Age-related macular degeneration: A two-level model hypothesis.

Age-related diseases, including age-related macular degeneration (AMD), are of growing importance in a world where population ageing has become a dominant global trend. Although a wide variety of risk factors for AMD have been identified, age itself remains by far the most important risk factor, making it an urgent priority to understand the connections between underlying ageing mechanisms and pathophysiology of AMD. Ageing is both multicausal and variable, so that differences between individuals in biological ageing processes are the focus of a growing number of pathophysiological studies seeking to explain how ageing contributes to chronic, age-related conditions. The aim of this review is to integrate the available knowledge on the pathophysiology of AMD within the framework of the biology of ageing. One highly significant feature of biological ageing is systemic inflammation, which arises as a second-level response to a first level of molecular damage involving oxidative stress, mutations etc. Combining these insights, the various co-existing pathophysiological explanations in AMD arrange themselves according to a two-level hypothesis. Accordingly, we describe how AMD can be considered the consequence of age-related random accumulation of molecular damage at the ocular level and the subsequent systemic inflammatory host response thereof. We summarize evidence and provide original data to enlighten where evidence is lacking. Finally, we discuss how this two-level hypothesis provides a foundation for thoughts and future studies in prevention, prognosis, and intervention.

Thyroid Stimulating Hormone and Bone Mineral Density: Evidence From a Two-Sample Mendelian Randomization Study and a Candidate Gene Association Study.

With population aging, prevalence of low bone mineral density (BMD) and associated fracture risk are increased. To determine whether low circulating thyroid stimulating hormone (TSH) levels within the normal range are causally related to BMD, we conducted a two-sample Mendelian randomization (MR) study. Furthermore, we tested whether common genetic variants in the TSH receptor (TSHR) gene and genetic variants influencing expression of TSHR (expression quantitative trait loci [eQTLs]) are associated with BMD. For both analyses, we used summary-level data of genomewide association studies (GWASs) investigating BMD of the femoral neck (n = 32,735) and the lumbar spine (n = 28,498) in cohorts of European ancestry from the Genetic Factors of Osteoporosis (GEFOS) Consortium. For the MR study, we selected 20 genetic variants that were previously identified for circulating TSH levels in a GWAS meta-analysis (n = 26,420). All independent genetic instruments for TSH were combined in analyses for both femoral neck and lumbar spine BMD. In these studies, we found no evidence that a genetically determined 1-standard deviation (SD) decrease in circulating TSH concentration was associated with femoral neck BMD (0.003 SD decrease in BMD per SD decrease of TSH; 95% CI, -0.053 to 0.048; p = 0.92) or lumbar spine BMD (0.010 SD decrease in BMD per SD decrease of TSH; 95% CI, -0.069 to 0.049; p = 0.73). A total of 706 common genetic variants have been mapped to the TSHR locus and expression loci for TSHR. However, none of these genetic variants were associated with BMD at the femoral neck or lumbar spine. In conclusion, we found no evidence for a causal effect of circulating TSH on BMD, nor did we find any association between genetic variation at the TSHR locus or expression thereof and BMD. © 2018 The Authors. Journal of Bone and Mineral Research Published by WileyPeriodicals, Inc.

Shift work, long working hours, and later risk of dementia: A long-term follow-up of the Copenhagen Male Study.

Objectives The aim of this study was to investigate the effect of shift work and long working hours in midlife on the risk of dementia in old age. Methods The present study comprised 4766 participants from the Copenhagen Male Study. We used information on shift work (collected in 1970-1971 and 1985-1986), long working hours defined as >45 hours per week (collected in 1970-1971), socioeconomic status, sleep, stress, and cardiovascular risk factors. Information about dementia diagnoses was obtained from registers. Participants were followed until 2014 (mean length of follow-up was 17.8 years). We employed Poisson regression for the survival analyses and estimated incidence rate ratios (IRR) and their 95% confidence intervals (CI). Results We found no statistically significant association between shift work (IRR 0.86, 95% CI 0.70-1.05) or long working hours (IRR 0.97, 95% CI 0.79-1.19) and dementia. Adjustment for potential confounders and mediators did not change the estimates. Working shifts at both time points of exposure assessment was not associated with a higher incidence of dementia compared with non-shift workers at both time points (IRR 0.99, 95% CI 0.69-1.42). The lowest incidence of dementia was observed among participants who reported shift work at one time point (only in 1985-1986: IRR 0.44, 95% CI 0.16-1.23 and only in 1970-1971: IRR 0.58, 95% CI 0.31-1.11). Conclusion We did not find positive evidence of an association between shift work or long working hours and the incidence of dementia, but the negative findings may reflect the crude assessment of shift work and long working hours, which is a major limitation of the present study.

High-sensitivity cardiac troponin T is associated with cognitive decline in older adults at high cardiovascular risk.

AIMS: Cardiac troponin T (cTnT), measured with a high-sensitivity (hs) assay, is associated with cognitive decline, but the underlying mechanism is unknown. We investigated the association of hs-cTnT with cognitive function and decline, and studied whether this association was independent of cardiovascular diseases or risk factors, and N-terminal pro-brain natriuretic peptide (NT-proBNP). METHODS AND RESULTS: We studied 5407 participants (mean age 75.31 years) from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), who all had cardiovascular diseases or risk factors thereof. Participants with pre-existent advanced clinical heart failure were excluded. Hs-cTnT and NT-proBNP obtained after 6 months of follow-up were related with cognitive function, tested repeatedly during a mean follow-up of 3.2 years. Participants with higher hs-cTnT performed worse at baseline on Stroop test (mean baseline score (standard error (SE)) lowest vs highest third 65.91 (1.16) vs 69.40 (1.10) seconds, p < 0.001), Letter-Digit Coding test (23.35 (0.32) vs 22.40 (0.31) digits coded, p < 0.001), immediate Picture-Word Learning test (9.45 (0.09) vs 9.31 (0.08) pictures remembered, p = 0.002) and delayed Picture-Word Learning test (10.33 (0.12) vs 10.10 (0.12) pictures remembered, p = 0.013). Furthermore, participants with higher hs-cTnT had steeper decline on Stroop test (mean annual change (SE) lowest vs highest third 0.34 (0.12) vs 1.06 (0.12) seconds, p = 0.013), Letter-Digit Coding test (-0.29 (0.03) vs -0.46 (0.03) digits coded, p < 0.001), immediate Picture-Word Learning test (0.01 (0.01) vs -0.06 (0.01) pictures remembered, p < 0.001) and delayed Picture-Word Learning test (-0.03 (0.01) vs -0.12 (0.02) pictures remembered, p = 0.001). Associations were independent of cardiovascular diseases risk factors or Apolipoprotein E genotype. Further adjusting for NT-proBNP levels revealed the same results. CONCLUSIONS: Higher levels of hs-cTnT associate with worse cognitive function and steeper cognitive decline in older adults independent of cardiovascular diseases, risk factors and NT-proBNP.

Effects of a web-based intervention on physical activity and metabolism in older adults: randomized controlled trial.

BACKGROUND: Lack of physical activity leads to detrimental changes in body composition and metabolism, functional decline, and increased risk of disease in old age. The potential of Web-assisted interventions for increasing physical activity and improving metabolism in older individuals holds great promise but to our knowledge it has not been studied. OBJECTIVE: The goal of our study was to assess whether a Web-based intervention increases physical activity and improves metabolic health in inactive older adults. METHODS: We conducted a 3-month randomized, waitlist-controlled trial in a volunteer sample of 235 inactive adults aged 60-70 years without diabetes. The intervention group received the Internet program Philips DirectLife, which was directed at increasing physical activity using monitoring and feedback by accelerometer and digital coaching. The primary outcome was relative increase in physical activity measured objectively using ankle- and wrist-worn accelerometers. Secondary outcomes of metabolic health included anthropometric measures and parameters of glucose metabolism. RESULTS: In total, 226 participants (97%) completed the study. At the ankle, activity counts increased by 46% (standard error [SE] 7%) in the intervention group, compared to 12% (SE 3%) in the control group (P(difference)<.001). Measured at the wrist, activity counts increased by 11% (SE 3%) in the intervention group and 5% (SE 2%) in the control group (P(difference)=.11). After processing of the data, this corresponded to a daily increase of 11 minutes in moderate-to-vigorous activity in the intervention group versus 0 minutes in the control group (P(difference)=.001). Weight decreased significantly more in the intervention group compared to controls (-1.5 kg vs -0.8 kg respectively, P=.046), as did waist circumference (-2.3 cm vs -1.3 cm respectively, P=.036) and fat mass (-0.6% vs 0.07% respectively, P=.025). Furthermore, insulin and HbA1c levels were significantly more reduced in the intervention group compared to controls (both P<.05). CONCLUSIONS: This was the first study to show that in inactive older adults, a 3-month Web-based physical activity intervention was effective in increasing objectively measured daily physical activity and improving metabolic health. Such Web-based interventions provide novel opportunities for large scale prevention of metabolic deregulation in our rapidly aging population.

Increased amygdalar and hippocampal volumes in elderly obese individuals with or at risk of cardiovascular disease.

BACKGROUND: The basal ganglia, hippocampus, and thalamus are involved in the regulation of human feeding behavior. Recent studies have shown that obesity [body mass index (BMI; in kg/m(2)) > 30] is associated with loss of gray and white matter. OBJECTIVE: It is unknown whether the subcortical brain structures that are actually involved in feeding behavior also show volume changes in obesity. Therefore, the purpose of this study was to evaluate the volumes of the basal ganglia, hippocampus, and thalamus in obesity. DESIGN: Three-dimensional T1-weighted magnetic resonance imaging scans of the brain were analyzed by using automatic segmentation to measure volumes of the nucleus accumbens, globus pallidus, amygdala, putamen, caudate nucleus, thalamus, and hippocampus in 471 subjects (mean age: 74.4 y; 56% men). RESULTS: Obese subjects had larger left (P = 0.013) and right (P = 0.003) amygdalar volumes and a larger left hippocampal volume (P = 0.040) than did normal-weight subjects (BMI < 25). None of the other subcortical structures differed in size between these groups. After correction for age, sex, smoking, hypertension, and pravastatin use, BMI was associated with left (ß = 0.175, P = 0.001) and right (ß = 0.157, P = 0.001) amygdalar volumes and with left hippocampal volume (ß = 0.121, P = 0.016). CONCLUSIONS: This study showed that the amygdala and hippocampus are enlarged in obesity. In consideration of the function of these structures, this finding may indicate that hedonic memories could be of major importance in the regulation of feeding. Because of the cross-sectional design, cause and effect could not be discriminated in this study.

TaqIB polymorphism in CETP gene: the influence on incidence of cardiovascular disease in statin-treated patients with familial hypercholesterolemia.

The effects of TaqI restriction fragment length polymorphism of the CETP gene on the occurrence of cardiovascular disease (CVD) events were investigated in patients with familial hypercholesterolemia (FH). A total of 300 FH patients, of which 116 (39%) had CVD at the start of the study, were treated with statins during a mean period of 8.5 years. The distribution of Taq1B genotypes was 31% B1B1, 49% B1B2, and 20% B2B2. No differences were found at baseline between the three genotypes, except for an association of the B1 allele with lower high-density lipoprotein (HDL)-cholesterol levels (P=0.003). All patients were put on statins within 6-8 weeks after the first visit; about 60% received simvastatin (20-40 mg daily) and 40% either pravastatin (40 mg daily) or atorvastatin (20-40 mg daily). The different statin treatments were similar for all groups. The mean change of plasma HDL-cholesterol, low-density lipoprotein-cholesterol, and triglyceride concentration during statin therapy was similar for the three genotypes. During follow-up, new CVD events were recorded in 22 (37%) of the B2B2 patients (n=59) and in 67 (28%) of B1 allele carriers (n=241) (P=0.36). The relative risk for CVD events, after adjustment for age, gender, and CVD at intake, was 1.8 (CI: 1.1-3.0) for B2B2 carriers compared to B1 allele carriers. The Taq1B polymorphism is a significant predictor of future CVD events in statin-treated patients with FH. In spite of similar improvement of the lipoprotein profile during statin therapy, our FH patients with the B2B2 genotype may have a higher CVD risk in comparison with the B1 allele carriers.

A Prospective Study of Pravastatin in the Elderly at Risk (PROSPER): Screening Experience and Baseline Characteristics.

BACKGROUND: PROSPER was designed to investigate the benefits of treatment with pravastatin in elderly patients for whom a typical doctor might consider the prescription of statin therapy to be a realistic option. METHODS: The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomised, double blind, placebo-controlled trial to test the hypothesis that treatment with pravastatin (40 mg/day) will reduce the risk of coronary heart disease death, non-fatal myocardial infarction, and fatal or non-fatal stroke in elderly men and women with pre-existing vascular disease or with significant risk of developing this condition. RESULTS: In Scotland, Ireland, and the Netherlands, 23,770 individuals were screened, and 5,804 subjects (2,804 men and 3,000 women), aged 70 to 82 years (average 75 years) and with baseline cholesterol 4.0-9.0 mmol/l, were randomised. Randomised subjects had similar distributions with respect to age, blood pressure, and body mass index when compared to the entire group of screenees, but had a higher prevalence of smoking, diabetes, hypertension, and a history of vascular disease. The average total cholesterol level at baseline was 5.4 mmol/l (men) and 6.0 mmol/l (women). CONCLUSIONS: Compared with previous prevention trials of cholesterol-lowering drugs, the PROSPER cohort is significantly older and for the first time includes a majority of women. The study, having achieved its initial goal of recruiting more than 5,500 elderly high-risk men and women, aims to complete all final subject follow-up visits in the first half of 2002 with the main results being available in the fourth quarter of 2002.