) of the FLCκ-IF for the detection of an intrathecal humoral immune response (CSF-specific OCB and/or IF IgG/A/M > 0%) was determined. Based on these data, a diagnostic algorithm was developed and prospectively validated in an independent validation cohort (VC, n = 278). The sensitivity of the FLCκ-IF was 98% in the DC and 97% in the VC with a corresponding NPV of 99%. The use of the FLCκ-IF as a first line analysis would have reduced the Ig and OCB analysis by 62% in the DC and 74% in the VC. The absence of a FLCκ-IF predicts the absence of a humoral intrathecal immune response with a very high NPV of 99%. Thus, integration of our proposed algorithm into routine CSF laboratory analysis could help to reduce analytical efforts.
Aim
To investigate the medium-term associations of serum protein subfractions derived from proton nuclear magnetic resonance (1H-NMR) spectroscopy with periodontitis and tooth loss.
Materials and Methods
A total of 3031 participants of the cohort Study of Health in Pomerania (SHIP-TREND) were included. In addition to conventional serum testing, serum lipoprotein contents and subfractions were analysed by 1H-NMR spectroscopy. Confounder-adjusted associations of lipoprotein variables with periodontitis and the number of missing teeth variables were analysed using mixed-effects models with random intercepts for time across individuals, accounting for multiple testing.
Results
While only spurious associations between lipoprotein levels from conventional blood tests were found—that is, triglycerides were associated with mean clinical attachment level (CAL) and low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/HDL-C) ratio with the number of missing teeth - several associations emerged from serum lipoprotein subfractions derived from 1H-NMR analysis. Specifically, elevated LDL triglycerides were associated with higher levels of mean probing depth (PD), mean CALs, and increased odds of having <20 teeth. HDL-4 cholesterol levels were inversely associated with mean PD. Systemic inflammation (C-reactive protein) might mediate the effects of LDL and HDL triglyceride contents on periodontitis severity.
Conclusions
Several associations between serum lipoprotein subfractions and periodontitis were observed. As the underlying biochemical mechanisms remain unclear, further research is needed.
Poor sleep quality or sleep deprivation may be related to decreased bone mineral density. We aimed to assess whether associations of sleep characteristics and bone turnover or strength are present in adults from the general population and whether these are independent of common risk factors such as sex, age, and obesity. A total of 1037 participants from the Study of Health in Pomerania-TREND underwent laboratory-based polysomnography and quantitative ultrasound measurements at the heel. Of these participants, 804 completed standardised questionnaires to assess daytime sleepiness, insomnia, and sleep quality. Serum concentrations of two bone turnover markers, intact amino-terminal propeptide of type 1 procollagen (P1NP) and carboxy-terminal telopeptide of type 1 collagen (CTX) were measured. Cross-sectional associations of polysomnography variables (total sleep time, sleep efficiency, time spent wake after sleep onset, oxygen desaturation index, apnea–hypopnea index, and obstructive sleep apnea [OSA]), as well as sleep questionnaire scores with the bone turnover markers and the ultrasound-based stiffness index were assessed in linear regression models. In adjusted models, higher insomnia scores and lower sleep quality scores were related to a higher bone turnover in women but not in men. However, associations between polysomnography variables or questionnaire scores and the stiffness index were absent. Our study provides limited evidence for relationships between sleep characteristics and bone turnover and strength independent of common risk factors for OSA and osteoporosis. Nevertheless, women reporting poor sleep or insomnia in combination with risk factors for osteoporosis might benefit from an evaluation of bone health.
Osteoporosis, a complex chronic disease with increasing prevalence, is characterised by reduced bone mineral density (BMD) and increased fracture risk. The high heritability of BMD suggests substantial impact of the individual genetic disposition on bone phenotypes and the development of osteoporosis. In the past years, genome-wide association studies (GWAS) identified hundreds of genetic variants associated with BMD or osteoporosis. Here, we analysed 1103 single nucleotide polymorphisms (SNPs), previously identified as associated with estimated BMD (eBMD) in the UK Biobank. We assessed whether these SNPs are related to heel stiffness index obtained by quantitative ultrasound in 5665 adult participants of the Study of Health in Pomerania (SHIP). We confirmed 45 significant associations after correction for multiple testing. Next, we analysed six selected SNPs in 631 patients evaluated for osteoporosis [rs2707518 (CPED1/WNT16), rs3779381 (WNT16), rs115242848 (LOC101927709/EN1), rs10239787 (JAZF1), rs603424 (PKD2L1) and rs6968704 (JAZF1)]. Differences in minor allele frequencies (MAF) of rs2707518 and rs3779381 between SHIP participants (higher MAF) and patients evaluated for osteoporosis (lower MAF) indicated a protective effect of the minor allele on bone integrity. In contrast, differences in MAF of rs603424 indicated a harmful effect. Co-localisation analyses indicated that the rs603424 effect may be mediated via stearoyl-CoA desaturase (SCD) expression, an enzyme highly expressed in adipose tissue with a crucial role in lipogenesis. Taken together, our results support the role of the WNT16 pathway in the regulation of bone properties and indicate a novel causal role of SCD expression in adipose tissue on bone integrity.
Deteriorations in slow wave sleep (SWS) have been linked to brain aging and Alzheimer’s disease (AD), possibly due to its key role in clearance of amyloid-beta and tau (Aß/tau), two pathogenic hallmarks of AD. Spermidine administration has been shown to improve sleep quality in animal models. So far, the association between spermidine levels in humans and parameters of SWS physiology are unknown but may be valuable for therapeutic strategies. Data from 216 participants (age range 50–81 years) of the population-based Study of Health in Pomerania TREND were included in our analysis. We investigated associations between spermidine plasma levels, key parameters of sleep macroarchitecture and microarchitecture that were previously associated with AD pathology, and brain health measured via a marker of structural brain atrophy (AD score). Higher spermidine levels were significantly associated with lower coupling between slow oscillations and spindle activity. No association was evident for SWS, slow oscillatory, and spindle activity throughout non-rapid eye movement sleep. Furthermore, elevated spermidine blood levels were significantly associated with a higher AD score, while sleep markers revealed no association with AD score. The association between higher spermidine levels and brain health was not mediated by coupling between slow oscillations and spindle activity. We report that higher spermidine blood levels are associated not only with deteriorated brain health but also with less advantageous markers of sleep quality in older adults. Future studies need to evaluate whether sleep, spermidine, and Aß/tau deposition are interrelated and whether sleep may play a mediating role.
Background and objectives
Various cross-sectional studies have observed an association between high circulating concentrations of the adipokine chemerin and an unfavorable metabolic profile. However, the prognostic value of chemerin for the risk of associated diseases and mortality was examined only in a few studies mostly using small and highly selected patient populations. We aimed to analyze the association between plasma chemerin concentrations and all-cause as well as cause-specific mortality in the general population.
Study design and methods
From the Study of Health in Pomerania (SHIP), participants of two independent cohorts (SHIP-START-1 [n = 3037], SHIP-TREND-0 [n = 4193]) were followed up for 15 and 9 years (median), respectively. The association between plasma chemerin and all-cause mortality was analyzed using multivariable Cox proportional hazard regression models. Additionally, cause-specific hazards for cardiovascular disease (CVD) and cancer mortality were modeled considering competing events.
Results
A total number of 507 and 208 deaths occurred during follow-up in SHIP-START-1 and SHIP-TREND-0, respectively. Multivariable regression analyses revealed a significant association between high plasma chemerin concentrations and greater overall mortality that was independent of major confounders. Each 30 ng/mL increase in chemerin was associated with a 17% higher risk of all-cause mortality (95%-confidence interval: 1.10–1.26). Cause-specific analyses further showed that the chemerin concentration was significantly associated with cancer mortality but not with CVD mortality.
Conclusion
The present study detected a positive association between plasma chemerin concentrations and all-cause mortality in a large population-based study sample. Cause-specific analyses have shown that chemerin is likely to play a decisive role in cancer-related deaths. However, a direct association with cardiovascular mortality could not be established.
The German Centre for Cardiovascular Research (DZHK) is one of the German Centres for Health Research and aims to conduct early and guideline-relevant studies to develop new therapies and diagnostics that impact the lives of people with cardiovascular disease. Therefore, DZHK members designed a collaboratively organised and integrated research platform connecting all sites and partners. The overarching objectives of the research platform are the standardisation of prospective data and biological sample collections among all studies and the development of a sustainable centrally standardised storage in compliance with general legal regulations and the FAIR principles. The main elements of the DZHK infrastructure are web-based and central units for data management, LIMS, IDMS, and transfer office, embedded in a framework consisting of the DZHK Use and Access Policy, and the Ethics and Data Protection Concept. This framework is characterised by a modular design allowing a high standardisation across all studies. For studies that require even tighter criteria additional quality levels are defined. In addition, the Public Open Data strategy is an important focus of DZHK. The DZHK operates as one legal entity holding all rights of data and biological sample usage, according to the DZHK Use and Access Policy. All DZHK studies collect a basic set of data and biosamples, accompanied by specific clinical and imaging data and biobanking. The DZHK infrastructure was constructed by scientists with the focus on the needs of scientists conducting clinical studies. Through this, the DZHK enables the interdisciplinary and multiple use of data and biological samples by scientists inside and outside the DZHK. So far, 27 DZHK studies recruited well over 11,200 participants suffering from major cardiovascular disorders such as myocardial infarction or heart failure. Currently, data and samples of five DZHK studies of the DZHK Heart Bank can be applied for.
Aims
Sphingosine-1-phosphate (S1P) is a signaling lipid, which is involved in several cellular processes including cell growth, proliferation, migration and apoptosis. The associations of serum S1P levels with cardiac geometry and function are still not clear. We investigated the associations of S1P with cardiac structure and systolic function in a population-based sample.
Methods and results
We performed cross-sectional analyses of 858 subjects (467 men; 54.4%), aged 22 to 81 years, from a sub-sample of the population-based Study of Health in Pomerania (SHIP-TREND-0). We analyzed the associations of serum S1P with structural and systolic function left ventricular (LV) and left atrial (LA) parameters as determined by magnetic resonance imaging (MRI) using sex-stratified multivariable-adjusted linear regression models. In men, MRI data showed that a 1 µmol/L lower S1P concentration was associated with an 18.1 mL (95% confidence interval [CI] 3.66–32.6; p = 0.014) larger LV end-diastolic volume (LVEDV), a 0.46 mm (95% CI 0.04–0.89; p = 0.034) greater LV wall thickness (LVWT) and a 16.3 g (95% CI 6.55–26.1; p = 0.001) higher LV mass (LVM). S1P was also associated with a 13.3 mL/beat (95% CI 4.49–22.1; p = 0.003) greater LV stroke volume (LVSV), an 18.7 cJ (95% CI 6.43–30.9; p = 0.003) greater LV stroke work (LVSW) and a 12.6 mL (95% CI 1.03–24.3; p = 0.033) larger LA end-diastolic volume (LAEDV). We did not find any significant associations in women.
Conclusions
In this population-based sample, lower levels of S1P were associated with higher LV wall thickness and mass, larger LV and LA chamber sizes and greater stroke volume and work of the LV in men, but not in women. Our results indicate that lower levels of S1P were associated with parameters related with cardiac geometry and systolic function in men, but not in women.