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PURPOSE: Specific genetic factors might serve as markers for risk stratification of AMD progression, but their association with key features of AMD has not been fully elucidated. Thus, we investigated the association between overall and pathway-specific genetic risk scores (GRS) and lead loci (ARMS2, CFH) with AMD stages and features of high-risk nonlate AMD, including reticular pseudodrusen (RPD) and large drusen area (LDA). METHODS: We performed a cross-sectional analysis of data from the Rhineland Study, a population-based study in Bonn, Germany. We included 4016 individuals aged 50 years and older of European descent. GRS and pathway-specific subscores were constructed based on a large genome-wide association study of AMD. Subscores were generated based on gene-pathways associations (complement, extracellular matrix remodeling (ECM) and lipid metabolism). Associations were assessed using logistic and multinomial regression. RESULTS: The mean age of participants was 63.36 years and 1813 (45.1%) were men. The GRS was positive in 48.1% of individuals and increased, but did not fully overlap, across AMD stages. Pathway-specific subscores increased across AMD stages except for the ECM subscore, which only showed a trend for increasing in late AMD. Increasing overall GRS was associated with RPD and LDA (OR [95%CI] for RPD: 1.70 [1.33-2.15], for LDA: 1.64 [1.29-2.07]) among individuals with AMD. Similarly, higher complement and ECM subscores was associated with RPD, while for LDA, only an association with complement subscore was observed. CONCLUSIONS: In a population-based setting, we confirmed higher genetic risk to be associated with more severe AMD and identified associations with high-risk features of intermediate AMD. Conjoint analyses suggested that high-risk features and late AMD might be differentially associated with genetic architecture in AMD, such as ECM remodeling. Incorporation of genetic information such as GRSs might improve AMD risk prediction strategies.
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IMPORTANCE: Olfactory dysfunction is among the earliest signs of many age-related neurodegenerative diseases and has been associated with increased mortality in older adults; however, its genetic basis remains largely unknown. OBJECTIVE: To identify the genetic loci associated with olfactory dysfunction in the general population. DESIGN SETTING AND PARTIICIPANTS: This genome-wide association study meta-analysis (GWMA) included participants of European ancestry (N = 22,730) enrolled in four different large population-based studies, followed by a multi-ancestry GWMA including participants of African ancestry (N = 1,030). The data analysis was performed from March 2023 through June 2024. EXPOSURES: Genome-wide single nucleotide polymorphisms. MAIN OUTCOMES AND MEASURES: Olfactory dysfunction was the outcome and assessed using a 12-item smell identification test. RESULTS: GWMA revealed a novel genome-wide significant locus (tagged by rs11228623 at 11q12) associated with olfactory dysfunction. Gene-based analysis revealed a high enrichment for olfactory receptor genes in this region. Phenome-wide association studies demonstrated associations between genetic variants related to olfactory dysfunction and blood cell counts, kidney function, skeletal muscle mass, cholesterol levels and cardiovascular disease. Using individual-level data, we also confirmed and quantified the strength of these associations on a phenotypic level. Moreover, employing two-sample Mendelian Randomization analyses, we found evidence for causal associations between olfactory dysfunction and these phenotypes. CONCLUSIONS: These findings provide novel insights into the genetic architecture of the sense of smell and highlight its importance for many aspects of human health.
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INTRODUCTION: Blood-derived microRNAs (miRNAs) are potential candidates for detecting and preventing subclinical cognitive dysfunction. However, replication of previous findings and identification of novel miRNAs associated with cognitive domains, including their relation to brain structure and the pathways they regulate, are still lacking. METHODS: We examined blood-derived miRNAs and miRNA co-expression clusters in relation to cognitive domains, structural magnetic resonance imaging measures, target gene expression, and genetic variants in 2869 participants of a population-based cohort. RESULTS: Five previously identified and 14 novel miRNAs were associated with cognitive domains. Eleven of these were also associated with cortical thickness and two with hippocampal volume. Multi-omics analysis showed that certain identified miRNAs were genetically influenced and regulated genes in pathways like neurogenesis and synapse assembly. DISCUSSION: We identified miRNAs associated with cognitive domains, brain regions, and neuronal processes affected by aging and neurodegeneration, making them promising candidate blood-based biomarkers or therapeutic targets of subclinical cognitive dysfunction. HIGHLIGHTS: We investigated the association of blood-derived microRNAs with cognitive domains. Five previously identified and 14 novel microRNAs were associated with cognition. Eleven cognition-related microRNAs were also associated with cortical thickness. Identified microRNAs were linked to genes associated with neuronal functions. Results provide putative biomarkers or therapeutic targets of cognitive aging.
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BACKGROUND: As key regulators of gene expression, microRNAs affect many cardiovascular mechanisms and have been associated with several cardiovascular diseases. In this study, we aimed to investigate the relation of whole blood microRNAs with several quantitative measurements of vascular function, and explore their biological role through an integrative microRNA-gene expression analysis. METHODS: Peripheral whole blood microRNA expression was assessed through RNA-Seq in 2606 participants (45.8% men, mean age: 53.93, age range: 30 to 95 years) from the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany. Weighted gene co-expression network analysis was used to cluster microRNAs with highly correlated expression levels into 14 modules. Through linear regression models, we investigated the association between each module's expression and quantitative markers of vascular health, including pulse wave velocity, total arterial compliance index, cardiac index, stroke index, systemic vascular resistance index, reactive skin hyperemia and white matter hyperintensity burden. For each module associated with at least one trait, one or more hub-microRNAs driving the association were defined. Hub-microRNAs were further characterized through mapping to putative target genes followed by gene ontology pathway analysis. RESULTS: Four modules, represented by hub-microRNAs miR-320 family, miR-378 family, miR-3605-3p, miR-6747-3p, miR-6786-3p, and miR-330-5p, were associated with total arterial compliance index. Importantly, the miR-320 family module was also associated with white matter hyperintensity burden, an effect partially mediated through arterial compliance. Furthermore, hub-microRNA miR-192-5p was related to cardiac index. Functional analysis corroborated the relevance of the identified microRNAs for vascular function by revealing, among others, enrichment for pathways involved in blood vessel morphogenesis and development, angiogenesis, telomere organization and maintenance, and insulin secretion. CONCLUSIONS: We identified several microRNAs robustly associated with cardiovascular function, especially arterial compliance and cardiac output. Moreover, our results highlight miR-320 as a regulator of cerebrovascular damage, partly through modulation of vascular function. As many of these microRNAs were involved in biological processes related to vasculature development and aging, our results contribute to the understanding of vascular physiology and provide putative targets for cardiovascular disease prevention.
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MicroRNAs , Humans , Male , Middle Aged , Female , MicroRNAs/blood , MicroRNAs/genetics , Aged , Adult , Aged, 80 and over , Gene Regulatory Networks , Gene Expression Regulation , Blood Vessels/physiology , Cohort Studies , Gene Ontology , Gene Expression ProfilingABSTRACT
Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia. Genetic risk loci for white matter hyperintensities (WMH), the most common MRI-marker of cSVD in older age, were recently shown to be significantly associated with white matter (WM) microstructure on diffusion tensor imaging (signal-based) in young adults. To provide new insights into these early changes in WM microstructure and their relation with cSVD, we sought to explore the genetic underpinnings of cutting-edge tissue-based diffusion imaging markers across the adult lifespan. We conducted a genome-wide association study of neurite orientation dispersion and density imaging (NODDI) markers in young adults (i-Share study: N = 1 758, (mean[range]) 22.1[18-35] years), with follow-up in young middle-aged (Rhineland Study: N = 714, 35.2[30-40] years) and late middle-aged to older individuals (UK Biobank: N = 33 224, 64.3[45-82] years). We identified 21 loci associated with NODDI markers across brain regions in young adults. The most robust association, replicated in both follow-up cohorts, was with Neurite Density Index (NDI) at chr5q14.3, a known WMH locus in VCAN. Two additional loci were replicated in UK Biobank, at chr17q21.2 with NDI, and chr19q13.12 with Orientation Dispersion Index (ODI). Transcriptome-wide association studies showed associations of STAT3 expression in arterial and adipose tissue (chr17q21.2) with NDI, and of several genes at chr19q13.12 with ODI. Genetic susceptibility to larger WMH volume, but not to vascular risk factors, was significantly associated with decreased NDI in young adults, especially in regions known to harbor WMH in older age. Individually, seven of 25 known WMH risk loci were associated with NDI in young adults. In conclusion, we identified multiple novel genetic risk loci associated with NODDI markers, particularly NDI, in early adulthood. These point to possible early-life mechanisms underlying cSVD and to processes involving remyelination, neurodevelopment and neurodegeneration, with a potential for novel approaches to prevention.
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Expansions of glutamine-coding CAG trinucleotide repeats cause a number of neurodegenerative diseases, including Huntington's disease and several of spinocerebellar ataxias. In general, age-at-onset of the polyglutamine diseases is inversely correlated with the size of the respective inherited expanded CAG repeat. Expanded CAG repeats are also somatically unstable in certain tissues, and age-at-onset of Huntington's disease corrected for individual HTT CAG repeat length (i.e. residual age-at-onset), is modified by repeat instability-related DNA maintenance/repair genes as demonstrated by recent genome-wide association studies. Modification of one polyglutamine disease (e.g. Huntington's disease) by the repeat length of another (e.g. ATXN3, CAG expansions in which cause spinocerebellar ataxia 3) has also been hypothesized. Consequently, we determined whether age-at-onset in Huntington's disease is modified by the CAG repeats of other polyglutamine disease genes. We found that the CAG measured repeat sizes of other polyglutamine disease genes that were polymorphic in Huntington's disease participants but did not influence Huntington's disease age-at-onset. Additional analysis focusing specifically on ATXN3 in a larger sample set (n = 1388) confirmed the lack of association between Huntington's disease residual age-at-onset and ATXN3 CAG repeat length. Additionally, neither our Huntington's disease onset modifier genome-wide association studies single nucleotide polymorphism data nor imputed short tandem repeat data supported the involvement of other polyglutamine disease genes in modifying Huntington's disease. By contrast, our genome-wide association studies based on imputed short tandem repeats revealed significant modification signals for other genomic regions. Together, our short tandem repeat genome-wide association studies show that modification of Huntington's disease is associated with short tandem repeats that do not involve other polyglutamine disease-causing genes, refining the landscape of Huntington's disease modification and highlighting the importance of rigorous data analysis, especially in genetic studies testing candidate modifiers.
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INTRODUCTION: Cleaners perform a vital role in environmental health by keeping the place clean, but they are also exposed to various hazards. Yet, there is a lack of effective and accessible occupational safety standard measures, thus making this to be difficult to monitor the long-term health effects of cleaners. This study aims to determine the respirable dust exposure on respiratory symptoms among cleaners in a public university in Selangor. MATERIALS AND METHODS: A cross-sectional study was carried out among 51 cleaners. The respondents' background information and respiratory symptoms were gathered using a series of standardised questionnaires validated by the American Thoracic Society (ATS-DLD-78-A). The 8- hour respirable dust exposure to cleaners was measured using an air sampling pump (Gillian & Sensodyne Gil Air 3). RESULTS: The mean of respirable dust was lower than permissible exposure limit with 0.63±0.57mg/m3. The respiratory symptoms among the cleaners showed no significant association between cough, phlegm, and breathing difficulties with working tenure. Meanwhile, wheezing and coughing with phlegm have an almost significant association with working tenure among cleaners with (Χ2=1.00, p=0.08) and (Χ2=1.00, p=0.07) respectively. Exposure to respirable dust has exhibited 6 times the prevalence of coughing with phlegm among cleaners (PR=6.28, 95% CI: 0.44, 89.38). CONCLUSION: The findings of this study demonstrated that the cleaners were significantly affected by the respirable dust. The cleaners' working environment has caused them to be exposed to respirable dust.
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Air Pollutants, Occupational , Lung Diseases , Occupational Exposure , Humans , Occupational Exposure/adverse effects , Air Pollutants, Occupational/analysis , Cross-Sectional Studies , Malaysia/epidemiology , Universities , Cough/epidemiology , Cough/etiology , Dust/analysisABSTRACT
Shorter leukocyte telomere length (LTL) is associated with cardiovascular dysfunction. Whether this association differs between measured and genetically predicted LTL is still unclear. Moreover, the molecular processes underlying the association remain largely unknown. We used baseline data of the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany [56.2% women, age: 55.5 ± 14.0 years (range 30 - 95 years)]. We calculated genetically predicted LTL in 4180 participants and measured LTL in a subset of 1828 participants with qPCR. Using multivariable regression, we examined the association of measured and genetically predicted LTL, and the difference between measured and genetically predicted LTL (ΔLTL), with four vascular functional domains and the overall vascular health. Moreover, we performed epigenome-wide association studies of three LTL measures. Longer measured LTL was associated with better microvascular and cardiac function. Longer predicted LTL was associated with better cardiac function. Larger ΔLTL was associated with better microvascular and cardiac function and overall vascular health, independent of genetically predicted LTL. Several CpGs were associated (p < 1e-05) with measured LTL (n = 5), genetically predicted LTL (n = 8), and ΔLTL (n = 27). Genes whose methylation status was associated with ΔLTL were enriched in vascular endothelial signaling pathways and have been linked to environmental exposures, cardiovascular diseases, and mortality. Our findings suggest that non-genetic causes of LTL contribute to microvascular and cardiac function and overall vascular health, through an effect on the vascular endothelial signaling pathway. Interventions that counteract LTL may thus improve vascular function.
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Leukocytes , Telomere , Humans , Female , Aged , Aged, 80 and over , Male , Cohort Studies , Longitudinal Studies , Phenotype , Leukocytes/metabolism , Telomere/geneticsABSTRACT
BACKGROUND: Postoperative shunt infection is a nightmare in neurosurgical practice with additional morbidity and mortality. A lot of protocols have contributed to the reduction of ventriculoperitoneal shunt (VPS) infections but not eradication. The aim of the study was to evaluate the rigid application of a modified Hydrocephalus Clinical Research Network (HCRN) protocol in the prevention of postoperative shunt infection. METHODS: We retrospectively evaluated children with congenital hydrocephalus who underwent VPS insertion, and in whom the protocol was applied from June 2019 to January 2020. Follow-up ranged from 11 to 24 months. RESULTS: Thirty-seven procedures were performed including 35 primary shunt insertions and two revision surgeries. The median age was 5 months (range, 1-30 months), and 25 patients were males. The most common cause for VPS placement was congenital hydrocephalus without identifiable cause in 28 cases (80%). The endoscope-assisted technique was used in the insertion of the proximal end in six cases (17%). The mean follow-up was 19.4 months (11-24 months). The rate of shunt infection was 0% till the last follow-up. CONCLUSION: The preliminary results showed an effective method for the prevention of postoperative shunt infections using the modified protocol. These initial findings need to be validated in a large prospective study before widespread application can be recommended.
Subject(s)
Hydrocephalus , Child , Male , Humans , Infant , Child, Preschool , Female , Retrospective Studies , Prospective Studies , Hydrocephalus/surgery , Hydrocephalus/etiology , Ventriculoperitoneal Shunt/adverse effects , Ventriculoperitoneal Shunt/methods , Postoperative Complications/epidemiology , Postoperative Complications/prevention & control , Postoperative Complications/surgeryABSTRACT
This study is concerned with the iridium-palladium (Ir-Pd) binary alloy as a counter electrode (CE) for DSSC. The CE was prepared using the liquid phase deposition (LPD) technique. The influence of the concentration of hydrogen hexachloroiridate(IV) hydrate (H2Cl6Ir·H2O) on the properties and the performance of the device was investigated. The source of iridium was H2Cl6Ir·H2O. XRD analysis confirmed that the dominant phase of Ir-Pd existed in the sample. The grain size of Ir-Pd increased with the increase in the concentration of H2Cl6Ir·H2O until an optimum concentration of 0.7 mM was reached. The % wt of Ir was found to increase with the concentration of H2Cl6Ir·H2O. The device utilizing Ir-Pd CE with 0.7 mM H2Cl6Ir·H2O demonstrated the highest power conversion efficiency (PCE) of 5.84%, beating that of the device with Pt CE having a PCE of 5.04%. This is because the device possesses the lowest charge transfer resistance (Rct), highest recombination resistance (Rcr), and longest carrier lifetime (τ), and the device possesses the highest reduction current (Jpc) and incident-photon conversion efficiency (IPCE). The PCE was significantly affected by Ir content in the binary alloy of Ir-Pd. According to the PCE result, Ir-Pd CE was found as a suitable substitution for Pt as CE for the device.
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Lipid signaling is involved in longevity regulation, but which specific lipid molecular species affect human biological aging remains largely unknown. We investigated the relation between complex lipids and DNA methylation-based metrics of biological aging among 4181 participants (mean age 55.1 years (range 30.0-95.0)) from the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany. The absolute concentration of 14 lipid classes, covering 964 molecular species and 267 fatty acid composites, was measured by Metabolon Complex Lipid Panel. DNA methylation-based metrics of biological aging (AgeAccelPheno and AgeAccelGrim) were calculated based on published algorithms. Epigenome-wide association analyses (EWAS) of biological aging-associated lipids and pathway analysis were performed to gain biological insights into the mechanisms underlying the effects of lipidomics on biological aging. We found that higher levels of molecular species belonging to neutral lipids, phosphatidylethanolamines, phosphatidylinositols, and dihydroceramides were associated with faster biological aging, whereas higher levels of lysophosphatidylcholine, hexosylceramide, and lactosylceramide species were associated with slower biological aging. Ceramide, phosphatidylcholine, and lysophosphatidylethanolamine species with odd-numbered fatty acid tail lengths were associated with slower biological aging, whereas those with even-numbered chain lengths were associated with faster biological aging. EWAS combined with functional pathway analysis revealed several complex lipids associated with biological aging as important regulators of known longevity and aging-related pathways.
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Lipidomics , Longevity , Adult , Humans , Middle Aged , Aged , Aged, 80 and over , Longevity/genetics , Cohort Studies , Aging/genetics , Aging/metabolism , DNA Methylation/genetics , Fatty Acids , Epigenesis, GeneticABSTRACT
OBJECTIVE: The study describes the development and testing of a dry surface stimulation flexible electrode (herein referred to as Flexatrode), a low-cost, flexible, and scalable elastomeric nanocomposite using carbon black (CB) and polydimethylsiloxane (PDMS). METHODS: Flexatrodes composed of CB and PDMS were developed and tested for mechanical and functional stability up to 7 days. Uniform CB distribution was achieved by optimizing the dispersion process using toluene and methyl-terminated PDMS. Electromechanical testing in the through thickness directions over a long-term duration demonstrated stability of Flexatrode. Thermal stability of Flexatrode for up to a week was tested and validated, thus mitigating concerns of heat generation and deleterious skin reactions such as vasodilation or erythema. RESULTS: 25 wt.% CB was determined to be the optimal concentration. Electrical and thermal stability were demonstrated in the through thickness direction. CONCLUSION: Flexatrode provides stable electrical properties combined with high flexibility and elasticity. Electrotherapy treated chronic wounds were 81.9% smaller than baseline at day 10. Wounds that received an inactive device (device without any electrical stimulation) were 58.1% smaller than baseline and wounds that received standard of care treatment were 62.2% smaller than baseline. SIGNIFICANCE: The increasing need for wearable bioelectronics requiring long-term monitoring/treatment has highlighted the limitations of sustained use of gel-based electrodes. These can include skin irritation, bacterial overgrowth at the electrode site, gel dehydration over time, and signal degradation due to eccrine sweat formation. Flexatrode provides stable performance in a nanocomposite with scalable fabrication, thus providing a promising platform technology for wearable bioelectronics.
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Nanocomposites , Electric Conductivity , Elasticity , ElectrodesABSTRACT
HostSeq was launched in April 2020 as a national initiative to integrate whole genome sequencing data from 10,000 Canadians infected with SARS-CoV-2 with clinical information related to their disease experience. The mandate of HostSeq is to support the Canadian and international research communities in their efforts to understand the risk factors for disease and associated health outcomes and support the development of interventions such as vaccines and therapeutics. HostSeq is a collaboration among 13 independent epidemiological studies of SARS-CoV-2 across five provinces in Canada. Aggregated data collected by HostSeq are made available to the public through two data portals: a phenotype portal showing summaries of major variables and their distributions, and a variant search portal enabling queries in a genomic region. Individual-level data is available to the global research community for health research through a Data Access Agreement and Data Access Compliance Office approval. Here we provide an overview of the collective project design along with summary level information for HostSeq. We highlight several statistical considerations for researchers using the HostSeq platform regarding data aggregation, sampling mechanism, covariate adjustment, and X chromosome analysis. In addition to serving as a rich data source, the diversity of study designs, sample sizes, and research objectives among the participating studies provides unique opportunities for the research community.
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COVID-19 , SARS-CoV-2 , Humans , SARS-CoV-2/genetics , COVID-19/epidemiology , Canada/epidemiology , Genomics , Whole Genome SequencingABSTRACT
INTRODUCTION: Mixed warm and cold autoimmune haemolytic anaemia (AIHA) secondary to COVID-19 is rarely reported. CASE REPORT: We present a case of a 65-year-old Malay lady with no known medical illness, who was admitted for COVID-19 category 3 and mixed warm and cold AIHA. She presented with lethargy, productive cough and on and off fever. Blood investigations showed severe anaemia with spurious macrocytosis, increased lactate dehydrogenase (LDH) and total bilirubin with indirect bilirubin predominance. On full blood picture (FBP), there was normocytic normochromic anaemia with reticulocytosis, red blood cells clumping and NRBC's were seen. Both anti-IgG and anti-C3d were positive for monospecific Coombs test. For indirect Coombs test, auto-IgG and cold agglutinin were detected. DISCUSSION: These findings were consistent with mixed warm and cold AIHA. She was treated with intravenous methylprednisolone, before being changed to high dose oral prednisolone. A total of 3 units packed cells were transfused.
Subject(s)
Anemia, Hemolytic, Autoimmune , COVID-19 , Female , Humans , Aged , Anemia, Hemolytic, Autoimmune/diagnosis , Anemia, Hemolytic, Autoimmune/drug therapy , COVID-19/complications , Prednisolone/therapeutic useABSTRACT
INTRODUCTION: Dementia is a global challenge for healthcare systems, including Malaysia. Despite evidence-based Clinical Practice Guidelines (CPG) for dementia management in primary care, detection is poor. Improving detection rates requires understanding current practice and influencing factors. This study aims to assess the practice of cognitive evaluation among primary care practitioners (PCPs) and its associated factors, as well as its correlation with their knowledge and attitudes towards early dementia diagnosis. MATERIALS AND METHODS: A cross-sectional study conducted online, using Google FormTM recruited 207 Medical Officers from 14 public primary health centres, with a response rate of 74%. The Knowledge, Attitude and Practice Questionnaire for Family Physicians (KAPQFP) was used to assess PCPs' knowledge, attitude and practice in dementia care. Items in each domain were scored on a 4-point Likert scale, with scores ranging from 1 to 4. Each domain's mean score was divided by 4 and converted to a scale of 100, with higher scores indicating better knowledge, attitude and practice. Bivariate analyses were conducted to determine the factors associated with cognitive evaluation practice. RESULTS: The overall mean practice score was 3.53±0.52 (88.3%), which is substantially higher than the mean score for perceived competency and knowledge of 2.46±0.51 (61.5%). The mean score for attitude towards dementia and collaboration with nurses and other healthcare professionals was 3.36±0.49 (84.0%) and 3.43±0.71 (85.8%), respectively. PCPs with prior dementia training showed better practice (p=0.006), as did PCPs with longer primary care work experience (p=0.038). A significant positive association was found between knowledge-practice ((rs=0.207, p=0.003), attitude towards dementia practice ((rs=0.478, p<0.001), and attitude towards collaboration with other healthcare professionals-practice (rs= 0.427, p<0.001). Limited time and inadequate knowledge regarding dementia diagnosis and cognitive evaluation tools were among the reasons cognitive evaluations were not performed. CONCLUSION: PCPs demonstrated better practice of cognitive evaluation, as compared to their knowledge and attitude. Given that their perceived competency and knowledge on dementia diagnosis is low and is positively associated with their practice, it is crucial to implement a comprehensive dementia training to enhance their knowledge and confidence on early detection of cognitive decline and cognitive evaluation in order to achieve better dementia detection in primary care.
Subject(s)
Attitude of Health Personnel , Dementia , Humans , Cross-Sectional Studies , Health Personnel , Dementia/diagnosis , Primary Health CareABSTRACT
Individuals with a similar chronological age can exhibit marked differences in cardiovascular risk profiles, but it is unknown whether this variation is related to different rates of biological aging. Therefore, we investigated the relation between nine domains of cardiovascular function and four epigenetic age acceleration estimators (i.e., AgeAccel.Horvath, AgeAccel.Hannum, AgeAccelPheno, and AgeAccelGrim), derived from DNA methylation profiles. Among 4194 participants (mean age 54.2 years (range 30.0-95.0)) from the Rhineland Study, an ongoing population-based cohort study in Bonn, Germany, epigenetic age acceleration increased by 0.19-1.84 years per standard deviation (SD) increase in cardiovascular risk across multiple domains, including measures of kidney function, adiposity, and a composite cardiovascular risk score. Measures of inflammation and glucose homeostasis were associated with AgeAccel.Hannum, AgeAccelPheno, and AgeAccelGrim, but not with AgeAccel.Horvath. Moreover, effect sizes were larger for AgeAccelPheno and AgeAccelGrim than for AgeAccel.Horvath and AgeAccel.Hannum. Similarly, epigenetic age acceleration increased by 0.15-0.81 years per SD increase in markers of vascular function (blood pressure, arterial stiffness, and hemodynamic measures), whereas better endothelial function was only associated with lower AgeAccelGrim. Most effects on epigenetic age acceleration were independent, which suggests they independently contribute to different rates of biological aging.
Subject(s)
Epigenesis, Genetic , Longevity , Humans , Aged , Aged, 80 and over , Longevity/genetics , Cohort Studies , Epigenesis, Genetic/genetics , DNA Methylation/genetics , Aging/geneticsABSTRACT
Visual impairment and retinal neurodegeneration are intrinsically connected and both have been associated with cognitive impairment and brain atrophy, but the underlying mechanisms remain unclear. To investigate whether transneuronal degeneration is implicated, we systematically assessed the relation between visual function and retinal, visual pathway, hippocampal and brain degeneration. We analyzed baseline data from 3316 eligible Rhineland Study participants with visual acuity (VA), optical coherence tomography (OCT), and magnetic resonance imaging (MRI) data available. Regional volumes, cortical volume, and fractional anisotropy (FA) were derived from T1-weighted and diffusion-weighted 3 T MRI scans. Statistical analyses were performed using multivariable linear regression and structural equation modeling. VA and ganglion cell layer (GCL) thinning were both associated with global brain atrophy (SD effect size [95% CI] -0.090 [-0.118 to -0.062] and 0.066 [0.053-0.080], respectively), and hippocampal atrophy (-0.029 [-0.055 to -0.003] and 0.114 [0.087-0.141], respectively). The effect of VA on whole brain and hippocampal volume was partly mediated by retinal neurodegeneration. Similarly, the effect of retinal neurodegeneration on brain and hippocampal atrophy was mediated through intermediate visual tracts, accounting for 5.2%-23.9% of the effect. Visual impairment and retinal neurodegeneration were robustly associated with worse brain atrophy, FA, and hippocampal atrophy, partly mediated through disintegration of intermediate visual tracts. Our findings support the use of OCT-derived retinal measures as markers of neurodegeneration, and indicate that both general and transneuronal neurodegeneration along the visual pathway, partly reflecting visual impairment, account for the association between retinal neurodegeneration and brain atrophy.
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Brain , Retina , Humans , Retina/pathology , Brain/pathology , Magnetic Resonance Imaging , Vision Disorders , Atrophy/pathologyABSTRACT
Objective: Maintaining muscle function throughout life is critical for healthy ageing. Although in vitro studies consistently indicate beneficial effects of 25-hydroxyvitamin D (25-OHD) on muscle function, findings from population-based studies remain inconclusive. We therefore aimed to examine the association between 25-OHD concentration and handgrip strength across a wide age range and assess potential modifying effects of age, sex and season. Methods: We analysed cross-sectional baseline data of 2576 eligible participants out of the first 3000 participants (recruited from March 2016 to March 2019) of the Rhineland Study, a community-based cohort study in Bonn, Germany. Multivariate linear regression models were used to assess the relation between 25-OHD levels and grip strength while adjusting for age, sex, education, smoking, season, body mass index, physical activity levels, osteoporosis and vitamin D supplementation. Results: Compared to participants with deficient 25-OHD levels (<30 nmol/L), grip strength was higher in those with inadequate (30 to <50 nmol/L) and adequate (≥50 to ≤125 nmol/L) levels (ßinadequate = 1.222, 95% CI: 0.377; 2.067, P = 0.005; ßadequate = 1.228, 95% CI: 0.437; 2.019, P = 0.002). Modelling on a continuous scale revealed grip strength to increase with higher 25-OHD levels up to ~100 nmol/L, after which the direction reversed (ßlinear = 0.505, 95% CI: 0.179; 0.830, P = 0.002; ßquadratic = -0.153, 95% CI: -0.269; -0.038, P = 0.009). Older adults showed weaker effects of 25-OHD levels on grip strength than younger adults (ß25OHDxAge = -0.309, 95% CI: -0.594; -0.024, P = 0.033). Conclusions: Our findings highlight the importance of sufficient 25-OHD levels for optimal muscle function across the adult life span. However, vitamin D supplementation should be closely monitored to avoid detrimental effects.