Limited information is available regarding genetic contributions to valvular calcification, which is an important precursor of clinical valve disease.
We determined genomewide associations with the presence of aorticvalve calcification (among 6942 participants) and mitral annular calcification (among 3795 participants), as detected by computed tomographic (CT) scanning; the study population for this analysis included persons of white European ancestry from three cohorts participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (discovery population). Findings were replicated in independent cohorts of persons with either CT-detected valvular calcification or clinical aortic stenosis.
One SNP in the lipoprotein(a) (LPA) locus (rs10455872) reached genomewide significance for the presence of aorticvalve calcification (odds ratio per allele, 2.05; P = 9.0×10−10), a finding that was replicated in additional white European, African-American, and Hispanic-American cohorts (P<0.05 for all comparisons). Genetically determined Lp(a) levels, as predicted by LPA genotype, were also associated with aorticvalve calcification, supporting a causal role for Lp(a). In prospective analyses, LPA genotype was associated with incident aortic stenosis (hazard ratio per allele, 1.68; 95% confidence interval [CI], 1.32 to 2.15) and aortic-valve replacement (hazard ratio, 1.54; 95% CI, 1.05 to 2.27) in a large Swedish cohort; the association with incident aortic stenosis was also replicated in an independent Danish cohort. Two SNPs (rs17659543 and rs13415097) near the proinflammatory gene IL1F9 achieved genomewide significance for mitral annular calcification (P = 1.5×10−8 and P = 1.8×10−8, respectively), but the findings were not replicated consistently.
Genetic variation in the LPA locus, mediated by Lp(a) levels, is associated with aorticvalve calcification across multiple ethnic groups and with incident clinical aortic stenosis. (Funded by the National Heart, Lung, and Blood Institute and others.)
Coronary Artery Calcium (CAC) is a sign of advanced atherosclerosis and an independent risk factor for cardiac events. Here, we describe CAC-distributions in an unselected aged population and compare modelling methods to characterize CAC-distribution. CAC is difficult to model because it has a skewed and zero inflated distribution with over-dispersion. Data are from the AGES-Reykjavik sample, a large population based study [2002-2006] in Iceland of 5,764 persons aged 66-96 years.
Linear regressions using logarithmic- and Box-Cox transformations on CAC+1, quantile regression and a Zero-Inflated Negative Binomial model (ZINB) were applied. Methods were compared visually and with the PRESS-statistic, R2 and number of detected associations with concurrently measured variables.
There were pronounced differences in CAC according to sex, age, history of coronary events and presence of plaque in the carotid artery. Associations with conventional coronary artery disease (CAD) risk factors varied between the sexes.
The ZINB model provided the best results with respect to the PRESS-statistic, R2, and predicted proportion of zero scores. The ZINB model detected similar numbers of associations as the linear regression on ln(CAC+1) and usually with the same risk factors.
Coronary artery calcium; epidemiology; older persons; skewed distribution; ZINB; statistical modelling
During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study in 8,175 community-dwelling elderly did not reveal any genome-wide significant associations (p<5*10−8) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (p=3.4*10−11), a known height locus on chromosome 6q22, and rs9915547, tagging the inversion on chromosome 17q21 (p=1.5*10−12). We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 older persons (p=1.1*10−3 for 6q22 and p=1.2*10−3 for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age 14.5 months). Our data identify two loci associated with head size, with the inversion on 17q21 also likely involved in attaining maximal brain size.
Recent case–control studies have shown an association between type 3 finger length pattern (longer ring finger than index finger) and knee osteoarthritis. This large cross-sectional study tests the hypothesis that the type 3 pattern is associated with total joint replacements due to osteoarthritis in a large population based study.
Finger length ratios were assessed visually on 5170 hand photographs (2975 females, 2195 males, mean age 76). In this population-based multidisciplinary study of aging in Reykjavik, Iceland, the prevalence of osteoarthritis associated total knee replacements was 223(4.3%) and total hip replacements 316(6.1%). We then performed a binary logistic regression analysis for total knee replacements and total hip replacements, including finger length patterns, osteoarthritis at other sites and other variables with possible association to osteoarthritis such as age, BMI and bone mineral density of the spine.
The prevalence of the type 3 pattern was 50% (43% in females, 58% in males). The regression analysis revealed an odds ratio for total knee replacements of 1.65 (1.24-2.2) p = 0.0007, in the type 3 finger pattern group, similar in both genders. This association was independent of the associations we have previously reported between total knee replacements and BMI and the presence of hand osteoarthritis. No association was seen between finger length patterns and total hip replacements.
Finger length patterns read from digital photographs in this large study confirm previous radiographic observations with significant associations between the type 3 pattern and total knee replacements but not total hip replacements in both genders in this elderly group.
Osteoarthritis; Finger length ratio; Epidemiology
Carotid-femoral pulse wave velocity (CFPWV) is a heritable measure of aortic stiffness that is strongly associated with increased risk for major cardiovascular disease events.
Methods and Results
We conducted a meta-analysis of genome-wide association data in 9 community-based European ancestry cohorts consisting of 20,634 participants. Results were replicated in 2 additional European ancestry cohorts involving 5,306 participants. Based on a preliminary analysis of 6 cohorts, we identified a locus on chromosome 14 in the 3′-BCL11B gene desert that is associated with CFPWV (rs7152623, minor allele frequency = 0.42, beta=−0.075±0.012 SD/allele, P = 2.8 x 10−10; replication beta=−0.086±0.020 SD/allele, P = 1.4 x 10−6). Combined results for rs7152623 from 11 cohorts gave beta=−0.076±0.010 SD/allele, P=3.1x10−15. The association persisted when adjusted for mean arterial pressure (beta=−0.060±0.009 SD/allele, P = 1.0 x 10−11). Results were consistent in younger (<55 years, 6 cohorts, N=13,914, beta=−0.081±0.014 SD/allele, P = 2.3 x 10−9) and older (9 cohorts, N=12,026, beta=−0.061±0.014 SD/allele, P=9.4x10−6) participants. In separate meta-analyses, the locus was associated with increased risk for coronary artery disease (hazard ratio [HR]=1.05, confidence interval [CI]=1.02 to 1.08, P=0.0013) and heart failure (HR=1.10, CI=1.03 to 1.16, P=0.004).
Common genetic variation in a locus in the BCL11B gene desert that is thought to harbor one or more gene enhancers is associated with higher CFPWV and increased risk for cardiovascular disease. Elucidation of the role this novel locus plays in aortic stiffness may facilitate development of therapeutic interventions that limit aortic stiffening and related cardiovascular disease events.
aorta; arterial stiffness; pulse wave velocity; genetics; cardiovascular disease
Coronary artery calcification (CAC) detected by computed tomography is a non-invasive measure of coronary atherosclerosis, that underlies most cases of myocardial infarction (MI). We aimed to identify common genetic variants associated with CAC and further investigate their associations with MI.
Methods and Results
Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was carried out in 9,961 men and women from five independent community-based cohorts, with replication in three additional independent cohorts (n=6,032). We examined the top single nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049, P=7.58×10−19) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene, P=2.65×10−11) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and with MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene).
SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.
cardiac computed tomography; coronary artery calcification; coronary atherosclerosis; genome-wide association studies; myocardial infarction
Aging is associated with reductions in hippocampal volume (HV) that are accelerated by Alzheimer’s disease and vascular risk factors. Our genome-wide association study of dementia-free persons (n=9,232) identified 46 SNPs at four loci with p-values <4.0×10-7. Two additional samples (n=2,318) replicated associations at 12q24 within MSRB3/WIF1 (discovery + replication, rs17178006; p=5.3×10-11) and at 12q14 near HRK/FBXW8 (rs7294919; p=2.9×10-11). Remaining associations included one 2q24 SNP within DPP4 (rs6741949; p=2.9×10-7) and nine 9p33 SNPs within ASTN2 (rs7852872; p=1.0×10-7) that were also associated with HV (p<0.05) in a third younger, more heterogeneous sample (n=7,794). The ASTN2 SNP was also associated with decline in cognition in a largely independent sample (n=1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8), enzymes targeted by new diabetes medications (DPP4), and neuronal migration (ASTN2), indicating novel genetic influences that influence hippocampal size and possibly the risk of cognitive decline and dementia.
Aortic stiffness increases with age and vascular risk factor exposure and is associated with increased risk for structural and functional abnormalities in the brain. High ambient flow and low impedance are thought to sensitize the cerebral microcirculation to harmful effects of excessive pressure and flow pulsatility. However, haemodynamic mechanisms contributing to structural brain lesions and cognitive impairment in the presence of high aortic stiffness remain unclear. We hypothesized that disproportionate stiffening of the proximal aorta as compared with the carotid arteries reduces wave reflection at this important interface and thereby facilitates transmission of excessive pulsatile energy into the cerebral microcirculation, leading to microvascular damage and impaired function. To assess this hypothesis, we evaluated carotid pressure and flow, carotid–femoral pulse wave velocity, brain magnetic resonance images and cognitive scores in participants in the community-based Age, Gene/Environment Susceptibility – Reykjavik study who had no history of stroke, transient ischaemic attack or dementia (n = 668, 378 females, 69–93 years of age). Aortic characteristic impedance was assessed in a random subset (n = 422) and the reflection coefficient at the aorta–carotid interface was computed. Carotid flow pulsatility index was negatively related to the aorta–carotid reflection coefficient (R = −0.66, P<0.001). Carotid pulse pressure, pulsatility index and carotid–femoral pulse wave velocity were each associated with increased risk for silent subcortical infarcts (hazard ratios of 1.62–1.71 per standard deviation, P<0.002). Carotid–femoral pulse wave velocity was associated with higher white matter hyperintensity volume (0.108 ± 0.045 SD/SD, P = 0.018). Pulsatility index was associated with lower whole brain (−0.127 ± 0.037 SD/SD, P<0.001), grey matter (−0.079 ± 0.038 SD/SD, P = 0.038) and white matter (−0.128 ± 0.039 SD/SD, P<0.001) volumes. Carotid–femoral pulse wave velocity (−0.095 ± 0.043 SD/SD, P = 0.028) and carotid pulse pressure (−0.114 ± 0.045 SD/SD, P = 0.013) were associated with lower memory scores. Pulsatility index was associated with lower memory scores (−0.165 ± 0.039 SD/SD, P<0.001), slower processing speed (−0.118 ± 0.033 SD/SD, P<0.001) and worse performance on tests assessing executive function (−0.155 ± 0.041 SD/SD, P<0.001). When magnetic resonance imaging measures (grey and white matter volumes, white matter hyperintensity volumes and prevalent subcortical infarcts) were included in cognitive models, haemodynamic associations were attenuated or no longer significant, consistent with the hypothesis that increased aortic stiffness and excessive flow pulsatility damage the microcirculation, leading to quantifiable tissue damage and reduced cognitive performance. Marked stiffening of the aorta is associated with reduced wave reflection at the interface between carotid and aorta, transmission of excessive flow pulsatility into the brain, microvascular structural brain damage and lower scores in various cognitive domains.
haemodynamics; aortic stiffness; magnetic resonance imaging; brain structure; cognitive function
White matter hyperintensities (WMH) detectable by magnetic resonance imaging (MRI)are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMH are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.
We performed a meta-analysis of genome-wide association studies (GWAS) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.
We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs)in one locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (Pdiscovery= 4.0×10−9; Preplication =1.3×10−7; Pcombined =4.0×10−15). Other SNPs in this region also reaching genome-wide significance are rs9894383 (P=5.3×10−9), rs11869977 (P=5.7×10−9), rs936393 (P=6.8×10−9), rs3744017 (P=7.3×10−9), and rs1055129 (P=4.1×10−8). Variant alleles at these loci conferred a small increase in WMH burden (4–8% of the overall mean WMH burden in the sample).
This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.
In this prospective nested case-control study we analyzed the circumferential differences in estimated cortical thickness (Est CTh) of the mid femoral neck as a risk factor for osteoporotic hip fractures in elderly women and men. Segmental QCT analysis of the mid femoral neck was applied to assess cortical thickness in anatomical quadrants. The superior region of the femoral neck was a stronger predictor for hip fracture than the inferior region, particularly in men. There were significant gender differences in Est CTh measurements in the control group but not in the case group. In multivariable analysis for risk of femoral neck (FN) fracture, Est CTh in the supero-anterior (SA) quadrant was significant in both women and men, and remained a significant predictor after adjustment for FN areal BMD (aBMD, dimensions g/cm2, DXA-like), (p=0.05 and p<0.0001, respectively). In conclusion, Est CTh in the SA quadrant best discriminated cases (n=143) from controls (n=298), especially in men. Cortical thinning superiorly in the hip might be of importance in determining resistance to fracture.
cortical thickness; hip fracture; quantitative computed tomography; proximal femur; BMD
Background and Purpose
Several cardiovascular risk factors are associated with cognitive disorders in older persons. Little is known about the association of the burden of coronary atherosclerosis with brain structure and function.
Cross-sectional analysis of data from the AGES Reykjavik Study cohort of men and women born 1907-35. Coronary artery calcification (CAC), a marker of atherosclerotic burden was measured with computed tomography. Memory, speed of processing, and executive function composites were calculated from a cognitive test battery. Dementia was assessed in a multi-step procedure and diagnosed according to international guidelines. Quantitative data on total intracranial and tissue volumes [total, Gray (GMV), White (WMV), and White Matter Lesions (WMLV)], cerebral infarcts and cerebral microbleeds (CMB) were obtained with brain MRI. The association of CAC with dementia (n=165 cases) and cognitive function in non-demented subjects (n=4085), and separately with MRI outcomes, was examined in multivariate models adjusting for demographic and vascular risk factors. Analyses tested whether brain structure mediated the associations of CAC to cognitive function.
Subjects with higher CAC were more likely to have dementia and lower cognitive scores, more likely to have lower WMV, GMV and total brain tissue, and more cerebral infarcts, CMB and WMLV. The relations of cognitive performance and dementia to CAC were significantly attenuated when the models were adjusted for brain lesions and volumes.
In a population-based sample increasing atherosclerotic load, assessed by CAC, is associated with poorer cognitive performance and dementia, and these relations are mediated by evidence of brain pathology.
Atherosclerosis; Coronary Artery Disease; Calcinosis/radiography; Dementia; Cognitive function
The objective of the study was to standardize a method using digital photographs to diagnose and grade hand osteoarthritis (HOA), to compare it with radiographs and clinical examination with regard to prevalence and relation to symptoms, and finally to construct a simple shortened version suitable for use in very large studies, where a global estimate may be preferable.
High quality photographs with standard distance and hand positioning were analysed for the presence of HOA and subsequently compared with standard radiographs and clinical examination in 381 random participants in the AGES-Reykjavik Study, a large population study. The mean age of the participants was 76 years.
Using the photographic method, the most commonly affected joints were the second DIP joints followed by the third DIP joints and second and third PIP joints. Both interobserver (ICC = 0.83) and intraobserver reading agreements (ICC = 0.89) were acceptable. On comparison with radiography and clinical examination, aggregate scores were significantly correlated (Rs 0.35-0.69), more so in females (Rs 0.53-0.72) than males. Hand pain in males showed very little association with HOA findings by the three methods but all methods showed a comparable moderate association with hand pain in females. The performance of photography in predicting pain on most days for at least a month in females was comparable to that of radiography and clinical examination (AUC 0.63 p = 0.004). Analysis of intermittent pain yielded similar results for in the DIP and PIP joints (OR 3.2-3.3, p < 0.01), but for the CMC1 joints, both radiography (OR 9.0, p < 0.0001), and clinical examination (OR 9.8, p < 0.0001), had higher predictive odds ratios for pain than photography (OR 3.6, p < 0.0001)., A shortened, rapidly performed form of reading photographs also showed a high degree of correlation with the other methods (Rs 0.56-0.82).
High quality hand photographs can be used to diagnose and grade hand osteoarthritis. The method has the advantage of being inexpensive and easy to perform. By using a slightly simplified method of reading, it appears to be highly suitable for use in large studies.
Hand ostearthritis; Generalized osteoarthritis; Epidemiology; Imaging; Photography
Background & Purpose
Cerebral infarcts increase the risk for cognitive impairment. The relevance of location and number of infarcts with respect to cognitive function is less clear.
We studied the cross-sectional association between number and location of infarcts and cognitive performance in 4030 non-demented participants of the Age Gene/Environment Susceptibility-Reykjavik Study. Composite scores for memory (MEM), processing speed (SP) and executive function (EF) were created from a neuropsychological battery. Subcortical, cortical, and cerebellar infarcts were identified on brain MRI. We performed linear-regression analyses adjusted for demographic and vascular risk factors, depression, white matter lesions, and atrophy.
Compared to participants with no infarcts, those with infarcts in multiple locations (n=287, 7%) had slower SP (β=-0.19, p<.001) and poorer MEM (β=-0.16, p<.001) and EF (β=-0.12, p=.003). Compared to no infarcts, the presence of either subcortical infarcts only (n=275) (β=-0.12, p=.016) or cortical infarcts only (n=215) (β=-0.17, p=.001) was associated with poorer MEM performance. Compared to no infarcts, a combination of cortical and subcortical infarcts (n=45) was associated with slower SP (β=-0.38, p<.001) and poorer EF (β=-0.22, p=.02), while a combination of cerebellar and subcortical infarcts (n=89) was associated with slower SP (β=-0.15, p=.04). Infarcts in all three locations was associated with slower SP (β=-0.33, p=.002).
Having infarcts in more than one location is associated with poor performance in memory, processing speed, and executive function, independent of cardiovascular comorbidities, white matter lesions and brain atrophy, suggesting that both the number and the distribution of infarcts jointly contribute to cognitive impairment.
This study examines the relationship between total knee replacements (TKR),total hip replacements (THR) or replacements of either joint (TJR) due to osteoarthritis (OA) and atherosclerosis in a large population-based study.
The participants were 2195 males and 2975 females, mean age 76±6 years. The OA data were analysed in relation to measures of atherosclerosis, including carotid artery intima media thickness and plaque severity (ultrasound), coronary and aortic calcifications (CT), cerebral white matter lesions (MRI) and history of previous cardiac and cerebral events.
The prevalence of TKR was 223(4.3%) and THR 316(6.1%). The presence of TJR’s in females was associated with a nonsignificant trend towards increased carotid plaque severity, coronary calcifications and periventricular white matter hyperintensities (PVHs) but not with history of cardiac or cerebral events. No associations were seen in males. When TJR’s were grouped according to the presence or absence of HOA there was a highly significant association in the order –TJR/−HOA < +TJR/−HOA < −TJR/+HOA < +TJR/+HOA, for carotid plaque severity, coronary calcifications and PVHs.
The presence of TJR’s did not show a significant independent association with atherosclerosis but enhanced the strength of the positive association between HOA and subclinical atherosclerosis in females.
Hand osteoarthritis; Total knee replacements; Total hip replacements; atherosclerosis; AGES-Reykjavik Study
Background and Purpose
Chronic effects of hypertension may be observed in multiple end-organs. Previous reports suggest that cardiovascular morphologic features can mirror cerebral infarction. In this cross-sectional analysis of elderly subjects, we investigated the relationship of a comprehensive set of echocardiographic measures with cerebral infarction detected by magnetic resonance imaging (MRI).
We compared echocardiographically determined left ventricular (LV) mass, left atrial (LA) volume, aortic root diameter, mitral annular calcification and measures of diastolic function with cerebral infarction determined by MRI using logistic regression in a random sample drawn from the Age Gene/Environment Susceptibility-Reykjavik Study cohort. The model was first adjusted for age and sex, and then for age, sex, and vascular risk factors.
Among 692 subjects aged 75 (standard deviation=6) years, 28% had at least one cerebral infarct. When adjusted for age and sex, the presence of cerebral infarction was modestly related to LV mass (1.01 [1.00, 1.02], odds ratio [95% confidence interval]) and LA volume (1.03 [1.01, 1.05]) as well as the lowest quartile of early to late pulsed Doppler velocity (E/A) ratio (E/A<0.75; 1.87 [1.22, 2.87]). The latter relation remained significant after adjustment for vascular risk factors and LV ejection fraction (1.82 [1.16, 2.86]).
Of all echocardiographic parameters, LV filling abnormality as indicated by low E/A ratio, displayed the strongest association with cerebral infarction and this relationship was independent of vascular risk factors. This simple marker of cerebral infarction may be useful when evaluating older patients.
epidemiology; aging; echocardiography; cerebral infarction; magnetic resonance imaging
Improving employees' posture may decrease the risk of musculoskeletal disorders. The current paper is a systematic replication and extension of Sigurdsson and Austin (2008), who found that an intervention consisting of information, real-time feedback, and self-monitoring improved participant posture at mock workstations. In the current study, participants worked in an applied setting, and posture data were collected at participants' own workstations and a mock workstation. Intervention in the mock setting was associated with consistent improvement in safe posture at the mock workstation, but generalization to the actual workstation was limited.
ergonomics; musculoskeletal disorders; real-time feedback; self-monitoring
Migraine is considered to be an episodic condition with no long-term consequences. However, recent studies suggest that migraine attacks may be associated with pathologic changes in the brain, particularly in the cerebellum.
To determine whether, compared to those not reporting symptoms, individuals reporting migraine symptoms in mid-life, particularly aura, are at increased risk of late-life infarct-like lesions (hereafter referred to as infarcts).
A population based cohort of men and women (b 1907-35) followed since 1967, answered questions about migraine symptoms in mid-life (mean age 51, range 33–65), more than 26 years prior to a late-life exam when brain MRI was acquired. Those reporting headaches once or more per month were asked about migraine symptoms, including nausea, unilateral location, photophobia, visual disturbance, and numbness. We classified headache sufferers as having migraine without aura (MO), migraine with aura (MA), or non-migraine headache. A comprehensive cardiovascular risk assessment was performed at both examinations.
Population-based study in Reykjavik, Iceland
Men and women (n=4689, 57% women).
Main Outcome Measure
Presence of infarcts – total and specifically located in the cortical, sub-cortical, and cerebellar regions.
After adjusting for age, sex, and follow-up time, compared to those not reporting headaches once or more per month (n=3243), those with mid-life MA (n=361) had an increased risk of late-life infarcts (adjusted OR, 1.4; 95% confidence interval [CI], 1.1–1.8) that specifically reflected an association with cerebellar lesions in women (Women: 23.0% vs. 14.5%, adjusted OR 1.9; 95% CI 1.4–2.6 vs. Men 19.3% vs. 21.3%, adjusted OR, 1.0; 95% CI 0.6–1.8, p<0.04 for interaction by sex). There was no increased risk associated with mid-life MO or non-migraine headache or for other brain regions.
Migraine with aura in mid-life was associated with late-life prevalence of cerebellar infarcts on MRI. This association was statistically significant only for women. This is consistent with the hypothesis that MA in mid-life is associated with late-life vascular disease that appears to be specific for the cerebellum and in women.
Visceral adipose tissue (VAT) is a key pathogenic fat depot in the metabolic syndrome (MetS), but liver fat (LF) may also play an important role. We evaluated associations of VAT and LF with MetS in normal weight, overweight, and obese men and women (BMI <25, 25-29.9, and ≥30 kg/m2, respectively). This analysis included 2495 participants from the AGES-Reykjavik Study with computed tomography measurements for VAT and LF. MetS was defined by ≥3 of the following: larger abdominal circumference, hypertension, elevated TG, low HDL, impaired fasting glucose, and microalbuminuria. We estimated the odds of MetS per 1-SD increase in VAT and LF, adjusting for key covariates. VAT was associated with an increased odds of MetS in normal weight, overweight, and obese women (OR=2.78, 1.63, and 1.43, respectively; all P<0.01) that diminished in magnitude with increasing BMI (VAT*BMI class interaction P<0.001). In men, VAT was related to MetS only among the overweight (OR=1.69, P<0.01). LF was associated with MetS in the overweight and obese groups in women (OR=1.38 and 1.45; both P<0.001) and in men (OR=1.38, P=0.01; and OR=1.27, P=0.10), but not in the normal weight groups. These BMI-specific relationships persisted when both fat depots were included in the model. VAT and LF were associated with MetS independently of each other, and these relationships were modified by BMI class such that, VAT was the more important depot at lower levels of obesity and LF at higher levels. Importantly, fatty liver may be a novel metabolic risk factor in overweight and obese individuals.
Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI-infarct, in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.
Using 2.2 million genotyped and imputed SNPs, each study performed cross-sectional genome-wide association analysis of MRI-infarct using age and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance weighted meta-analysis, including 9401 participants with mean age 69.7, 19.4% of whom had ≥1 MRI-infarct.
The most significant association was found with rs2208454 (minor allele frequency: 20%), located in intron 3 of MACRO Domain Containing 2 gene and in the downstream region of Fibronectin Leucine Rich Transmembrane Protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI-infarcts: odds ratio=0.76, 95% confidence interval=0.68–0.84, p=4.64×10−7. Highly suggestive associations (p<1.0×10−5) were also found for 22 other SNPs in linkage disequilibrium (r2>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 African-American participants, although 4 SNPs within 200kb from rs2208454 were associated with MRI-infarcts in African-American sample.
This first community-based, genome-wide association study on covert MRI-infarcts uncovered novel associations. Although replication of the association with top SNP failed, possibly due to insufficient power, results in the African American sample are encouraging, and further efforts at replication are needed.
genome-wide association study; brain infarction; MRI; cohort study; meta-analysis
To identify factors associated with having total knee replacement due to osteoarthritis in the AGES-Reykjavik Study, a large population based study of elderly Icelanders.
Information about total knee and hip joint replacements (TKR,THR) and hand OA (HOA) severity was available in 2195 males and 2975 females, mean age 76±6 years. The prevalence of TKR was 223 (4.3%) and THR 316 (6.1%). We performed a backwards binary logistic regression analysis of possible OA associated variables including age, gender, abdominal circumference, BMI, hs-CRP, cholesterol, statin use, bone mineral density of the spine, education and smoking history as well as HOA severity and the presence of THR.
Only three factors showed significant associations with TKR; BMI (p=3.5x10-17), HOA severity (p=2.9x10-8) and THR (p=0.0002). The highest quintile of BMI was associated with a fivefold risk of TKR compared with the lowest (8% vs 1.6%), and severe HOA had a 2.4 fold risk compared with those with no HOA (8% vs 3.3%). There was no statistical interaction between BMI and HOA. Thus, individuals with BMI<23.5 with no evidence of HOA had a prevalence of TKR of 1.1%, while those with BMI>30.3 and severe HOA had a prevalence of 13.4%.
Hand and hip osteoarthritis in conjunction with BMI are strongly associated with the prevalence of TKR due to osteoarthritis. Together, BMI and HOA severity seem to contribute to the majority of the total TKR prevalence. While BMI has long been recognized as the major risk factor for TKR, the influence of osteoarthritis at other sites may have been underestimated.
Epidemiology; knee osteoarthritis; knee joint replacement; Body Mass index (BMI); hand osteoarthritis; AGES-Reykjavk Study.
To assess whether markers of micro- and macro-structural brain abnormalities are associated with slower gait in older men and women independent of each other, and also independent of health-related conditions and of behavioral, cognitive and peripheral function.
Magnetization transfer ratio [MTR], white matter hyperintensities [WMH], brain atrophy [BA] and brain infarcts [BI] were measured in 795 participants of the AGES-Reykjavik Study cohort (mean 75.6yrs, 58.9% women).
In women, lower MTR, higher WMH and BA, but not BI, remained associated with slower gait independent of each other and of other covariates. In men, WMH and BA, but not MTR or BI, remained associated with slower gait independently of each other. Only muscle strength, executive control function and depression test scores substantially attenuated these associations.
MTR in older adults may be an important additional marker of brain abnormalities associated with slower gait. Studies to explore the relationship between brain micro- and macrostructural abnormalities with gait and the role of mediating factors are warranted.
MTR; gait speed; community-dwelling seniors
To investigate whether the severity and location of cerebral white matter hyperintensities (WMHs) and brain infarcts are correlated with the signs of retinal microvascular abnormalities in the elderly.
The study included 4176 men and women (mean age, 76 years) who participated in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study. Digital retinal images of both dilated eyes were taken and evaluated for the presence of retinal focal arteriolar signs (focal arteriolar narrowing and arteriovenous nicking) and retinopathy lesions (retinal blot hemorrhages and microaneurysms). Brain MRI scans were acquired and evaluated for the presence and distribution of cerebral infarcts and WMHs. Logistic and multinomial logistic models were constructed to estimate the association of retinal microvascular signs to brain lesions.
Controlling for demographic and major cardiovascular risk factors, retinal focal arteriolar signs, but not retinopathy lesions, were significantly associated with an increasing load of subcortical and periventricular WMHs. The strongest association was found between retinal arteriolar signs and a heavier WMH load, specifically in subcortical frontal lobe and periventricular frontal and parietal caps. There was a tendency towards bilateral retinal focal arteriolar narrowing being more strongly associated with the heavier load of subcortical WMHs. Arteriovenous nicking was significantly associated with subcortical infarcts.
In older adults, retinal focal arteriolar signs, but not retinopathy lesions, are correlated with the load of diffuse WMHs, particularly those located in the subcortical frontal lobe and the periventricular frontal and parietal caps of the brain.
This study evaluated video scoring and feedback about scoring as a safety intervention among 6 nursing staff. The dependent variable was safety behavior on one-person transfers. Following baseline, 5 nursing staff participated in an information phase. A video scoring phase was then introduced for all 6. A feedback phase was added for 2 participants. All participants experienced treatment withdrawal. Information resulted in improvements for all 5 participants who received it. Further improvements were observed during video scoring for the 5 participants who improved following information. No improvements were observed for the participant who received only video scoring. Safety feedback further improved safety for the 2 participants who received it. However, participants' behavior returned to video scoring levels during withdrawal.
behavioral safety; lifting; musculoskeletal disorders; nurse injuries; video modeling
The purpose of the current study was to examine the effects of a multicomponent intervention that included discrimination training, real-time visual feedback, and self-monitoring on postural behavior at a computer workstation in a simulated office environment. Using a nonconcurrent multiple baseline design across 8 participants, the study assessed the effects of the intervention across three postural variables. Following an information phase, the intervention started for the lowest stable postural variable. The intervention led to substantial improvements in safety behavior for most targeted postural variables. A reversal to the information phase for 2 participants did not lead to decreases in safety. Postures self-monitored with high accuracy improved to a greater degree than postures self-monitored with low accuracy.
behavioral safety; computer workstations; ergonomics; feedback; occupational safety