Associations between Proportion of Plasma Phospholipid Fatty Acids, Depressive Symptoms and Major Depressive Disorder. Cross-Sectional Analyses from the AGES Reykjavik Study.

BACKGROUND: Deficits in n-3 fatty acids may be associated with depression. However, data are scarce from older adults who are at greater risk of poor dietary intake and of developing depression. OBJECTIVE: To investigate proportion of plasma phospholipid fatty acids with respect to depressive symptoms and major depressive disorder in community dwelling older adults. METHODS: Cross-sectional analyses of 1571 participants in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study aged 67-93 years. Depressive symptoms were measured using the 15-item Geriatric Depression Scale (GDS-15). Major depressive disorder was assessed according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria using the Mini-International Neuropsychiatric Interview (MINI). RESULTS: Depressive symptoms were observed in 195 (12.4%) subjects and there were 27 (1.7%) cases of major depressive disorder. Participants with depressive symptoms were less educated, more likely to be smokers, less physically active and consumed cod liver oil less frequently. Difference in GDS-15 scores by tertiles of n-3 fatty acid proportion was not significant. Proportion of long chain n-3 fatty acids (Eicosapentaenoic- + Docosahexaenoic acid) were inversely related to major depressive disorder, (tertile 2 vs. tertile 1) OR: 0.31 (95% CI: 0.11, 0.86); tertile 3 vs. tertile 1, OR: 0.45 (95% CI: 0.17, 1.21). CONCLUSION: In our cross sectional analyses low proportions of long chain n-3 fatty acids in plasma phospholipids appear to be associated with increased risk of major depressive disorder. However, the results from this study warrant further investigation in prospective setting with sufficiently long follow-up.

15q11.2 CNV affects cognitive, structural and functional correlates of dyslexia and dyscalculia.

Several copy number variants have been associated with neuropsychiatric disorders and these variants have been shown to also influence cognitive abilities in carriers unaffected by psychiatric disorders. Previously, we associated the 15q11.2(BP1-BP2) deletion with specific learning disabilities and a larger corpus callosum. Here we investigate, in a much larger sample, the effect of the 15q11.2(BP1-BP2) deletion on cognitive, structural and functional correlates of dyslexia and dyscalculia. We report that the deletion confers greatest risk of the combined phenotype of dyslexia and dyscalculia. We also show that the deletion associates with a smaller left fusiform gyrus. Moreover, tailored functional magnetic resonance imaging experiments using phonological lexical decision and multiplication verification tasks demonstrate altered activation in the left fusiform and the left angular gyri in carriers. Thus, by using convergent evidence from neuropsychological testing, and structural and functional neuroimaging, we show that the 15q11.2(BP1-BP2) deletion affects cognitive, structural and functional correlates of both dyslexia and dyscalculia.

Association of bone turnover markers with volumetric bone loss, periosteal apposition, and fracture risk in older men and women: the AGES-Reykjavik longitudinal study.

Association between serum bone formation and resorption markers and cortical and trabecular bone loss and the concurrent periosteal apposition in a population-based cohort of 1069 older adults was assessed. BTM levels moderately reflect the cellular events at the endosteal and periosteal surfaces but are not associated with fracture risk. INTRODUCTION: We assessed whether circulating bone formation and resorption markers (BTM) were individual predictors for trabecular and cortical bone loss, periosteal expansion, and fracture risk in older adults aged 66 to 93 years from the AGES-Reykjavik study. METHODS: The sample for the quantitative computed tomography (QCT)-derived cortical and trabecular BMD and periosteal expansion analysis consisted of 1069 participants (474 men and 595 women) who had complete baseline (2002 to 2006) and follow-up (2007 to 2011) hip QCT scans and serum baseline BTM. During the median follow-up of 11.7 years (range 5.4-12.5), 54 (11.4 %) men and 182 (30.6 %) women sustained at least one fracture of any type. RESULTS: Increase in BTM levels was associated with faster cortical and trabecular bone loss at the femoral neck and proximal femur in men and women. Higher BTM levels were positively related with periosteal expansion rate at the femoral neck in men. Markers were not associated with fracture risk. CONCLUSION: This data corroborates the notion from few previous studies that both envelopes are metabolically active and that BTM levels may moderately reflect the cellular events at the endosteal and periosteal surfaces. However, our results do not support the routine use of BTM to assess fracture risk in older men and women. In light of these findings, further studies are justified to examine whether systemic markers of bone turnover might prove useful in monitoring skeletal remodeling events and the effects of current osteoporosis drugs at the periosteum.

Are bone turnover markers associated with volumetric bone density, size, and strength in older men and women? The AGES-Reykjavik study.

UNLABELLED: Association between serum bone formation and resorption markers and bone mineral, structural, and strength variables derived from quantitative computed tomography (QCT) in a population-based cohort of 1745 older adults was assessed. The association was weak for lumbar spine and femoral neck areal and volumetric bone mineral density. INTRODUCTION: The aim of this study was to examine the relationship between levels of bone turnover markers (BTMs; osteocalcin (OC), C-terminal cross-linking telopeptide of type I collagen (CTX), and procollagen type 1N propeptide (P1NP)) and quantitative computed tomography (QCT)-derived bone density, geometry, and strength indices in the lumbar spine and femoral neck (FN). METHODS: A total of 1745 older individuals (773 men and 972 women, aged 66-92 years) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort were studied. QCT was performed in the lumbar spine and hip to estimate volumetric trabecular, cortical, and integral bone mineral density (BMD), areal BMD, bone geometry, and bone strength indices. Association between BTMs and QCT variables were explored using multivariable linear regression. RESULTS: Major findings showed that all BMD measures, FN cortical index, and compressive strength had a low negative correlation with the BTM levels in both men and women. Correlations between BTMs and bone size parameters were minimal or not significant. No associations were found between BTMs and vertebral cross-sectional area in women. BTMs alone accounted for only a relatively small percentage of the bone parameter variance (1-10 %). CONCLUSION: Serum CTX, OC, and P1NP were weakly correlated with lumbar spine and FN areal and volumetric BMD and strength measures. Most of the bone size indices were not associated with BTMs; thus, the selected bone remodeling markers do not reflect periosteal bone formation. These results confirmed the limited ability of the most sensitive established BTMs to predict bone structural integrity in older adults.

Polyunsaturated fatty acids in relation to incident mobility disability and decline in gait speed; the Age, Gene/Environment Susceptibility-Reykjavik Study.

BACKGROUND/OBJECTIVES: Low intake of long chain polyunsaturated fatty acids (PUFAs) are associated with physical disability; however, prospective studies of circulating PUFAs are scarce. We examined associations between plasma phospholipid n-3 and n-6 PUFAs with risk of incident mobility disability and gait speed decline. SUBJECTS/METHODS: Data are from a subgroup of the Age, Gene/Environment Susceptibility-Reykjavik Study, a population-based study of risk factors for disease and disability in old age. In this subgroup (n = 556, mean age 75.1 ± 5.0 years, 47.5% men), plasma phospholipid PUFAs were assessed at baseline using gas chromatography. Mobility disability and usual gait speed were assessed at baseline and after 5.2 ± 0.2 years. Mobility disability was defined as the following: having much difficulty, or being unable to walk 500 m or climb up 10 steps; decline in gait speed was defined as change ⩾ 0.10 m/s. Logistic regression analyses were performed to determine associations between sex-specific s.d. increments in PUFAs with risk of incident mobility disability and gait speed decline. Odds ratios (95% confidence intervals) adjusted for demographics, follow-up time, risk factors and serum vitamin D were reported. RESULTS: In women, but not men, every s.d. increment increase of total n-3 PUFAs and docosahexaenoic acid (DHA) was associated with lower mobility disability risk, odds ratio 0.48 (0.25; 0.93) and odds ratio 0.45 (0.24; 0.83), respectively. There was no association between n-6 PUFAs and the risk of incident mobility disability or gait speed decline. CONCLUSIONS: Higher concentrations of n-3 PUFAs and, particularly, DHA may protect women from impaired mobility but does not appear to have such an effect in men.

Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 × 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 × 10(-4)). The strongest combined association was at rs1823125 (P=1.5 × 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

Effect of finite element model loading condition on fracture risk assessment in men and women: the AGES-Reykjavik study.

Proximal femoral (hip) strength computed by subject-specific CT scan-based finite element (FE) models has been explored as an improved measure for identifying subjects at risk of hip fracture. However, to our knowledge, no published study has reported the effect of loading condition on the association between incident hip fracture and hip strength. In the present study, we performed a nested age- and sex-matched case-control study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. Baseline (pre-fracture) quantitative CT (QCT) scans of 5500 older male and female subjects were obtained. During 4-7years follow-up, 51 men and 77 women sustained hip fractures. Ninety-seven men and 152 women were randomly selected as controls from a pool of age- and sex-matched subjects. From the QCT data, FE models employing nonlinear material properties computed FE-strength of the left hip of each subject in loading from a fall onto the posterolateral (FPL), posterior (FP) and lateral (FL) aspects of the greater trochanter (patent pending). For comparison, FE strength in stance loading (FStance) and total femur areal bone mineral density (aBMD) were also computed. For all loading conditions, the reductions in strength associated with fracture in men were more than twice those in women (p≤0.01). For fall loading specifically, posterolateral loading in men and posterior loading in women were most strongly associated with incident hip fracture. After adjusting for aBMD, the association between FP and fracture in women fell short of statistical significance (p=0.08), indicating that FE strength provides little advantage over aBMD for identifying female hip fracture subjects. However, in men, after controlling for aBMD, FPL was 424N (11%) less in subjects with fractures than in controls (p=0.003). Thus, in men, FE models of posterolateral loading include information about incident hip fracture beyond that in aBMD.

Serum vitamin D and parathyroid hormone in relation to cardiac structure and function: the ICELAND-MI substudy of AGES-Reykjavik.

CONTEXT: Emerging evidence suggests that vitamin D and PTH may play a role in the development of cardiac diseases. OBJECTIVE: We investigated whether 25-hydroxyvitamin D (25OHD) and PTH concentrations are cross-sectionally associated with cardiac structure and function using magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: ICELAND-MI is a substudy of the Age, Gene/Environment Susceptibility-Reykjavik Study, an older-aged community-dwelling cohort with oversampling of participants with diabetes (29%) and measurements between 2004 and 2007. Serum 25OHD concentrations were measured using an immunoassay (n = 992). Intact PTH concentrations were measured using a 2-site immunoassay (n = 203). We included 969 participants for this cross-sectional analysis (mean age 76 ± 5.3 years, 51% female). Mean 25OHD was 54.2 ± 25.5 nmol/L and the median PTH was 4.5 pmol/L (range 1.5-18). MAIN OUTCOMES: MRI to measure cardiac structure and function was the main outcome. RESULTS: The lowest 25OHD category (<25 nmol/L) compared with the highest category (≥75 nmol/L) was associated with a smaller left and right atrial area in unadjusted analyses; however, the associations became nonsignificant after adjustment for covariates. The highest PTH quartile compared with the lowest quartile was significantly associated with a 7.3 g (95% confidence interval 0.8, 13.8) greater left ventricular (LV) mass and a 5.1% (-9.1, -1.1) lower LV ejection fraction compared with the lowest PTH quartile in the fully adjusted model. CONCLUSIONS: Serum 25OHD concentrations were not associated with MRI measures in an older white population. Higher PTH concentrations were associated with greater LV mass and lower systolic function and may point to a potential role for PTH as a determinant of cardiac remodeling.

Associations of current and remitted major depressive disorder with brain atrophy: the AGES-Reykjavik Study.

BACKGROUND: To examine whether lifetime DSM-IV diagnosis of major depressive disorder (MDD), including age at onset and number of episodes, is associated with brain atrophy in older persons without dementia. METHOD: Within the population-based Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study, 4354 persons (mean age 76 ± 5 years, 58% women) without dementia had a 1.5-T brain magnetic resonance imaging (MRI) scan. Automated brain segmentation total and regional brain volumes were calculated. History of MDD, including age at onset and number of episodes, and MDD in the past 2 weeks was diagnosed according to DSM-IV criteria using the Mini-International Neuropsychiatric Interview (MINI). RESULTS: Of the total sample, 4.5% reported a lifetime history of MDD; 1.5% had a current diagnosis of MDD (including 75% with a prior history of depression) and 3.0% had a past but no current diagnosis (remission). After adjusting for multiple covariates, compared to participants never depressed, those with current MDD (irrespective of past) had more global brain atrophy [B = -1.25%, 95% confidence interval (CI) -2.05 to -0.44], including more gray- and white-matter atrophy in most lobes, and also more atrophy of the hippocampus and thalamus. Participants with current, first-onset MDD also had more brain atrophy (B = -1.62%, 95% CI -3.30 to 0.05) whereas those remitted did not (B = 0.06%, 95% CI -0.54 to 0.66). CONCLUSIONS: In older persons without dementia, current MDD, irrespective of prior history, but not remitted MDD was associated with widespread gray- and white-matter brain atrophy. Prospective studies should examine whether MDD is a consequence of, or contributes to, brain volume loss and development of dementia.

Lifelong physical activity in maintaining bone strength in older men and women of the Age, Gene/Environment Susceptibility-Reykjavik Study.

UNLABELLED: We examined if lifelong physical activity is important for maintaining bone strength in the elderly. Associations of quantitative computerized tomography-acquired bone measures (vertebral and femoral) and self-reported physical activity in mid-life (mean age, 50 years), in old age (≥65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. Results conclude lifelong physical activity with continuation into old age (≥65 years) best maintains better bone health later in life. INTRODUCTION: Skeletal loading is thought to modulate the loss of bone in later life, and physical activity is a chief means of affecting bone strength by skeletal loading. Despite much discussion regarding lifelong versus early adulthood physical activity for preventing bone loss later in life, inconsistency still exists regarding how to maintain bone mass later in life (≥65 years). METHODS: We examined if lifelong physical activity is important for maintaining bone strength in the elderly. RESULTS: The associations of quantitative computerized tomography-acquired vertebral and femoral bone measures and self-reported physical activity in mid-life (mean age, 50 years), in old age (≥65 years), and throughout life (recalled during old age) were investigated in 2,110 men and 2,682 women in the AGES-Reykjavik Study. CONCLUSION: Our findings conclude that lifelong physical activity with continuation into old age (≥65 years) best maintains better bone health in the elderly.

Age-related loss of proximal femoral strength in elderly men and women: the Age Gene/Environment Susceptibility Study--Reykjavik.

The risk of hip fracture rises rapidly with age, and is particularly high in women. This increase in fracture risk reflects both the age-related change in the risk of falling and decrements in the strength of the proximal femur. To better understand the extent to which proximal femoral density, structure and strength change with age as a function of gender, we have carried out a longitudinal analysis of proximal femoral volumetric quantitative computed tomographic (vQCT) images in men and women, analyzing changes in trabecular and cortical bone properties, and using subject-specific finite element modeling (FEM) to estimate changes in bone strength. In the AGES-Reykjavik Study vQCT scans of the hip were performed at a baseline visit in 2002-2006 and at a second visit 5.05±0.25 years later. From these, 223 subjects (111 men, 112 women, aged 68-87 years) were randomly selected. The subjects were evaluated for longitudinal changes in three bone variables assessed in a region similar to the total femur region quantified by DXA: areal bone mineral density (aBMD), trabecular volumetric bone mineral density (tBMD) and the ratio of cortical to total tissue volume (cvol/ivol). They were also evaluated for changes in bone strength using FEM models of the left proximal femur. Models were analyzed under single-limb stance loading (F(Stance)), which approximates normal physiologic loading of the hip, as well as a load approximating a fall onto the posterolateral aspect of the greater trochanter (F(Fall)). We computed five-year absolute and percentage changes in aBMD, tBMD, cvol/ivol, F(Fall) and F(Stance). The Mann-Whitney Test was employed to compare changes in bone variables between genders and the Wilcoxon Signed Rank Test was used to compare changes in bone strength between loading conditions. Multiple (linear) regression was employed to determine the association of changes in F(Fall) and F(Stance) with baseline age and five-year weight loss. Both men and women showed declines in indices of proximal femoral density and structure (aBMD: men -3.9±6.0%, women -6.1±6.2%; tBMD: men -14.8±20.3%, women -23.9±26.8%; cvol/ivol: men -2.6±4.6%, women -4.7±4.8%, gender difference: p<0.001). Both men and women lost bone strength in each loading condition (F(Stance): men -4.2±9.9%, women -8.3±8.5%; F(Fall): men -7.0±15.7%, women -12.8±13.2%; all changes from baseline p<0.0001). The gender difference in bone strength loss was statistically significant in both loading conditions (p<0.001 for F(Stance) and P<0.01 for F(Fall)) and F(Fall) was lost at a higher rate than F(Stance) in men (p<0.01) and women (p<0.0001). The gender difference in strength loss was statistically significant after adjustment for baseline age and weight loss in both loading conditions (p<0.01). In these multi-linear models, men showed increasing rates of bone loss with increasing age (F(Fall): p=0.002; F(Stance): p=0.03), and women showed increasing bone strength loss with higher degrees of weight loss (F(Stance): p=0.003). The higher loss of F(Fall) compared to F(Stance) supports previous findings in animal and human studies that the sub-volumes of bone stressed under normal physiologic loading are relatively better protected in aging. The gender difference in hip bone strength loss is consistent with the higher incidence of hip fracture among elderly women.

Retinopathy in old persons with and without diabetes mellitus: the Age, Gene/Environment Susceptibility--Reykjavik Study (AGES-R).

AIMS/HYPOTHESIS: We aimed to describe the prevalence of retinopathy in an aged cohort of Icelanders with and without diabetes mellitus. METHODS: The study population consisted of 4,994 persons aged ≥ 67 years, who participated in the Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-R). Type 2 diabetes mellitus was defined as HbA(1c) ≥ 6.5% (>48 mmol/mol). Retinopathy was assessed by grading fundus photographs using the modified Airlie House adaptation of the Early Treatment Diabetic Retinopathy Study protocol. Associations between retinopathy and risk factors were estimated using odds ratios obtained from multivariate analyses. RESULTS: The overall prevalence of retinopathy in AGES-R was 12.4%. Diabetes mellitus was present in 516 persons (10.3%), for 512 of whom gradable fundus photos were available, including 138 persons (27.0%, 95% CI 23.2, 31.0) with any retinopathy. Five persons (1.0%, 95% CI 0.3, 2.3) had proliferative retinopathy. Clinically significant macular oedema was present in five persons (1.0%, 95% CI 0.3, 2.3). Independent risk factors for retinopathy in diabetic patients in a multivariate model included HbA(1c), insulin use and use of oral hypoglycaemic agents, the last two being indicators of longer disease duration. In 4478 participants without diabetes mellitus, gradable fundus photos were available for 4,453 participants, with retinopathy present in 476 (10.7%, 95% CI 9.8, 11.6) and clinically significant macular oedema in three persons. Independent risk factors included increasing age and microalbuminuria. CONCLUSIONS/INTERPRETATION: Over three-quarters (78%) of retinopathy cases were found in persons without diabetes and a strong association between microalbuminuria and non-diabetic retinopathy was found. These results may have implications for patient management of the aged.

Male-female differences in the association between incident hip fracture and proximal femoral strength: a finite element analysis study.

Hip fracture risk is usually evaluated using dual energy X-ray absorptiometry (DXA) or quantitative computed tomography (QCT) which provide surrogate measures for proximal femoral strength. However, proximal femoral strength can best be estimated explicitly by combining QCT with finite element (FE) analysis. To evaluate this technique for predicting hip fracture in older men and women, we performed a nested age- and sex-matched case-control study in the Age Gene/Environment Susceptibility (AGES) Reykjavik cohort. Baseline (pre-fracture) QCT scans of 5500 subjects were obtained. During 4-7 years follow-up, 51 men and 77 women sustained hip fractures. Ninety-seven men and 152 women were randomly selected as age- and sex-matched controls. FE-strength of the left hip of each subject for stance (F(Stance)) and posterolateral fall (F(Fall)) loading, and total femur areal bone mineral density (aBMD) were computed from the QCT data. F(Stance) and F(Fall) in incident hip fracture subjects were 13%-25% less than in control subjects (p ≤ 0.006) after controlling for demographic parameters. The difference between FE strengths of fracture and control subjects was disproportionately greater in men (stance, 22%; fall, 25%) than in women (stance, 13%; fall, 18%) (p ≤ 0.033), considering that F(Stance) and F(Fall) in fracture subjects were greater in men than in women (p < 0.001). For men, F(Stance) was associated with hip fracture after accounting for aBMD (p = 0.013). These data indicate that F(Stance) provides information about fracture risk that is beyond that provided by aBMD (p = 0.013). These findings support further exploration of possible sex differences in the predictors of hip fracture and of sex-specific strategies for using FE analysis to manage osteoporosis.

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

A 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.

Cerebral microbleeds, retinopathy, and dementia: the AGES-Reykjavik Study.

OBJECTIVE: To determine whether microvascular damage, indicated by cerebral microbleeds (CMBs) and retinal microvascular signs, is associated with cognitive function and dementia in older persons. METHODS: This is a cross-sectional study of 3,906 participants (mean age 76 years; 58% women) in the AGES-Reykjavik Study (2002-2006). We assessed CMBs on MRI and retinal microvascular signs on digital retinal images. Composite Z scores of memory, processing speed, and executive function were derived from a battery of neurocognitive tests. Dementia and subtypes were diagnosed following international criteria. Regression models were used to relate cognitive Z scores and dementia to CMBs and retinal microvascular signs, adjusting for demographics, cardiovascular factors, and brain ischemic lesions. RESULTS: People with multiple (≥ 2) CMBs had lower Z scores on tests of processing speed (ß-coefficient -0.16; 95% confidence interval -0.26 to -0.05) and executive function (-0.14; -0.24 to -0.04); results were strongest for having multiple CMBs located in the deep hemispheric or infratentorial areas. The odds ratio of vascular dementia was 2.32 (95% confidence interval 1.02 to 5.25) for multiple CMBs and 1.95 (1.04 to 3.62) for retinopathy. Having both CMBs and retinopathy, compared to having neither, was significantly associated with markedly slower processing speed (-0.25; -0.37 to -0.12), poorer executive function (-0.19; -0.31 to -0.07), and an increased odds ratio of vascular dementia (3.10; 1.11 to 8.62). CONCLUSION: Having multiple CMBs or concomitant CMBs and retinopathy is associated with a profile of vascular cognitive impairment. These findings suggest that microvascular damage, as indicated by CMBs and retinopathy lesions, has functional consequences in older men and women living in the community.

IGF2BP1, IGF2BP2 and IGF2BP3 genotype, haplotype and genetic model studies in metabolic syndrome traits and diabetes.

OBJECTIVE: Genetic variation at the insulin-like binding protein 2 (IGF2BP2) gene has been associated with type 2 diabetes (T2D) by genome-wide association studies and by replication analyses. Our aim was to explore the underlying genetic model and mechanism of action, factors accounting for non-replications of the associations, and the effect of variation from pathway-related genes IGF2BP1 and IGF2BP3. METHOD: We analysed here the association between T2D (and related traits) and rs4402960 and rs1470579 in IGF2BP2, and rs46522 and rs6949019 (marking IGF2BP1 and IGF2BP3 respectively) from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study (N approximately 2500 aged 65-96 years). We undertook a retrospective analysis of the deviations from the multiplicative model in previous studies and the present study. RESULTS: We replicated an association between rs4402960 and T2D status, and reported significant associations with anthropometric traits, fasting insulin, HOMA-IR and HOMA-%B. These associations were also observed for rs1470579, but not for the SNPs marking IGF2BP1 and IGF2BP3. CONCLUSIONS: The lower fasting insulin levels and the impaired beta-cell function associated with IGF2BP2 SNPs are independent of obesity phenotypes. The action of these SNPs on T2D may result from an effect on beta-cell function. This could lead to lower insulin levels, the association with anthropometric traits being secondary. We discuss possible mechanisms of action relating IGF2BP2 with T2D traits. The occurrence of null alleles, the inclusion of T2D patients in analyses of metabolic syndrome risk traits and the genetic model, are possible factors accounting for non-replications of IGF2BP2 associations with T2D.

The interaction of adiposity with the CRP gene affects CRP levels: age, gene/environment susceptibilty-Reykjavik study.

OBJECTIVE: Common diseases often have an inflammatory component reflected by associated markers such as serum C-reactive protein (CRP) levels. Circulating CRP levels have also been associated with adipose tissue as well as with specific CRP genotypes. We examined the interaction between measures of body mass index (BMI), waist circumference and fat percent (total fat measured by bioimpedance) with genotypes of the CRP gene in the determination of CRP levels. METHODS: The first 2296 participants (mean age 76+/-6 years, 42% men) in the Age, Gene/Environment Susceptibility-Reykjavik Study, a multidisciplinary epidemiological study to determine risk factors in aging, were genotyped for 10 single nucleotide polymorphisms (SNPs) in the CRP gene. General linear models with age and terms for interaction of CRP genotypes with BMI, waist circumference and percent fat were used to evaluate the association of genotypes to CRP levels (high-sensitivity method, range 0-10 mg l(-1)) in men and women separately. RESULTS: We focused on the SNP rs1205 that represents the allele that captures the strongest effects of the gene on CRP levels. Carriers of the rs1205 G allele had significantly higher CRP levels than noncarriers in a dose-dependent manner. Compared to the AA genotype, the slope of the increase in CRP with increasing BMI (P=0.045) and waist circumference (P=0.014) was different for the G allele carriers and of similar magnitude in both men and women. The rs1205 interactions were not significant for fat mass percent, suggesting a possible association with fat localization. CONCLUSIONS: This study further illuminates the known association between measures of adiposity and CRP levels and is shown to be dependent on variation in the rs1205 SNP of the CRP gene. The correlated increase in CRP levels with adiposity is accentuated by presence of the G allele.

High hand joint mobility is associated with radiological CMC1 osteoarthritis: the AGES-Reykjavik study.

OBJECTIVE: Previous studies have indicated that joint hypermobility may affect the development of clinical and radiological hand osteoarthritis (OA), but this question has not been addressed in epidemiological studies. Our objective was to investigate this relationship in a population-based study. PATIENTS AND METHODS: The study group consisted of 384 unselected older participants in the Age, Gene/Environment Susceptibility-Reykjavik Study (161 males, median age 76, range 69-90, and 223 females median age 75, range 69-92). The criterion used for joint mobility was the single maximal degree of hyperextension of digits 2 and 5 on both hands (HYP degrees). RESULTS: HYP degrees was more prevalent in females and on the left hand in both men and women. Both genders had a positive association between the degree of mobility measured by HYP degrees and radiological scores for the first carpometacarpal joint (CMC1) OA. Thus, those with HYP degrees >or=70 had an odds ratio of 3.05 (1.69-5.5, P<0.001) of having a Kellgren-Lawrence score of >or=3 in a CMC1 joint. There was also a trend towards a negative association between HYP degrees and proximal interphalangeal joint scores. CONCLUSION: Hand joint mobility, defined as hyperextension in the metacarpophalangeal joints (HYP degrees ) is more prevalent in females and on the left side. It was associated with more severe radiographic OA in the CMC1 joints in this population. The reasons for this relationship are not known, but likely explanations involve ligament laxity and CMC1 joint stability. These findings may relate to the left-sided predominance of radiographic OA in the CMC1 joints observed in many prevalence studies.

Hand osteoarthritis in older women is associated with carotid and coronary atherosclerosis: the AGES Reykjavik study.

OBJECTIVE: There is evidence that atherosclerosis may contribute to the initiation or progression of osteoarthritis. To test this hypothesis, the presence and severity of hand osteoarthritis (HOA) was compared with markers of atherosclerotic vascular disease in an elderly population. PATIENTS AND METHODS: The AGES Reykjavik Study is a population-based multidisciplinary study of ageing in the elderly population of Reykjavik. In a study of 2264 men (mean age 76 years; SD 6) and 3078 women (mean age 76 years; SD 6) the severity of HOA, scored from photographs, was compared with measures of atherosclerosis. These included carotid intimal thickness and plaque severity, coronary calcifications (CAC) and aortic calcifications and reported cardiac and cerebrovascular events. RESULTS: After adjustment for confounders, both carotid plaque severity and CAC were significantly associated with HOA in women, with an odds ratio of 1.42 (95% CI 1.14 to 1.76, p = 0.002) for having CAC and 1.25 (95% CI 1.04 to 1.49, p = 0.016) for having moderate or severe carotid plaques. Both carotid plaques and CAC also exhibited significant linear trends in relation to HOA severity in women in the whole AGES Reykjavik cohort (p<0.001 and p = 0.027, respectively, for trend). No significant associations were seen in men. Despite this evidence of increased atherosclerosis, women with HOA did not report proportionally more previous cardiovascular or cerebrovascular events. CONCLUSIONS: The results indicate a linear association between the severity of HOA and atherosclerosis in older women. The pathological process of HOA seems to have some components in common with atherosclerosis. Prospective studies may help elucidate the possible mechanisms of this relationship.