Search

Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; P het  = .0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups., (© 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

We examined whether the often-reported protective association of alcohol with cardiovascular disease (CVD) risk could arise from confounding. Our sample comprised 908 men (56−67 years), free of prevalent CVD. Participants were categorized into 6 groups: never drinkers, former drinkers, and very light (1−4 drinks in past 14 days), light (5−14 drinks), moderate (15−28 drinks), and at-risk (>28 drinks) drinkers. Generalized linear mixed effect models examined the associations of alcohol use with three established CVD risk scores: The Framingham Risk Score (FRS); the atherosclerotic CVD (ASCVD) risk score; and the Metabolic Syndrome (MetS) Severity score, adjusting for group differences in demographics, body size, and health-related behaviors. In separate models we additionally adjusted for several groups of potentially explanatory factors including socioeconomic status, social support, physical and mental health status, childhood factors, and prior history of alcohol misuse. Results showed lower CVD risk among light and moderate alcohol drinkers, relative to very light drinkers, for all CVD risk scores, independent of demographics, body size, and health-related behaviors. Alcohol-CVD risk associations were robust to further adjustment for several groups of potential explanatory factors. Study limitations include the all-male sample with limited racial and ethnic diversity, and the inability to adjust for sugar consumption and for patterns of alcohol consumption. Although this observational study does not address causation, results show that middle-aged men who consume alcohol in moderation have lower CVD risk and better cardiometabolic health than men who consume little or no alcohol, independent of a variety of health, behavioral, psychosocial, and earlier life factors.

Background: We examined the associations between dual impairments in visual and hearing acuity and aging-related cognitive decline., Methods: This was a longitudinal study of adults who had visual and hearing acuity and cognitive function assessed in 1992-1996 and were followed for up to 24 years (mean = 7.3 years), with up to five additional cognitive assessments. Visual impairment was defined as vision worse than 20/40, hearing impairment as pure-tone average thresholds >25 dB. Associations were tested using linear mixed-effects regressions., Results: Of 1,383 participants, 293 had visual impairment, 990 had a hearing impairment and 251 had both deficits. In fully adjusted models, low visual acuity was associated with poorer Mini-Mental State Examination (MMSE; β = -0.29) and Trail-Making Test Part B (Trails B; β = 13.22) performance, and with faster declines in MMSE (β = -0.12) and Trails B (β = 1.84). The combination of low visual and low hearing acuity was associated with poorer MMSE (β = -0.44) and Trails B (β = 11.20) scores, and with faster declines in MMSE (β = -0.19), Trails B (β = 3.50), and Verbal Fluency Test (VFT; β = -0.14) performance. Associations were similar in men and women., Conclusion: Impairments in both vision and hearing are associated with a more rapid decline in cognitive function with aging., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Midlife vascular disease increases risk for dementia and effects of vascular dysfunction on brain health differ between men and women. Elevated pulse pressure, a surrogate for arterial stiffness, contributes to cerebrovascular pathology and white matter damage that may advance cognitive aging; however, it remains unclear how associations between pulse pressure and neural integrity differ by sex and age. This study used restriction spectrum imaging to examine associations between pulse pressure and brain microstructure in community-dwelling women (N=88) and men (N=55), aged 56 to 97 (mean, 76.3) years. Restricted isotropic (presumed intracellular), hindered isotropic (presumed extracellular), neurite density, and free water diffusion were computed in white matter tracts and subcortical regions. After adjustment for age and sex, higher pulse pressure correlated with lower restricted isotropic diffusion in global white matter, with more pronounced associations in parahippocampal cingulum, as well as in thalamus and hippocampus. Subgroup analyses demonstrated stronger correlations between pulse pressure and restricted isotropic diffusion in association fibers for participants ≤75 years than for older participants, with stronger effects for women than men of this age group. Microstructure in parahippocampal cingulum and thalamus differed by pulse pressure level regardless of antihypertensive treatment. Increased pulse pressure may lead to widespread injury to white matter and subcortical structures, with greatest vulnerability for women in late middle to early older age. Restriction spectrum imaging could be useful for monitoring microstructural changes indicative of neuronal loss or shrinkage, demyelination, or inflammation that accompany age-related cerebrovascular dysfunction.

We examined the association between dietary potassium intake and all-cause and cause-specific mortality among community-dwelling older adults. Potassium intake was assessed with a food frequency questionnaire administered to 1,363 older adults (mean age 71.0 ± 10.6 years). Cox proportional hazard regressions estimated hazard ratios for sex-specific quintiles of calorie-adjusted potassium in relation to all-cause and cause-specific (cardiovascular disease, CVD, and stroke) mortality, adjusting for numerous covariates. There were 855 deaths (63% mortality) during the 20-year follow-up. Relative to the third quintile, potassium intake in the lowest quintile only was associated with increased risk of all-cause mortality (fully-adjusted hazard ratio 1.33; 95% CI 1.06, 1.67). Potassium intake was not significantly associated with CVD or stroke mortality. These results suggest that low potassium intake is associated with increased risk of mortality independent of overall health status. Ensuring adequate potassium in the diet may be an important strategy for reducing risk of earlier mortality among older adults.

Importance: It is uncertain whether depressive symptoms are independently associated with subsequent risk of cardiovascular diseases (CVDs)., Objective: To characterize the association between depressive symptoms and CVD incidence across the spectrum of lower mood., Design, Setting, and Participants: A pooled analysis of individual-participant data from the Emerging Risk Factors Collaboration (ERFC; 162 036 participants; 21 cohorts; baseline surveys, 1960-2008; latest follow-up, March 2020) and the UK Biobank (401 219 participants; baseline surveys, 2006-2010; latest follow-up, March 2020). Eligible participants had information about self-reported depressive symptoms and no CVD history at baseline., Exposures: Depressive symptoms were recorded using validated instruments. ERFC scores were harmonized across studies to a scale representative of the Center for Epidemiological Studies Depression (CES-D) scale (range, 0-60; ≥16 indicates possible depressive disorder). The UK Biobank recorded the 2-item Patient Health Questionnaire 2 (PHQ-2; range, 0-6; ≥3 indicates possible depressive disorder)., Main Outcomes and Measures: Primary outcomes were incident fatal or nonfatal coronary heart disease (CHD), stroke, and CVD (composite of the 2). Hazard ratios (HRs) per 1-SD higher log CES-D or PHQ-2 adjusted for age, sex, smoking, and diabetes were reported., Results: Among 162 036 participants from the ERFC (73%, women; mean age at baseline, 63 years [SD, 9 years]), 5078 CHD and 3932 stroke events were recorded (median follow-up, 9.5 years). Associations with CHD, stroke, and CVD were log linear. The HR per 1-SD higher depression score for CHD was 1.07 (95% CI, 1.03-1.11); stroke, 1.05 (95% CI, 1.01-1.10); and CVD, 1.06 (95% CI, 1.04-1.08). The corresponding incidence rates per 10 000 person-years of follow-up in the highest vs the lowest quintile of CES-D score (geometric mean CES-D score, 19 vs 1) were 36.3 vs 29.0 for CHD events, 28.0 vs 24.7 for stroke events, and 62.8 vs 53.5 for CVD events. Among 401 219 participants from the UK Biobank (55% were women, mean age at baseline, 56 years [SD, 8 years]), 4607 CHD and 3253 stroke events were recorded (median follow-up, 8.1 years). The HR per 1-SD higher depression score for CHD was 1.11 (95% CI, 1.08-1.14); stroke, 1.10 (95% CI, 1.06-1.14); and CVD, 1.10 (95% CI, 1.08-1.13). The corresponding incidence rates per 10 000 person-years of follow-up among individuals with PHQ-2 scores of 4 or higher vs 0 were 20.9 vs 14.2 for CHD events, 15.3 vs 10.2 for stroke events, and 36.2 vs 24.5 for CVD events. The magnitude and statistical significance of the HRs were not materially changed after adjustment for additional risk factors., Conclusions and Relevance: In a pooled analysis of 563 255 participants in 22 cohorts, baseline depressive symptoms were associated with CVD incidence, including at symptom levels lower than the threshold indicative of a depressive disorder. However, the magnitude of associations was modest.

Objective: High consumption of soft drinks has been associated with lower bone mineral density among postmenopausal women. This study explores the association of soft drink consumption, osteoporosis, and incidental fractures in this population., Methods: Cross-sectional (at baseline) and cohort combined designs, over 11.9 years of median follow-up for 72,342 postmenopausal women participating in the Women's Health Initiative Observational Study. Multiple linear regression models were used to examine the cross-sectional associations between soft drink consumption and hip and lumbar spine bone mineral density. Cox proportional hazards regression models were used to examine the association of soft drink consumption with incident hip fractures., Results: There were no associations between soft drink consumption and hip or lumbar spine t scores. During 700,388 person-years of follow-up, 2,578 hip fractures occurred. Adjusted hazard ratios for incident hip fracture for the highest consumption category compared with no consumption were 1.26 (95% confidence interval [CI] 1.01-1.56) for total soda and 1.32 (95% CI 1.00-1.75) for caffeine-free soda. There was no association between caffeinated soda and incident hip fracture (hazard ratio = 1.16; 95% CI 0.86-1.57). There was no apparent linear trend in the risk of hip fracture across categories of soda consumption in the fully adjusted models, suggesting a threshold effect. A sensitivity analysis using adjudicated hip fractures showed significant associations for all three soda exposures in the highest intake groups., Conclusions: Consuming more than two servings of soft drinks per day on average showed potential associations with higher risk of hip fracture among postmenopausal women.

Objective: The aim of the study was to examine the association of pregnancy history with trajectories of cognitive function in older women., Methods: Participants were 1,025 women (mean age = 73.1 ± 9.6 y) enrolled in the Rancho Bernardo Study who attended a clinic visit between 1988 and 1992, when pregnancy history (ever pregnant, number of pregnancies, ages at first and last pregnancy) was recorded and cognitive function was assessed with a battery of four tests repeated up to 7 times through 2016. Linear mixed-effects regression models were used to examine the association between pregnancy history and longitudinal change in cognitive function., Results: Overall, 77% of women had at least one pregnancy; number of pregnancies ranged from 1 to 14 (mean = 2.9 ± 1.7). Ages at first and last pregnancy ranged from 16 to 44 years (mean = 24.9 ± 4.7) and 16 to 49 years (mean = 30.7 ± 5.5), respectively. Of 16 associations tested (4 pregnancy exposures by 4 cognitive tests), one was statistically significant without correction for multiple comparisons. Women who reported ever being pregnant recalled 0.12 fewer words on the Buschke Selective Reminding Test for every year increase in age than women who had never been pregnant (P = 0.05). No other significant associations of pregnancy history with cognitive decline were observed., Conclusions: Our results show no clinically meaningful long-term influence of pregnancy history on age-related change in cognitive function. These reassuring findings suggest childbearing decisions and timing will not affect cognitive function in older age.

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).

Background: physical activity in older age has been associated with better cognitive function, but the role of earlier life physical activity is less well understood., Objective: determine associations between physical activity throughout the lifespan and cognitive function in older age., Design: cross-sectional study., Setting: the Rancho Bernardo Study of Healthy Aging in southern California., Subjects: A total of 1,826 community-dwelling men and women (60-99 years) who attended a research visit in 1988-92., Methods: participants underwent cognitive testing at older age, and reported physical activity as a teenager, at age 30 years, 50 years and currently. For each time-point, participants were classified as regularly active (3+ times/week) or inactive., Results: regular physical activity was associated with better cognitive function, with physical activity at older ages showing the strongest associations. Physical activity in older age was associated with better global cognitive function, executive function and episodic memory, regardless of intensity. Intense physical activity in teenage years was associated with better late-life global cognitive function in women. Teenage physical activity interacted with older age physical activity on executive function; those active at both periods performed better than those active at only one period. Similar patterns of associations were observed after excluding individuals with poor health., Conclusions: regular physical activity in older age, regardless of intensity, is associated with better cognitive function. Physical activity in teenage years may enhance cognitive reserve to protect against age-related decline in executive function. Further research is needed to assess the effect of physical activity across the lifespan on healthy brain ageing., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Although physical activity has been associated with better cognitive function and reduced dementia risk, its association with cognitive decline in normal aging remains uncertain., Objective: To determine whether physical activity in youth and older age are associated with age-related cognitive change., Methods: Over a period of 27 years, 2,027 community-dwelling adults (mean age 73.5; 60% women) of the Rancho Bernardo Study of Healthy Aging completed up to seven cognitive assessments, including tests of global cognitive function, executive function, verbal fluency, and episodic memory. At each visit, participants reported concurrent physical activity. At baseline (1988- 1992), participants additionally reported physical activity as a teenager and at age 30. For each age period, participants were classified as regularly active (3+ times/week) or inactive., Results: Associations between concurrent physical activity and better cognitive function were stronger with advancing age on all tests, even after accounting for education, health, and lifestyle factors, as well as survival differences (ps < 0.05). Baseline physical activity did not predict rates of cognitive decline (ps > 0.40). Individuals who were physically active at age 30 and older age maintained the highest global cognitive function with advancing age (p = 0.002)., Conclusion: Regular physical activity is associated with better cognitive function with advancing age. Physical activity in young adulthood may contribute to cognitive reserve, which together with physical activity in later years, may act to preserve cognitive function with age.

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., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: This study investigated how cognitive function changes with age and whether rates of decline vary by sex or education in a large, homogenous longitudinal cohort characterized by high participation rates, long duration of follow-up, and minimal loss to follow-up., Design/setting/participants: Between 1988 and 2016, 2,225 community-dwelling participants of the Rancho Bernardo Study, aged 31 to 99 years at their initial cognitive assessment, completed neuropsychological testing approximately every 4 years, over a maximum 27-year follow-up., Measurements: Linear mixed effects regression models defined sex-specific cognitive trajectories, adjusting for education and retest effects., Results: Significant decline across all cognitive domains began around age 65 years and accelerated after age 80 years. Patterns of decline were generally similar between sexes, although men declined more rapidly than women on the global function test. Higher education was associated with slower decline on the tests of executive and global functions. After excluding 517 participants with evidence of cognitive impairment, accelerating decline with age remained for all tests, and women declined more rapidly than men on the executive function test., Conclusions: Accelerating decline with advancing age occurs across multiple cognitive domains in community-dwelling older adults, with few differences in rates of decline between men and women. Higher education may provide some protection against executive and global function decline with age. These findings better characterize normal cognitive aging, a critical prerequisite for identifying individuals at risk for cognitive impairment, and lay the groundwork for future studies of health and behavioral factors that affect age-related decline in this cohort., (Copyright © 2017 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.)

Purpose: To examine associations of prediagnosis high-sensitivity C-reactive protein (hsCRP) with breast cancer incidence and postdiagnosis survival and to assess whether associations are modified by body mass index (BMI). Methods: A prospective analysis of the Women's Health Initiative was conducted among 17,841 cancer-free postmenopausal women with baseline hsCRP measurements. Cox proportional hazards models were used to examine associations between hsCRP concentrations and (i) breast cancer risk ( n cases = 1,114) and (ii) all-cause mortality after breast cancer diagnosis. HRs are per 1 SD in log hsCRP. Results: hsCRP was not associated with breast cancer risk overall [HR = 1.05; 95% confidence interval (CI), 0.98-1.12]; however, an interaction between BMI and hsCRP was observed ( P interaction = 0.02). A 1 SD increase in log hsCRP was associated with 17% increased breast cancer risk (HR = 1.17; 95% CI, 1.03-1.33) among lean women (BMI < 25), whereas no association was observed among overweight/obese (BMI ≥ 25) women. Prediagnosis hsCRP was not associated with overall mortality (HR, 1.04; 95% CI, 0.88-1.21) after breast cancer diagnosis; however, an increased mortality risk was apparent among leaner women with higher hsCRP levels (HR, 1.39, 95% CI, 1.03-1.88). Conclusions: Prediagnosis hsCRP levels are not associated with postmenopausal breast cancer incidence or survival overall; however, increased risks are suggested among leaner women. The observed effect modification is in the opposite direction of a previous case-control study finding and warrants further investigation. Impact: Associations of higher CRP levels with incident breast cancer and survival after breast cancer may depend on BMI. Cancer Epidemiol Biomarkers Prev; 26(7); 1100-6. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Purpose: Hyperkyphosis, accentuated curvature of the thoracic spine, is often attributed to osteoporosis, yet its underlying pathophysiology is not well understood. Bone turnover markers (BTM) reflect the dynamic process of bone formation and resorption. This study examined the association between serum BTM levels and kyphosis in community-dwelling older adults., Methods: Between 2003 and 2006, 760 men and women in the Rancho Bernardo Study age 60 and older had blood drawn and kyphosis measured. Fasting serum was assayed for N-telopeptide (NTX) and procollagen type 1 n-terminal propeptide (P1NP), markers of bone resorption and formation, respectively. Participants requiring two or more 1.7 cm blocks under their head to achieve a neutral supine position were classified as having accentuated kyphosis. Analyses were stratified by sex and use of estrogen therapy (ET). Odds of accentuated kyphosis were calculated for each standard deviation increase in log-transformed BTM., Results: Mean age was 75 years. Overall, 51% of 341 non-ET using women, 41% of 111 ET-using women, and 75% of 308 men had accentuated kyphosis. In adjusted models, higher P1NP and NTX were associated with decreased odds of accentuated kyphosis in non-ET using women (P1NP: OR = 0.78 [95% CI, 0.58-0.92]; NTX: OR = 0.68 [95% CI, 0.54-0.86]), but not in men or ET-using women ( p  > 0.05)., Conclusions: The selective association of higher bone turnover with reduced odds of accentuated kyphosis in non-ET using women suggests that elevated BTM were associated with a lower likelihood of hyperkyphosis only in the low estrogen/high BTM environment characteristic of postmenopausal women who are not using ET., Competing Interests: Dr. Sarah Johnson is a Senior Research Scientist at SPD Development Company Limited, the entity that performed the NTX assays.

Objective: To examine the association of abdominal muscle area with coronary artery calcium (CAC) presence, extent, and progression in a multi-ethnic cohort of older, community-dwelling post-menopausal women., Design and Setting: Cross-sectional and longitudinal population-based cohort., Participants: The sample comprised 179 non-Hispanic White women, 116 Filipina women and 144 African American women, all without known CVD, who underwent chest and abdominal computed tomography (CT) scans twice about four years apart for abdominal muscle and fat, as well as CAC., Main Outcome Measures: CAC presence, extent and progression., Results: There was a significant interaction of ethnicity with baseline oblique muscle area (p-for-interaction .01), and marginally significant interactions with baseline total and paraspinal muscle for change in CAC (p-for-interactions both .09). Among Filipina women, each standard deviation (SD) greater total muscle area was associated with a 26% (95% CI (-43%, -4%), P=.02) reduced rate of change in CAC; higher paraspinal and oblique muscle area were associated with a 24% (-38%, -6%, P=.01) and a 37% (-53%, -16%, P=.0002) reduced rate of change in CAC, respectively. These associations were not significant in African American or non-Hispanic White women. There were no significant associations of abdominal muscle with CAC presence or extent, nor were there significant ethnicity by muscle interactions in these models., Conclusions: Among Filipina women, greater abdominal muscle mass is associated with a decreased rate of CAC progression. Higher muscle mass may be important for this group in reducing CVD outcomes.

Objective: Persons with diabetes have accelerated muscle loss. The association of fasting and postchallenge glucose levels per se to grip strength, a clinical marker of poor physical function, and potential sex differences in this relationship has not been previously described., Design: Longitudinal cohort., Setting: USA., Participants: Participants were community-dwelling older adults (mean age 71.3 years) without self-reported diabetes and/or use of diabetes medication with glucose measured at baseline (1992-1996)., Measurements: Fasting plasma glucose (FPG) was measured in 1019 women and 636 men. Two-hour glucose (2HG) levels after a 75 g oral glucose tolerance test were also available (women, n=870; men, n=559). Dominant hand grip strength was assessed using a hand-held dynamometer at 3.0±1.6 visits over a median 7.0 years. Mixed linear models examined the association of baseline glucose levels with grip strength, accounting for repeated visits, and adjusting for covariates., Results: Sex-specific FPG quartiles were associated with unadjusted differences in grip strength among women (p=0.03) but not men (p=0.50). However, in men, adjusting for age, education, height, weight, peripheral neuropathy, physical activity, and comorbidities, each SD (SD=17 mg/dL) higher FPG was associated with persistently lower grip strength (-0.44±0.22 kg, p=0.049); 2HG (SD=50 mg/dL) was unrelated to grip strength (-0.39±0.25 kg, p=0.13). In women, neither FPG (SD=16 mg/dL) nor 2HG (SD=45 mg/dL) was associated with grip strength (0.02±0.12 kg, p=0.90; and -0.20±0.14 kg, p=0.14; respectively) after adjustment. The rate of change in grip strength did not differ across FPG or 2HG quartiles in either sex., Conclusions: In age-adjusted analyses, elevated fasting glucose levels are associated with persistently lower grip strength in older men, but not women. Future studies are needed to elucidate reasons for these sex differences and may provide further insight into accelerated loss of muscle function as a complication of diabetes in older adults.

Objective: Pericardial and intra-thoracic fat are associated with prevalent cardiovascular disease (CVD) and CVD risk factors. However, it is unclear if these fat depots predict incident CVD events and/or all-cause mortality. We examined prospective associations between areas of pericardial and intra-thoracic fat and incident CVD and mortality over a 12-year follow-up in a subset of participants without baseline clinical CVD from the Rancho Bernardo Study (RBS)., Methods: Participants were 343 community-dwelling older adults (mean baseline age = 67) who completed a clinic visit in 2001-02, including a computed tomography scan of the chest. Incident CVD and mortality were recorded through January 2013., Results: Over a 12.6-year median follow-up, there were 60 incident CVD events and 49 deaths. Pericardial fat was associated with all-cause mortality, such that each standard deviation increment predicted a 34% higher chance of death after adjusting for demographics, lifestyle factors, comorbidities, and visceral fat (95% CI = 1.01-1.78). When categorized by tertile, those in the middle tertile of pericardial fat showed no increased risk of mortality, while those in the highest tertile had 2.6 times the risk (95% CI = 1.10-5.97) compared to the lowest tertile. There was a marginal association between intra-thoracic fat and mortality (p = 0.06). Neither pericardial nor intra-thoracic fat was significantly associated with incident CVD. There were no significant interactions by sex., Conclusions: Higher pericardial, but not intra-thoracic, fat was associated with earlier all-cause mortality in older adults over a 12-year follow-up. This association was primarily driven by a higher mortality rate in those in the highest tertile of pericardial fat., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: We examined the association between breastfeeding and postmenopausal visceral adiposity., Methods: Participants were community-dwelling women aged 55-80 from the Caucasian Rancho Bernardo Study, the Filipino Women's Health Study, and the Health Assessment Study of African-American Women who had visceral adipose tissue (VAT) measurements by computed tomography between 2000 and 2002. Linear regression was used to determine the association between average breastfeeding duration per child and VAT., Results: In Caucasian, Filipino, and African-American women, average number of live births was 3, 4, and 3; average breastfeeding duration was 4.3, 1.8, and 5.1 months, respectively. Filipino women had more live births, were more likely to breastfeed, and breastfed shorter durations. African-American women had lower VAT, despite higher subcutaneous adipose tissue (SAT), BMI, and waist girth. Women who breastfed >3 months on average had 8.8 cm(3) lower VAT than women who breastfed ≤3 months, independent of covariates. Women who initiated breastfeeding had lower BMI and waist girth than those who did not, but they did not differ by VAT unless they breastfed >3 months. Associations were independent of race/ethnicity., Conclusions: Results suggest breastfeeding initiation is associated with reduced BMI and smaller waist girth, and breastfeeding >3 months is associated with lower postmenopausal VAT., (© 2014 The Obesity Society.)

Context: Despite the key role of muscle in glucose regulation, little is known about the association between muscle area and prevalence of metabolic disorders, or the role low muscle may play in normal weight metabolic obesity., Objective: The objective was to assess the independent associations between both abdominal muscle and fat depositions (measured by computed tomography) and the prevalence of type II diabetes, and to explore the modifying role of weight category., Design: We conducted a cross-sectional analysis of the 2001-2002 visit for the Rancho Bernardo Study, Filipino Women's Health Study, and Health Assessment Study of African American Women., Setting and Participants: Participants were 392 community-dwelling older women (mean age = 64) free of clinical cardiovascular disease., Main Outcome Measure: The main outcome was prevalence of type II diabetes, defined as use of anti-diabetes medication, fasting plasma glucose ≥ 126 mg/dL, and/or OGTT ≥ 200 mg/dL., Results: Adjusting for demographics, hypertension, estrogen use, lipids, smoking, physical activity, visceral fat area, and height, a greater muscle-to-total abdominal area ratio (MAR) was associated with lower odds of diabetes [OR = 0.63 per standard deviation, 95% CI (0.43-0.92), p = .02]. Higher visceral fat was associated with greater odds of diabetes in fully adjusted models including total muscle area [OR = 1.48, 95% CI (1.09, 2.01), p = .01]. Associations between MAR and diabetes were stronger for normal weight (BMI 18.5-24.9; OR = 0.32) than overweight/obese women (BMI ≥ 25, OR = 0.71, p-for-interaction = 0.046). Associations with visceral fat did not differ by BMI (p-for-interaction = 0.71)., Conclusions: In older women, abdominal muscle area is inversely associated with type II diabetes independent of visceral adiposity, particularly for normal weight women.

Objectives: Fetuin-A is an abundant plasma protein known to predict vascular disease. Fetuin-A levels are lower in patients with Alzheimer's disease in proportion to the severity of cognitive impairment, but their association with normal cognitive ageing is unknown. We evaluated the association of serum fetuin-A levels with cognitive function in community-dwelling older adults., Design/patients/measurements: A population-based study of 1382 older adults (median age 75) who had plasma fetuin-A levels and cognitive function evaluated in 1992-1996; 855 had repeat cognitive function assessment a median of 4 years later., Results: Adjusting for age, sex, education and depression, higher levels of fetuin-A were associated with better baseline performance on the Mini-Mental Status Exam (MMSE; P = 0·012) and a tendency for better Trails Making B scores (P = 0·066). In longitudinal analyses, the likelihood of a major decline (highest decile of change) in Trails B was 29% lower (P = 0·010) for each SD higher baseline fetuin-A level; odds of major decline in MMSE was 42% lower (P = 0·005) per SD higher fetuin-A for individuals with no known CVD, but were not related to fetuin-A in those with CVD (P = 0·33). Fetuin-A was not related to Category Fluency performance. Results were independent of multiple vascular risk factors and comorbid conditions., Conclusions: Higher plasma fetuin-A concentrations are associated with better performance on tests of global cognitive function and executive function and with less likelihood of major decline in these cognitive abilities over a 4-year period. Fetuin-A may serve as a biological link between vascular disease and normal age-related cognitive decline., (© 2013 John Wiley & Sons Ltd.)

Background: Estrogen therapy (ET) is associated with lower serum calcium and phosphorus concentrations and is known to increase bone mineral density (BMD). Other biomarkers of mineral metabolism may help understand the biological basis of these actions., Methods: We studied 2767 postmenopausal women in the Multi-Ethnic Study of Atherosclerosis, 862 (31%) of whom were using ET. We measured serum concentrations of calcium, phosphorus, 25-hydroxyvitamin D, 24,25-dihydoxyvitamin D, and fibroblast growth factor-23 and urinary fractional excretion of calcium (FEca) and phosphorus (FEphos). We examined the associations of ET with each biomarker. In addition, we tested whether the adjustment for biomarkers attenuated the association of ET with lumbar BMD measured by abdominal computed tomography in a subset of 810 women., Results: In adjusted models, women who used ET were younger in age [62 (SD 8) vs 66 (9) y, P < .001], had lower mean serum calcium [-13 mg/dL (95% confidence interval [CI] -0.17, -0.10), P < .001] and lower FEca [-0.15% (95% CI -0.21, -0.09), P < .001]. Mean serum phosphorus was lower [-0.19 mg/dL (95% CI -0.23, -0.15), P < .001] and FEphos [0.56% (95% CI 0.16, 0.96), P = .007] was higher in women on ET. Mean 25-hydroxyvitamin D and 24,25-dihydroxyvitamin D were higher [1.52 ng/dL (95% CI 0.57, 2.47), P = .002, and 0.26 ng/mL (95% CI 0.03, 0.48), P = .03, respectively] in women who used ET. Mean PTH and fibroblast growth factor-23 did not differ significantly by the use of ET. ET use was strongly associated with higher lumbar BMD [12.75 mg/cm³ (95% CI 7.77-17.73), P < .001]; however, mineral metabolism measures did not meaningfully alter this association., Conclusions: In a multiethnic cohort of postmenopausal women, ET use was associated with lower serum calcium, lower FEca, lower serum phosphorus, and higher FEphos, suggesting these associations are attributable to increased calcium intake into bone and increased urinary phosphorus excretion. ET use was also associated with greater concentrations of vitamin D metabolites. ET-associated differences in these mineral metabolism measures did not meaningfully attenuate the strong association between ET use and lumbar BMD.

Context: Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone that also inhibits calcitriol synthesis., Objective: Our objective was to evaluate the relationships of plasma FGF23 concentrations with bone mineral density (BMD) and hip fracture in community-dwelling older adults., Design and Setting: Linear regression and Cox proportional hazard models were used to examine the associations of plasma FGF23 concentrations with BMD and incident hip fracture, respectively. Analyses were also stratified by chronic kidney disease., Participants: Participants included 2008 women and 1329 men ≥65 years from the 1996 to 1997 Cardiovascular Health Study visit., Main Outcome Measures: Dual x-ray absorptiometry measured total hip (TH) and lumbar spine (LS) BMD in 1291 participants. Hip fracture incidence was assessed prospectively through June 30, 2008 by hospitalization records in all participants., Results: Women had higher plasma FGF23 concentrations than men (75 [56-107] vs 66 [interquartile range = 52-92] relative units/mL; P < .001). After adjustment, higher FGF23 concentrations were associated with greater total hip and lumbar spine BMD in men only (β per doubling of FGF23 = 0.02, with 95% confidence interval [CI] = 0.001-0.04 g/cm(2), and 0.03 with 95% CI = 0.01-0.06 g/cm(2)). During 9.6 ± 5.1-11.0 years of follow-up, 328 hip fractures occurred. Higher FGF23 concentrations were not associated with hip fracture risk in women or men (adjusted hazard ratio = 0.95, with 95% CI = 0.78-1.15, and 1.09 with 95% CI = 0.82-1.46 per doubling of FGF23). Results did not differ by chronic kidney disease status (P > .4 for interactions)., Conclusions: In this large prospective cohort of community-dwelling older adults, higher FGF23 concentrations were weakly associated with greater lumbar spine and total hip BMD but not with hip fracture risk.

IGF1, IGF-binding protein-3 (IGFBP-3), IGFBP-1, insulin, leptin, and adiponectin have been inconsistently associated with breast cancer incidence. We explore how these factors are related to breast cancer recurrence and how tamoxifen treatment is related to IGF1 levels among breast cancer survivors in the Women's Healthy Eating and Living (WHEL) study. A nested case-control design was used to match breast cancer cases (who had an additional breast cancer event) to controls. Baseline blood samples from 510 matched cases and controls were analyzed for IGF1 levels; a subset of 188 pairs were analyzed for five other hormones and binding proteins. Median follow-up was 7.3 years. Matching was on recruitment site, cancer stage, age at cancer diagnosis, dates of cancer diagnosis, and randomization. Cox proportional hazards regression models, stratified on case-control pair, were used to assess the associations. Insulin, IGFBP-1, IGFBP-3, leptin, and adiponectin did not significantly predict recurrence of breast cancer. IGF1 was positively, but not significantly, associated with recurrence (hazard ratio (HR): 1.33 (95% confidence interval (CI) 0.98-1.81)) in the unadjusted analyses. Adjusting for menopausal status and tamoxifen use attenuated the HR to 1.07 (95% CI 0.76-1.40). Analyses of case-control pairs with discordant tamoxifen use show opposing HR: IGF1 predicts higher risk of recurrence if cases did not receive tamoxifen treatment. In conclusion, no significant association was found between IGF1 levels, or other related factors, and risk of additional breast cancer among breast cancer survivors. Tamoxifen can confound analysis of IGF1 and recurrence. This supports re-evaluating significance of IGF1 to breast cancer recurrence.

Context: Accumulating evidence indicates that vascular and bone mineralization may be related, although the exact mechanism remains unknown., Objective: Our objective was to investigate whether an observed inverse association between bone mineral density (BMD) and coronary artery calcification (CAC) in postmenopausal women currently taking estrogen therapy is mediated by osteoprotegerin (OPG) or receptor activator of nuclear factor-kappaB ligand (RANKL)., Design: Participants were 92 postmenopausal women (aged 58-81 yr) taking estrogen therapy who had hip and spine BMD assessed by dual-energy x-ray absorptiometry and CAC measured by electron-beam computed tomography in 1998-2002 and serum RANKL and OPG levels measured in samples collected in 1997-1999. Total CAC score was dichotomized as none/minimal (10)., Results: OPG serum levels were higher in women who had some CAC compared with those who had none/minimal (126.8 +/- 1.08 vs. 102.9 +/- 1.07 pg/ml, respectively, P = 0.03); these differences became nonsignificant after adjustment for age and other risk factors (P = 0.51). A 1 sd increase in hip BMD was associated with significantly lower odds of having CAC > 10 (odds ratio = 0.52; 95% confidence interval = 0.29-0.93) independent of age, fat-free mass, high-density lipoprotein cholesterol, current smoking, and use of cholesterol-lowering medications. Other skeletal sites demonstrated a similar pattern. Addition of RANKL and/or OPG to the model had minimal effect on the magnitude or statistical significance of the BMD-CAC association. Additionally, a test of interaction indicated that RANKL and OPG are not significant effect modifiers., Conclusions: Serum OPG and RANKL do not account for the observed association between bone and coronary artery calcification among postmenopausal women using hormone therapy.

Background: Prolactin is a polypeptide hormone that promotes normal breast proliferation and differentiation, but it is also implicated in the development and growth of mammary tumors. Mammographic density is a strong, independent predictor of breast cancer and, therefore, a potential surrogate indicator of breast cancer risk., Methods: To test the hypothesis that serum prolactin is positively related to mammographic density, we conducted a cross-sectional analysis of baseline data from the Postmenopausal Estrogen/Progestin Interventions (PEPI) Mammographic Density Study. Based on prior work, we further hypothesized that this association would be apparent only in women who had not recently used postmenopausal hormone therapy (HT)., Results: In linear regression models adjusted for age, body mass index, race, smoking, alcohol use, parity and physical activity, among the 400 women who were not recent users of HT, prolactin was positively and statistically significantly associated with mammographic density (Beta log base 2 prolactin 0.0369 [95% CI: 0.0094-0.0645]. Thus, for each doubling of serum prolactin, there was an absolute increase in mammographic density of 3.69%. Additional adjustment for serum levels of estradiol, progesterone, sex hormone binding globulin and age at first pregnancy did not affect this result. There was no association between prolactin and mammographic density among the 169 participants who had recently used HT., Conclusion: The correspondence between higher prolactin and higher mammographic density is consistent with prolactin's mitogenic properties and the associations between prolactin and breast tumor promotion. These results support the thesis that prolactin deserves investigation as a target for breast cancer risk reduction.

Objective: The role of osteoprotegerin (OPG) and its receptor activator of nuclear factor kappaB legend (RANKL) in the regulation of bone in humans remain unclear. We examined the sex-specific associations of serum OPG, RANKL, and their ratio with bone mineral density (BMD) in older adults., Design: Participants were 681 community-dwelling adults, ages 45-90 years, who had serum OPG and RANKL measured and bone density scans in 1988-1991, with follow-up scans 5 and/or 10 years later., Methods: Analyses were sex-specific; women using and not using estrogen were evaluated separately. Cross-sectional analyses used multivariable regression models; longitudinal analyses used repeated measures mixed effects models., Results: In cross-sectional analyses, age- and weight-adjusted serum OPG levels were significantly positively associated with BMD at the lumbar spine in men, and at the femoral neck, total hip, and lumbar spine in women using estrogen, but not in non-users of estrogen. RANKL concentrations were significantly and inversely associated with BMD in men only, and at the total hip. Neither OPG nor RANKL was significantly associated with bone loss. Results for the RANKL/OPG ratio were the same as those for RANKL alone., Conclusions: These results suggest a modulatory effect of both endogenous and exogenous sex hormones on the biologic interaction of OPG, RANKL, and bone.