Prevalence and correlates of mild cognitive impairment among diverse Hispanics/Latinos: Study of Latinos-Investigation of Neurocognitive Aging results.

IntroductionWe estimated the prevalence and correlates of mild cognitive impairment (MCI) among middle-aged and older diverse Hispanics/Latinos.MethodsMiddle-aged and older diverse Hispanics/Latinos enrolled (n = 6377; 50-86 years) in this multisite prospective cohort study were evaluated for MCI using the National Institute on Aging-Alzheimer's Association diagnostic criteria.ResultsThe overall MCI prevalence was 9.8%, which varied between Hispanic/Latino groups. Older age, high cardiovascular disease (CVD) risk, and elevated depressive symptoms were significant correlates of MCI prevalence. Apolipoprotein E4 (APOE) and APOE2 were not significantly associated with MCI.DiscussionMCI prevalence varied among Hispanic/Latino backgrounds, but not as widely as reported in the previous studies. CVD risk and depressive symptoms were associated with increased MCI, whereas APOE4 was not, suggesting alternative etiologies for MCI among diverse Hispanics/Latinos. Our findings suggest that mitigating CVD risk factors may offer important pathways to understanding and reducing MCI and possibly dementia among diverse Hispanics/Latinos

Associations of NINJ2 sequence variants with incident ischemic stroke in the Cohorts for Heart and Aging in Genomic Epidemiology (CHARGE) consortium

Background<p></p> Stroke, the leading neurologic cause of death and disability, has a substantial genetic component. We previously conducted a genome-wide association study (GWAS) in four prospective studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and demonstrated that sequence variants near the NINJ2 gene are associated with incident ischemic stroke. Here, we sought to fine-map functional variants in the region and evaluate the contribution of rare variants to ischemic stroke risk.<p></p> Methods and Results<p></p> We sequenced 196 kb around NINJ2 on chromosome 12p13 among 3,986 European ancestry participants, including 475 ischemic stroke cases, from the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, and Framingham Heart Study. Meta-analyses of single-variant tests for 425 common variants (minor allele frequency [MAF] ≥ 1%) confirmed the original GWAS results and identified an independent intronic variant, rs34166160 (MAF = 0.012), most significantly associated with incident ischemic stroke (HR = 1.80, p = 0.0003). Aggregating 278 putatively-functional variants with MAF≤ 1% using count statistics, we observed a nominally statistically significant association, with the burden of rare NINJ2 variants contributing to decreased ischemic stroke incidence (HR = 0.81; p = 0.026).<p></p> Conclusion<p></p> Common and rare variants in the NINJ2 region were nominally associated with incident ischemic stroke among a subset of CHARGE participants. Allelic heterogeneity at this locus, caused by multiple rare, low frequency, and common variants with disparate effects on risk, may explain the difficulties in replicating the original GWAS results. Additional studies that take into account the complex allelic architecture at this locus are needed to confirm these findings

Genome-wide association studies suggest sex-specific loci associated with abdominal and visceral fat

Background: To identify loci associated with abdominal fat and replicate prior findings, we performed genome-wide association (GWA) studies of abdominal fat traits: subcutaneous adipose tissue (SAT); visceral adipose tissue (VAT); total adipose tissue (TAT) and visceral to subcutaneous adipose tissue ratio (VSR). Subjects and Methods: Sex-combined and sex-stratified analyses were performed on each trait with (TRAIT–BMI) or without (TRAIT) adjustment for body mass index (BMI), and cohort-specific results were combined via a fixed effects meta-analysis. A total of 2513 subjects of European descent were available for the discovery phase. For replication, 2171 European Americans and 772 African Americans were available. Results: A total of 52 single-nucleotide polymorphisms (SNPs) encompassing 7 loci showed suggestive evidence of association (P\u3c1.0 × 10−6) with abdominal fat in the sex-combined analyses. The strongest evidence was found on chromosome 7p14.3 between a SNP near BBS9 gene and VAT (rs12374818; P=1.10 × 10−7), an association that was replicated (P=0.02). For the BMI-adjusted trait, the strongest evidence of association was found between a SNP near CYCSP30 and VAT–BMI (rs10506943; P=2.42 × 10−7). Our sex-specific analyses identified one genome-wide significant (P\u3c5.0 × 10−8) locus for SAT in women with 11 SNPs encompassing the MLLT10, DNAJC1 and EBLN1 genes on chromosome 10p12.31 (P=3.97 × 10–8 to 1.13 × 10−8). The THNSL2 gene previously associated with VAT in women was also replicated (P=0.006). The six gene/loci showing the strongest evidence of association with VAT or VAT-BMI were interrogated for their functional links with obesity and inflammation using the Biograph knowledge-mining software. Genes showing the closest functional links with obesity and inflammation were ADCY8 and KCNK9, respectively. Conclusions: Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women

The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRScommon) with a rare variant PRS (PRSrare) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m2), obesity (BMI ≥ 30 kg/m2), and extreme obesity (BMI ≥ 40 kg/m2). We built PRSscommon and PRSsrare using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRScommon explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRSrare explained 1.49%, and 2.97% and 3.68%, respectively. The PRSrare was associated with an increased risk of obesity and extreme obesity (ORobesity = 1.37 per SDPRS, P obesity = 1.7x10-85; ORextremeobesity = 1.55 per SDPRS, P extremeobesity = 3.8x10-40), which was attenuated, after adjusting for PRScommon (ORobesity = 1.08 per SDPRS, P obesity = 9.8x10-6; ORextremeobesity= 1.09 per SDPRS, P extremeobesity = 0.02). When PRSrare and PRScommon are combined, the increase in explained variance attributed to PRSrare was small (incremental Nagelkerke R2 = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRSrare to PRScommon provided little improvement to the prediction of obesity (PRSrare AUC = 0.591; PRScommon AUC = 0.708; PRScombined AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRSrare provides limited improvement over PRScommon in the prediction of obesity risk, based on these large populations

Genetic variants of the NOTCH3 gene in the elderly and magnetic resonance imaging correlates of age-related cerebral small vessel disease

Cerebral small vessel disease-related brain lesions such as white matter lesions and lacunes are common findings of magnetic resonance imaging in the elderly. These lesions are thought to be major contributors to disability in old age, and risk factors that include age and hypertension have been established. The radiological, histopathologic and clinical phenotypes of age-related cerebral small vessel disease remarkably resemble autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy, which is caused by mutations in NOTCH3. We hypothesized that genetic variations in NOTCH3 also play a role in age-related cerebral small vessel disease. We directly sequenced all 33 exons, the promoter and 3′-untranslated region of NOTCH3 in 195 participants with either coalescent white matter lesions or lacunes and compared the results to 82 randomly selected participants with no focal changes on magnetic resonance images in the Austrian Stroke Prevention Study. We detected nine common and 33 rare single nucleotide polymorphisms, of which 20 were novel. All common single nucleotide polymorphisms were genotyped in the entire cohort (n = 888), and four of them, rs1043994, rs10404382, rs10423702 and rs1043997, were associated significantly with both the presence and progression of white matter lesions. The association was confined to hypertensives, a result which we replicated in the Cohorts for Heart and Ageing Research in Genomic Epidemiology Consortium on an independent sample of 4773 stroke-free hypertensive elderly individuals of European descent (P = 0.04). The 33 rare single nucleotide polymorphisms were scattered over the NOTCH3 gene with three being located in the promoter region, 24 in exons (18 non-synonymous), three in introns and three in the 3′-untranslated region. None of the single nucleotide polymorphisms affected a cysteine residue. Sorting Intolerant From Tolerant, PolyPhen2 analyses and protein structure simulation consistently predicted six of the non-synonymous single nucleotide polymorphisms (H170R, P496L, V1183M, L1518M, D1823N and V1952M) to be functional, with four being exclusively or mainly detected in subjects with severe white matter lesions. In four individuals with rare non-synonymous single nucleotide polymorphisms, we noted anterior temporal lobe hyperintensity, hyperintensity in the external capsule, lacunar infarcts or subcortical lacunar lesions. None of the observed abnormalities were specific to cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy. This is the first comprehensive study investigating (i) the frequency of NOTCH3 variations in community-dwelling elderly and (ii) their effect on cerebral small vessel disease related magnetic resonance imaging phenotypes. We show that the NOTCH3 gene is highly variable with both common and rare single nucleotide polymorphisms spreading across the gene, and that common variants at the NOTCH3 gene increase the risk of age-related white matter lesions in hypertensives. Additional investigations are required to explore the biological mechanisms underlying the observed association

How does a cadaver model work for testing ultrasound diagnostic capability for rheumatic-like tendon damage?

To establish whether a cadaver model can serve as an effective surrogate for the detection of tendon damage characteristic of rheumatoid arthritis (RA). In addition, we evaluated intraobserver and interobserver agreement in the grading of RA-like tendon tears shown by US, as well as the concordance between the US findings and the surgically induced lesions in the cadaver model. RA-like tendon damage was surgically induced in the tibialis anterior tendon (TAT) and tibialis posterior tendon (TPT) of ten ankle/foot fresh-frozen cadaveric specimens. Of the 20 tendons examined, six were randomly assigned a surgically induced partial tear; six a complete tear; and eight left undamaged. Three rheumatologists, experts in musculoskeletal US, assessed from 1 to 5 the quality of US imaging of the cadaveric models on a Likert scale. Tendons were then categorized as having either no damage, (0); partial tear, (1); or complete tear (2). All 20 tendons were blindly and independently evaluated twice, over two rounds, by each of the three observers. Overall, technical performance was satisfactory for all items in the two rounds (all values over 2.9 in a Likert scale 1-5). Intraobserver and interobserver agreement for US grading of tendon damage was good (mean κ values 0.62 and 0.71, respectively), with greater reliability found in the TAT than the TPT. Concordance between US findings and experimental tendon lesions was acceptable (70-100 %), again greater for the TAT than for the TPT. A cadaver model with surgically created tendon damage can be useful in evaluating US metric properties of RA tendon lesions

Genetic Loci of Beta-Aminoisobutyric Acid Are Associated With Aging-Related Mild Cognitive Impairment

We studied the genetic associations of a previously developed Metabolomic Risk Score (MRS) for Mild Cognitive Impairment (MCI) and beta-aminoisobutyric acid metabolite (BAIBA)-the metabolite highlighted by results from a genome-wide association study (GWAS) of the MCI-MRS, and assessed their association with MCI in datasets of diverse race/ethnicities. We first performed a GWAS for the MCI-MRS and BAIBA, in Hispanic/Latino adults (n = 3890) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We identified ten independent genome-wide significant (p value \u3c5 × 10-8) variants associated with MCI-MRS or BAIBA. Variants associated with the MCI-MRS are located in the Alanine-Glyoxylate Aminotransferase 2 (AGXT2 gene), which is known to be associated with BAIBA metabolism. Variants associated with BAIBA are located in the AGXT2 gene and in the SLC6A13 gene. Next, we tested the variants\u27 association with MCI in independent datasets of n = 3178 HCHS/SOL older individuals, n = 3775 European Americans, and n = 1032 African Americans from the Atherosclerosis Risk In Communities (ARIC) study. Variants were considered associated with MCI if their p value \u3c0.05 in the meta-analysis of the three datasets and their direction of association was consistent with expectation. Rs16899972 and rs37369 from the AGXT2 region were associated with MCI. Mediation analysis supported the mediation effect of BAIBA between the two genetic variants and MCI (p value = 0.004 for causal mediated effect). In summary, genetic variants in the AGXT2 region are associated with MCI in Hispanic/Latino, African, and European American populations in the USA, and their effect is likely mediated by changes in BAIBA levels

Reversal of endothelial dysfunction reduces white matter vulnerability in cerebral small vessel disease in rats

Dementia is a major social and economic problem for our aging population. One of the most common of dementia in the elderly is cerebral small vessel disease (SVD). Magnetic resonance scans of SVD patients typically show white matter abnormalities, but we do not understand the mechanistic pathological link between blood vessels and white matter myelin damage. Hypertension is suggested as the cause of sporadic SVD, but a recent alternative hypothesis invokes dysfunction of the blood-brain barrier as the primary cause. In a rat model of SVD, we show that endothelial cell (EC) dysfunction is the first change in development of the disease. Dysfunctional ECs secrete heat shock protein 90α, which blocks oligodendroglial differentiation, contributing to impaired myelination. Treatment with EC-stabilizing drugs reversed these EC and oligodendroglial pathologies in the rat model. EC and oligodendroglial dysfunction were also observed in humans with early, asymptomatic SVD pathology. We identified a loss-of-function mutation in ATPase11B, which caused the EC dysfunction in the rat SVD model, and a single-nucleotide polymorphism in ATPase11B that was associated with white matter abnormalities in humans with SVD. We show that EC dysfunction is a cause of SVD white matter vulnerability and provide a therapeutic strategy to treat and reverse SVD in the rat model, which may also be of relevance to human SVD

Genetic determinants of cortical structure (thickness, surface area and volumes) among disease free adults in the CHARGE Consortium

Cortical thickness, surface area and volumes (MRI cortical measures) vary with age and cognitive function, and in neurological and psychiatric diseases. We examined heritability, genetic correlations and genome-wide associations of cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprised 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the United Kingdom Biobank. Significant associations were replicated in the Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium, and their biological implications explored using bioinformatic annotation and pathway analyses. We identified genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There was enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging

Coronary Heart Disease and Ischemic Stroke Polygenic Risk Scores and atherosclerotic Cardiovascular Disease in a Diverse, Population-Based Cohort Study

The predictive ability of coronary heart disease (CHD) and ischemic stroke (IS) polygenic risk scores (PRS) have been evaluated individually, but whether they predict the combined outcome of atherosclerotic cardiovascular disease (ASCVD) remains insufficiently researched. It is also unclear whether associations of the CHD and IS PRS with ASCVD are independent of subclinical atherosclerosis measures. 7,286 White and 2,016 Black participants from the population-based Atherosclerosis Risk in Communities study who were free of cardiovascular disease and type 2 diabetes at baseline were included. We computed previously validated CHD and IS PRS consisting of 1,745,179 and 3,225,583 genetic variants, respectively. Cox proportional hazards models were used to test the association between each PRS and ASCVD, adjusting for traditional risk factors, ankle-brachial index, carotid intima media thickness, and carotid plaque. The hazard ratios (HR) for the CHD and IS PRS were significant with HR of 1.50 (95% CI: 1.36-1.66) and 1.31 (95% CI: 1.18-1.45) respectively for the risk of incident ASCVD per standard deviation increase in CHD and IS PRS among White participants after adjusting for traditional risk factors. The HR for the CHD PRS was not significant with an HR of 0.95 (95% CI: 0.79-1.13) for the risk of incident ASCVD in Black participants. The HR for the IS PRS was significant with an HR of 1.26 (95%CI: 1.05-1.51) for the risk of incident ASCVD in Black participants. The association of the CHD and IS PRS with ASCVD was not attenuated in White participants after adjustment for ankle-brachial index, carotid intima media thickness, and carotid plaque. The CHD and IS PRS do not cross-predict well, and predict better the outcome for which they were created than the composite ASCVD outcome. Thus, the use of the composite outcome of ASCVD may not be ideal for genetic risk prediction