Age , Gene/Environment Susceptibility Research Articles

Urinary Melatonin Levels, Sleep Disruption, and Risk of Prostate Cancer in Elderly Men

Melatonin has anticarcinogenic properties in experimental models. We undertook a case–cohort study of 928 Icelandic men without prostate cancer (PCa) nested within the Age, Gene/Environment Susceptibility (AGES)-Reykjavik cohort to investigate the prospective association between first morning-void urinary 6-sulfatoxymelatonin (aMT6s) levels and the subsequent risk for PCa, under the hypothesis that men with lower aMT6s levels have an increased risk for advanced PCa. We used weighted Cox proportional hazards models to assess the association between first morning-void aMT6s levels and PCa risk, adjusting for potential confounders. A total of 111 men were diagnosed with incident PCa, including 24 with advanced disease. Men who reported sleep problems at baseline had lower morning aMT6s levels compared with those who reported no sleep problems. Men with morning aMT6s levels below the median had a fourfold statistically significant increased risk for advanced disease compared with men with levels above the median (hazard ratio: 4.04; 95% confidence interval, 1.26–12.98). These results require replication in larger prospective studies with longer follow-up. Patient summaryIn this report, we evaluated the prospective association between urinary aMT6s levels and risk of PCa in an Icelandic population. We found that lower levels of aMT6s were associated with an increased risk for advanced PCa.

Segmental Kidney Volumes Measured by Dynamic Contrast-Enhanced Magnetic Resonance Imaging and Their Association With CKD in Older People

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a potentially powerful tool for analysis of kidney structure and function. The ability to measure functional and hypofunctional tissues could provide important information in groups at risk for chronic kidney disease (CKD), such as the elderly. Observational study with a cross-sectional design. 493 volunteers (aged 72-94 years; 278 women; mean estimated glomerular filtration rate [eGFR], 67±15mL/min/1.73m(2); 40% with CKD) in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study. DCE-MRI kidney segmentation data. eGFR, urine albumin-creatinine ratio (ACR), and risk factors for and complications of CKD. After adjustment for age, sex, and height, eGFR was related to kidney volume (ΔR²=0.19; P<0.001), cortex volume (ΔR²=0.14; P<0.001), medulla volume (ΔR²=0.18; P<0.001), and volume percentages of fibrosis (ΔR²=0.03; P<0.001) and fat (ΔR²=0.01; P=0.03). In similarly adjusted models, log(ACR) was related to kidney volume (ΔR²=0.02; P<0.001) and fibrosis volume percentage (ΔR²=0.03; P<0.001). Using multivariable regression models adjusted for eGFR, ACR, age, sex, and height, kidney volume was related positively to body mass index (B=29.9±2.1[SE]mL; P<0.001), smoking (B=19.7±7.7mL; P=0.01), and diabetes mellitus (B=14.8±7.1mL; P=0.04) and negatively to hematocrit (B=-4.4±2.1mL; P=0.04 [model R²=0.72; P<0.001]); relations were per 1-SD greater value of the variable. Fibrosis volume percentage was associated positively with body mass index (B=0.28±0.03; P<0.001), cardiac output (B=0.15±0.03; P<0.001), and heart rate (B=0.08±0.03; P=0.01) and negatively with hematocrit (B=-0.07±0.3; P=0.02) and augmentation index (B=-0.06±0.03; P=0.04 [model R²=0.49; P<0.001]); again, relations are per 1-SD greater value of the variable. Automatic segmentations were not validated by histology. The limited age range prevented meaningful interpretation of age effects on measured data or the automatic segmentation procedure. Kidney volume, cortex volume, and hypofunctional volume fraction assessed by DCE-MRI may provide information about CKD risk and prognosis beyond that provided by eGFR and urine ACR.

Joint effect of mid- and late-life blood pressure on the brain: the AGES-Reykjavik study.

We hypothesized that in participants with a history of hypertension, lower late-life blood pressure (BP) will be associated with more brain pathology. Participants are 4,057 older men and women without dementia with midlife (mean age 50 ± 6 years) and late-life (mean age 76 ± 5 years) vascular screening, cognitive function, and brain structures on MRI ascertained as part of the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study. The association of late-life BP to brain measures depended on midlife hypertension history. Higher late-life systolic and diastolic BP (DBP) was associated with an increased risk of white matter lesions and cerebral microbleeds, and this was most pronounced in participants without a history of midlife hypertension. In contrast, in participants with a history of midlife hypertension, lower late-life DBP was associated with smaller total brain and gray matter volumes. This finding was reflected back in cognitive performance; in participants with midlife hypertension, lower DBP was associated with lower memory scores. In this large population-based cohort, late-life BP differentially affects brain pathology and cognitive performance, depending on the history of midlife hypertension. Our study suggests history of hypertension is critical to understand how late-life BP affects brain structure and function.

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.

Socioeconomic factors from midlife predict mobility limitation and depressed mood three decades later; Findings from the AGES-Reykjavik Study

BackgroundTaking into account our rapidly ageing population, older people are of particular interest in studying health inequalities. Most studies of older persons only include measures of current socioeconomic status (SES) and do not take into account data from earlier stages of life. In addition, only classic SES measures are used, while alternative measures, such as car ownership and house ownership, might equally well predict health. The present study aims to examine the effect of midlife socioeconomic factors on mobility limitation and depressed mood three decades later.MethodsData were from 4,809 men and women aged 33–65 years who participated in the Reykjavik Study (1967–1992) and who were re-examined in old age in the Age, Gene/Environment Susceptibility (AGES) -Reykjavik Study (2002–2006).ResultsEducation and occupation predicted mobility limitation and depressed mood. Independently, home and car ownership and the availability of housing features predicted mobility limitation. Shortages of food in childhood and lack of a car in midlife predicted depressed mood.ConclusionSocioeconomic factors from midlife and from childhood affect mobility limitation and depressed mood in old age. Prevention of health problems in old age should begin as early as midlife.

Abstract B90: Variation in circadian rhythm genes and risk of prostate cancer in the AGES-Reykjavik cohort

Abstract Background: Disruption of sleep duration or circadian rhythms has been associated with an increased risk of prostate cancer. Studies have suggested that circadian genes may be involved in regulating cancer-related pathways, such as cell proliferation, DNA damage response and apoptosis. As such, we hypothesized that genetic susceptibility to prostate cancer may be in part due to common variation in the core circadian rhythm genes. We assessed the association of genetic variation in core circadian rhythm genes with risk of prostate cancer and with urinary levels of melatonin among men in the prospective Age, Gene/Environment Susceptibility (AGES)-Reykjavik study. Methods: The study population was 1,352 men in the AGES-Reykjavik cohort with data from a previous genome wide association study. We examined 96 single-nucleotide polymorphisms (SNPs) across twelve genes chosen to represent common variation in genes that control the circadian rhythm (CLOCK, neuronal PAS domain protein 2 (NPAS2), aryl hydrocarbon receptor nuclear translocator-like (ARNTL), cryptochrome 1(CRY1), cryptochrome 2 (CRY2), period 1 (PER1), period 2 (PER2), period 3 (PER3), casein kinase 1-epsilon (CSNK1E)), two melatonin receptor genes (MTNR1A and MTNR1B), and the Timeless (TIM) gene. Melatonin levels were determined from first morning void urine samples using an ELISA assay. Prostate cancer (N = 138) was identified from hospital records using ICD codes; death from prostate cancer (N = 24) was determined from nationwide death records. We used unconditional logistic regression to evaluate the association between each SNP and overall and lethal prostate cancer. Linear regression was used to assess the association between each SNP and log-transformed melatonin levels. Finally, to test whether multimarker SNP-sets in the pathway were associated with prostate cancer or melatonin levels, we used a kernel machine test. Results: None of the 96 SNPs evaluated were significantly associated with prostate cancer overall. The variant allele in two SNPs in CRY1 (rs7297614 and rs1921126) and one in PER1 (rs2289591) were nominally (p-value &amp;lt;0.05 without adjusting for multiple testing) associated with an elevated risk of lethal prostate cancer, while SNPs in NPAS2 (rs3754674), ARNTL (rs969485) and PER2 (rs10462023) were nominally associated with a reduced risk of lethal disease. Among men without cancer, 4 SNPs in TIM and 6 in NPAS2 were nominally associated with lower levels of urinary melatonin; 2 SNPs in PER3 and 1 in CSNK1E were associated with higher levels of urinary melatonin. Pathway analyses showed that variability across the individual genes CRY1 and PER2 were nominally associated with lethal prostate cancer (p-value 0.01 and 0.05, respectively). For melatonin levels, the set of SNPs across all 12 genes and TIM was nominally associated with urinary melatonin levels (p-value 0.05 and 0.02, respectively). Conclusion: Variation in circadian genes, such as PER1, CRY1, and CRY2, has been previously associated with increased prostate cancer risk; variation in NPAS2 has been associated with reduced prostate cancer risk. Similar to previously reported literature, we observed several suggestive associations between variation in genes that regulate the circadian rhythm and lethal prostate cancer risk as well as urinary melatonin levels. Our findings provide further support for a role of circadian disruption in prostate cancer progression. Citation Format: Sarah Coseo Markt, Unnur A. Valdimarsdottir, Lara G. Sigurdardottir, Irene M. Shui, Jennifer R. Rider, Julie L. Kasperzyk, Steven W. Lockley, Charles A. Czeisler, Meir J. Stampfer, Thor Aspelund, Albert Vernon Smith, Vilmundur Gudnason, Lorelei A. Mucci. Variation in circadian rhythm genes and risk of prostate cancer in the AGES-Reykjavik cohort. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B90.

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

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. 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). 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). 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.

Cerebral microbleeds and age-related macular degeneration: the AGES-Reykjavik Study

We test the hypothesis that cerebral microbleeds (CMB) and age-related macular degeneration (AMD), both linked to amyloid-β deposition, are correlated. This study includes 4205 participants (mean age 76.2; 57.8% women) in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study (2002–2006). CMB were assessed from magnetic resonance images, and AMD was assessed using digital retinal images. Data were analyzed with multinomial logistic models controlling for major confounders. Evidence of CMB was detected in 476 persons (272 with strict lobar CMB and 204 with nonlobar CMB). AMD was detected in 1098 persons (869 with early AMD, 140 with exudative AMD, and 89 with pure geographic atrophy). Early and exudative AMD were not associated with CMB. The adjusted odds ratio of pure geographic atrophy was 1.62 (95% confidence interval 0.93–2.82, p = 0.089) for having any CMB, 1.43 (0.66–3.06, p = 0.363) for strict lobar CMB, and 1.85 (0.89–3.87, p = 0.100) for nonlobar CMB. This study provides no evidence that amyloid deposits in the brain and AMD are correlated. However, the suggestive association of geographic atrophy with CMB warrants further investigation.

Effect of vertebral fractures on function, quality of life and hospitalisation the AGES-Reykjavik study

understanding the determinants of health burden after a fracture in ageing populations is important. assess the effect of clinical vertebral and other osteoporotic fractures on function and the subsequent risk of hospitalisation. individuals from the prospective population-based cohort study Age, Gene/Environment Susceptibility (AGES)-Reykjavik study were examined between 2002 and 2006 and followed up for 5.4 years. a total of 5,764 individuals, 57.7% women, born 1907-35, mean age 77. four groups with a verified fracture status were used; vertebral fractures, other osteoporotic fractures excluding vertebral, non-osteoporotic fractures and not-fractured were compared and analysed for the effect on mobility, strength, QoL, ADL, co-morbidity and hospitalisation. worst performance on functional tests was in the vertebral fracture group for women (P<0.0001) and the other osteoporotic fractures group for men (P<0.05). Both vertebral and other osteoporotic fractures, showed an increased risk of hospitalisation, HR=1.4 (95% CI: 1.3-1.7) and 1.2 (95% CI: 1.1-1.2) respectively (P<0.0001). Individuals with vertebral fractures had 50% (P<0.0001) longer hospitalisation than not-fractured and 33% (P<0.002) longer than the other osteoporotic fractures group. individuals with a history of clinical vertebral fracture seem to carry the greatest health burden compared with other fracture groups, emphasising the attention which should be given to those individuals.

Associations of Visceral and Liver Fat With the Metabolic Syndrome Across the Spectrum of Obesity: The AGES‐Reykjavik Study

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 2,495 participants from the Age, Gene/Environment Susceptibility (AGES)-Reykjavik study with computed tomography measurements for VAT and LF. MetS was defined by ≥3 of the following: larger abdominal circumference, hypertension, elevated triglyceride (TG), low high-density lipoprotein (HDL), impaired fasting glucose (IFG), and microalbuminuria. We estimated the odds of MetS per 1-s.d. 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 (odds ratios (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.

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.

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 ∼ 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 β-cell function associated with IGF2BP2 SNPs are independent of obesity phenotypes. The action of these SNPs on T2D may result from an effect on β-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.

Coronary Artery Calcium, Brain Function and Structure

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. This is a cross-sectional analysis of data from the Age, Gene, Environment Susceptibility (AGES)-Reykjavik Study cohort of men and women born 1907 to 1935. Coronary artery calcification (CAC), a marker of atherosclerotic burden, was measured with CT. Memory, speed of processing, and executive function composites were calculated from a cognitive test battery. Dementia was assessed in a multistep procedure and diagnosed according to international guidelines. Quantitative data on total intracranial and tissue volumes (total, gray matter volume, white matter volume, and white matter lesion volume), cerebral infarcts, and cerebral microbleeds were obtained with brain MRI. The association of CAC with dementia (n=165 cases) and cognitive function in nondemented 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 white matter volume, gray matter volume, and total brain tissue, and to have more cerebral infarcts, cerebral microbleeds, and white matter lesions. 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.

Microvascular lesions in the brain and retina: The age, gene/environment susceptibility–Reykjavik study

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 4,176 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 magnetic resonance imaging 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, we found that 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 the subcortical frontal lobe, and periventricular frontal and parietal caps. There was a tendency toward 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.

Cerebral microbleeds in the population based AGES-Reykjavik study: prevalence and location

Background and purpose: Incidental foci of signal loss suggestive of cerebral microbleeds (CMBs) are frequent findings on gradient echo T2* weighted MRI (T2* MRI) of patients with haemorrhagic or ischaemic...