Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer's disease.

The current demand for early intervention, prevention, and treatment of late onset Alzheimer's disease (LOAD) warrants deeper understanding of the underlying molecular processes which could contribute to biomarker and drug target discovery. Utilizing high-throughput proteomic measurements in serum from a prospective population-based cohort of older adults (n = 5,294), we identified 303 unique proteins associated with incident LOAD (median follow-up 12.8 years). Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status. These proteins were implicated in neuronal processes and overlapped with protein signatures of LOAD in brain and cerebrospinal fluid. We found 17 proteins which LOAD-association was strongly dependent on APOE-ε4 carrier status. Most of them showed consistent associations with LOAD in cerebrospinal fluid and a third had brain-specific gene expression. Remarkably, four proteins in this group (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated as a consequence of LOAD as determined in a bi-directional Mendelian randomization analysis, reflecting a potential response to the disease onset. Accordingly, the direct association of these proteins to LOAD was reversed upon APOE-ε4 genotype adjustment, a finding which we replicate in an external cohort (n = 719). Our findings provide an insight into the dysregulated pathways that may lead to the development and early detection of LOAD, including those both independent and dependent on APOE-ε4. Importantly, many of the LOAD-associated proteins we find in the circulation have been found to be expressed - and have a direct link with AD - in brain tissue. Thus, the proteins identified here, and their upstream modulating pathways, provide a new source of circulating biomarker and therapeutic target candidates for LOAD.

User Engagement, Acceptability, and Clinical Markers in a Digital Health Program for Nonalcoholic Fatty Liver Disease: Prospective, Single-Arm Feasibility Study.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in the world. Common comorbidities are central obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome. Cardiovascular disease is the most common cause of death among people with NAFLD, and lifestyle changes can improve health outcomes. OBJECTIVE: This study aims to explore the acceptability of a digital health program in terms of engagement, retention, and user satisfaction in addition to exploring changes in clinical outcomes, such as weight, cardiometabolic risk factors, and health-related quality of life. METHODS: We conducted a prospective, open-label, single-arm, 12-week study including 38 individuals with either a BMI >30, metabolic syndrome, or type 2 diabetes mellitus and NAFLD screened by FibroScan. An NAFLD-specific digital health program focused on disease education, lowering carbohydrates in the diet, food logging, increasing activity level, reducing stress, and healthy lifestyle coaching was offered to participants. The coach provided weekly feedback on food logs and other in-app activities and opportunities for participants to ask questions. The coaching was active throughout the 12-week intervention period. The primary outcome was feasibility and acceptability of the 12-week program, assessed through patient engagement, retention, and satisfaction with the program. Secondary outcomes included changes in weight, liver fat, body composition, and other cardiometabolic clinical parameters at baseline and 12 weeks. RESULTS: In total, 38 individuals were included in the study (median age 59.5, IQR 46.3-68.8 years; n=23, 61% female). Overall, 34 (89%) participants completed the program and 29 (76%) were active during the 12-week program period. The median satisfaction score was 6.3 (IQR 5.8-6.7) of 7. Mean weight loss was 3.5 (SD 3.7) kg (P<.001) or 3.2% (SD 3.4%), with a 2.2 (SD 2.7) kg reduction in fat mass (P<.001). Relative liver fat reduction was 19.4% (SD 23.9%). Systolic blood pressure was reduced by 6.0 (SD 13.5) mmHg (P=.009). The median reduction was 0.14 (IQR 0-0.47) mmol/L for triglyceride levels (P=.003), 3.2 (IQR 0.0-5.4) µU/ml for serum insulin (s-insulin) levels (P=.003), and 0.5 (IQR -0.7 to 3.8) mmol/mol for hemoglobin A1c (HbA1c) levels (P=.03). Participants who were highly engaged (ie, who used the app at least 5 days per week) had greater weight loss and liver fat reduction. CONCLUSIONS: The 12-week-long digital health program was feasible for individuals with NAFLD, receiving high user engagement, retention, and satisfaction. Improved liver-specific and cardiometabolic health was observed, and more engaged participants showed greater improvements. This digital health program could provide a new tool to improve health outcomes in people with NAFLD. TRIAL REGISTRATION: Clinicaltrials.gov NCT05426382; https://clinicaltrials.gov/study/NCT05426382.

Serum proteomics reveals APOE dependent and independent protein signatures in Alzheimer's disease.

The current demand for early intervention, prevention, and treatment of late onset Alzheimer's disease (LOAD) warrants deeper understanding of the underlying molecular processes which could contribute to biomarker and drug target discovery. Utilizing high-throughput proteomic measurements in serum from a prospective population-based cohort of older adults (n=5,294), we identified 303 unique proteins associated with incident LOAD (median follow-up 12.8 years). Over 40% of these proteins were associated with LOAD independently of APOE-ε4 carrier status. These proteins were implicated in neuronal processes and overlapped with protein signatures of LOAD in brain and cerebrospinal fluid. We found 17 proteins which LOAD-association was strongly dependent on APOE-ε4 carrier status. Most of them showed consistent associations with LOAD in cerebrospinal fluid and a third had brain-specific gene expression. Remarkably, four proteins in this group (TBCA, ARL2, S100A13 and IRF6) were downregulated by APOE-ε4 yet upregulated as a consequence of LOAD as determined in a bi-directional Mendelian randomization analysis, reflecting a potential response to the disease onset. Accordingly, the direct association of these proteins to LOAD was reversed upon APOE-ε4 genotype adjustment, a finding which we replicate in an external cohort (n=719). Our findings provide an insight into the dysregulated pathways that may lead to the development and early detection of LOAD, including those both independent and dependent on APOE-ε4. Importantly, many of the LOAD-associated proteins we find in the circulation have been found to be expressed - and have a direct link with AD - in brain tissue. Thus, the proteins identified here, and their upstream modulating pathways, provide a new source of circulating biomarker and therapeutic target candidates for LOAD.

Serum DHEA and Testosterone Levels Associate Inversely With Coronary Artery Calcification in Elderly Men.

CONTEXT: Epidemiological and preclinical data support cardiovascular, mainly protective, effects of sex steroids in men, but the mechanisms underlying the cardiovascular actions of sex steroids are poorly understood. Vascular calcification parallels the development of atherosclerosis, but is increasingly recognized as a diversified, highly regulated process, which itself may have pathophysiological importance for clinical cardiovascular events. OBJECTIVE: To investigate the association between serum sex steroids and coronary artery calcification (CAC) in elderly men. METHODS: We used gas chromatography tandem mass spectrometry to analyze a comprehensive sex steroid profile, including levels of dehydroepiandrosterone (DHEA), androstenedione, estrone, testosterone, estradiol, and dihydrotestosterone, in men from the population-based AGES-Reykjavik study (n = 1287, mean 76 years). Further, sex hormone-binding globulin (SHBG) was assayed and bioavailable hormone levels calculated. CAC score was determined by computed tomography. The main outcome measures were cross-sectional associations between dehydroepiandrosterone, androstenedione, estrone, testosterone, dihydrotestosterone, and estradiol and quintiles of CAC. RESULTS: Serum levels of DHEA, androstenedione, testosterone, dihydrotestosterone, and bioavailable testosterone showed significant inverse associations with CAC, while estrone, estradiol, bioavailable estradiol, and SHBG did not. DHEA, testosterone, and bioavailable testosterone remained associated with CAC after adjustment for traditional cardiovascular risk factors. In addition, our results support partially independent associations between adrenal-derived DHEA and testes-derived testosterone and CAC. CONCLUSION: Serum levels of DHEA and testosterone are inversely associated with CAC in elderly men, partially independently from each other. These results raise the question whether androgens from both the adrenals and the testes may contribute to male cardiovascular health.

Improving outpatient care for heart failure through digital innovation: a feasibility study.

BACKGROUND: Heart failure (HF) affects over 26 million people worldwide. Multidisciplinary management strategies that include symptom monitoring and patient self-care support reduce HF hospitalization and mortality rates. Ideally, HF follow-up and self-care support includes lifestyle-change recommendations and remote monitoring of weight and HF symptoms. Providing these via a digital solution may be ideal for improving HF disease outcomes and reducing the burden on providers and healthcare systems. This study's main objective was to assess the feasibility of a digital solution including remote monitoring, lifestyle-change, and self-care support for HF outpatients in Iceland. METHODS: Twenty HF patients (mean age 57.5 years, 80% males) participated in an 8-week study. They were provided with a digital solution (SK-141), including lifestyle-change and disease self-care support, a remote symptom monitoring system, and a secure messaging platform between healthcare providers and patients. This feasibility study aimed to assess patient acceptability of this new intervention, retention rate, and to evaluate trends in clinical outcomes. To assess the acceptability of SK-141, participants completed a questionnaire about their experience after the 8-week study. Participants performed daily assigned activities (missions), including self-reporting symptoms. Clinical outcomes were assessed with the Hospital Anxiety and Depression Scale and the Kansas City Cardiomyopathy Questionnaire at the study's beginning and end with an online survey. RESULTS: Of the 24 patients invited, 20 were elected to participate. The retention rate of participants throughout the 8-week period was high (80%). At the end of the 8 weeks, thirteen participants completed a questionnaire about their experience and acceptability of the SK-141. They rated their experience positively including on questions whether they would recommend the solution to others (6.8 on a scale of 1-7), whether the solution had improved their life and well-being (5.7 on a scale of 1-7), and whether it was user friendly (5.5 on a scale of 1-7). Many of the clinical parameters studied exhibited a promising trend towards improvement over the 8-week period. CONCLUSION: The digital solution, SK-141, was very acceptable to patients and also showed promising clinical results in this small feasibility study. These results encourage us to conduct a longer, more extensive, adequately powered, randomized-controlled study to assess whether this digital solution can improve the quality of life and clinical outcomes among HF patients.

Associations of Pulmonary Function with MRI Brain Volumes: A Coordinated Multi-Study Analysis.

BACKGROUND: Previous studies suggest poor pulmonary function is associated with increased burden of cerebral white matter hyperintensities and brain atrophy among elderly individuals, but the results are inconsistent. OBJECTIVE: To study the cross-sectional associations of pulmonary function with structural brain variables. METHODS: Data from six large community-based samples (N = 11,091) were analyzed. Spirometric measurements were standardized with respect to age, sex, height, and ethnicity using reference equations of the Global Lung Function Initiative. Associations of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio FEV1/FVC with brain volume, gray matter volume, hippocampal volume, and volume of white matter hyperintensities were investigated using multivariable linear regressions for each study separately and then combined using random-effect meta-analyses. RESULTS: FEV1 and FVC were positively associated with brain volume, gray matter volume, and hippocampal volume, and negatively associated with white matter hyperintensities volume after multiple testing correction, with little heterogeneity present between the studies. For instance, an increase of FVC by one unit was associated with 3.5 ml higher brain volume (95% CI: [2.2, 4.9]). In contrast, results for FEV1/FVC were more heterogeneous across studies, with significant positive associations with brain volume, gray matter volume, and hippocampal volume, but not white matter hyperintensities volume. Associations of brain variables with both FEV1 and FVC were consistently stronger than with FEV1/FVC, specifically with brain volume and white matter hyperintensities volume. CONCLUSION: In cross-sectional analyses, worse pulmonary function is associated with smaller brain volumes and higher white matter hyperintensities burden.

[The relationship between lack of educational attainment, cardiovascular risk factors, atherosclerosis and coronary artery disease].

INTRODUCTION: Educational attainment is related to improved health and longevity. We investigated the relationship between educational attainment and cardiovascular risk factors, subclinical atherosclerosis, and incidence of coronary artery disease. MATERIAL AND METHODS: The Reykjavik REFINE study is a population-based study recruiting 6616 subjects, 25-69 years of age from the greater Reykjavik area in 2005-2011. Baseline measurements of cardiovascular risk factors were performed, and all participants had a carotid ultrasound examination to detect subclinical atherosclerotic lesions. Clinical follow-up of cardiovascular disease during a ten-year period was performed. Educational attainment was related to clinical outcome measures. RESULTS: The study population comprised of 3251 men and 3365 women. The proportion of the study population with primary school education only was 20.1%, 31.2% had vocational training, 12.3% had high school education and 36.4% were university graduates. Traditional cardiovascular risk factors were generally higher among subjects with primary school education only. Compared to subjects with university education, the odds ratio of having severe atherosclerotic plaque was 1.84 (95% CI 1.40-2.43) among those with primary school education only and 1.49 (95% CI 1.16-1.91) among subjects with vocational training. The subjects with high school or university education were less likely to develop significant cardiovascular disease during the 10-year follow-up period. CONCLUSION: Primary school and vocational training compared to university education are associated with risk factors of atherosclerotic disease, subclinical carotid plaque, and incidence of cardiovascular disease. The reason for this disparity remains to be clarified but socioeconomic inequality related to less educational attainment might be involved.

A proteogenomic signature of age-related macular degeneration in blood.

Age-related macular degeneration (AMD) is one of the most common causes of visual impairment in the elderly, with a complex and still poorly understood etiology. Whole-genome association studies have discovered 34 genomic regions associated with AMD. However, the genes and cognate proteins that mediate the risk, are largely unknown. In the current study, we integrate levels of 4782 human serum proteins with all genetic risk loci for AMD in a large population-based study of the elderly, revealing many proteins and pathways linked to the disease. Serum proteins are also found to reflect AMD severity independent of genetics and predict progression from early to advanced AMD after five years in this population. A two-sample Mendelian randomization study identifies several proteins that are causally related to the disease and are directionally consistent with the observational estimates. In this work, we present a robust and unique framework for elucidating the pathobiology of AMD.

The Proteomic Profile of Interstitial Lung Abnormalities.

Rationale: Knowledge on biomarkers of interstitial lung disease is incomplete. Interstitial lung abnormalities (ILAs) are radiologic changes that may present in its early stages. Objectives: To uncover blood proteins associated with ILAs using large-scale proteomics methods. Methods: Data from two prospective cohort studies, the AGES-Reykjavik (Age, Gene/Environment Susceptibility-Reykjavik) study (N = 5,259) for biomarker discovery and the COPDGene (Genetic Epidemiology of COPD) study (N = 4,899) for replication, were used. Blood proteins were measured using DNA aptamers, targeting more than 4,700 protein analytes. The association of proteins with ILAs and ILA progression was assessed with regression modeling, as were associations with genetic risk factors. Adaptive Least Absolute Shrinkage and Selection Operator models were applied to bootstrap data samples to discover sets of proteins predictive of ILAs and their progression. Measurements and Main Results: Of 287 associations, SFTPB (surfactant protein B) (odds ratio [OR], 3.71 [95% confidence interval (CI), 3.20-4.30]; P = 4.28 × 10-67), SCGB3A1 (Secretoglobin family 3A member 1) (OR, 2.43 [95% CI, 2.13-2.77]; P = 8.01 × 10-40), and WFDC2 (WAP four-disulfide core domain protein 2) (OR, 2.42 [95% CI, 2.11-2.78]; P = 4.01 × 10-36) were most significantly associated with ILA in AGES-Reykjavik and were replicated in COPDGene. In AGES-Reykjavik, concentrations of SFTPB were associated with the rs35705950 MUC5B (mucin 5B) promoter polymorphism, and SFTPB and WFDC2 had the strongest associations with ILA progression. Multivariate models of ILAs in AGES-Reykjavik, ILAs in COPDGene, and ILA progression in AGES-Reykjavik had validated areas under the receiver operating characteristic curve of 0.880, 0.826, and 0.824, respectively. Conclusions: Novel, replicated associations of ILA, its progression, and genetic risk factors with numerous blood proteins are demonstrated as well as machine-learning-based models with favorable predictive potential. Several proteins are revealed as potential markers of early fibrotic lung disease.

Interstitial lung abnormalities are associated with decreased mean telomere length.

BACKGROUND: Interstitial lung abnormalities (ILA) share many features with idiopathic pulmonary fibrosis; however, it is not known if ILA are associated with decreased mean telomere length (MTL). METHODS: Telomere length was measured with quantitative PCR in the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease (COPDGene) and Age Gene/Environment Susceptibility Reykjavik (AGES-Reykjavik) cohorts and Southern blot analysis was used in the Framingham Heart Study (FHS). Logistic and linear regression were used to assess the association between ILA and MTL; Cox proportional hazards models were used to assess the association between MTL and mortality. RESULTS: In all three cohorts, ILA were associated with decreased MTL. In the COPDGene and AGES-Reykjavik cohorts, after adjustment there was greater than twofold increase in the odds of ILA when comparing the shortest quartile of telomere length to the longest quartile (OR 2.2, 95% CI 1.5-3.4, p=0.0001, and OR 2.6, 95% CI 1.4-4.9, p=0.003, respectively). In the FHS, those with ILA had shorter telomeres than those without ILA (-767 bp, 95% CI 76-1584 bp, p=0.03). Although decreased MTL was associated with chronic obstructive pulmonary disease (OR 1.3, 95% CI 1.1-1.6, p=0.01) in COPDGene, the effect estimate was less than that noted with ILA. There was no consistent association between MTL and risk of death when comparing the shortest quartile of telomere length in COPDGene and AGES-Reykjavik (HR 0.82, 95% CI 0.4-1.7, p=0.6, and HR 1.2, 95% CI 0.6-2.2, p=0.5, respectively). CONCLUSION: ILA are associated with decreased MTL.

Carotid plaque is strongly associated with coronary artery calcium and predicts incident coronary heart disease in a population-based cohort.

BACKGROUND AND AIMS: Coronary artery calcium (CAC) and carotid plaque are markers of atherosclerosis and predict future coronary heart disease (CHD) events. The aim of this study was to investigate associations between CAC and carotid plaque in asymptomatic individuals, also in relation to predicted CHD-risk and incident events. A secondary aim was to compare predictive value between CAC, carotid plaque, and total carotid plaque area (TPA) as predictors for future CHD-events. METHODS: The REFINE-Reykjavik study is prospective and population-based with CAC-scoring and carotid plaque ultrasound assessment, both presence and area. A total of 948 individuals without clinical CHD were included in the study. CAC scores were categorized into 0,1-100,101-300 and > 300, and carotid plaque into none, minimal and significant. Three models were applied adjusted for age, sex, and each of the Framingham risk score (FRS), local CHD risk score and established CHD risk factors. RESULTS: Combined carotid plaque- and CAC-presence was highly prevalent, 69.5% for males and 41.7% for females (54.5% overall). TPA outperformed base models in CHD prediction, resulting in statistically significant area under the receiver operator characteristic curve (AUC) increase ranging from 0.02 to 0.05. Most CHD-events in females occurred in individuals classified as low-risk with respect to traditional risk factors but with a gradient in observed risk across carotid plaque categories. CONCLUSIONS: Carotid plaque was strongly associated with the presence and extent of CAC in asymptomatic individuals in a population-based cohort. Carotid plaque predicts incident CHD events over risk scores and may be useful for refined risk prediction in females.

Circulating serum microRNAs including senescent miR-31-5p are associated with incident fragility fractures in older postmenopausal women with type 2 diabetes mellitus.

Fragility fractures are an important hallmark of aging and an increasingly recognized complication of Type 2 diabetes (T2D). T2D individuals have been found to exhibit an increased fracture risk despite elevated bone mineral density (BMD) by dual x-ray absorptiometry (DXA). However, BMD and FRAX-scores tend to underestimate fracture risk in T2D. New, reliable biomarkers are therefore needed. MicroRNAs (miRNAs) are secreted into the circulation from cells of various tissues proportional to local disease severity. Serum miRNA-classifiers were recently found to discriminate T2D women with and without prevalent fragility fractures with high specificity and sensitivity (AUC > 0.90). However, the association of circulating miRNAs with incident fractures in T2D has not been examined yet. In 168 T2D postmenopausal women in the AGES-Reykjavik cohort, miRNAs were extracted from baseline serum and a panel of 10 circulating miRNAs known to be involved in diabetic bone disease and aging was quantified by qPCR and Ct-values extracted. Unadjusted and adjusted Cox proportional hazard models assessed the associations between serum miRNAs and incident fragility fracture. Additionally, Receiver operating curve (ROC) analyses were performed. Of the included 168 T2D postmenopausal women who were on average 77.2 ±â€¯5.6 years old, 70 experienced at least one incident fragility fracture during the mean follow-up of 5.8 ±â€¯2.7 years. We found that 3 serum miRNAs were significantly associated with incident diabetic fragility fracture: while low expression of miR-19b-1-5p was associated with significantly lower risk of incident fragility fracture (HR 0.84 (95% CI: 0.71-0.99, p = 0.0323)), low expression of miR-203a and miR-31-5p was each significantly associated with a higher risk of incident fragility fracture per unit increase in Ct-value (miR-203a: HR 1.29 (95% CI: 1.12-1.49), p = 0.0004, miR-31-5p HR 1.27 (95% CI: 1.06-1.52), p = 0.009). Hazard ratios of the latter two miRNAs remained significant after adjustments for age, body mass index (BMI), areal bone mineral density (aBMD), clinical FRAX or FRAXaBMD. Women with miR-203a and miR-31-5p serum levels in the lowest expression quartiles exhibited a 2.4-3.4-fold larger fracture risk than women with miR-31-5p and miR-203a serum expressions in the highest expression quartile (0.002 ≤ p ≤ 0.039). Women with both miR-203a and miR-31-5p serum levels below the median had a significantly increased fracture risk (Unadjusted HR 3.26 (95% CI: 1.57-6.78, p = 0.001) compared to those with both expression levels above the median, stable to adjustments. We next built a diabetic fragility signature consisting of the 3 miRNAs that showed the largest associations with incident fracture (miR-203a, miR-31-5p, miR-19b-1-5p). This 3-miRNA signature showed with an AUC of 0.722 comparable diagnostic accuracy in identifying incident fractures to any of the clinical parameters such as aBMD, Clinical FRAX or FRAXaBMD alone. When the 3 miRNAs were combined with aBMD, this combined 4-feature signature performed with an AUC of 0.756 (95% CI: 0.680, 0.823) significantly better than aBMD alone (AUC 0.666, 95% CI: 0.585, 0.741) (p = 0.009). Our data indicate that specific serum microRNAs including senescent miR-31-5p are associated with incident fragility fracture in older diabetic women and can significantly improve fracture risk prediction in diabetics when combined with aBMD measurements of the femoral neck.

A genome-wide association study of serum proteins reveals shared loci with common diseases.

With the growing number of genetic association studies, the genotype-phenotype atlas has become increasingly more complex, yet the functional consequences of most disease associated alleles is not understood. The measurement of protein level variation in solid tissues and biofluids integrated with genetic variants offers a path to deeper functional insights. Here we present a large-scale proteogenomic study in 5,368 individuals, revealing 4,035 independent associations between genetic variants and 2,091 serum proteins, of which 36% are previously unreported. The majority of both cis- and trans-acting genetic signals are unique for a single protein, although our results also highlight numerous highly pleiotropic genetic effects on protein levels and demonstrate that a protein's genetic association profile reflects certain characteristics of the protein, including its location in protein networks, tissue specificity and intolerance to loss of function mutations. Integrating protein measurements with deep phenotyping of the cohort, we observe substantial enrichment of phenotype associations for serum proteins regulated by established GWAS loci, and offer new insights into the interplay between genetics, serum protein levels and complex disease.

Coding and regulatory variants are associated with serum protein levels and disease.

Circulating proteins can be used to diagnose and predict disease-related outcomes. A deep serum proteome survey recently revealed close associations between serum protein networks and common disease. In the current study, 54,469 low-frequency and common exome-array variants were compared to 4782 protein measurements in the serum of 5343 individuals from the AGES Reykjavik cohort. This analysis identifies a large number of serum proteins with genetic signatures overlapping those of many diseases. More specifically, using a study-wide significance threshold, we find that 2021 independent exome array variants are associated with serum levels of 1942 proteins. These variants reside in genetic loci shared by hundreds of complex disease traits, highlighting serum proteins' emerging role as biomarkers and potential causative agents of a wide range of diseases.

Cerebrovascular Risk-Factors of Prevalent and Incident Brain Infarcts in the General Population: The AGES-Reykjavik Study.

BACKGROUND: Studies on the association of cerebrovascular risk factors to magnetic resonance imaging detected brain infarcts have been inconsistent, partly reflecting limits of assessment to infarcts anywhere in the brain, as opposed to specific brain regions. We hypothesized that risk-factors may differ depending on where the infarct is located in subcortical-, cortical-, and cerebellar regions. METHODS: Participants (n=2662, mean age 74.6±4.8) from the longitudinal population-based AGES (Age, Gene/Environment Susceptibility)-Reykjavik Study underwent brain magnetic resonance imaging at baseline and on average 5.2 years later. We assessed the number and location of brain infarcts (prevalent versus incident). We estimated the risk-ratios of prevalent (PRR) and incident (IRR) infarcts by baseline cerebrovascular risk-factors using Poisson regression. RESULTS: Thirty-one percent of the study participants had prevalent brain infarcts and 21% developed new infarcts over 5 years. Prevalent subcortical infarcts were associated with hypertension (PRR, 2.7 [95% CI, 1.1-6.8]), systolic blood pressure (PRR, 1.2 [95% CI, 1.1-1.4]), and diabetes (PRR, 2.8 [95% CI, 1.9-4.1]); incident subcortical infarcts were associated with systolic (IRR, 1.2 [95% CI, 1.0-1.4]) and diastolic (IRR, 1.3 [95% CI, 1.0-1.6]) blood pressure. Prevalent and incident cortical infarcts were associated with carotid plaques (PRR, 1.8 [95% CI, 1.3-2.5] and IRR, 1.9 [95% CI, 1.3-2.9], respectively), and atrial fibrillation was significantly associated with prevalent cortical infarcts (PRR, 1.8 [95% CI, 1.2-2.7]). Risk-factors for prevalent cerebellar infarcts included hypertension (PRR, 2.45 [95% CI, 1.5-4.0]), carotid plaques (PRR, 1.45 [95% CI, 1.2-1.8]), and migraine with aura (PRR, 1.6 [95% CI, 1.1-2.2]). Incident cerebellar infarcts were only associated with any migraine (IRR, 1.4 [95% CI, 1.0-2.0]). CONCLUSIONS: The risk for subcortical infarcts tends to increase with small vessel disease risk-factors such as hypertension and diabetes. Risk for cortical infarcts tends to increase with atherosclerotic/coronary processes and risk for cerebellar infarcts with a more mixed profile of factors. Assessment of risk-factors by location of asymptomatic infarcts found on magnetic resonance imaging may improve the ability to target and optimize preventive therapeutic approaches to prevent stroke.

Multiethnic Genome-Wide Association Study of Subclinical Atherosclerosis in Individuals With Type 2 Diabetes.

BACKGROUND: Coronary artery calcification (CAC) and carotid artery intima-media thickness (cIMT) are measures of subclinical atherosclerosis in asymptomatic individuals and strong risk factors for cardiovascular disease. Type 2 diabetes (T2D) is an independent cardiovascular disease risk factor that accelerates atherosclerosis. METHODS: We performed meta-analyses of genome-wide association studies in up to 2500 T2D individuals of European ancestry (EA) and 1590 T2D individuals of African ancestry with or without exclusion of prevalent cardiovascular disease, for CAC measured by cardiac computed tomography, and 3608 individuals of EA and 838 individuals of African ancestry with T2D for cIMT measured by ultrasonography within the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium. RESULTS: We replicated 2 loci (rs9369640 and rs9349379 near PHACTR1 and rs10757278 near CDKN2B) for CAC and one locus for cIMT (rs7412 and rs445925 near APOE-APOC1) that were previously reported in the general EA populations. We identified one novel CAC locus (rs8000449 near CSNK1A1L/LINC00547/POSTN at 13q13.3) at P=2.0×10-8 in EA. No additional loci were identified with the meta-analyses of EA and African ancestry. The expression quantitative trait loci analysis with nearby expressed genes derived from arterial wall and metabolic tissues from the Genotype-Tissue Expression project pinpoints POSTN, encoding a matricellular protein involved in bone formation and bone matrix organization, as the potential candidate gene at this locus. In addition, we found significant associations (P<3.1×10-4) for 3 previously reported coronary artery disease loci for these subclinical atherosclerotic phenotypes (rs2891168 near CDKN2B-AS1 and rs11170820 near FLJ12825 for CAC, and rs7412 near APOE for cIMT). CONCLUSIONS: Our results provide potential biological mechanisms that could link CAC and cIMT to increased cardiovascular disease risk in individuals with T2D.

Serum levels of ACE2 are higher in patients with obesity and diabetes.

OBJECTIVE: As severity of outcome in COVID-19 is disproportionately higher among individuals with obesity, smokers, patients with hypertension, kidney disease, chronic pulmonary disease, coronary heart disease (CHD), and/or type 2 diabetes (T2D), serum levels of ACE2, the cellular entry point for the coronavirus SARS-CoV-2, were examined in these high-risk groups. METHODS: Associations of ACE2 levels to smokers and patients with hypertension, T2D, obesity, CHD, or COPD were investigated in a single center population-based study of 5457 Icelanders from the Age, Gene/Environment Susceptibility Reykjavík Study (AGES-RS) of the elderly (mean age 75 ± 6 years), using multiple linear regression analysis. RESULTS: Serum levels of ACE2 were higher in smokers and individuals with T2D and/or obesity while they were unaffected in the other patient groups. CONCLUSION: ACE2 levels are higher in some patient groups with comorbidities linked to COVID-19 including obesity and T2D and as such may have an emerging role as a circulating biomarker for severity of outcome in the disease.

[Prevalence and incidence of type 2 diabetes in Iceland 2005-2018].

INTRODUCTION: The number of people with type 2 diabetes has increased in Iceland in the last few decades. We utilized the national database on prescribed medication from the Directorate of Health to estimate the prevalence and incidence of type 2 diabetes in Iceland and made prediction on the prevalence of type 2 diabetes in Iceland in 10 and 20 years. MATERIAL AND METHODS: Prevalence and incidence of type 2 diabetes for the period 2005-2018 was estimated based on prescriptions of diabetes medication in the national prescription database containing all prescriptions in Iceland during the period. The result was compared to the result from the REFINE-Reykjavik study (prospective, population-based cohort study) from 2004 to 2011 and published data from the USA from 1980 to 2016. RESULTS: The prevalence of type 2 diabetes more than doubled in near all age groups in both men and women in the period 2005-2018. The incidence increased by 2.8% annually (in 18-79 years old). The number of people in Iceland with type 2 diabetes was 10600 in 2018 and had increased from 4200 in the year 2005. Comparison with the results of the REFINE-Reykjavik study showed an underestimation (29% in men and women) of the prevalence of type 2 diabetes. If the increase in type 2 diabetes continues at a similar rate as in the years 2005-2018 the number of people with diabetes in Iceland could be near 24000 in the year 2040. CONCLUSION: Linear increase was seen in incidence and prevalence of people with type 2 diabetes in the years 2005-2018. Similar evolution was seen in USA from 1984. In order to counteract the increase of type 2 diabetes following the same path as has been seen in the USA, targeted measures are needed.

Progression of traction bronchiectasis/bronchiolectasis in interstitial lung abnormalities is associated with increased all-cause mortality: Age Gene/Environment Susceptibility-Reykjavik Study.

PURPOSE: The aim of this study is to assess the role of traction bronchiectasis/bronchiolectasis and its progression as a predictor for early fibrosis in interstitial lung abnormalities (ILA). METHODS: Three hundred twenty-seven ILA participants out of 5764 in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study who had undergone chest CT twice with an interval of approximately five-years were enrolled in this study. Traction bronchiectasis/bronchiolectasis index (TBI) was classified on a four-point scale: 0, ILA without traction bronchiectasis/bronchiolectasis; 1, ILA with bronchiolectasis but without bronchiectasis or architectural distortion; 2, ILA with mild to moderate traction bronchiectasis; 3, ILA and severe traction bronchiectasis and/or honeycombing. Traction bronchiectasis (TB) progression was classified on a five-point scale: 1, Improved; 2, Probably improved; 3, No change; 4, Probably progressed; 5, Progressed. Overall survival (OS) among participants with different TB Progression Score and between the TB progression group and No TB progression group was also investigated. Hazard radio (HR) was estimated with Cox proportional hazards model. RESULTS: The higher the TBI at baseline, the higher TB Progression Score (P < 0.001). All five participants with TBI = 3 at baseline progressed; 46 (90 %) of 51 participants with TBI = 2 progressed. TB progression was also associated with shorter OS with statistically significant difference (adjusted HR = 1.68, P < 0.001). CONCLUSION: TB progression was visualized on chest CT frequently and clearly. It has the potential to be the predictor for poorer prognosis of ILA.

Large-scale plasma proteomic analysis identifies proteins and pathways associated with dementia risk.

The plasma proteomic changes that precede the onset of dementia could yield insights into disease biology and highlight new biomarkers and avenues for intervention. We quantified 4,877 plasma proteins in nondemented older adults in the Atherosclerosis Risk in Communities cohort and performed a proteome-wide association study of dementia risk over five years (n = 4,110; 428 incident cases). Thirty-eight proteins were associated with incident dementia after Bonferroni correction. Of these, 16 were also associated with late-life dementia risk when measured in plasma collected nearly 20 years earlier, during mid-life. Two-sample Mendelian randomization causally implicated two dementia-associated proteins (SVEP1 and angiostatin) in Alzheimer's disease. SVEP1, an immunologically relevant cellular adhesion protein, was found to be part of larger dementia-associated protein networks, and circulating levels were associated with atrophy in brain regions vulnerable to Alzheimer's pathology. Pathway analyses for the broader set of dementia-associated proteins implicated immune, lipid, metabolic signaling and hemostasis pathways in dementia pathogenesis.