Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

OBJECTIVE: To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.METHODS: We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.RESULTS: The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p [BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p [BI] = 4.4 × 10-10; p [SSBI] = 1.2 × 10-4), diabetes (p [BI] = 1.7 × 10-8; p [SSBI] = 2.8 × 10-3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10-24), and MRI-defined white matter hyperintensity burden (p [BI] = 1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy.CONCLUSION: In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.</p

Front entrance of Clarendon Terrace, Clarendon St., East Melbourne, 1977, 8 [picture] /

Condition: Good.; Title devised by cataloguer based on inscription on reverse.; Part of the collection: Wolfgang Sievers photographic archive.; Sievers number: 4540 W.; Also available in an electronic version via the internet at: http://nla.gov.au/nla.pic-vn4192798. Illustrates the architecture and exterior design of the Clarendon Terrace, 210 Clarendon Street, East Melbourne, 1977

The effects of 6 months' multimodal training on functional performance, strength, endurance, and body mass index of older individuals. Are the benefits of training similar among women and men?.

Góð hreyfigeta hefur umtalsverð áhrif á sjálfstæði og vellíðan eldra fólks. Slök hreyfigeta getur aftur á móti skert athafnir daglegs lífs. Markmið þessarar rannsóknar var að skoða áhrif 6 mánaða þjálfunar og íhlutunar á hreyfigetu karla og kvenna, hvort þjálfunin hefði ólík áhrif á kynin og hver árangur þjálfunarinnar væri 6 og 12 mánuðum eftir að henni lauk. Rannsóknin var gerð á 117 einstaklingum á aldrinum 71–90 ára sem höfðu tekið þátt í Öldrunarrannsókn Hjartaverndar. Snið rannsóknarinnar var víxlað með handahófskenndu vali í tvo hópa. Rannsóknin var gerð á þremur 6 mánaða tímabilum að loknum grunnmælingum. Sex mánaða þjálfun var þreytt af þjálfunarhópi (hópi 1) á fyrsta tímabili meðan seinni þjálfunarhópur (hópur 2) var til viðmiðunar. Hópur 2 tók síðan þátt í sams konar þjálfun á öðru tímabili en formleg þjálfun rannsóknaraðila var ekki lengur til staðar fyrir hóp 1. Sex mánuðum eftir að þjálfun hjá hópi 2 var lokið voru mælingar endurteknar í fjórða skiptið. Eftir 6 mánaða íhlutun varð 32% bæting á daglegri hreyfingu karla (p<0,001) og 39% hjá konum (p<0,001). Á hreyfigetu karla varð um 5% bæting (p<0,01) og 7% hjá konum (p<0,001). Fótkraftur karla jókst um 8% (p<0,001) og kvenna um 13% (p<0,001). Bæði karlar og konur bættu hreyfijafnvægi um 10% (p<0,001), gönguvegalengd jókst hjá báðum kynjum um 5–6% (p<0,001) og líkamsþyngdarstuðull kynjanna lækkaði um tæplega 2% (p<0,001). Enginn kynjamunur var af áhrifum þjálfunar. Heildaráhrif þjálfunar á hreyfigetu og hreyfijafnvægi héldust í allt að 12 mánuði eftir að íhlutun lauk. Fjölþætt þjálfun hefur jákvæð áhrif á hreyfigetu eldri einstaklinga, kynin bregðast á sambærilegan hátt við þjálfun og varðveita áunnar breytingar í hreyfigetu í allt að 12 mánuði. Rannsóknin bendir eindregið til þess að hófleg kerfisbundin þjálfun fyrir þennan aldurshóp ætti að vera hluti af hefðbundinni heilsugæslu aldraðra.Good functional performance in elderly people greatly improves their changes of independence and well-being. Conversely, bad functional performance can impair their capability of managing the activities of daily life.. The main goal of this study was to investigate the effects of a 6-months' multimodal training intervention on the physical performance of males and females, possible gender differences and the outcome 6 and 12 months after its completion. This study examined 71-90 year old healthy seniors (n=117) participating in the AGES Reykjavik Study. It was a randomized and controlled cross-over trial, conducted in three 6-months' phases (time-points). After enrollment and baseline assessments, the study group was divided in two. Group 1 received 6-months' training while group 2 served as a control. In the second 6 months' phase, group 1 received no formal training while group 2 did. In the third phase, neither group received training. The groups' physical conditions were assessed after each phase. After 6-months' training, 32% improvement was seen in physical activity among males (p<0.001) and 39% among females (p<0.001). In physical performance, 5% improvement was seen for males (p<0.01) and 7% for females (p<0.001). Strength increased by 8% for males (p<0.001) and 13% for females (p<0.001). For both sexes, about 10% increase was seen in dynamic balance in the 8-foot up-and-go test (p<0.001) and 5-6% in walking distance for both sexes in the six minutes walking test (p<0.001). For both sexes, body mass index decreased by about 2% (p<0.001). No difference was seen between the sexes.in the training results. Both sexes retained long-term effects of the training on physical performance and dynamic balance for at least 12 months. Multimodal training intervention has positive effects on physical performance in older individuals, the sexes respond similarly to the training and retain achieved improvement for at least 12 months. The research indicates that moderate and systemic training for this age group could be a part of conventional health service for this age group

Associations of Quadriceps Torque Properties with Muscle Size, Attenuation, and Intramuscular Adipose Tissue in Older Adults

To access publisher's full text version of this article click on the hyperlink belowBACKGROUND: Atrophy and fatty infiltration of muscle with aging are associated with fractures and falls, however, their direct associations with muscle function are not well described. It was hypothesized that participants with lower quadriceps muscle attenuation, area, and greater intramuscular adipose tissue (IMAT) will exhibit slower rates of torque development (RTD) and lower peak knee extension torques. METHODS: Data from 4,842 participants (2,041 men, 2,801 women) from the Age Gene/Environment Susceptibility Reykjavik Study (mean age 76 ± 0.1 years) with complete thigh computed tomography and isometric knee testing. Regression models were adjusted for health, behavior, and comorbidities. Muscle attenuation was further adjusted for muscle area and IMAT; muscle area adjusted for IMAT and attenuation; and IMAT adjusted for muscle area and attenuation. Standardized betas (β) indicate association effect sizes. RESULTS: In the fully-adjusted models, attenuation (men β = 0.06, 95% CI: 0.01, 0.11; women β = 0.07, 95% CI: 0.03, 0.11) and muscle area (men β = 0.13, 95% CI: 0.07, 0.19; women β = 0.10, 95% CI: 0.06, 0.15) were associated with knee RTD. Attenuation (men β = 0.12, 95% CI: 0.08, 0.16; women β = 0.12, 95% CI: 0.09, 0.16) and muscle area (men β = 0.38, 95% CI: 0.33, 0.43; women β = 0.33, 95% CI: 0.29, 0.37) were associated with peak torque. CONCLUSIONS: These data suggest that muscle attenuation and area are independently associated with RTD and peak torque; and that area and attenuation demonstrate similar contributions to RTD.National Institutes of Health National Institute on Aging Intramural Research Program Hjartavernd (the Icelandic Heart Association) Althingi (the Icelandic Parliament

Effects of age and sex on the strength and cortical thickness of the femoral neck.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldA group of 48 men (22 aged 65-75 years, 26 aged 80-90 years) and 59 women (32 aged 65-75 years, 27 aged 80-90 years) were enrolled in the Age, Gene/Environment Susceptibility-Reykjavik study and imaged with in vivo volumetric Quantitative Computed Tomography (QCT) to investigate the effects of age and sex on femoral neck structure and strength. Femoral neck cross-sectional moment of inertia for bending directions near those of standing and walking (I(AP)), bending strength (M(y)), and axial compressive strength (F(y)) were computed at the location of minimum cross-sectional area (minCSA). Local cortical thickness was computed in the inferior femoral neck based on density profiles extending through the cortex of the minCSA femoral neck section. Multivariate models accounting for height, weight, and age group (younger or older) showed that men had a 46% higher M(y) and a 23% higher F(y) than women, while women had a 13% thicker inferior cortex than men. Cortical thickness in the inferoposterior region of the femoral neck was significantly related to bending and axial strength after adjusting for overall volumetric bone mineral density. Both minCSA and I(AP) were higher in the older, gender-pooled age group, but F(y) and M(y) did not differ between the two age groups. The results suggest that age-related expansion of the femoral neck primarily occurs in the superior and inferior directions and helps maintain homeostasis of femoral neck stiffness and strength. The higher bending strength of the male femoral neck may partly explain why elderly men have a lower risk of hip fracture than elderly women

Antihypertensive medications and risk for incident dementia and Alzheimer's disease: a meta-analysis of individual participant data from prospective cohort studies.

BACKGROUND: Dementia is a major health concern for which prevention and treatment strategies remain elusive. Lowering high blood pressure with specific antihypertensive medications (AHMs) could reduce the burden of disease. We investigated whether specific AHM classes reduced the risk for dementia. METHODS: We did a meta-analysis of individual participant data from eligible observational studies published between Jan 1, 1980, and Jan 1, 2019. Cohorts were eligible for inclusion if they prospectively recruited community-dwelling adults; included more than 2000 participants; collected data for dementia events over at least 5 years; had measured blood pressure and verified use of AHMs; included in-person exams, supplemented with additional data, to capture dementia events; and had followed up cases for mortality. We assessed the association of incident dementia and clinical Alzheimer's disease with use of five AHM classes, within strata of baseline high (systolic blood pressure [SBP] ≥140 mm Hg or diastolic blood pressure [DBP] ≥90 mm Hg) and normal (SBP <140 mm Hg and DBP <90 mm Hg) blood pressure. We used a propensity score to control for confounding factors related to the probability of receiving AHM. Study-specific effect estimates were pooled using random-effects meta-analyses. RESULTS: Six prospective community-based studies (n=31 090 well phenotyped dementia-free adults older than 55 years) with median follow-ups across cohorts of 7-22 years were eligible for analysis. There were 3728 incident cases of dementia and 1741 incident Alzheimer's disease diagnoses. In the high blood pressure stratum (n=15 537), those using any AHM had a reduced risk for developing dementia (hazard ratio [HR] 0·88, 95% CI 0·79-0·98; p=0·019) and Alzheimer's disease (HR 0·84, 0·73-0·97; p=0·021) compared with those not using AHM. We did not find any significant differences between one drug class versus all others on risk of dementia. In the normal blood pressure stratum (n=15 553), there was no association between AHM use and incident dementia or Alzheimer's disease. INTERPRETATION: Over a long period of observation, no evidence was found that a specific AHM drug class was more effective than others in lowering risk of dementia. Among people with hypertensive levels of blood pressure, use of any AHM with efficacy to lower blood pressure might reduce the risk for dementia. These findings suggest future clinical guidelines for hypertension management should also consider the beneficial effect of AHM on the risk for dementia. FUNDING: The Alzheimer's Drug Discovery Foundation and the National Institute on Aging Intramural Research Program

Abstract 150: Trans-ethnic GWAS of Mri-defined Brain Infarcts: Charge Consortium

Introduction: MRI-defined brain infarcts (BI), most of which are small sub-cortical brain infarcts (SSBI), are highly prevalent in older persons. Most BI are covert, which is not associated with clinically overt stroke. Nonetheless, they are powerful predictors of future risk for stroke, cognitive decline, and dementia. Little is known about the genetic determinants of BI. Methods: We performed a trans-ethnic meta-analysis of GWAS of MRI-defined BI and SSBI in 20,949 participants belonging to 5 ethnic groups: Europeans, African-Americans, Hispanic-Americans, Malays, and Chinese. A total of 23 population-based studies from the CHARGE consortium participated in this effort, comprising of 3,726 cases and 17,223 controls for BI, 2,112 cases and 15,432 controls for SSBI. GWAS based on imputed genotypes using the 1000 Genomes phase 1, version 3 panel was performed in each study [using logistic regression]. Meta-analysis of association statistics was performed using a Bayesian partition model (MANTRA); secondary analyses used fixed effect (FE) inverse variance weighting. Loci with log 10 [Bayesian factor (BF)]>5 were considered genome-wide significant and loci with log 10 [BF]>4.5 and mean imputation accuracy score >0.80 were chosen for replication. Results: 33 variants (3 loci) reached genome-wide significance, in association with BI, on chromosome: 13q12 (Index SNP: log 10 [BF]=7, P FE =5.8х10 -9 , OR FE =1.2, minor allele frequency [MAF]=0.34), 5q23 (Index SNP: log 10 [BF]=6.5, P FE =1.8х10 -8 , OR FE =1.2, MAF=0.21) and 15q26 (Index SNP: log 10 [BF]=5.3, P FE =3.4х10 -7 , OR FE =1.8, MAF=0.03). These loci comprise genes involved in response to anti-hypertensive drugs, glucose transport, connective tissue assembly and synaptic transmission. Three additional loci showed suggestive associations (log 10 [BF] 4.5 to 5). Five of these six loci were associated with both BI and SSBI (Index SNP log 10 [BF]>2), but none reached genome-wide significance for SSBI. Conclusion: This large scale trans-ethnic GWAS meta-analysis identified three novel risk loci for MRI-defined BI. Replication analysis and functional validation are ongoing. These findings may provide novel insight into biological mechanisms underlying covert vascular brain injur

Large-Scale Screening for Monogenic and Clinically Defined Familial Hypercholesterolemia in Iceland.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadObjective: Familial hypercholesterolemia (FH) is traditionally defined as a monogenic disease characterized by severely elevated LDL-C (low-density lipoprotein cholesterol) levels. In practice, FH is commonly a clinical diagnosis without confirmation of a causative mutation. In this study, we sought to characterize and compare monogenic and clinically defined FH in a large sample of Icelanders. Approach and Results: We whole-genome sequenced 49 962 Icelanders and imputed the identified variants into an overall sample of 166 281 chip-genotyped Icelanders. We identified 20 FH mutations in LDLR, APOB, and PCSK9 with combined prevalence of 1 in 836. Monogenic FH was associated with severely elevated LDL-C levels and increased risk of premature coronary disease, aortic valve stenosis, and high burden of coronary atherosclerosis. We used a modified version of the Dutch Lipid Clinic Network criteria to screen for the clinical FH phenotype among living adult participants (N=79 058). Clinical FH was found in 2.2% of participants, of whom only 5.2% had monogenic FH. Mutation-negative clinical FH has a strong polygenic basis. Both individuals with monogenic FH and individuals with mutation-negative clinical FH were markedly undertreated with cholesterol-lowering medications and only a minority attained an LDL-C target of <2.6 mmol/L (<100 mg/dL; 11.0% and 24.9%, respectively) or <1.8 mmol/L (<70 mg/dL; 0.0% and 5.2%, respectively), as recommended for primary prevention by European Society of Cardiology/European Atherosclerosis Society cholesterol guidelines. Conclusions: Clinically defined FH is a relatively common phenotype that is explained by monogenic FH in only a minority of cases. Both monogenic and clinical FH confer high cardiovascular risk but are markedly undertreated.Landspitali University Hospital Research Fun