Effects of APOE on cognitive aging in community-dwelling older adults.

OBJECTIVE: The apolipoprotein E (APOE) gene is an established risk factor for sporadic Alzheimer's disease, with elevated risk for ε4-carriers and reduced risk for ε2-carriers. However, it is unclear whether APOE modifies risk for cognitive decline in normal aging. The objective of this study was to determine whether ε2 and ε4 are associated with rates of normal cognitive aging, and whether associations of ε4 with cognitive decline are modified by sex, education or health behaviors (exercise, alcohol consumption, smoking). METHOD: A community-based sample of 1,393 older adults were genotyped for APOE and underwent cognitive assessment up to seven times over a maximum of period of 27 years. RESULTS: ε2-carriers showed slower executive function decline with age relative to ε3 homozygotes or ε4-carriers, whereas ε4-carriers demonstrated more rapid executive function and verbal fluency decline. Accelerated executive function decline was particularly pronounced in ε4-carriers with lower education. After excluding individuals with cognitive impairment, faster executive function decline was still apparent in ε4-carriers, and the effect of ε4 on episodic memory interacted with alcohol consumption, such that only ε4-carriers who did not drink showed more rapid memory decline than ε4 noncarriers. The influence of ε4 on cognitive aging did not differ by sex, nor was it modified by smoking or exercise. CONCLUSIONS: These findings indicate that the ε2 and ε4 alleles have differential effects on cognitive aging, and that negative effects of ε4 may be partly mitigated by behavioral choices. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Cardiovascular Risk Factors Associated With Venous Thromboembolism.

Importance: It is uncertain to what extent established cardiovascular risk factors are associated with venous thromboembolism (VTE). Objective: To estimate the associations of major cardiovascular risk factors with VTE, ie, deep vein thrombosis and pulmonary embolism. Design, Setting, and Participants: This study included individual participant data mostly from essentially population-based cohort studies from the Emerging Risk Factors Collaboration (ERFC; 731 728 participants; 75 cohorts; years of baseline surveys, February 1960 to June 2008; latest date of follow-up, December 2015) and the UK Biobank (421 537 participants; years of baseline surveys, March 2006 to September 2010; latest date of follow-up, February 2016). Participants without cardiovascular disease at baseline were included. Data were analyzed from June 2017 to September 2018. Exposures: A panel of several established cardiovascular risk factors. Main Outcomes and Measures: Hazard ratios (HRs) per 1-SD higher usual risk factor levels (or presence/absence). Incident fatal outcomes in ERFC (VTE, 1041; coronary heart disease [CHD], 25 131) and incident fatal/nonfatal outcomes in UK Biobank (VTE, 2321; CHD, 3385). Hazard ratios were adjusted for age, sex, smoking status, diabetes, and body mass index (BMI). Results: Of the 731 728 participants from the ERFC, 403 396 (55.1%) were female, and the mean (SD) age at the time of the survey was 51.9 (9.0) years; of the 421 537 participants from the UK Biobank, 233 699 (55.4%) were female, and the mean (SD) age at the time of the survey was 56.4 (8.1) years. Risk factors for VTE included older age (ERFC: HR per decade, 2.67; 95% CI, 2.45-2.91; UK Biobank: HR, 1.81; 95% CI, 1.71-1.92), current smoking (ERFC: HR, 1.38; 95% CI, 1.20-1.58; UK Biobank: HR, 1.23; 95% CI, 1.08-1.40), and BMI (ERFC: HR per 1-SD higher BMI, 1.43; 95% CI, 1.35-1.50; UK Biobank: HR, 1.37; 95% CI, 1.32-1.41). For these factors, there were similar HRs for pulmonary embolism and deep vein thrombosis in UK Biobank (except adiposity was more strongly associated with pulmonary embolism) and similar HRs for unprovoked vs provoked VTE. Apart from adiposity, these risk factors were less strongly associated with VTE than CHD. There were inconsistent associations of VTEs with diabetes and blood pressure across ERFC and UK Biobank, and there was limited ability to study lipid and inflammation markers. Conclusions and Relevance: Older age, smoking, and adiposity were consistently associated with higher VTE risk.

Central Obesity and Visceral Adipose Tissue Are Not Associated With Incident Atherosclerotic Cardiovascular Disease Events in Older Men.

Background Visceral adipose tissue ( VAT ) and other measures of central obesity predict incident atherosclerotic cardiovascular disease ( ASCVD ) events in middle-aged individuals, but these associations are less certain in older individuals age 70 years and older. Our objective was to estimate the associations of VAT and the android-gynoid fat mass ratio, another measure of central obesity, with incident ASCVD events among a large cohort of older men. Methods and Results Two thousand eight hundred ninety-nine men (mean [ SD ] age 76.3 [5.5] years) enrolled in the Outcomes of Sleep Disorders in Older Men study had rigorous adjudication of incident ASCVD events (myocardial infarction, coronary heart disease death, or fatal or nonfatal stroke). We used proportional hazards models to estimate the hazard ratios for incident ASCVD per SD increase of VAT or android-gynoid fat mass ratio (measured at baseline with dual-energy absorptiometry), adjusted for age, race, education, systolic blood pressure, smoking status, oxidized low-density lipoprotein level, treatment for hypertension, statin use, aspirin use, presence of diabetes mellitus, and study enrollment site. Over a mean ( SD ) follow-up period of 7.9 (3.4) years, 424 men (14.6%) had an incident ASCVD event. Neither VAT nor android-gynoid fat mass ratio were associated with incident ASCVD events, either unadjusted or after multivariable-adjustment (hazard ratios [95% confidence interval ] per SD increase 1.02 [0.92-1.13] and 1.05 [0.95-1.17], respectively). Conclusions Central adipose tissue, as measured by VAT or android-gynoid fat mass ratio, was not associated with incident ASCVD events in this study of older men.

Rest-activity circadian rhythms and bone mineral density in elderly men.

BACKGROUND: Disrupted rest-activity circadian rhythm (RAR) patterns have been associated with poor health outcomes (i.e. diminished cognitive function, increased risk of dementia and falls). Circadian time cues in bone influence the differentiation of osteoblasts and osteoclasts, and bone turnover markers exhibit circadian variation; relationships between bone outcomes and RAR are emerging areas of research. We evaluated associations between RAR and areal bone mineral density (aBMD) at the total hip and femoral neck in older men from the Osteoporotic Fractures in Men (MrOS) cohort. We hypothesized that weaker RAR patterns would be associated with lower aBMD. METHODS: MrOS is an ongoing prospective cohort study following ambulatory men ≥ 65 years (n = 5994) at 6 U.S. clinics (baseline enrollment 3/2000-4/2002); participants for this analysis are from an ancillary study, Outcomes of Sleep Disorders in Older Men (MrOS Sleep). We included data from men who had technically adequate measures of RAR and aBMD at Sleep Visit 1 (12/2003-3/2005), with repeat aBMD at core Visit 3 (3/2007-3/2009) (n = 2412; mean age at Sleep Visit 1: 75.7 ± 5.2 years). aBMD was measured by dual energy x-ray absorptiometry (DXA). Actigraphs worn on the non-dominant wrist were used to collect circadian activity data over 4.8 ± 0.8 consecutive 24-hour periods. An extension of the traditional cosine curve was used to fit RAR to the activity data [Ancoli-Israel et al., 2003; Marler et al., 2006]. Six RAR parameters were evaluated: acrophase (time of peak activity), amplitude (rhythm strength), mesor (mean of activity fitted curve), pseudo F-statistic (overall circadian rhythmicity of rest and activity), alpha statistic (daytime to nighttime activity ratio), and beta statistic (daytime activity). Associations between RAR and aBMD (Sleep Visit 1), and RAR and ΔaBMD (Sleep Visit 1-Visit 3) were assessed with generalized linear models. Covariates included age, clinic site, physical activity, race, comorbidity, body mass index (BMI), smoking, alcohol, caffeine, beta blocker use, serum 25(OH) vitamin D and urinary melatonin and calcium. RESULTS: Pseudo F-statistic was significantly associated with total hip aBMD (p-trend = 0.009), femoral neck aBMD (p-trend = 0.007) and total hip ΔaBMD (p-trend = 0.017) in minimally adjusted models but not after multivariate (MV) adjustment. Alpha statistic was significantly associated with femoral neck aBMD (p-trend = 0.029) and femoral neck ΔaBMD (p-trend = 0.019) in minimally adjusted models; significance was retained in the femoral neck ΔaBMD model (p-trend = 0.034) after MV adjustment. There were no consistent, significant associations between the other RAR variables and aBMD or ΔaBMD. CONCLUSIONS: The data demonstrate modest associations between overall circadian rhythmicity of rest and activity (measured by pseudo F-statistic), as well as daytime to nighttime activity ratio (measured by alpha statistic), aBMD and ΔaBMD, but adjustment for covariates related to lifestyle, BMI and comorbidities attenuated most of these associations. These results suggest that RAR patterns are not independently associated with aBMD or four-year ΔaBMD at the total hip or femoral neck in older men, but additional research is needed.

Adipokines and severity and progression of coronary artery calcium: Findings from the Rancho Bernardo Study.

BACKGROUND AND AIMS: Adipokines are known to predict cardiovascular events, yet their association with coronary artery calcium (CAC), a surrogate marker of coronary atherosclerosis and risk factor for cardiovascular disease (CVD), is unclear. We aimed at assessing the association between adipokines and the severity and progression of CAC in healthy older adults, and at exploring potential modification by gender. METHODS: 409 men and women from the Rancho Bernardo Study with no known CVD underwent a chest computed tomography scan to determine baseline CAC severity; 329 returned 4.5 years later for a repeat scan to evaluate CAC progression. Adipokines (IL-6, adiponectin, leptin, and TNF-α) were measured from baseline blood samples. Ordinal linear and logistic regression models were used to determine the association of each adipokine with baseline severity and future progression of CAC. RESULTS: Adjusting for age and sex, IL-6 and leptin were associated with greater odds of increasing CAC severity (OR = 1.63, 95% CI 1.22-2.19; OR = 1.19, 95% CI 0.99-1.43, respectively, per SD). The association with IL-6 remained significant in models further adjusted for lifestyle, body size, CVD risk factors, and body fat distribution. Adiponectin was associated with CAC progression (OR = 0.68, 95% CI 0.51-0.92 in fully adjusted models). This was modified by sex, with protective effects seen for men (OR = 0.57, 95% CI 0.38-0.85), but not for women (OR = 0.93, 95% CI 0.67-1.32; p-for-interaction = 0.04). CONCLUSIONS: IL-6 and leptin predicted greater CAC severity while adiponectin predicted lower odds of CAC progression. More research is needed to explore biological mechanisms, including differences by sex.

Changes in Visceral Adiposity, Subcutaneous Adiposity, and Sex Hormones in the Diabetes Prevention Program.

Context: The degree to which changes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) relate to corresponding changes in plasma sex steroids is not known. Objective: We examined whether changes in VAT and SAT areas assessed by computed tomography were associated with changes in sex hormones [dehydroepiandrosterone sulfate (DHEAS), testosterone, estradiol, estrone, and sex hormone binding globulin (SHBG)] among Diabetes Prevention Program participants. Design: Secondary analysis of a randomized trial. Participants: Overweight and glucose-intolerant men (n = 246) and women (n = 309). Interventions: Intensive lifestyle change with goals of weight reduction and 150 min/wk of moderate intensity exercise or metformin administered 850 mg twice a day or placebo. Main Outcome Measures: Associations between changes in VAT, SAT, and sex hormone changes over 1 year. Results: Among men, reductions in VAT and SAT were both independently associated with significant increases in total testosterone and SHBG in fully adjusted models. Among women, reductions in VAT and SAT were both independently associated with increases in SHBG and associations with estrone differed by menopausal status. Associations were similar by race/ethnicity and by randomization arm. No significant associations were observed between change in fat depot with change in estradiol or DHEAS. Conclusions: Among overweight adults with impaired glucose intolerance, reductions in either VAT and SAT were associated with increased total testosterone in men and higher SHBG in men and women. Weight loss may affect sex hormone profiles via reductions in visceral and subcutaneous fat.

Comparison of Associations of DXA and CT Visceral Adipose Tissue Measures With Insulin Resistance, Lipid Levels, and Inflammatory Markers.

Visceral adipose tissue (VAT) measured by computed tomography (CT) is related to insulin resistance, lipids, and serum inflammatory markers. Our objective was to compare the strength of the associations of VAT measured using dual-energy X-ray absorptiometry (DXA-VAT) and CT (CT-VAT) with insulin resistance, serum lipids, and serum markers of inflammation. For 1117 men aged 65 and older enrolled in the Osteoporotic Fractures in Men Study, the cross-sectional associations of DXA-VAT and CT-VAT with homeostasis model assessment of insulin resistance (homa2ir), C-reactive protein, and high-density lipoprotein (HDL) cholesterol were estimated with regression models and compared using a Hausman test. Adjusted for age and body mass index, DXA-VAT was moderately associated with homa2ir (effect size 0.38, 95% confidence interval [CI]: 0.28-0.47) and modestly associated with HDL cholesterol (DXA effect size -0.29, 95% CI: -0.38 to -0.21). These associations were significantly greater than those for CT-VAT with homa2ir (0.30, 95% CI: 0.24-0.37; p value for effect size difference 0.03) and CT-VAT with HDL cholesterol (-0.22, 95% CI: -0.29 to -0.15; p value for difference 0.005). Neither DXA-VAT nor CT-VAT was associated with C-reactive protein after adjustment for age and body mass index (DXA-VAT effect size 0.14, 95% CI: -0.04 to 0.32; CT-VAT effect size 0.08, 95% CI: -0.08 to 0.25; p value for difference 0.35). DXA-VAT has similar or greater associations with insulin resistance and HDL cholesterol as does CT-VAT in older men, confirming the concurrent validity of DXA-VAT. Investigations of how well DXA measurements of VAT predict incident cardiovascular disease events are warranted.

Different impacts of hypertension and diabetes mellitus on all-cause and cardiovascular mortality in community-dwelling older adults: the Rancho Bernardo Study.

OBJECTIVES: Although the prevalence rates of hypertension (HTN) and diabetes mellitus are slowing in some high-income countries, HTN and diabetes mellitus remain as the two major risk factors for atherosclerotic cardiovascular disease (CVD), the leading cause of death in the United States and worldwide. We aimed to observe the association of HTN and diabetes mellitus with all-cause and CVD mortality in older white adults. METHODS: All community-dwelling Rancho Bernardo Study participants who were at least 55 years old and had carefully measured blood pressure and plasma glucose from 75-g oral glucose tolerance test at the baseline visit (1984-1987, n = 2186) were followed up until death or the last clinic visit in 2013 (median 14.3 years, interquartile range 8.4-21.3). RESULTS: In unadjusted analyses, diabetes mellitus was associated with all-cause mortality [hazard ratio 1.40, 95% confidence interval (CI) 1.23-1.60] and CVD mortality (hazard ratio 1.67, 95% CI 1.39-2.00); HTN with all-cause mortality [hazard ratio 1.93 (1.73-2.15)] and CVD mortality [hazard ratio 2.45 (2.10-2.93)]. After adjustment for cardiovascular risk factors, including age, BMI, triglycerides, HDL-cholesterol, smoking, exercise, and alcohol consumption, diabetes mellitus was associated with CVD mortality only (hazard ratio 1.25, P = 0.0213). Conversely, HTN was associated with both all-cause (hazard ratio 1.34, P < 0.0001) and CVD mortality (hazard ratio 1.40, P = 0.0003). Having both diabetes mellitus and HTN was associated with all-cause (hazard ratio 1.38, P = 0.0002) and CVD mortality (hazard ratio 1.70, P < 0.0001). CONCLUSION: We report the novel finding that HTN is more strongly associated with all-cause and CVD mortality than diabetes mellitus. Having both confers a modest increase in the hazards for these types of mortality.

Novel Genetic Variants for Cartilage Thickness and Hip Osteoarthritis.

Osteoarthritis is one of the most frequent and disabling diseases of the elderly. Only few genetic variants have been identified for osteoarthritis, which is partly due to large phenotype heterogeneity. To reduce heterogeneity, we here examined cartilage thickness, one of the structural components of joint health. We conducted a genome-wide association study of minimal joint space width (mJSW), a proxy for cartilage thickness, in a discovery set of 13,013 participants from five different cohorts and replication in 8,227 individuals from seven independent cohorts. We identified five genome-wide significant (GWS, P≤5·0×10-8) SNPs annotated to four distinct loci. In addition, we found two additional loci that were significantly replicated, but results of combined meta-analysis fell just below the genome wide significance threshold. The four novel associated genetic loci were located in/near TGFA (rs2862851), PIK3R1 (rs10471753), SLBP/FGFR3 (rs2236995), and TREH/DDX6 (rs496547), while the other two (DOT1L and SUPT3H/RUNX2) were previously identified. A systematic prioritization for underlying causal genes was performed using diverse lines of evidence. Exome sequencing data (n = 2,050 individuals) indicated that there were no rare exonic variants that could explain the identified associations. In addition, TGFA, FGFR3 and PIK3R1 were differentially expressed in OA cartilage lesions versus non-lesioned cartilage in the same individuals. In conclusion, we identified four novel loci (TGFA, PIK3R1, FGFR3 and TREH) and confirmed two loci known to be associated with cartilage thickness.The identified associations were not caused by rare exonic variants. This is the first report linking TGFA to human OA, which may serve as a new target for future therapies.

Estimated GFR and Mortality in Older Men: Are All eGFR Formulae Equal.

BACKGROUND: Recently, the first estimated glomerular filtration rate (eGFR) formula specifically developed for community-dwelling older adults, the Berlin Initiative Study Equation 2 (BIS2), was reported. To date, however, no study has examined the performance of the BIS2 to predict death in older adults as compared to equations used clinically and in research. METHODS: We prospectively followed 2,994 community-dwelling men (age 76.4 ± 5.6) enrolled in the MrOS Sleep Study. We calculated baseline eGFR from serum creatinine and cystatin-C using the BIS2, Chronic Kidney Disease Epidemiology (CKD-EPIcr,cysc), CKD-EPIcysc and CKD-EPIcr equations. Analyses included Cox-proportional hazards regression and net reclassification improvement (NRI) for the outcomes of all-cause and cardiovascular death. RESULTS: Follow-up time was 7.3 ± 1.9 years. By BIS2, 42 and 11% had eGFR <60 and <45, respectively, compared to CKD-EPIcr (23 and 6%), CKD-EPIcysc (36 and 13%) and CKD-EPIcr,cysc (28 and 8%). BIS2 eGFR <45 was associated with twofold higher rate of all-cause mortality when compared to eGFR ≥75 after multivariate adjustment (HR 2.1, 95% CI 1.5-2.8). Results were similar for CKD-EPIcr,cysc <45 (HR 2.1, 95% CI 1.6-2.7) and CKD-EPIcysc <45 (HR 2.1, 95% CI 1.7-2.7) and weaker for CKD-EPIcr <45 (HR 1.5, 95% CI 1.2-2.0). In NRI analyses, when compared to CKD-EPIcr,cysc, both BIS2 and CKD-EPIcr equations more often misclassified participants with respect to mortality. We found similar results for cardiovascular death. CONCLUSION: The BIS2 did not outperform and the CKD-EPIcr was inferior to the cystatin C-based CKD-EPI equations to predict death in this cohort of older men. Thus, the cystatin C-based CKD-EPI equations are the formulae of choice to predict death in community-dwelling older men.

Optimism and Mortality in Older Men and Women: The Rancho Bernardo Study.

Purpose. To examine the associations of optimism and pessimism with all-cause, cardiovascular disease (CVD), coronary heart disease (CHD), and cancer mortality in a population-based sample of older men and women followed ≤12 years. Methods. 367 men and 509 women aged ≥50 from the Rancho Bernardo Study attended a 1999-2002 research clinic visit when demographic, behavioral, and medical history were obtained and completed a 1999 mailed survey including the Life Orientation Test-Revised (LOT-R). Mortality outcomes were followed through 2012. Results. Average age at baseline was 74.1 years; during follow-up (mean = 8.1 years), 198 participants died, 62 from CVD, 22 from CHD, and 49 from cancer. Total LOT-R, optimism and pessimism scores were calculated. Participants with the highest optimism were younger and reported less alcohol use and smoking and more exercise. Cox proportional hazard models showed that higher total LOT-R and optimism, but not pessimism scores, were associated with reduced odds of CHD mortality after adjusting for age, sex, alcohol, smoking, obesity, physical exercise, and medication (HR = 0.86, 95% CI = 0.75, 0.99; HR = 0.77, 95% CI = 0.61, 0.99, resp.). No associations were found for all-cause, CVD, or cancer mortality. Conclusions. Optimism was associated with reduced CHD mortality in older men and women. The association of positive attitudes with mortality merits further study.

Sleep Disordered Breathing and Risk of Stroke in Older Community-Dwelling Men.

STUDY OBJECTIVES: Men with sleep disordered breathing (SDB) may be at increased stroke risk, due to nocturnal hypoxemia, sleep loss or fragmentation, or other mechanisms. We examined the association of SDB with risk of incident stroke in a large cohort of older men. METHODS: Participants were 2,872 community-dwelling men (mean age 76 years) enrolled in the MrOS Sleep Study, which gathered data from 2003 to 2005 at six clinical sites in the Unites States. SDB predictors (obstructive apnea-hypopnea index, apnea-hypopnea index, central apnea index, and nocturnal hypoxemia) were measured using overnight polysomnography. Incident stroke over an average follow-up of 7.3 years was centrally adjudicated by physician review of medical records. RESULTS: One hundred fifty-six men (5.4%) had a stroke during follow-up. After adjustment for age, clinic site, race, body mass index, and smoking status, older men with severe nocturnal hypoxemia (≥ 10% of the night with SpO2 levels below 90%) had a 1.8-fold increased risk of incident stroke compared to those without nocturnal hypoxemia (relative hazard = 1.83; 95% confidence interval 1.12-2.98; P trend = 0.02). Results were similar after further adjustment for other potential covariates and after excluding men with a history of stroke. Other indices of SDB were not associated with incident stroke. CONCLUSIONS: Older men with severe nocturnal hypoxemia are at significantly increased risk of incident stroke. Measures of overnight oxygen saturation may better identify older men at risk for stroke than measures of apnea frequency.

Effects of Testosterone Treatment in Older Men.

BACKGROUND: Serum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established. METHODS: We assigned 790 men 65 years of age or older with a serum testosterone concentration of less than 275 ng per deciliter and symptoms suggesting hypoandrogenism to receive either testosterone gel or placebo gel for 1 year. Each man participated in one or more of three trials--the Sexual Function Trial, the Physical Function Trial, and the Vitality Trial. The primary outcome of each of the individual trials was also evaluated in all participants. RESULTS: Testosterone treatment increased serum testosterone levels to the mid-normal range for men 19 to 40 years of age. The increase in testosterone levels was associated with significantly increased sexual activity, as assessed by the Psychosexual Daily Questionnaire (P<0.001), as well as significantly increased sexual desire and erectile function. The percentage of men who had an increase of at least 50 m in the 6-minute walking distance did not differ significantly between the two study groups in the Physical Function Trial but did differ significantly when men in all three trials were included (20.5% of men who received testosterone vs. 12.6% of men who received placebo, P=0.003). Testosterone had no significant benefit with respect to vitality, as assessed by the Functional Assessment of Chronic Illness Therapy-Fatigue scale, but men who received testosterone reported slightly better mood and lower severity of depressive symptoms than those who received placebo. The rates of adverse events were similar in the two groups. CONCLUSIONS: In symptomatic men 65 years of age or older, raising testosterone concentrations for 1 year from moderately low to the mid-normal range for men 19 to 40 years of age had a moderate benefit with respect to sexual function and some benefit with respect to mood and depressive symptoms but no benefit with respect to vitality or walking distance. The number of participants was too few to draw conclusions about the risks of testosterone treatment. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT00799617.).

Actigraphy- and Polysomnography-Measured Sleep Disturbances, Inflammation, and Mortality Among Older Men.

OBJECTIVES: To evaluate whether objectively measured sleep characteristics are associated with mortality risk independent of inflammatory burden and comorbidity. METHODS: The Osteoporotic Fractures in Men Sleep Study (conducted in 2003-2005) included community-dwelling older men (n = 2531; average [standard deviation {SD}] age = 76.3 (5.5) years). Sleep measures from in-home polysomnography and wrist actigraphy and assessments of serum inflammatory markers levels (C-reactive protein, interleukin-6, tumor necrosis factor α, tumor necrosis factor α soluble receptor II, and interferon-γ) were obtained. Vital status was ascertained over an average (SD) follow-up of 7.4 (1.9 SD) years. RESULTS: Three of the seven main sleep measures examined were independently associated with greater inflammatory burden. Mortality risk associated with prolonged (≥10% total sleep time) blood oxygen desaturation and short (<5 hours) sleep duration was attenuated to nonsignificance after adjusting for inflammatory burden or medical burden/lifestyle factors. Severe blood oxygen desaturation (adjusted hazard ratio [aHR] = 1.57, 95% confidence interval [CI] = 1.11-2.22), sleep fragmentation (aHR = 1.32, 95% CI = 1.12-1.57), and a lower percentage of sleep in rapid eye movement (aHR per SD = 0.90, 95% CI = 0.93-0.97) were independently associated with mortality. CONCLUSIONS: Short sleep duration and prolonged blood oxygen desaturation were independently associated with inflammatory burden, which attenuated associations between these sleep characteristics and mortality. Medical and life-style factors also substantially attenuated most sleep-mortality associations, suggesting complex relations between sleep, inflammation, and disease. Sleep fragmentation, severe blood oxygen desaturation, and the percentage of sleep time in rapid eye movement were independently related to mortality risk. Future studies with repeated measures of mediators/confounds will be necessary to achieve a mechanistic understanding of sleep-related mortality risk.

Relation of Depressive Symptoms With Coronary Artery Calcium Determined by Electron-Beam Computed Tomography (from the Rancho Bernardo Study).

Studies linking depressive symptoms and coronary artery calcium (CAC), a measure of subclinical atherosclerosis, have yielded mixed results. No longitudinal studies of depressive symptoms and CAC have included older adults of both genders. This study examined the association of depressive symptoms with CAC and CAC progression in older men and women. Participants were 417 community-dwelling older adults (mean age = 67 ± 7) with no history of heart disease who attended a 1997 to 1999 research clinic visit when depressive symptoms were assessed using the Beck Depression Inventory (BDI). CAC was measured using electron-beam computed tomography in 2000 to 2002 and again in 2005 to 2007. Median BDI was 3, range = 0 to 37; 39% of men and 10% of women had severe CAC (Agatston score ≥ 400) in 2000 to 2002. Ordinal logistic regression analyses examining the odds of greater compared with lesser CAC severity by BDI quartiles showed an unexpected negative association whereby women with the lowest depressive symptoms had 2.4 times the odds of increasing CAC severity compared with women in the second BDI quartile (95% CI 1.1 to 5.4). A nonlinear, U-shaped association was observed in men with those in the first and fourth BDI quartiles having 2.6 and 3.0 times higher odds of increasing CAC severity than subjects in the second quartile (95% CI 1.2 to 5.6 and 1.3 to 6.9, respectively) after adjustment for coronary heart disease risk factors. No significant associations were observed for CAC progression although similar nonlinear patterns were observed in men. In conclusion, our results suggest that depressive symptoms have a gender-specific, cross-sectional association with CAC but no statistically significant associations with CAC progression.

Dietary Antioxidants and Longitudinal Changes in Lower Urinary Tract Symptoms in Elderly Men: The Osteoporotic Fractures in Men Study.

BACKGROUND: Antioxidants can potentially alter the progression of lower urinary tract symptoms (LUTS) through anti-inflammatory mechanisms. OBJECTIVE: To determine if dietary antioxidants are associated with reduced likelihood of LUTS progression or increased likelihood of LUTS remission in untreated elderly men. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study of 1670 US men aged 65-100 yr. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Baseline variables included the American Urological Association Symptom Index, dietary intake assessed via a 69-item Block food frequency questionnaire (FFQ), demographics, lifestyle characteristics, quality of life (SF-12), and medication use. LUTS was assessed at four time points over a mean ± standard deviation period of 6.9±0.4 yr. Group-based trajectory modeling was performed for men without prostate cancer who did not undergo LUTS treatment with medication or surgery during follow-up (n=1670). Analyses were stratified by LUTS symptoms at baseline. For men with mild baseline LUTS, we examined the likelihood of LUTS progression relative to LUTS stability. For men with moderate baseline LUTS, we analyzed the likelihood of both LUTS progression relative to LUTS stability and LUTS remission relative to progression. Odds ratios and 95% confidence intervals were estimated for quartiles of daily antioxidant intake using multivariable logistic regression. RESULTS AND LIMITATIONS: None of the dietary antioxidants (vitamin C, vitamin E, ß-carotene, α-carotene, ß-cryptoxanthin, lycopene, lutein/zeaxanthin) was associated with a lower probability of LUTS progression or LUTS remission. The study was limited by use of the brief Block FFQ, which contains only 69 food items and may have biased results toward the null hypothesis because of nondifferential misclassification. CONCLUSIONS: In this large cohort of US men, there were no significant associations between multiple dietary antioxidants and LUTS progression or remission over 7 yr. PATIENT SUMMARY: In a large cohort of elderly men, there were no significant longitudinal associations between multiple dietary antioxidants and lower urinary tract symptoms (LUTS). Our data suggest that dietary antioxidant consumption may not influence the natural history of LUTS in older men.

Pain and falls and fractures in community-dwelling older men.

BACKGROUND: Pain may reduce stability and increase falls and subsequent fractures in older men. OBJECTIVES: To examine the association between joint pain and any pain with falls, hip and non-spine fractures in older community-dwelling men. DESIGN: A cohort study. SETTING AND PARTICIPANTS: Analyses included 5,993 community-dwelling men aged ≥65 years from the MrOS cohort. MEASUREMENTS: Pain at hip, knee and elsewhere (any) was assessed by self-report. Men reported falls via questionnaires mailed 3× per year during the year following the baseline visit. Fractures were verified centrally. Mean follow-up time for fractures was 9.7 (SD 3.1) years. Logistic regression models estimated likelihood of falls and proportional hazards models estimated risk of fractures. Models were adjusted for age, BMI, race, smoking, alcohol use, medications use, co-morbidities and arthritis; fracture models additionally adjusted for bone mineral density. RESULTS: One quarter (25%, n = 1,519) reported ≥1 fall; 710 reported ≥2 falls in the year after baseline. In multivariate models, baseline pain at hip, knee or any pain increased likelihood of ≥1 fall and ≥2 falls over the following year. For example, knee pain increased likelihood of ≥1 fall (odds ratio, OR 1.44; 95% confidence interval, CI 1.25-1.65) and ≥2 falls (OR 1.75; 95% CI 1.46-2.10). During follow-up, 936 (15.6%) men suffered a non-spine fracture (n = 217, 3.6% hip). In multivariate models, baseline pain was not associated with incident hip or non-spine fractures. CONCLUSIONS: Any pain, knee pain and hip pain were each strong independent risk factors for falls in older men. Increased risk of falls did not translate into an increased risk of fractures.

Association of Cardiometabolic Multimorbidity With Mortality.

IMPORTANCE: The prevalence of cardiometabolic multimorbidity is increasing. OBJECTIVE: To estimate reductions in life expectancy associated with cardiometabolic multimorbidity. DESIGN, SETTING, AND PARTICIPANTS: Age- and sex-adjusted mortality rates and hazard ratios (HRs) were calculated using individual participant data from the Emerging Risk Factors Collaboration (689,300 participants; 91 cohorts; years of baseline surveys: 1960-2007; latest mortality follow-up: April 2013; 128,843 deaths). The HRs from the Emerging Risk Factors Collaboration were compared with those from the UK Biobank (499,808 participants; years of baseline surveys: 2006-2010; latest mortality follow-up: November 2013; 7995 deaths). Cumulative survival was estimated by applying calculated age-specific HRs for mortality to contemporary US age-specific death rates. EXPOSURES: A history of 2 or more of the following: diabetes mellitus, stroke, myocardial infarction (MI). MAIN OUTCOMES AND MEASURES: All-cause mortality and estimated reductions in life expectancy. RESULTS: In participants in the Emerging Risk Factors Collaboration without a history of diabetes, stroke, or MI at baseline (reference group), the all-cause mortality rate adjusted to the age of 60 years was 6.8 per 1000 person-years. Mortality rates per 1000 person-years were 15.6 in participants with a history of diabetes, 16.1 in those with stroke, 16.8 in those with MI, 32.0 in those with both diabetes and MI, 32.5 in those with both diabetes and stroke, 32.8 in those with both stroke and MI, and 59.5 in those with diabetes, stroke, and MI. Compared with the reference group, the HRs for all-cause mortality were 1.9 (95% CI, 1.8-2.0) in participants with a history of diabetes, 2.1 (95% CI, 2.0-2.2) in those with stroke, 2.0 (95% CI, 1.9-2.2) in those with MI, 3.7 (95% CI, 3.3-4.1) in those with both diabetes and MI, 3.8 (95% CI, 3.5-4.2) in those with both diabetes and stroke, 3.5 (95% CI, 3.1-4.0) in those with both stroke and MI, and 6.9 (95% CI, 5.7-8.3) in those with diabetes, stroke, and MI. The HRs from the Emerging Risk Factors Collaboration were similar to those from the more recently recruited UK Biobank. The HRs were little changed after further adjustment for markers of established intermediate pathways (eg, levels of lipids and blood pressure) and lifestyle factors (eg, smoking, diet). At the age of 60 years, a history of any 2 of these conditions was associated with 12 years of reduced life expectancy and a history of all 3 of these conditions was associated with 15 years of reduced life expectancy. CONCLUSIONS AND RELEVANCE: Mortality associated with a history of diabetes, stroke, or MI was similar for each condition. Because any combination of these conditions was associated with multiplicative mortality risk, life expectancy was substantially lower in people with multimorbidity.

Body adiposity index as a risk factor for the metabolic syndrome in postmenopausal Caucasian, African American, and Filipina women.

AIMS: To investigate the utility of the body adiposity index (BAI) and its association with the metabolic syndrome (MetS) in older Caucasian (n=369), African American (n=336) and Filipina (n=275) women. METHODS: Dual energy X-ray absorptiometry, anthropometric measures, plasma glucose and medical history were assessed in 1993-1999. RESULTS: Despite smaller body size, 32.7% of Filipina women had higher MetS compared to African American and Caucasian women based on the National Cholesterol Education Program (NCEP) (32.7% vs 19.6% and 13.3%, respectively) or the International Diabetes Federation (IDF) (42.6% vs 33.0% and 18.7%, respectively ps<0.05). BAI had higher positive correlations with BMI, %body fat (%BF), and %truncal fat in Caucasian than African American and Filipina women. Adjusted for age, smoking, estrogen use, exercise, and alcohol intake, odds of the MetS (NCEP) were 2.08 (95%CI: 1.52-2.85) by BAI, 3.04 (95%CI: 2.11-4.38) by BMI, and 2.13 (95%CI: 1.52-3.00) by %BF for Caucasian women; 0.92 (95%CI: 0.69-1.23) by BAI, 1.44 (95%CI: 1.09-1.90) by BMI, and 1.12 (95%CI: 0.84-1.50) by %BF for African American women; and 1.14 (95%CI: 0.88-1.47) by BAI, 1.51 (95%CI: 1.15-1.97) by BMI, and 0.96 (95%CI: 0.74-1.25) by %BF for Filipinas. CONCLUSION: BAI was better able to assess adiposity in postmenopausal Caucasian women compared to African American and Filipina women. This index can distinguish ethnic differences in MetS confirmed by %BF.

Factors affecting the decline in incidence of diabetes in the Diabetes Prevention Program Outcomes Study (DPPOS).

During the first 7 years of the Diabetes Prevention Program Outcomes Study (DPPOS), diabetes incidence rates, when compared with the Diabetes Prevention Program (DPP), decreased in the placebo (-42%) and metformin (-25%), groups compared with the rates in the intensive lifestyle intervention (+31%) group. Participants in the placebo and metformin groups were offered group intensive lifestyle intervention prior to entering the DPPOS. The following two hypotheses were explored to explain the rate differences: "effective intervention" (changes in weight and other factors due to intensive lifestyle intervention) and "exhaustion of susceptible" (changes in mean genetic and diabetes risk scores). No combination of behavioral risk factors (weight, physical activity, diet, smoking, and antidepressant or statin use) explained the lower DPPOS rates of diabetes progression in the placebo and metformin groups, whereas weight gain was the factor associated with higher rates of progression in the intensive lifestyle intervention group. Different patterns in the average genetic risk score over time were consistent with exhaustion of susceptibles. Results were consistent with exhaustion of susceptibles for the change in incidence rates, but not the availability of intensive lifestyle intervention to all persons before the beginning of the DPPOS. Thus, effective intervention did not explain the lower diabetes rates in the DPPOS among subjects in the placebo and metformin groups compared with those in the DPP.