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1.  Adipose Tissue Density, a Novel Biomarker Predicting Mortality Risk in Older Adults 
Knowledge of adipose composition in relation to mortality may help delineate inconsistent relationships between obesity and mortality in old age. We evaluated relationships between abdominal visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) density, mortality, biomarkers, and characteristics.
VAT and SAT density were determined from computed tomography scans in persons aged 65 and older, Health ABC (n = 2,735) and AGES-Reykjavik (n = 5,131), and 24 nonhuman primates (NHPs). Associations between adipose density and mortality (4–13 years follow-up) were assessed with Cox proportional hazards models. In NHPs, adipose density was related to serum markers and tissue characteristics.
Higher density adipose tissue was associated with mortality in both studies with adjustment for risk factors including adipose area, total fat, and body mass index. In women, hazard ratio and 95% CI for the densest quintile (Q5) versus least dense (Q1) for VAT density were 1.95 (1.36–2.80; Health ABC) and 1.88 (1.31–2.69; AGES-Reykjavik) and for SAT density, 1.76 (1.35–2.28; Health ABC) and 1.56 (1.15–2.11; AGES-Reykjavik). In men, VAT density was associated with mortality in Health ABC, 1.52 (1.12–2.08), whereas SAT density was associated with mortality in both Health ABC, 1.58 (1.21–2.07), and AGES-Reykjavik, 1.43 (1.07–1.91). Higher density adipose tissue was associated with smaller adipocytes in NHPs. There were no consistent associations with inflammation in any group. Higher density adipose tissue was associated with lower serum leptin in Health ABC and NHPs, lower leptin mRNA expression in NHPs, and higher serum adiponectin in Health ABC and NHPs.
VAT and SAT density provide a unique marker of mortality risk that does not appear to be inflammation related.
PMCID: PMC3859360  PMID: 23707956
Obesity; Aging; Leptin; Adiponectin.
2.  Body Composition Explains Sex Differential in Physical Performance Among Older Adults 
Older women have higher percent body fat, poorer physical function, lower strength, and higher rates of nonfatal chronic conditions than men. We sought to determine whether these differences explained physical performance differences between men and women.
Physical performance was assessed in the Health, Aging and Body Composition study in 2,863 men and women aged 70–79 with a composite 0–4 point score consisting of chair stands, standing balance including one-leg stand, and 6-m usual and narrow walk tests. Total body composition was measured by dual x-ray absorptiometry, thigh composition by computed tomography, and knee extensor strength by isokinetic dynamometer. Analysis of covariance estimated least square mean performance scores for men and women.
Men had higher performance scores than women (least square means: 2.33±0.02 vs 2.03±0.02, p < .0001), adjusted for race, study site, age, and height. Body composition measures (total body fat and thigh muscle area, muscle density, subcutaneous fat, and intermuscular fat) accounted for differences between men and women (least square means: 2.15±0.02 vs 2.17±0.02, p = .53). Higher strength in men partly explained the sex difference (least square means: 2.28±0.02 vs 2.12±0.02, p < .0001). Strength attenuated the association of thigh muscle mass with performance. Chronic health conditions did not explain the sex difference.
In a well-functioning cohort, poorer physical function in women compared with men can be explained predominantly by their higher fat mass, but also by other body composition differences. The higher proportion of body fat in women may put them at significant biomechanical disadvantage for greater disability in old age.
PMCID: PMC3859364  PMID: 23682159
Body composition; Physical performance; Epidemiology.
3.  The QT Interval and Risk of Incident Atrial Fibrillation 
Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine.
To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF.
We examined a prolonged QT corrected by the Framingham formula (QTFram) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (Health ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by other formulae.
Among 14,538 ARIC participants, a prolonged QTFram predicted a roughly two-fold increased risk of AF (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.42–2.96, p<0.001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in CHS and Health ABC and were similar across various QT correction methods. Also in ARIC, each 10-ms increase in QTFram was associated with an increased unadjusted (HR 1.14, 95%CI 1.10–1.17, p<0.001) and adjusted (HR 1.11, 95%CI 1.07–1.14, p<0.001) risk of AF. Findings regarding a short QT were inconsistent across cohorts.
A prolonged QT interval is associated with an increased risk of incident AF.
PMCID: PMC3787974  PMID: 23872693
atrial fibrillation; epidemiology; risk; QT interval; electrocardiography; ECG
4.  Anemia and risk of dementia in older adults 
Neurology  2013;81(6):528-533.
To determine whether anemia is associated with incident dementia in older adults.
We studied 2,552 older adults (mean age 76.1 years; 38.9% black; 51.8% female) participating in the Health, Aging, and Body Composition study and free of dementia at baseline. We defined anemia using WHO criteria (hemoglobin concentration <13 g/dL for men and <12 g/dL for women). Dementia diagnosis was determined by dementia medication use, hospital records, or a change in Modified Mini-Mental State (3MS) score of more than 1.5 SD from mean. Discrete time Cox proportional hazard regression models were used to examine the hazard for developing dementia associated with anemia.
Of 2,552 participants, 392 (15.4%) older adults had anemia at baseline. Over 11 years of follow-up, 455 (17.8%) participants developed dementia. In the unadjusted model, those with baseline anemia had an increased risk of dementia (23% vs 17%, hazard ratio = 1.64; 95% confidence interval 1.30, 2.07) compared to those without anemia. The association remained significant after adjusting for demographics, APOE ε4, baseline 3MS score, comorbidities, and renal function. Additional adjustment for other anemia measures (mean corpuscular volume, red cell distribution width), erythropoietin, and C-reactive protein did not appreciably change the results. There was no interaction by sex and race on risk of developing dementia.
Among older adults, anemia is associated with an increased risk of developing dementia. Findings suggest that further study of anemia as a risk factor for dementia and a target for intervention for cognitive health is warranted.
PMCID: PMC3775683  PMID: 23902706
5.  Association of total and computed tomographic measures of regional adiposity with incident cancer risk: a prospective population-based study of older adults 
Obesity is associated with increased risk of many types of cancer. Less is known regarding associations between adipose depots and cancer risk. We aimed to explore relationships between adipose depots, risk of cancer and obesity-related cancer (per NCI definition) in participants initially aged 70–79 without prevalent cancer (1,179 men, 1,340 women), and followed for incident cancer for 13 years. Measures included body mass index (BMI), total adipose tissue from dual-energy X-ray absorptiometry and computed tomography measures: visceral adipose tissue (VAT), abdominal subcutaneous adipose tissue (SAT), thigh intermuscular adipose tissue and thigh muscle attenuation (Hounsfield Unit, HU), low HU indicates fatty infiltration. Hazard ratios (HR) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression adjusted for demographics, lifestyle variables and medical conditions. During follow-up 617 participants developed cancer of which 224 were obesity-related cancers. Total adipose tissue and VAT were positively associated with cancer risk among women (HR 1.14, 95% CI 1.01–1.30 per SD increase, HR 1.15, 95% CI 1.02–1.30 per SD increase). There were no associations with cancer risk among men. Total adipose tissue was positively associated with obesity-related cancer risk among women (HR 1.23, 95% CI 1.03–1.46 per SD increase). VAT was positively associated with obesity-related cancer risk among men (HR 1.30, 95% CI 1.06–1.60 per SD increase) and remained associated even with adjustment for BMI (HR 1.40, 95% CI 1.08–1.82 per SD increase). These findings provide insight into relationships between specific adipose depots and cancer risk and suggest differential relationships among men and women.
PMCID: PMC4071344  PMID: 24869972
Obesity; weight; adipose; body fat; cancer incidence; cancer risk; aging
6.  Association of Major and Minor ECG Abnormalities With Coronary Heart Disease Events 
In populations of older adults, prediction of coronary heart disease (CHD) events through traditional risk factors is less accurate than in middle-aged adults. Electrocardiographic (ECG) abnormalities are common in older adults and might be of value for CHD prediction.
To determine whether baseline ECG abnormalities or development of new and persistent ECG abnormalities are associated with increased CHD events.
Design, Setting, and Participants
A population-based study of 2192 white and black older adults aged 70 to 79 years from the Health, Aging, and Body Composition Study (Health ABC Study) without known cardiovascular disease. Adjudicated CHD events were collected over 8 years between 1997–1998 and 2006–2007. Baseline and 4-year ECG abnormalities were classified according to the Minnesota Code as major and minor. Using Cox proportional hazards regression models, the addition of ECG abnormalities to traditional risk factors were examined to predict CHD events.
Main Outcome Measure
Adjudicated CHD events (acute myocardial infarction [MI], CHD death, and hospitalization for angina or coronary revascularization).
At baseline, 276 participants (13%) had minor and 506 (23%) had major ECG abnormalities. During follow-up, 351 participants had CHD events (96 CHD deaths, 101 acute MIs, and 154 hospitalizations for angina or coronary revascularizations). Both baseline minor and major ECG abnormalities were associated with an increased risk of CHD after adjustment for traditional risk factors (17.2 per 1000 person-years among those with no abnormalities; 29.3 per 1000 person-years; hazard ratio [HR], 1.35; 95% CI, 1.02–1.81; for minor abnormalities; and 31.6 per 1000 person-years; HR, 1.51; 95% CI, 1.20–1.90; for major abnormalities). When ECG abnormalities were added to a model containing traditional risk factors alone, 13.6% of intermediate-risk participants with both major and minor ECG abnormalities were correctly reclassified (overall net reclassification improvement [NRI], 7.4%; 95% CI, 3.1%–19.0%; integrated discrimination improvement, 0.99%; 95% CI, 0.32%–2.15%). After 4 years, 208 participants had new and 416 had persistent abnormalities. Both new and persistent ECG abnormalities were associated with an increased risk of subsequent CHD events (HR, 2.01; 95% CI, 1.33–3.02; and HR, 1.66; 95% CI, 1.18–2.34; respectively). When added to the Framingham Risk Score, the NRI was not significant (5.7%; 95% CI, −0.4% to 11.8%).
Major and minor ECG abnormalities among older adults were associated with an increased risk of CHD events. Depending on the model, adding ECG abnormalities was associated with improved risk prediction beyond traditional risk factors.
PMCID: PMC4006989  PMID: 22496264
7.  The Associations between Serum Brain-Derived Neurotrophic Factor, Potential Confounders, and Cognitive Decline: A Longitudinal Study 
PLoS ONE  2014;9(3):e91339.
Brain-derived neurotrophic factor (BDNF) plays a role in the maintenance and function of neurons. Although persons with Alzheimer’s disease have lower cortical levels of BDNF, evidence regarding the association between circulating BDNF and cognitive function is conflicting. We sought to determine the correlates of BDNF level and whether BDNF level was prospectively associated with cognitive decline in healthy older adults. We measured serum BDNF near baseline in 912 individuals. Cognitive status was assessed repeatedly with the modified Mini-Mental Status Examination and the Digit Symbol Substitution test over the next 10 years. We evaluated the association between BDNF and cognitive decline with longitudinal models. We also assessed the association between BDNF level and demographics, comorbidities and health behaviors. We found an association between serum BDNF and several characteristics that are also associated with dementia (race and depression), suggesting that future studies should control for these potential confounders. We did not find evidence of a longitudinal association between serum BDNF and subsequent cognitive test trajectories in older adults, although we did identify a potential trend toward a cross-sectional association. Our results suggest that serum BDNF may have limited utility as a biomarker of prospective cognitive decline.
PMCID: PMC3966768  PMID: 24670553
8.  Reproducibility of peroneal motor nerve conduction measurement in older adults 
While neuropathy is common in the elderly, nerve conduction (NC) reproducibility in older adults is not well-established. We sought to evaluate intraobserver reproducibility of peroneal motor NC measures in a diverse sample of older adults.
We measured peroneal motor NC amplitude and velocity in a subset of participants (mean age=82.9 ± 2.7, n=62, 50% female, 51.6% black, 35.5% DM) in the Health, Aging, and Body Composition Study. Using coefficients of variation (CVs), intraclass correlation coefficients (ICCs), and Bland Altman Plots, we compared two sets of measurements taken by the same examiner hours apart on the same day.
Low CVs (2.15–4.24%) and moderate to high ICCs (0.75–0.99) were observed. No systematic variation was found across measures. Despite small numbers in some subgroups, we found no differences in reproducibility by diabetes, race, or study site.
NC measures have moderate to high intraobsever reproducibility in older adults and are not affected by diabetes, race, or gender.
These data provide evidence to support use of these measures in aging research.
PMCID: PMC3562564  PMID: 23022036
Motor nerve conduction; aging; peripheral nerve function; reproducibility; diabetes
9.  Hypertension and Low HDL-Cholesterol were Associated with Reduced Kidney Function Across the Age Spectrum: A Collaborative Study 
Annals of epidemiology  2013;23(3):106-111.
To determine if the associations among established risk factors and reduced kidney function vary by age.
We pooled cross-sectional data from 14,788 non-diabetics aged 40–100 years in 4 studies: Cardiovascular Health Study, Health, Aging, and Body Composition Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-Stage Disease cohort.
Hypertension and low HDL-cholesterol were associated with reduced cystatin C-based estimated glomerular filtration rate (eGFR) across the age spectrum. In adjusted analyses, hypertension was associated with a 2.3 (95% CI 0.1, 4.4), 5.1 (4.1, 6.1), and 6.9 (3.0, 10.4) mL/min/1.73 m2 lower eGFR in participants 40–59, 60–79, and 80+ years, respectively (p-value for interaction <0.001). The association of low HDL-cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (3.5, 6.3), 7.1 (CI 6.0, 8.3), 8.9 (CI 5.4, 11.9) mL/min/1.73 m2 (p-value for interaction <0.001). Smoking and obesity were associated with reduced kidney function in participants under 80 years. All estimates of the potential population impact of the risk factors were modest.
Hypertension, obesity, smoking, and low HDL-cholesterol are modestly associated with reduced kidney function in non-diabetics. The associations of hypertension and HDL-cholesterol with reduced kidney function appear stronger in older adults.
PMCID: PMC3570601  PMID: 23313266
Chronic kidney insufficiency; aged; hypertension; cholesterol; obesity; smoking
10.  Macro- and Microstructural Magnetic Resonance Imaging Indices Associated With Diabetes Among Community-Dwelling Older Adults 
Diabetes Care  2013;36(3):677-682.
To better understand the association between diabetes and cognitive impairment, we evaluated macro- and microstructural brain MRI measures for the total brain and regions of interest (ROIs) in a group of community-dwelling elders with and without diabetes.
MRI measures were obtained on 308 elders (mean age 83.3 years; n = 85 with diabetes) from the Health ABC Healthy Brain Substudy. We performed a series of linear regressions and used standardized β values to estimate the cross-sectional association between diabetes and macrostructural (gray matter volume [GMV] and white matter hyperintensities [WMHs]) and microstructural (mean diffusivity [MD] and fractional anisotropy [FA]) measures for the total brain and ROIs. Models were adjusted for age, race, and sex; GMV values for ROIs were also adjusted for total brain volume (TBV).
In multivariate-adjusted models, diabetes was associated with lower total GMV (P = 0.0006), GMV in the putamen (P = 0.02 for left and right), and TBV (P = 0.04) and greater cerebral atrophy (P = 0.02). There was no association with WMHs. On microstructural measures, diabetes was associated with reduced FA for total white matter (P = 0.006) and greater MD for the hippocampus (P = 0.006 left; P = 0.01 right), dorsolateral prefrontal cortex (P = 0.0007, left; P = 0.002, right), left posterior cingulate (P = 0.02), and right putamen (P = 0.02). Further adjustment for stroke, hypertension, and myocardial infarction produced similar results.
In this cross-sectional study, elders with diabetes compared with those without had greater brain atrophy and early signs of neurodegeneration. Further studies are needed to determine whether these structural changes associated with diabetes predict risk of cognitive decline.
PMCID: PMC3579347  PMID: 23160721
11.  Assistive Walking Device Use and Knee Osteoarthritis: the Health, Aging, and Body Composition Study (Health ABC Study) 
To identify factors that predicted incident use of assistive walking devices (AWDs) and to explore whether AWD use was associated with changes in osteoarthritis of the knee.
Prospective cohort study.
2,639 elderly men and women in the Health ABC (Health, Aging and Body Composition). Study followed for incident use of AWDs, including a subset of 874 with prevalent knee pain.
Main Outcome Measures
Incident use of AWDs, mean Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain scores and frequency of joint space narrowing on knee radiographs over a three year time period.
AWD use was initiated by 9% of the entire Health ABC cohort and 12% of the knee pain subset. Factors that predicted use in both groups were age ≥73 [entire cohort: OR 2.07 (95% CI 1.43, 3.01); knee pain subset: OR 1.87 (95% CI 1.16, 3.03)], black race [entire cohort: OR 2.95 (95% CI 2.09, 4.16); knee pain subset: OR 3.21 (95% CI 2.01, 5.11)] and lower balance ratios [entire cohort: OR 3.18 (95% CI 2.21, 4.59); knee pain subset: OR 3.77 (95% CI 2.34, 6.07)]. Mean WOMAC pain scores decreased slightly over time in both AWD and non-AWD users. 20% of non-AWD users and 28% of AWD users had radiographic progression in joint space narrowing of the tibiofemoral joint in at least one knee. 14% of non-AWD users and 12% of AWD users had radiographic progression in joint space narrowing in the patellofemoral joint in at least one knee.
Assistive walking devices are frequently used by elderly men and women. Knee pain and balance problems are significant reasons why elderly individuals initiate use of an assistive walking device. In an exploratory analysis, there was no consistent relationship between use or nonuse of an AWD and WOMAC pain scores or knee joint space narrowing progression. Further studies of the relationship of use of AWDs to changes in knee osteoarthritis are needed.
PMCID: PMC3557749  PMID: 23041146
AWDs; Balance; Knee pain
12.  Pulse wave velocity and cognitive decline in elders: The Health, Aging and Body Composition study 
Background and Purpose
Arterial stiffness is a measure of subclinical cardiovascular disease (CVD) and increases with age. This study examines the association between arterial stiffness and cognitive decline in a cohort of older adults.
2,488 subjects with baseline measure of arterial stiffness (mean age, 74.2 years; 52.3% women) were prospectively followed over 9 years in the Health, Aging and Body Composition study. Arterial stiffness was measured as pulse wave velocity (PWV) and analyzed in tertiles. Cognitive function was assessed using the Modified Mini-Mental State Exam (3MS) at baseline and repeated at years 3, 5, 8 and 10. Lower 3MS scores indicate worse function. We fit linear mixed models to examine longitudinal changes in cognitive function over the 9 years of follow-up and logistic regression models, restricted to 1,331 participants, to examine cognitive impairment defined as a decrease of ≥5 points after 9 years. We adjusted for socio-demographics, Apoe4 and CVD risk factors.
The annual decrease in 3MS scores was 0.30 points at low PWV (95%CI=−0.37;-0.22), 0.46 points at middle PWV (95%CI=−0.54;-0.39) and 0.45 points at high PWV (95%CI=−0.53;-0.38), from fully-adjusted linear mixed models. In fully-adjusted models, the odds of cognitive impairment after 9 years of follow-up was 40% greater for subjects with middle PWV (OR=1.40; 95% CI=1.03; 1.92) and 59% greater for subjects with high PWV (OR=1.59; 95% CI=1.16; 2.18), compared to low PWV.
High arterial stiffness was modestly associated with cognitive decline and impairment. Interventions to prevent arterial stiffness may be effective in delaying cognitive decline.
PMCID: PMC3572783  PMID: 23321445
13.  Adverse Oral Health and Cognitive Decline: The Health, Aging and Body Composition Study 
Periodontal disease has been associated with poorer cross-sectional cognitive function and is correlated with adverse vascular outcomes, but has received little prospective investigation in relation to cognitive decline.
Analysis of a prospective cohort study.
The Health, Aging and Body Composition (Health ABC) Study
Participants and measurements
We examined the prospective association between a range of oral health parameters and cognitive function using data on 1053 participants who were administered the Modified Mini-Mental State Examination (3MS) at year 1 (baseline) and year 3, and had participated in a comprehensive periodontal examination at year 2. We investigated 3MS decline from year 3 to 5 in 947 (89.9%) participants. Covariates included age, sex, education, race, cardiovascular disease/risk and depressive symptoms.
Most indicators of adverse oral health at year 2 were associated with cognitive impairment based on averaged 3MS scores <80 for years 1 and 3, but these associations were substantially confounded by education and race. Higher gingival index, a measure of gingival inflammation, at year 2 remained independently associated with this definition of cognitive impairment and, in fully adjusted analyses, was also an independent predictor of a 5+ point cognitive decline from years 3 to 5.
Periodontitis may be a risk factor for cognitive decline. Gingivitis is reversible and periodontitis to some degree is preventable and controllable when manifest. Therefore, further research is needed to clarify potential underlying mechanisms and oral health interventions that potentially might ameliorate cognitive decline.
PMCID: PMC3578234  PMID: 23405916
cognitive decline; cognitive impairment; periodontitis; periodontal diseases; gingivitis
14.  Plasma Beta Amyloid Level and Depression in Older Adults 
Older adults with depression have an increased risk of developing dementia. Low plasma beta-amyloid 42 (Aβ42) and Aβ42/Aβ40 have emerged as promising biomarkers of dementia. The association between depression and plasma Aβ is unclear.
In this longitudinal study of 988 community-dwelling elders from the Health Aging and Body Composition study, depression was assessed with the Center for Epidemiologic Studies-Depression Scale 10-item version. We determined the association between Aβ42 and Aβ42/Aβ40 tertile and depression at baseline and over 9 years. We also stratified the models to determine if apolipoprotein E e4 allele status modified the associations.
Mean baseline age was 74.0 ± 3.0 years, 51 (5.2%) participants had depression, 545 (55.2%) were women, 531 (53.7%) were black, and 286 (30.7%) had one or more apolipoprotein E e4 allele. At baseline, there was no association between Aβ42/Aβ40 or Aβ42 and depression. Over 9 years, 220 (23.5%) participants developed depression. In adjusted Cox proportional hazards models, among those with one or more e4 allele, low Aβ42/Aβ40 was associated with an increased risk of developing depression over time (low 10.8% vs high 3.2%, hazard ratio = 2.38, 95% confidence interval: 1.15–4.92). Among those with no e4 allele, there was no association between Aβ42/Aβ40 and risk of depression over time (13.3% vs 17.5%, hazard ratio = 0.80, 95% confidence interval: 0.52–1.23; p value for interaction = .003).
The association between low plasma Aβ42/Aβ40 and increased risk of incident depression among those with one or more apolipoprotein E e4 allele implies a synergistic relationship similar to that found with dementia. Future work should investigate the interrelationships among plasma Aβ42/Aβ40, depression, and dementia.
PMCID: PMC3598362  PMID: 22499763
Depression; Epidemiology; Plasma beta amyloid
15.  Hyperleptinemia, Adiposity, and Risk of Metabolic Syndrome in Older Adults 
Background. Abdominal adiposity and serum leptin increase with age as does risk of metabolic syndrome. This study investigates the prospective association between leptin and metabolic syndrome risk in relation to adiposity and cytokines. Methods. The Health, Aging, and Body Composition study is a prospective cohort of older adults aged 70 to 79 years. Baseline measurements included leptin, cytokines, BMI, total percent fat, and visceral and subcutaneous fat. Multivariate logistic regression was used to determine the association between leptin and metabolic syndrome (defined per NCEP ATP III) incidence after 6 years of follow-up among 1,120 men and women. Results. Leptin predicted metabolic syndrome in men (P for trend = 0.0002) and women (P for trend = 0.0001). In women, risk of metabolic syndrome increased with higher levels of leptin (compared with quintile 1, quintile 2 RR = 3.29, CI = 1.36, 7.95; quintile 3 RR = 3.25, CI = 1.33, 7.93; quintile 4 RR = 5.21, CI = 2.16, 12.56; and quintile 5 RR = 7.97, CI = 3.30, 19.24) after adjusting for potential confounders. Leptin remained independently associated with metabolic syndrome risk after additional adjustment for adiposity, cytokines, and CRP. Among men, this association was no longer significant after controlling for adiposity. Conclusion. Among older women, elevated concentrations of leptin may increase the risk of metabolic syndrome independent of adiposity and cytokines.
PMCID: PMC3888758  PMID: 24455217
16.  Hearing Loss and Cognitive Decline Among Older Adults 
JAMA internal medicine  2013;173(4):10.1001/jamainternmed.2013.1868.
Whether hearing loss is independently associated with accelerated cognitive decline in older adults is unknown.
We studied 1984 older adults (mean age 77.4 years) enrolled in the HealthABC study, a prospective observational study begun in 1997–98. Our baseline cohort consisted of participants without prevalent cognitive impairment (Modified Mini-Mental State [3MS] scores ≥ 80) who underwent audiometric testing in Year 5. Participants were followed for 6 years. Hearing was defined at baseline using a pure-tone average (PTA) of thresholds at 0.5 – 4 kHz in the better-hearing ear. Cognitive testing was performed in Years 5, 8, 10, and 11 and consisted of the 3MS (measuring global function) and the Digit Symbol Substitution test (DSS, measuring executive function). Incident cognitive impairment was defined as a 3MS score < 80 or a decline in 3MS > 5 points from baseline. Mixed-effects regression and Cox models were adjusted for demographic and cardiovascular risk factors.
Individuals with baseline hearing loss (PTA > 25 dB, n = 1162) had rates of decline in 3MS and DSS scores that were 41% and 32% greater, respectively, than those in normal hearing individuals (3MS: −0.65 points/year [95% CI: −0.73 – −0.56] vs. −0.46 points/year [95% CI: −0.55 – −0.36], p=.004; DSS: −0.83 points/year [95% CI: −0.94 – −0.73] vs. −0.63 points/year [95% CI: −0.75 – −0.51], p=.015). Compared to those with normal hearing, individuals with hearing loss had a 24% (Hazard ratio: 1.24 [95% CI: 1.05 – 1.48]) increased risk of incident cognitive impairment. Rates of cognitive decline and the risk of incident cognitive impairment were linearly associated with the severity of an individual’s baseline hearing loss.
Hearing loss is independently associated with accelerated cognitive decline and incident cognitive impairment in community-dwelling older adults. Further studies investigating the mechanistic basis of this association and whether hearing rehabilitative interventions could affect cognitive decline are needed.
PMCID: PMC3869227  PMID: 23337978
17.  Association of a Modified Physiologic Index With Mortality and Incident Disability: The Health, Aging, and Body Composition Study 
Indexes constructed from components may identify individuals who age well across systems. We studied the associations of a Modified Physiologic Index (systolic blood pressure, forced vital capacity, Digit Symbol Substitution Test score, serum cystatin-C, serum fasting glucose) with mortality and incident disability.
Data are from the Health, Aging, and Body Composition study on 2,737 persons (51.2% women, 40.3% black) aged 70–79 years at baseline and followed on average 9.3 (2.9) years. Components were graded 0 (healthiest), 1 (middle), or 2 (unhealthiest) by tertile or clinical cutpoints and summed to calculate a continuous index score (range 0–10). We used multivariate Cox proportional hazards regression to calculate risk of death or disability and determined accuracy predicting death using the area under the curve.
Mortality was 19% greater per index unit (p < .05). Those with highest index scores (scores 7–10) had 3.53-fold greater mortality than those with lowest scores (scores 0–2). The unadjusted index (c-statistic = 0.656, 95% CI 0.636–0.677, p < .0001) predicted death better than age (c-statistic = 0.591, 95% CI 0.568–0.613, p < .0001; for comparison, p < .0001). The index attenuated the age association with mortality by 33%. A model including age and the index did not predict death better than the index alone (c-statistic = 0.671). Prediction was improved with the addition of other markers of health (c-statistic = 0.710, 95% CI 0.689–0.730). The index was associated with incident disability (adjusted hazard ratio per index unit = 1.04, 95% CI 1.01–1.07).
A simple index of available physiologic measurements was associated with mortality and incident disability and may prove useful for identifying persons who age well across systems.
PMCID: PMC3636673  PMID: 22546961
Aging; Index; Mortality; Disability; Longevity
18.  Genome-wide association analysis identifies TYW3/CRYZ and NDST4 loci associated with circulating resistin levels 
Human Molecular Genetics  2012;21(21):4774-4780.
Resistin is a polypeptide hormone that was reported to be associated with insulin resistance, inflammation and risk of type 2 diabetes and cardiovascular disease. We conducted a genome-wide association (GWA) study on circulating resistin levels in individuals of European ancestry drawn from the two independent studies: the Nurses' Health Study (n = 1590) and the Health, Aging and Body Composition Study (n = 1658). Single-nucleotide polymorphisms (SNPs) identified in the GWA analysis were replicated in an independent cohort of Europeans: the Gargano Family Study (n = 659). We confirmed the association with a previously known locus, the RETN gene (19p13.2), and identified two novel loci near the TYW3/CRYZ gene (1p31) and the NDST4 gene (4q25), associated with resistin levels at a genome-wide significant level, best represented by SNP rs3931020 (P = 6.37 × 10–12) and SNP rs13144478 (P = 6.19 × 10−18), respectively. Gene expression quantitative trait loci analyses showed a significant cis association between the SNP rs3931020 and CRYZ gene expression levels (P = 3.68 × 10−7). We also found that both of these two SNPs were significantly associated with resistin gene (RETN) mRNA levels in white blood cells from 68 subjects with type 2 diabetes (both P = 0.02). In addition, the resistin-rising allele of the TYW3/CRYZ SNP rs3931020, but not the NDST4 SNP rs13144478, showed a consistent association with increased coronary heart disease risk [odds ratio = 1.18 (95% CI, 1.03–1.34); P = 0.01]. Our results suggest that genetic variants in TYW3/CRYZ and NDST4 loci may be involved in the regulation of circulating resistin levels. More studies are needed to verify the associations of the SNP rs13144478 with NDST4 gene expression and resistin-related disease.
PMCID: PMC3471394  PMID: 22843503
19.  Personality and Reduced Incidence of Walking Limitation in Late Life: Findings From the Health, Aging, and Body Composition Study 
To examine the association between openness to experience and conscientiousness and incident reported walking limitation.
The study population consisted of 786 men and women aged 71–81 years (M = 75 years, SD = 2.7) participating in the Health, Aging, and Body Composition—Cognitive Vitality Substudy.
Nearly 20% of participants (155/786) developed walking limitation during 6 years of follow-up. High openness was associated with a reduced risk of walking limitation (hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.69–0.98), independent of sociodemographic factors, health conditions, and conscientiousness. This association was not mediated by lifestyle factors and was not substantially modified by other risk factors for functional disability. Conscientiousness was not associated with risk of walking limitation (HR = 0.91, 95% CI = 0.77–1.07).
Findings suggest that personality dimensions, specifically higher openness to experience, may contribute to functional resilience in late life.
PMCID: PMC3478729  PMID: 22437204
Conscientiousness; Functional limitations; Openness to experience; Personality
20.  Physical Performance and Subsequent Disability and Survival in Older Adults with Malignancy: Results from the Health, Aging and Body Composition Study 
To evaluate objective physical performance measures as predictors of survival and subsequent disability in older patients with cancer.
Longitudinal cohort study.
Health, Aging and Body Composition (Health ABC) Study.
Four hundred twenty-nine individuals diagnosed with cancer during the first 6 years of follow-up of the Health ABC Study.
The associations between precancer measures of physical performance (20-m usual gait speed, 400-m long-distance corridor walk (LDCW), and grip strength) and overall survival and a short-term outcome of 2-year progression to disability or death were evaluated. Cox proportional hazards and logistic regression models, stratified for metastatic disease, respectively, were used for outcomes.
Mean age was 77.2, 36.1% were women, and 45.7% were black. Faster 20-m usual walking speed was associated with a lower risk of death in the metastatic group (hazard ratio = 0.89, 95% confidence interval (CI) = 0.79–0.99) and lower 2-year progression to disability or death in the nonmetastatic group (odds ratio (OR) = 0.77, 95% CI = 0.64–0.94). Ability to complete the 400-m LDCW was associated with lower 2-year progression to disability or death in the nonmetastatic group (OR = 0.24, 95% CI = 0.10–0.62). There were no associations between grip strength and disability or death.
Lower extremity physical performance tests (usual gait speed and 400-m LDCW) were associated with survival and 2-year progression to disability or death. Objective physical performance measures may help inform pretreatment evaluations in older adults with cancer.
PMCID: PMC3760384  PMID: 20122042
physical performance; elderly; cancer; disability; survival
21.  Diabetes, glucose control and 9 year cognitive decline among non-demented older adults 
Archives of neurology  2012;69(9):1170-1175.
While several studies report an association between prevalent diabetes mellitus (DM) and cognitive impairment, less is known about incident DM in late life and cognitive decline. Glycemic control among elders with DM may also be associated with cognitive function, but findings are inconsistent.
To determine if prevalent and incident DM increases risk of cognitive decline, and if, among elders with DM, poor glucose control is related to worse cognitive performance.
Prospective cohort study.
Health Aging and Body Composition Study at two community clinics.
A total of 3,069 elders (mean age 74.2 years; 42% black; 52% female).
Main Outcome Measures
Participants completed the Modified Mini-Mental State Examination (3MS) and Digit Symbol Substitution Test (DSST) at baseline and selected intervals over 10 years. DM status was determined at baseline and during follow-up visits. Glycosylated hemoglobin A1c (HbA1c) was measured at year 1 (baseline), 4, 6, and 10 from fasting whole blood.
At baseline 717 (23.4%) participants had prevalent DM and 2352 (76.6%) were without diabetes, 159 of whom developed incident DM during follow-up. Participants with prevalent DM had lower baseline test scores than participants without DM (3MS: 88.8 vs. 90.9; DSST: 32.5 vs 36.3, respectively; |t|=6.09, p=0.001 for both tests). Results from mixed-effects models showed a similar pattern for 9-year decline (3MS: −6.0 vs. −4.5 point decline; |t|=2.66, p=0.008; DSST: −7.9 vs. −5.7, point decline; |t|=3.69, p=0.001, respectively). Participants with incident DM tended to have baseline and 9-year decline scores between the other two groups but were not statistically different from the group without diabetes. Multivariate adjustment for demographics and medical co-morbidities produced similar results. Among participants with prevalent DM, HbA1c level was associated with lower average mean cognitive scores (3MS p for overall=0.003; DSST p for overall=0.04), even after multivariate adjustment.
Among well-functioning older adults, DM and poor glucose control among those with DM are associated with worse cognitive function and greater decline. This suggests severity of DM may contribute to accelerated cognitive aging.
PMCID: PMC3752423  PMID: 22710333
22.  Data Mining Identifies Digit Symbol Substitution Test Score and Serum Cystatin C as Dominant Predictors of Mortality in Older Men and Women 
Rejuvenation Research  2012;15(4):405-413.
Characterization of long-term health trajectory in older individuals is important for proactive health management. However, the relative prognostic value of information contained in clinical profiles of nonfrail older adults is often unclear.
We screened 825 phenotypic and genetic measures evaluated during the Health, Aging, and Body Composition Study (Health ABC) baseline visit (3,067 men and women aged 70–79). Variables that best predicted mortality over 13 years of follow-up were identified using 10-fold cross-validation.
Mortality was most strongly associated with low Digit Symbol Substitution Test (DSST) score (DSST<25; 21.9% of cohort; hazard ratio [HR]=1.87±0.06) and elevated serum cystatin C (≥1.30 mg/mL; 12.1% of cohort; HR=2.25±0.07). These variables predicted mortality better than 823 other measures, including baseline age and a 45-variable health deficit index. Given elevated cystatin C (≥1.30 mg/mL), mortality risk was further increased by high serum creatinine, high abdominal visceral fat density, and smoking history (2.52≤HR ≤3.73). Given a low DSST score (<25) combined with low-to-moderate cystatin C (<1.30 mg/mL), mortality risk was highest among those with elevated plasma resistin and smoking history (1.90≤HR≤2.02).
DSST score and serum cystatin C warrant priority consideration for the evaluation of mortality risk in older individuals. Both variables, taken individually, predict mortality better than chronological age or a health deficit index in well-functioning older adults (ages 70–79). DSST score and serum cystatin C can thus provide evidence-based tools for geriatric assessment.
PMCID: PMC3419847  PMID: 22607624
23.  Neuroimaging differences between older adults with maintained versus declining cognition over a 10-year period 
NeuroImage  2012;62(1):307-313.
Maintaining cognitive function protects older adults from developing functional decline. This study aims to identify the neuroimaging correlates of maintenance of higher global cognition as measured by the Modified Mini Mental State Test (3MS) score.
Repeated 3MS measures from 1997–98 through 2006–07 and magnetic resonance imaging with diffusion tensor in 2006–07 were obtained in a biracial cohort of 258 adults free from dementia (mean age 82.9 years, 56% women, 42% blacks). Participants were classified as having shown either maintenance (3MS slope>0) or decline (3MS slopeb1 SD below the mean) of cognition using linear mixed models. Measures of interest were white matter hyperintensity volume (WMHv) from total brain, volume of the gray matter (GMv) and microstructure (mean diffusivity, MD) for total brain and for brain areas known to be related to memory and executive control function: medial temporal area (hippocampus, parahippocampus and entorhinal cortex), cingulate cortex, dorsolateral prefrontal and posterior parietal cortex.
Differences between cognitive maintainers (n=153) and non-maintainers (n=107) were significant for GMv of the medial temporal area (35.8%, p=0.004) and lower MD of the cingulate cortex (37.9%, p=0.008), but not for other neuroimaging markers. In multivariable regression models adjusted for age, race, WMHv and GMV from the total brain and vascular conditions, each standard deviation of GMv of the medial temporal area and each standard deviation of MD of the cingulate cortex were associated with a nearly 4 times greater probability (odds ratio [standard deviation]: 3.80 [1.16, 12.44]) and a 34% lower probability (0.66, [0.46, 0.97]) of maintaining cognitive function, respectively. In these models neither WMHv nor GMv from total brain were significantly associated with probability of maintaining cognitive function.
Preserving the volume of the medial temporal area and the microstructure of the cingulate cortex may contribute to maintaining cognitive function late in life.
PMCID: PMC3690545  PMID: 22542701
24.  Changes in Cholesterol-Lowering Medications Use Over a Decade in Community-Dwelling Older Adults 
The Annals of pharmacotherapy  2013;47(0):984-992.
The impact of evidence-based guidelines and controlled trial data on use of cholesterol-lowering medications in older adults is unclear.
To examine whether utilization patterns of cholesterol-lowering medications in community-dwelling older adults changed following the release of the National Cholesterol Education Program Adult Treatment Panel III guidelines and results from the Prospective Study of Pravastatin in the Elderly at Risk in 2002.
Community dwelling elders enrolled in the Health, Aging and Body Composition Study in 1997/1998, and followed for up to 11 years. An interrupted time-series analysis with multivariable generalized estimating equations (GEE) was used to examine level and trend changes in cholesterol-lowering medication use before and after 2002, adjusting for sociodemographic, health-related behaviors and health status.
Cholesterol-lowering medication use increased nearly 3-fold from 14.9% in 1997/1998 to 42.6% in 2007/2008 with statins representing the most common class used (87%–94%). Multivariable GEE results revealed no difference in the level of cholesterol-lowering medication use after 2002 (adjusted odds ratio: 0.95, 95% confidence interval [CI] 0.89–1.02). Multivariable GEE results revealed trends changes in the rate of increase in cholesterol-lowering medication declined after 2002 (adjusted ratio of odds ratios 0.92, 95% CI 0.89–0.95).
The use of cholesterol-lowering medication increased substantially over a decade in community dwelling elders, but was not related to a change in level or trend following the release of the guidelines and evidence-based data.
PMCID: PMC3707940  PMID: 23780807
aged; anticholesteremic agents; hydroxymethylglutaryl-CoA reductase inhibitors; statins; drug utilization
25.  Association of Lower Limb Cutaneous Sensitivity with Gait Speed in the Elderly 
To examine the association of fast-adapting receptor-mediated vibrotactile sensitivity and slow-adapting receptor-mediated pressure sensitivity with self-selected usual gait speed and gait speed over a challenging narrow (20 cm wide) course.
Participants from the population-based older cohort of the Health ABC study were included (n = 1721; age: 76.4 ± 2.8 yrs). Usual gait speed over 6 m and gait speed over a 6-m narrow course were measured. Vibration perception threshold (100 Hz) was measured on the plantar surface, and monofilament testing (1.4 and 10 g) was performed on the dorsum of the great toe. Covariates including knee extensor torque, standing balance, visual acuity and contrast sensitivity, knee pain, depressive symptoms, high fasting glucose levels, and peripheral arterial disease were evaluated.
Vibrotactile and monofilament sensitivity were significantly worse in slower gait speed groups in both walking conditions (P < 0.001 to P = 0.015). Adjusting for covariates, vibrotactile (P < 0.001) but not monofilament sensitivity (P = 0.655) was independently associated with self-selected normal gait speed. Neither sensory function was associated with narrow-base gait speed.
In the elderly, poor lower limb vibrotactile sensitivity measured on the plantar surface of the great toe, but not the pressure sensitivity as measured by monofilament testing on the dorsum of the great toe, is independently associated with slower self-selected normal gait speed. Narrow-based walking seems to depend on other neuromuscular mechanisms.
PMCID: PMC3697864  PMID: 18936557
Aging; Gait Speed; Cutaneous Vibration Sensitivity; Monofilament Sensitivity

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