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1.  At the Tipping Point 
To identify clinical measures that aid detection of impending severe mobility difficulty in older women.
Cross-sectional and longitudinal cohort study.
Urban community in Baltimore, Maryland.
One thousand two community-dwelling, moderate to severely disabled women aged 65 and older in the Women’s Health and Aging Study I.
Self-report and performance measures representing six domains necessary for mobility: central and peripheral nervous systems, muscles, bones and joints, perception, and energy. Severe mobility difficulty was defined as usual gait of 0.5 m/s or less, any reported difficulty walking across a small room, or dependence on a walking aid during a 4-m walking test.
Four hundred sixty-seven out of 984 (47%) had severe mobility difficulty at baseline, and 104/474 (22%) developed it within 12 months. Baseline mobility difficulty was correlated with poor vision, knee pain, feelings of helplessness, inability to stand with feet side by side for 10 seconds, difficulty keeping balance while dressing or walking, inability to rise from a chair five times, and cognitive impairment. Of these, knee pain (odds ratio (OR) = 1.74, 95% confidence interval (CI) = 1.05–2.89), helplessness (OR = 1.87, 95% CI = 1.10–3.24), poor vision (OR = 2.03, 95% CI = 1.06–3.89), inability to rise from a chair five times (OR = 2.50, 95% CI = 1.15–5.41), and cognitive impairment (OR = 4.75, 95% CI = 1.67–13.48) predicted incident severe mobility difficulty within 12 months, independent of age.
Five simple measures may aid identification of disabled older women at high risk of severe mobility difficulty. Further studies should determine generalizability to men and higher-functioning individuals.
PMCID: PMC2775519  PMID: 18808598
aging; mobility difficulty; clinical assessment
3.  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.
4.  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.
5.  Self-Reported Sleep and β-Amyloid Deposition in Community-Dwelling Older Adults 
JAMA neurology  2013;70(12):1537-1543.
Older adults commonly report disturbed sleep, and recent studies in humans and animals suggest links between sleep and Alzheimer disease biomarkers. Studies are needed that evaluate whether sleep variables are associated with neuroimaging evidence of β-amyloid deposition.
To determine the association between self-reported sleep parameters and β-amyloid deposition in community-dwelling older adults.
Baltimore Longitudinal Study of Aging, a prospective study of normative aging
70 adults (mean age = 76; range 53 - 91) in the BLSA neuroimaging study
Main Outcome Measure
β-amyloid burden, measured by [11C] Pittsburgh compound B (PiB) positron emission tomography (PET) distribution volume ratios (DVR)
After adjustment for potential confounders, reports of shorter sleep duration were associated with greater β-amyloid burden, measured by mean cortical DVR (cDVR; B = 0.08, 95% confidence interval (CI) 0.03, 0.14, p = 0.005) and precuneus DVR (B = 0.11, 95% CI 0.03, 0.18, p = 0.007). Reports of lower sleep quality were associated with greater β-amyloid burden measured by precuneus DVR (B = 0.08, 95% CI 0.01, 0.15, p = 0.025).
Among community-dwelling older adults, reports of shorter sleep duration and lower sleep quality are associated with greater β-amyloid burden. Further studies with objective sleep measures are needed to determine whether sleep disturbance causes or accelerates Alzheimer disease.
PMCID: PMC3918480  PMID: 24145859
6.  Prevalence and Correlates of Self-Reported Medication Non-Adherence among Older Adults with Coronary Heart Disease, Diabetes Mellitus, and/or Hypertension 
Research in social & administrative pharmacy : RSAP  2013;9(6):10.1016/j.sapharm.2012.12.002.
Information about the about the prevalence and correlates of self-reported medication nonadherence using multiple measures in older adults with chronic cardiovascular conditions is needed.
To examine the prevalence and correlates of self-reported medication nonadherence among community-dwelling elders with chronic cardiovascular conditions.
Participants (n=897) included members from the Health, Aging and Body Composition study with coronary heart disease, diabetes mellitus, and/or hypertension at year 10. Self-reported nonadherence was measured by the 4-item Morisky Medication Adherence Scale (MMAS-4) and 2-item cost-related nonadherence (CRN-2) scale at year 11. Factors (demographic, health status, and access to care) were examined for association with the MMAS-4 and then for association with the CRN-2 scale.
Nonadherence per the MMAS-4 and CRN-2 scale was reported by 40.7% and 7.7% of participants, respectively, with little overlap (3.7%). Multivariable logistic regression analyses found that black race was significantly associated with nonadherence per the MMAS-4 (p=0.002) and the CRN-2 scale (p=0.005). Other correlates of nonadherence per the MMAS-4 (with independent associations) included having cancer (p=0.04), a history of falls (p=0.02), sleep disturbances (p=0.04) and having a hospitalization in the previous 6 months (p=0.005). Conversely, being unmarried (p=0.049), having worse self-reported health (p=0.04) and needs being poorly met by income (p=0.02) showed significant independent associations with nonadherence per the CRN-2 scale.
Self-reported medication nonadherence was common in older adults with chronic cardiovascular conditions and only one factor – race – was associated with both types. The research implication of this finding is that it highlights the need to measure both types of self-reported nonadherence in older adults. Moreover, the administration of these quick measures in the clinical setting should help identify specific actions such as patient education or greater use of generic medications or pill boxes that may address barriers to medication nonadherence.
PMCID: PMC3620923  PMID: 23291338
medication adherence; chronic disease; aged
7.  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
8.  Unhealthy lifestyles do not mediate the relationship between socioeconomic status and incident depressive symptoms; The Health ABC study 
The relationship between low socioeconomic status (SES) and depressive symptoms is well described, also in older persons. Although studies have found associations between low SES and unhealthy lifestyle factors and between unhealthy lifestyle factors and depressive symptoms, not much is known about unhealthy lifestyles as a potential explanation of socioeconomic differences in depressive symptoms in older persons.
To study the independent pathways between SES (education, income, perceived income, and financial assets), lifestyle factors (smoking, alcohol use, body mass index, and physical activity), and incident depressive symptoms (CES-D 10 and reported use of antidepressant medication), we used 9 years of follow-up data (1997–2007) from 2,694 American black and white participants aged 70–79 from the Health, Aging, and Body Composition (Health ABC) study. At baseline, 12.1% of the study population showed prevalent depressive symptoms, use of antidepressant medication, or treatment of depression in the five years prior to baseline. These persons were excluded from the analyses.
Over a period of 9 years time, 860 participants (31.9%) developed depressive symptoms. Adjusted hazard ratios for incident depressive symptoms were higher in participants from lower SES groups compared to the highest SES group. The strongest relationships were found for black men. Although unhealthy lifestyle factors were consistently associated with low SES, they were weakly related to incident depressive symptoms. Lifestyle factors did not significantly reduce hazard ratios for depressive symptoms by SES.
In generally healthy persons aged 70–79 years lifestyle factors do not explain the relationship between SES and depressive symptoms. (250)
PMCID: PMC3402597  PMID: 23567402
Health ABC study; Socioeconomic status; Lifestyle factors; Depressive symptoms; Elderly; United States
9.  Association Between Hypoglycemia and Dementia in a Biracial Cohort of Older Adults With Diabetes Mellitus 
JAMA internal medicine  2013;173(14):1300-1306.
Hypoglycemia commonly occurs in patients with diabetes mellitus (DM) and may negatively influence cognitive performance. Cognitive impairment in turn can compromise DM management and lead to hypoglycemia.
To prospectively evaluate the association between hypoglycemia and dementia in a biracial cohort of older adults with DM.
Prospective population-based study.
We studied 783 older adults with DM (mean age, 74.0 years; 47.0% of black race/ethnicity; and 47.6% female) who were participating in the prospective population-based Health, Aging, and Body Composition Study beginning in 1997 and who had baseline Modified Mini-Mental State Examination scores of 80 or higher.
Dementia diagnosis was determined during the follow-up period from hospital records indicating an admission associated with dementia or the use of prescribed dementia medications. Hypoglycemic events were determined during the follow-up period by hospital records.
During the 12-year follow-up period, 61 participants (7.8%) had a reported hypoglycemic event, and 148 (18.9%) developed dementia. Those who experienced a hypoglycemic event had a 2-fold increased risk for developing dementia compared with those who did not have a hypoglycemic event (34.4% vs 17.6%, P < .001; multivariate-adjusted hazard ratio, 2.1; 95% CI, 1.0–4.4). Similarly, older adults with DM who developed dementia had a greater risk for having a subsequent hypoglycemic event compared with participants who did not develop dementia (14.2% vs 6.3%, P < .001; multivariate-adjusted hazard ratio, 3.1; 95% CI, 1.5–6.6). Further adjustment for stroke, hypertension, myocardial infarction, and cognitive change scores produced similar results.
Among older adults with DM, there seems to be a bidirectional association between hypoglycemia and dementia.
PMCID: PMC4041621  PMID: 23753199
10.  The Role of Metabolic Syndrome, Adiposity, and Inflammation in Physical Performance in the Health ABC Study 
Metabolic syndrome (MetS) and functional limitation have been linked, but whether and how specific components of MetS and associated factors, such as inflammation, drive this relationship is unknown.
Data are from 2,822 men and women, aged 70–79 years, participating in the Health, Aging, and Body Composition (Health ABC) study and followed for 5 years. Presence of MetS at baseline was defined according to the National Cholesterol Education Program Adult Treatment Panel III guidelines. Interleukin-6, C-reactive protein, and body fat mass were measured at baseline. Measures of physical performance, including 400-m walk time, 20-m walking speed, and the Health ABC physical performance battery (PPB) were obtained at baseline and examination years 2, 4, and 6.
A total of 1,036 (37%) individuals met criteria for MetS. MetS was associated with poorer physical performance at baseline. Effect estimates between MetS and gait speed, and components of the Health ABC PPB (standing balance and repeated sit-to-stand performance) were modestly attenuated after adjustment for inflammation. All associations were attenuated to nonsignificance after adding total body fat mass to the model. Longitudinal analyses yielded similar results. Individual MetS component analysis revealed that abdominal obesity explained the largest fraction of the variation in physical performance.
Although inflammatory biomarkers partially accounted for the relationship between MetS and aspects of physical performance, overall findings implicate adiposity as the primary factor explaining poorer physical performance in older adults with MetS.
PMCID: PMC3623483  PMID: 23109678
Metabolic syndrome; Physical function; Inflammation; Obesity.
11.  Hearing Loss and Gait Speed Among Older Adults in the United States 
Gait & posture  2012;38(1):10.1016/j.gaitpost.2012.10.006.
Previous studies have suggested that hearing loss, which is highly prevalent but undertreated in older adults, may be associated with gait and physical functioning. Determining if hearing loss is independently associated with gait speed is critical toward understanding whether hearing rehabilitative interventions could help mitigate declines in physical functioning in older adults.
We analyzed cross-sectional data from the 1999–2002 cycles of the National Health and Nutritional Examination Survey during which participants 50–69 years (n = 1180) underwent hearing and gait speed assessments. Hearing was defined by a pure tone average of hearing thresholds at 0.5–4 kHz tones in the better-hearing ear. Gait speed was obtained in a timed 20-foot (6.1 meter) walk. Linear and logistic regression models were used to examine the association between hearing loss and gait speed while adjusting for demographic and cardiovascular risk factors. Analyses incorporated sampling weights to yield results generalizable to the U.S. population.
In a model adjusted for demographic and cardiovascular risk factors, a 25 dB hearing loss was associated with slower gait speed (−0.05 m/s per 25 dB HL [95% CI: −0.09 – −0.02]) and a nearly two-fold increased odds of having a gait speed < 1.0 m/s (OR 2.0, 95% CI: 1.2 –3.3). The reduction in gait speed associated with a 25 dB hearing loss was equivalent to that associated with an age difference of nearly 12 years.
Greater hearing loss is independently associated with slower gait speed. Further studies investigating the mechanistic basis of this association and whether hearing rehabilitative interventions could affect gait and physical functioning are needed.
PMCID: PMC3845825  PMID: 23177614
12.  Trajectories of Gait Speed Predict Mortality in Well-Functioning Older Adults: The Health, Aging and Body Composition Study 
Although gait speed slows with age, the rate of slowing varies greatly. To date, little is known about the trajectories of gait speed, their correlates, and their risk for mortality in older adults.
Gait speed during a 20-m walk was measured for a period of 8 years in initially well-functioning men and women aged 70–79 years participating in the Health, Aging and Body Composition study. We described the trajectories of gait speed and examined their correlates using a group-based mixture model. Also risk associated with different gait speed trajectories on all-cause mortality was estimated using a Cox-proportional hazard model.
Of 2,364 participants (mean age, 73.5±2.9 years; 52% women), we identified three gait speed trajectories: slow (n = 637), moderate (n = 1,209), and fast decline (n = 518). Those with fast decline slowed 0.030 m/s per year or 2.4% per year from baseline to the last follow-up visit. Women, blacks, and participants who were obese, had limited knee extensor strength, and had low physical activity were more likely to have fast decline than their counterparts. Participants with fast decline in gait speed had a 90% greater risk of mortality than those with slow decline.
Despite being well-functioning at baseline, a quarter of older adults experienced fast decline in gait speed, which was associated with an increased risk of mortality.
PMCID: PMC3593620  PMID: 23051974
Gait speed; Older adults; Mortality.
13.  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
14.  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
Archives of internal medicine  2011;171(14):1251-1257.
Studies suggest that physically active people have reduced risk of incident cognitive impairment in late life. However, these studies are limited by reliance on subjective self-reports of physical activity, which only moderately correlate to objective measures and often exclude activity not readily quantifiable by frequency and duration. The objective of this study was to investigate the relationship between activity energy expenditure (AEE), an objective measure of total activity, and incidence of cognitive impairment.
We calculated AEE as 90% of total energy expenditure (assessed over two weeks using doubly-labeled water) minus resting metabolic rate (measured using indirect calorimetry) in 197 men and women (mean 74.8 years) who were free of mobility and cognitive impairments at study baseline (1998–2000). Cognitive function was assessed at baseline and 2 or 5 years later using the Modified Mini-Mental State Examination (3MS). Cognitive impairment was defined as a decline of >1.0 SD (9 points) between baseline and follow-up.
After adjustment for baseline 3MS, demographics, fat free mass, sleep duration, self-reported health, and diabetes, older adults in the highest sex-specific tertile of AEE had lower odds of incident cognitive impairment than those in the lowest tertile (OR, 95% CI 0.09, 0.01–0.79). There was also a significant dose response between AEE and incidence of cognitive impairment (p-for-trend over tertiles=0.05).
These findings indicate that greater activity energy expenditure may be protective against cognitive impairment in a dose-response manner. The significance of overall activity in contrast to vigorous or light activity should be determined.
PMCID: PMC3923462  PMID: 21771893
16.  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
17.  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
18.  A variant of sparse partial least squares for variable selection and data exploration 
When data are sparse and/or predictors multicollinear, current implementation of sparse partial least squares (SPLS) does not give estimates for non-selected predictors nor provide a measure of inference. In response, an approach termed “all-possible” SPLS is proposed, which fits a SPLS model for all tuning parameter values across a set grid. Noted is the percentage of time a given predictor is chosen, as well as the average non-zero parameter estimate. Using a “large” number of multicollinear predictors, simulation confirmed variables not associated with the outcome were least likely to be chosen as sparsity increased across the grid of tuning parameters, while the opposite was true for those strongly associated. Lastly, variables with a weak association were chosen more often than those with no association, but less often than those with a strong relationship to the outcome. Similarly, predictors most strongly related to the outcome had the largest average parameter estimate magnitude, followed by those with a weak relationship, followed by those with no relationship. Across two independent studies regarding the relationship between volumetric MRI measures and a cognitive test score, this method confirmed a priori hypotheses about which brain regions would be selected most often and have the largest average parameter estimates. In conclusion, the percentage of time a predictor is chosen is a useful measure for ordering the strength of the relationship between the independent and dependent variables, serving as a form of inference. The average parameter estimates give further insight regarding the direction and strength of association. As a result, all-possible SPLS gives more information than the dichotomous output of traditional SPLS, making it useful when undertaking data exploration and hypothesis generation for a large number of potential predictors.
PMCID: PMC3939647  PMID: 24624079
high-dimensional; multicollinearity; over-fitting; SPLS; inference; tuning parameters; network; MRI
19.  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
20.  Antihypertensive Drug Class Use and Differential Risk of Urinary Incontinence in Community-Dwelling Older Women 
Medication use is a potentially reversible cause of urinary incontinence (UI). The objective of this longitudinal cohort study was to evaluate whether self-reported UI in community-dwelling older women is associated with the use of different classes of antihypertensive agents.
The sample consisted of 959 black and white women aged 72–81 years without baseline (Year 1) UI from the Health, Aging, and Body Composition Study. Use of any antihypertensive from 10 drug classes (ie, alpha blockers [central], alpha blockers [peripheral], angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, beta blockers, calcium channel blockers, diuretics [loop], diuretics [potassium-sparing], diuretics [thiazide], and vasodilators) was determined during Year 3 in-person interviews. The number of unique antihypertensive agents used and the standardized daily dosage were also examined. Self-reported UI, operationally defined as leaking urine at least weekly during the previous 12 months, was assessed at Year 4 visits.
A total of 197 women (20.5%) reported UI at Year 4. Although any antihypertensive use, number of agents used, and standardized daily dosage at Year 3 were not associated with UI at Year 4, use of one particular drug class—peripheral alpha blockers (ie, doxazosin, prazosin, and terazosin)—was associated with fourfold greater odds of UI (adjusted odds ratio = 4.47; 95% confidence interval = 1.79–11.21; p = .0014). Further, in post hoc analyses, these odds nearly doubled in those also taking loop diuretics (adjusted odds ratio = 8.81; 95% confidence interval = 1.78–43.53; p = .0076).
In community-dwelling older women, peripheral alpha blocker use was associated with UI, and the odds nearly doubled when used with loop diuretics.
PMCID: PMC3636671  PMID: 22972942
21.  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
22.  25-Hydroxyvitamin D Status and Change in Physical Performance and Strength in Older Adults 
American Journal of Epidemiology  2012;176(11):1025-1034.
Low 25-hydroxyvitamin D (25(OH)D) concentrations are common among older adults and are associated with poorer physical performance and strength, but results from longitudinal studies have been inconsistent. The 25(OH)D threshold for physical performance and strength was determined, and both cross-sectional and longitudinal associations between 25(OH)D and physical performance and strength were examined, in men and women aged 71–80 years from the Health, Aging, and Body Composition Study (n = 2,641). Baseline serum 25(OH)D was measured in 1998–1999, and physical performance and strength were measured at baseline and at 2- and 4-year follow-up. Piecewise regression models were used to determine 25(OH)D thresholds. Linear regression and mixed models were used to examine cross-sectional and longitudinal associations. The 25(OH)D thresholds were 70–80 nmol/L for physical performance and 55–70 nmol/L for strength. Participants with 25(OH)D <50 nmol/L had poorer physical performance at baseline and at 2- and 4-year follow-up than participants with 25(OH)D ≥75 nmol/L (P < 0.01). Although physical performance and strength declined over 4 years of follow-up (P < 0.0001), in general, the rate of decline was not associated with baseline 25(OH)D. Older adults with low 25(OH)D concentrations had poorer physical performance over 4 years of follow-up, but low 25(OH)D concentrations were not associated with a faster rate of decline in physical performance or strength.
PMCID: PMC3571245  PMID: 23118104
aged; 25-hydroxyvitamin D; muscle strength; physical performance
23.  Associations of Openness and Conscientiousness With Walking Speed Decline: Findings From the Health, Aging, and Body Composition Study 
The objective of this study was to explore the associations between openness to experience and conscientiousness, two dimensions of the five-factor model of personality, and usual gait speed and gait speed decline.
Baseline analyses were conducted on 907 men and women aged 71–82 years participating in the Cognitive Vitality substudy of the Health, Aging, and Body Composition study. The longitudinal analytic sample consisted of 740 participants who had walking speed assessed 3 years later.
At baseline, gait speed averaged 1.2 m/s, and an average decline of 5% over the 3-year follow-up period was observed. Higher conscientiousness was associated with faster initial walking speed and less decline in walking speed over the study period, independent of sociodemographic characteristics. Lifestyle factors and disease status appear to play a role in the baseline but not the longitudinal association between conscientiousness and gait speed. Openness was not associated with either initial or decline in gait speed.
These findings extend the body of evidence suggesting a protective association between conscientiousness and physical function to performance-based assessment of gait speed. Future studies are needed to confirm these associations and to explore mechanisms that underlie the conscientiousness mobility connection in aging adults.
PMCID: PMC3478724  PMID: 22451484
Chronic conditions; Conscientiousness; Lifestyle factors; Openness to experience; Walking speed
24.  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
25.  Racial Differences in Antilipemic Use and Lipid Control in High Risk Older Adults Post Medicare Part D 
American heart journal  2013;166(4):792-797.
Older blacks are less likely to receive guideline-recommended antilipemic therapy and achieve lipid control than older whites due in part to out-of-pocket costs. We sought to determine whether racial differences in antilipemic use and lipid control narrowed after Medicare Part D’s implementation.
This before-after study included 1091 black and white adults age >70 with coronary heart disease and/or diabetes mellitus from the Health Aging and Body Composition Study. Primary outcomes were antilipemic use and LDL-C control. Key independent variables were race, time (pre- vs. post-Part D), and their interaction.
Before Part D, fewer blacks than whites reported taking an antilipemic (32.70% vs 49.35%) and this difference was sustained after Part D (blacks 48.30% vs whites 64.57%). Multivariable generalized estimating equations confirmed no post Part D change in racial differences in antilipemic use (adjusted ratio of the odds ratios [AROR] 1.07, 95% CI 0.79–1.45). Compared to whites, more blacks had poor lipid control both before Part D (24.30% vs 12.36% respectively) and after Part D (24.46% vs 13.72% respectively), with no post Part D change in racial differences in lipid control (AROR 0.82, 95% CI 0.51–1.33).
While antilipemic use increased after Medicare Part D for both races, this policy change was associated neither with a change in lipid control for either racial group nor in the racial differences in antilipemic use or lipid control.
PMCID: PMC3801224  PMID: 24093862

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