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2.  Cardiovascular risks and brain function: a functional magnetic resonance imaging study of executive function in older adults 
Neurobiology of aging  2013;35(6):1396-1403.
Cardiovascular (CV) risk factors, such as hypertension, diabetes, and hyperlipidemia are associated with cognitive impairment and risk of dementia in older adults. However, the mechanisms linking them are not clear. This study aims to investigate the association between aggregate CV risk, assessed by the Framingham general cardiovascular risk profile, and functional brain activation in a group of community-dwelling older adults. Sixty participants (mean age: 64.6 years) from the Brain Health Study, a nested study of the Baltimore Experience Corps Trial, underwent functional magnetic resonance imaging using the Flanker task. We found that participants with higher CV risk had greater task-related activation in the left inferior parietal region, and this increased activation was associated with poorer task performance. Our results provide insights into the neural systems underlying the relationship between CV risk and executive function. Increased activation of the inferior parietal region may offer a pathway through which CV risk increases risk for cognitive impairment.
doi:10.1016/j.neurobiolaging.2013.12.008
PMCID: PMC4282177  PMID: 24439485
Cardiovascular risk; Framingham risk score; fMRI; Brain function; Executive function; Older adults
3.  Low-Intensity Walking Activity is Associated with Better Health 
Recommended levels of physical activity may represent challenging targets for many older adults at risk for disability, leading to the importance of evaluating whether low-intensity activity is associated with health benefits. We examined the cross-sectional association between low-intensity walking activity (<100 steps/minute) and health and physical function in a group of older adults. Participants (n=187; age: 66.8; 91.4% African-American; 76.5% female) wore a StepWatch Activity Monitor to measure components of low-intensity walking activity. Only 7% of participants met physical activity guidelines and moderate-intensity activity (≥100 steps/min) contributed only 10% of total steps/day and two percent of total minutes/day. Greater amount, frequency, and duration of low-intensity activity were associated with better self-report and performance-based measures of physical function, better quality of life, and fewer depressive symptoms (ps<0.05). The cross-sectional relationship between low-intensity activity and health outcomes important to independent function suggest that we further explore the longitudinal benefits of low-intensity activity.
doi:10.1177/0733464813512896
PMCID: PMC4053519  PMID: 24652915
mobility; physical activity; African Americans; low-intensity activity; walking
4.  Hyperglycemia is Associated with the Incidence of Frailty and Lower Extremity Mobility Limitations in Older Women 
Objectives
To determine the degree to which hyperglycemia predicts the development of frailty and/or lower extremity mobility limitations.
Design
Secondary data analysis of longitudinal data collected in a prospective cohort study.
Setting
Baltimore, Maryland
Participants
We examined 329 women from the Women’s Health and Aging Studies II aged 70–79 years at baseline who had all variables needed for analysis.
Methods
Hemoglobin A1c [HbA1c] at baseline was the independent variable and categorized as: <5.5%, 5.5 to 5.9%, 6.0–6.4%, 6.5–7.9%, ≥8%. The incidence of frailty and lower extremity mobility limitations (based on self-reported walking difficulty, walking speed, and short performance physical battery [SPPB] score) was determined (follow-up≈9 years). Frailty was assessed using the Cardiovascular Health Study criteria. Covariates included demographics, body mass index, interleukin-6, and clinical history of comorbidities. Statistical analyses included Kaplan-Meier survival curves and Cox regression models adjusting for key covariates.
Results
In time-to-event analyses, HbA1c category was associated with incidence of walking difficulty (p=0.049) and low physical performance (p=0.001); association with incidence of frailty and low walking speed had a trend towards significance (both p=0.10). In demographics-adjusted regression models, HbA1c≥8% (versus<5.5%) was associated with an approximately three-times increased risk of incident frailty and three-to-five times increased risk of lower extremity mobility limitations (all p<0.05). In fully adjusted models, HbA1c≥8% (versus<5.5%) was associated with incident frailty (hazard ratio[HR]=3.33, 95% confidence interval=1.24–8.93), walking difficulty (HR=3.47,1.26–9.55), low walking speed (HR=2.82,1.19–6.71), and low physical performance (HR=3.60,1.52–8.53).
Conclusions
Hyperglycemia is associated with the development of frailty and lower extremity mobility limitations in older women; future studies should identify mediators of these relationships.
doi:10.1111/j.1532-5415.2012.04099.x
PMCID: PMC4144067  PMID: 22882211
Hyperglycemia; Elderly; Frailty; Mobility; Disability
5.  Is hyperglycemia associated with frailty status in older women? 
OBJECTIVES
To determine whether hyperglycemia is related to prevalent frailty status in older women.
DESIGN
Secondary data analysis of baseline data of a prospective cohort study.
SETTING
Baltimore, Maryland.
PARTICIPANTS
Five hundred forty-three women aged 70 to 79.
METHODS
Research used baseline data from 543 participants in the Women’s Health and Aging Studies I and II aged 70 to 79 who had all variables needed for analyses. The dependent variable was baseline frailty status (not frail, prefrail, frail), measured using an empirically derived model defining frailty according to weight loss, slow walking speed, weakness, exhaustion, and low activity (1–2 characteristics Present = prefrail, ≥3 = frail). Covariates included body mass index (BMI), interleukin-6 (IL-6), age, race, and several chronic diseases. Analyses included descriptive methods and multinomial logistic regression to adjust for key covariates.
RESULTS
A hemoglobin A1c (HbA1c) level of 6.5% or greater in older women was significantly associated with higher likelihood of prefrail and frail status (normal HbA1c <6.0% was reference). The association between HbA1C levels of 6.0% to 6.5% and frailty status was not different from that of normal HbA1c, but HbA1c levels of 6.5% to 6.9% had nearly twice the likelihood of frailty (odds ratio (OR) = 1.96, 95% confidence interval (CI) = 1.47–2.59) as normal HbA1c. A HbA1c level of 9.0% or greater was also strongly associated (OR = 2.57, 95% CI = 1.99,3.32). Significant associations were also seen between baseline prefrail and frail status and low (18.5–20.0 kg/m2) and high (.30.0 kg/m2) body mass index (BMI), interleukin-6, and all chronic diseases evaluated, but controlling for these covariates only minimally attenuated the independent association between HbA1c and frailty status.
CONCLUSION
Hyperglycemia is associated with greater prevalence of prefrail and frail status; BMI, inflammation, and comorbidities do not explain the association. Longitudinal research and study of alternative pathways are needed.
PMCID: PMC4120964  PMID: 19484839
hyperglycemia; frailty; older women
6.  Experience Corps: A dual trial to promote the health of older adults and children's academic success 
Contemporary clinical trials  2013;36(1):1-13.
Background
As the population ages, older adults are seeking meaningful, and impactful, post-retirement roles. As a society, improving the health of people throughout longer lives is a major public health goal. This paper presents the design and rationale for an effectiveness trial of Experience Corps™, an intervention created to address both these needs. This trial evaluates (1) whether senior volunteer roles within Experience Corps™ beneficially impact children's academic achievement and classroom behavior in public elementary schools and (2) impact on the health of volunteers.
Methods
Dual evaluations of (1) an intention-to-treat trial randomizing eligible adults 60 and older to volunteer service in Experience Corps™, or to a control arm of usual volunteering opportunities, and (2) a comparison of eligible public elementary schools receiving Experience Corps™ to matched, eligible control schools in a 1:1 control:intervention school ratio.
Outcomes
For older adults, the primary outcome is decreased disability in mobility and Instrumental Activities of Daily Living (IADL). Secondary outcomes are decreased frailty, falls, and memory loss; slowed loss of strength, balance, walking speed, cortical plasticity, and executive function; objective performance of IADLs; and increased social and psychological engagement. For children, primary outcomes are improved reading achievement and classroom behavior in Kindergarten through the 3rd grade; secondary outcomes are improvements in school climate, teacher morale and retention, and teacher perceptions of older adults.
Summary
This trial incorporates principles and practices of community-based participatory research and evaluates the dual benefit of a single intervention, versus usual opportunities, for two generations: older adults and children.
doi:10.1016/j.cct.2013.05.003
PMCID: PMC4112377  PMID: 23680986
Healthy aging; Health promotion; Senior service; Children's academic success; Intergenerational programs; Community-based participatory research
7.  Frailty Consensus: A Call to Action 
Frailty is a clinical state in which there is an increase in an individual’s vulnerability for developing increased dependency and/or mortality when exposed to a stressor. Frailty can occur as the result of a range of diseases and medical conditions. A consensus group consisting of delegates from 6 major international, European, and US societies created 4 major consensus points on a specific form of frailty: physical frailty. Physical frailty is an important medical syndrome. The group defined physical frailty as “a medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and reduced physiologic function that increases an individual’s vulnerability for developing increased dependency and/or death.”Physical frailty can potentially be prevented or treated with specific modalities, such as exercise, protein-calorie supplementation, vitamin D, and reduction of polypharmacy.Simple, rapid screening tests have been developed and validated, such as the simple FRAIL scale, to allow physicians to objectively recognize frail persons.For the purposes of optimally managing individuals with physical frailty, all persons older than 70 years and all individuals with significant weight loss (≥5%) due to chronic disease should be screened for frailty.
doi:10.1016/j.jamda.2013.03.022
PMCID: PMC4084863  PMID: 23764209
Frailty; physical frailty; rapid screening tests; weight loss; comorbidities
8.  Association Between Combined Interleukin-6 and C-Reactive Protein Levels and Pulmonary Function in Older Women: Results from the Women’s Health and Aging Studies I and II 
OBJECTIVES
To determine whether combined higher interleukin-6 (IL-6) and C-reactive protein (CRP) levels are associated with lower pulmonary function levels in older women, accounting for chronic inflammatory diseases, physical function, and other factors associated with inflammation.
DESIGN
Cross-sectional study using data from two prospective cohorts.
SETTING
Baltimore, Maryland.
PARTICIPANTS
Eight hundred forty disabled and 332 higher-functioning community-dwelling women aged 65 and older from the Women’s Health and Aging Studies (WHAS) I and II, respectively.
MEASUREMENTS
IL-6 and CRP, combined according to their tertile concentrations, and pulmonary function measures, assessed according to forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC).
RESULTS
In WHAS I and II, similar dose-response trends were observed between combined higher IL-6 and CRP levels and lower pulmonary function levels. In WHAS I (disabled women), the combined highest IL-6 and CRP levels were associated with the lowest levels of FEV1 (mean 137.0 mL, 95% confidence interval (CI) = 128.4–145.7 mL) and FVC (mean 191.7 mL, 95% CI = 180.4–202.9 mL). Similarly, in WHAS II (higher-functioning women), the combined highest IL-6 and CRP levels were associated with the lowest levels of FEV1 (mean 158.3 mL, 95% CI = 146.3–170.4 mL) and FVC (mean 224.2 mL, 95% CI = 209.9–238.5 mL).
CONCLUSION
Combined elevations in IL-6 and CRP were associated with the lowest pulmonary function levels in older women. These findings suggest that high IL-6 and CRP levels may be an indication of prevalent impaired pulmonary function. Future studies should determine whether measurement of IL-6 and CRP could enhance current methods of monitoring respiratory diseases beyond that provided by pulmonary function measures.
doi:10.1111/j.1532-5415.2010.03203.x
PMCID: PMC4050638  PMID: 21226682
pulmonary function; inflammation; older women
9.  A novel statistical approach shows evidence for multi-system physiological dysregulation during aging 
Previous studies have identified many biomarkers that are associated with aging and related outcomes, but the relevance of these markers for underlying processes and their relationship to hypothesized systemic dysregulation is not clear. We address this gap by presenting a novel method for measuring dysregulation via the joint distribution of multiple biomarkers and assessing associations of dysregulation with age and mortality. Using longitudinal data from the Women's Health and Aging Study, we selected a 14-marker subset from 63 blood measures: those that diverged from the baseline population mean with age. For the 14 markers and all combinatorial sub-subsets we calculated a multivariate distance called the Mahalanobis distance (MHBD)2 for all observations, indicating how “strange” each individual's biomarker profile was relative to the baseline population mean. In most models, MHBD correlated positively with age, MHBD increased within individuals over time, and higher MHBD predicted higher risk of subsequent mortality. Predictive power increased as more variables were incorporated into the calculation of MHBD. Biomarkers from multiple systems were implicated. These results support hypotheses of simultaneous dysregulation in multiple systems and confirm the need for longitudinal, multivariate approaches to understanding biomarkers in aging.
doi:10.1016/j.mad.2013.01.004
PMCID: PMC3971434  PMID: 23376244
Dysregulation; biomarker; multivariate; aging; physiology
10.  Heterogeneity in Rate of Decline in Grip, Hip, and Knee Strength and the Risk of All-Cause Mortality: The Women’s Health and Aging Study II 
OBJECTIVES
To assess the relationship between rate of change in muscle strength and all-cause mortality.
DESIGN
A prospective observational study of the causes and course of physical disability.
SETTING
Twelve contiguous ZIP code areas in Baltimore, Maryland.
PARTICIPANTS
Three hundred and seven community-dwelling women aged 70–79 years at study baseline.
MEASUREMENTS
The outcome is all-cause mortality (1994–2009); predictors include up to seven repeated measurements of handgrip, knee extension, and hip flexion strength, with a median follow-up time of 9 years. Demographic factors, body mass index, smoking status, number of chronic diseases, depressive symptoms, physical activity, Interlukin-6, and albumin were assessed at baseline and included as confounders. The associations between declining muscle strength and mortality were assessed using a joint longitudinal and survival model..
RESULTS
Grip and hip strength declined an average of 1.10 and 1.31 kg per year between age 70 and 75and 0.50 and 0.39 kg/year thereafter, respectively; knee strength declined at a constant rate of 0.57 kg/year. Faster rates of decline in grip and hip strength, but not knee strength, independently predicted of mortality after accounting for their baseline levels and potential confounders (Hazard Ratio (HR)=1.33 (95% confidence interval (CI)=1.06–1.67), 1.14 (CI=0.91–1.41), and 2.62 (CI=1.43–4.78) for every 0.5 standard deviation increase in rate of decline in grip, knee, and hip strength, respectively.
CONCLUSION
Monitoring the rate of decline in grip and hip flexion strength in addition to the absolute levels may greatly improve the identification of women most at risk of dying.
doi:10.1111/j.1532-5415.2010.03154.x
PMCID: PMC3058914  PMID: 21054287
handgrip strength; hip strength; knee strength; mortality; older women
11.  Marketing Public Health Through Older Adult Volunteering: Experience Corps as a Social Marketing Intervention 
American journal of public health  2010;100(4):727-734.
Objectives
We present a social marketing conceptual framework for Experience Corps Baltimore City (EC) in which the desired health outcome is not the promoted product or behavior. We also demonstrate the feasibility of a social marketing–based recruitment campaign for the first year of the Baltimore Experience Corps Trial (BECT), a randomized, controlled trial of the health benefits of EC participation for older adults.
Methods
We recruited older adults from the Baltimore, MD, area. Participants randomized to the intervention were placed in public schools in volunteer roles designed to increase healthy behaviors. We examined the effectiveness of a recruitment message that appealed to generativity (i.e., to make a difference for the next generation), rather than potential health benefits.
Results
Among the 155 participants recruited in the first year of the BECT, the average age was 69 years; 87% were women and 85% were African American. Participants reported primarily generative motives as their reason for interest in the BECT.
Conclusions
Public health interventions embedded in civic engagement have the potential to engage older adults who might not respond to a direct appeal to improve their health.
doi:10.2105/AJPH.2009.169151
PMCID: PMC2836353  PMID: 20167888
12.  Searching for an Operational Definition of Frailty: A Delphi Method Based Consensus Statement. The Frailty Operative Definition-Consensus Conference Project 
Background.
There is no consensus regarding the definition of frailty for clinical uses.
Methods.
A modified Delphi process was used to attempt to achieve consensus definition. Experts were selected from different fields and organized into five Focus Groups. A questionnaire was developed and sent to experts in the area of frailty. Responses and comments were analyzed using a pre-established strategy. Statements with an agreement more than or equal to 80% were accepted.
Results.
Overall, 44% of the statements regarding the concept of frailty and 18% of the statements regarding diagnostic criteria were accepted. There was consensus on the value of screening for frailty and about the identification of six domains of frailty for inclusion in a clinical definition, but no agreement was reached concerning a specific set of clinical/laboratory biomarkers useful for diagnosis.
Conclusions.
There is agreement on the usefulness of defining frailty in clinical settings as well as on its main dimensions. However, additional research is needed before an operative definition of frailty can be established.
doi:10.1093/gerona/gls119
PMCID: PMC3598366  PMID: 22511289
Frailty; Consensus definition; Older people; Biomarkers
13.  Frailty Status and Altered Glucose-Insulin Dynamics 
Background.
We examined women in their 80s and 90s and evaluated the hypothesis that abnormalities in the dynamic response of glucose and insulin to a glucose load are associated with frailty status.
Methods.
We performed a 75 g oral glucose tolerance test in 73 community-dwelling women aged 84–95 years without known diabetes enrolled in the Women’s Health and Aging Study II. We examined the association of frailty status (nonfrail, prefrail, or frail) with oral glucose tolerance test glucose and insulin levels at 0, 30, 60, 120, and 180 minutes using multiple linear regression models.
Results.
Using American Diabetes Association criteria, only 27% of older women had normal glucose status, 48% had prediabetes, and 25% had undiagnosed diabetes. Fasting glucose, fasting insulin, homeostasis model of assessment-insulin resistance, and Matsuda index were similar by frailty status, adjusting for age and body mass index. Conversely, mean oral glucose tolerance test glucose levels were higher at 60 minutes (44.6 ± 18.1 mg/dL higher) and 120 minutes (67.1 ± 23.5 mg/dL higher) and to a lesser extent at 180 minutes (44.3 ± 22.5 mg/dL higher) in frail versus nonfrail women as was integrated glucose area after adjustment. Mean 120-minute insulin level was also higher in frail versus nonfrail women (45.7 ± 22.4 μU/mL higher). Overall, glucose and insulin responses were more exaggerated and prolonged in frail versus nonfrail or prefrail women.
Conclusions.
Our data demonstrate dysregulation in response to glucose challenge as a component of physiologic vulnerability associated with frailty in old–old women. Future studies should examine the timing of abnormal glucose–insulin dynamics with respect to the pathogenesis of frailty.
doi:10.1093/gerona/glr141
PMCID: PMC3670159  PMID: 21873592
Glucose; Insulin; Dynamics; Elderly; Frailty
14.  Nonlinear Multisystem Physiological Dysregulation Associated With Frailty in Older Women: Implications for Etiology and Treatment 
Background
Frailty in older adults, defined as a constellation of signs and symptoms, is associated with abnormal levels in individual physiological systems. We tested the hypothesis that it is the critical mass of physiological systems abnormal that is associated with frailty, over and above the status of each individual system, and that the relationship is nonlinear.
Methods
Using data on women aged 70–79 years from the Women’s Health and Aging Studies I and II, multiple analytic approaches assessed the cross-sectional association of frailty with eight physiological measures.
Results
Abnormality in each system (anemia, inflammation, insulin-like growth factor-1, dehydroepiandrosterone-sulfate, hemoglobin A1c, micronutrients, adiposity, and fine motor speed) was significantly associated with frailty status. However, adjusting for the level of each system measure, the mean number of systems impaired significantly and nonlinearly predicted frailty. Those with three or more systems impaired were most likely to be frail, with odds of frailty increasing with number of systems at abnormal level, from odds ratios (ORs) of 4.8 to 11 to 26 for those with one to two, three to four, and five or more systems abnormal (p < .05 for all). Finally, two subgroups were identified, one with isolated or no systems abnormal and a second (in 30%) with multiple systems abnormal. The latter group was independently associated with being frail (OR = 2.6, p < .05), adjusting for confounders and chronic diseases and then controlling for individual systems.
Conclusions
Overall, these findings indicate that the likelihood of frailty increases nonlinearly in relationship to the number of physiological systems abnormal, and the number of abnormal systems is more predictive than the individual abnormal system. These findings support theories that aggregate loss of complexity, with aging, in physiological systems is an important cause of frailty. Implications are that a threshold loss of complexity, as indicated by number of systems abnormal, may undermine homeostatic adaptive capacity, leading to the development of frailty and its associated risk for subsequent adverse outcomes. It further suggests that replacement of any one deficient system may not be sufficient to prevent or ameliorate frailty.
doi:10.1093/gerona/glp076
PMCID: PMC2737590  PMID: 19567825
Frailty etiology; Aging
15.  Financial Strain Is Associated with Malnutrition Risk in Community-Dwelling Older Women 
This study examined the relationship between financial strain, or difficulty acquiring necessities, and malnutrition risk in a community dwelling sample of frail and nonfrail women aged 70–79 in the Women’s Health and Aging Study (n = 679). Malnutrition risk was measured with a modified version of the Mini-Nutritional Assessment Short Form (MNA-SF) and defined as a score <11, financial strain was measured by (1) sufficiency of money on a monthly basis and (2) adequacy of income for food, and income was measured by ordinal categories. Mean (SD) modified MNA-SF score was 12.2 (1.80), and 14.7% of women had malnutrition risk. Women who usually did not have enough money to make ends meet had more than four-fold increased odds of malnutrition risk (OR = 4.54; 95% CI: 2.26, 9.14) compared to their counterparts who had some money left over each month. This was only slightly attenuated after control for income and education, (OR = 4.08; 95% CI: 1.95, 8.52) remaining robust. These results show an association between financial strain and malnutrition risk, independent of income, in older women. Self-reported financial strain may be preferable to income as a screener for malnutrition risk in older adults in clinical and research settings.
doi:10.1155/2012/696518
PMCID: PMC3806140  PMID: 24163772
16.  Lifestyle Activities in Sociodemographically at-risk Urban, Older Adults Prior to Participation in the Baltimore Experience Corps® Trial 
Activities, adaptation & aging  2012;36(3):242-260.
Experience Corps® places teams of trained volunteers in elementary school classrooms to promote academic achievement in children, and serve as a health promotion intervention for older adults. Prior to randomization, individuals reported participation in several activities of varying cognitive, physical, and social demands. Maintaining an active lifestyle, particularly in intellectually demanding activities, was associated with physical, mental, and cognitive health in adulthood. Establishing how individuals allocated their time before randomization to this program provides insight to prevalent health behaviors for at-risk older adults, and can provide the basis for examining intervention-related changes in lifestyle as a result of volunteer participation
doi:10.1080/01924788.2012.702306
PMCID: PMC3490448  PMID: 23144524
Engagement; Activities; Intervention; Cognition; Aging; Volunteers
17.  Patterns of 12-Year Change in Physical Activity Levels in Community-Dwelling Older Women: Can Modest Levels of Physical Activity Help Older Women Live Longer? 
American Journal of Epidemiology  2012;176(6):534-543.
Few studies have addressed changes in physical activity participation over time among the elderly. The authors hypothesized that there were distinct trajectories of physical activity level over time and identifiable predictors of such trajectories, as well as that the maintenance of regular physical activity, even below recommended levels, was associated with lower mortality risk. Using longitudinal data (1994–2009) from 433 initially high-functioning older women aged 70–79 years at baseline, a joint latent class and survival mixture model identified 4 activity trajectory classes: always active (16.6%), fast declining (19.2%), stable moderate (32.3%), and always sedentary (31.9%). Obesity, coronary artery disease, chronic obstructive pulmonary disease, depressive symptoms, low self-efficacy, mobility disability, and low energy were associated with sedentary behavior and/or a fast decline in activity. Women in the fast declining and always sedentary classes had hazard ratios for death of 2.34 (95% confidence interval: 1.20, 4.59) and 3.34 (95% confidence interval: 1.72, 6.47), respectively, compared with the always active class; no mortality difference was found between the stable moderate and always active groups (hazard ratio = 1.24, 95% confidence interval: 0.63, 2.47). Our findings suggest that physical activity does not have to be vigorous to be beneficial and that the gain may be the greatest among women who reported the lowest levels of activity.
doi:10.1093/aje/kws125
PMCID: PMC3530350  PMID: 22935515
aging; exercise; healthy people programs; lifestyle; motor activity; risk factors; survival; walking
18.  Long-term Assessment of Inflammation and Healthy Aging in Late Life: The Cardiovascular Health Study All Stars 
Background.
Associations of inflammation with age-related pathologies are documented; however, it is not understood how changes in inflammation over time impact healthy aging.
Methods.
We examined associations of long-term change in C-reactive protein (CRP) and interleukin-6 (IL-6) with concurrent onset of physical and cognitive impairment, subsequent cardiovascular disease (CVD), and mortality in 1,051 participants in the Cardiovascular Health Study All Stars Study. Biomarkers were measured in 1996–1997 and 2005–2006.
Results.
In 2005–2006, median age was 84.9 years, 63% were women and 17% non-white; 21% had at least a doubling in CRP over time and 23% had at least a doubling in IL-6. Adjusting for demographics, CVD risk factors, and 1996–1997 CRP level, each doubling in CRP change over 9 years was associated with higher risk of physical or cognitive impairment (odds ratio 1.29; 95% confidence interval 1.15, 1.45). Results were similar for IL-6 (1.45; 1.20, 1.76). A doubling in IL-6 change over time, but not CRP, was associated with incident CVD events; hazard ratio (95% confidence interval) 1.34 (1.03, 1.75). Doubling in change in each biomarker was individually associated with mortality (CRP: 1.12 [1.03, 1.22]; IL-6 1.39 [1.16, 1.65]). In models containing both change and 2005–2006 level, only level was associated with CVD events and mortality.
Conclusions.
Although increases in inflammation markers over 9 years were associated with higher concurrent risk of functional impairment and subsequent CVD events and mortality, final levels of each biomarker appeared to be more important in determining risk of subsequent events than change over time.
doi:10.1093/gerona/glr261
PMCID: PMC3436091  PMID: 22367431
Inflammation; Aging; Physical function; Cognitive function
19.  Resting Metabolic Rate Among Old-Old Women With and Without Frailty: Variability and Estimation of Energy Requirements 
Objectives
Resting metabolic rate (RMR) is the largest component of total energy expenditure. It has not been studied in old-old adults living in the community, though abnormalities in RMR may play a critical role in the development of the clinical syndrome of frailty. The objective was to measure RMR and examine the association of measured RMR with frailty status and compare it to expected RMR generated by a predictive equation.
Design
Physiologic sub-study conducted as a home visit within an observational cohort study.
Setting
Baltimore City and County, Maryland.
Participants
77 women age 83–93 years enrolled in the Women’s Health and Aging Study II.
Measurements
RMR with indirect calorimetry; frailty status; fat-free mass; ambient and body temperature; expected RMR via the Mifflin-St. Jeor equation.
Results
Average RMR was 1119 kcal/d (s.d.± 205; range 595–1560). Agreement between observed and expected RMR was biased and very poor (between-subject coefficient of variation 38.0%, 95%CI: 35.1–40.8). Variability of RMR was increased in frail subjects (heteroscedasticity F test P value=0.02). Both low and high RMR were associated with being frail (Odds Ratio 5.4, P value=0.04) and slower self-selected walking speed (P value<0.001) after adjustment for covariates.
Conclusion
Equations to predict RMR that are not validated in old-old adults appear to correlate poorly with measured RMR. RMR values are highly variable among old-old women, with deviations from the mean predicting clinical frailty. These exploratory findings suggest a pathway to clinical frailty through either high or low RMR.
doi:10.1111/j.1532-5415.2012.04101.x
PMCID: PMC3458581  PMID: 22985142
resting metabolic rate; frailty; older adults
20.  Serum ceramides increase the risk of Alzheimer disease 
Neurology  2012;79(7):633-641.
Objectives:
Previous studies have shown that high serum ceramides are associated with memory impairment and hippocampal volume loss, but have not examined dementia as an outcome. The aim of this study was to examine whether serum ceramides and sphingomyelins (SM) were associated with an increased risk of all-cause dementia and Alzheimer disease (AD).
Methods:
Participants included 99 women without dementia aged 70–79, with baseline serum SM and ceramides, enrolled in a longitudinal population-based study and followed for up to 6 visits over 9 years. Baseline lipids, in tertiles, were examined in relation to all-cause dementia and AD using discrete time Cox proportional survival analysis. Lipids were analyzed using electrospray ionization tandem mass spectrometry.
Results:
Twenty-seven (27.3%) of the 99 women developed incident dementia. Of these, 18 (66.7%) were diagnosed with probable AD. Higher baseline serum ceramides, but not SM, were associated with an increased risk of AD; these relationships were stronger than with all-cause dementia. Compared to the lowest tertile, the middle and highest tertiles of ceramide d18:1–C16:0 were associated with a 10-fold (95% confidence interval [CI] 1.2–85.1) and 7.6-fold increased risk of AD (95% CI 0.9–62.1), respectively. The highest tertiles of ceramide d18:1–C24:0 (hazard ratio [HR] = 5.1, 95% CI 1.1–23.6) and lactosylceramide (HR = 9.8, 95% CI 1.2–80.1) were also associated with risk of AD. Total and high-density lipoprotein cholesterol and triglycerides were not associated with dementia or AD.
Conclusions:
Results from this preliminary study suggest that particular species of serum ceramides are associated with incident AD and warrant continued examination in larger studies.
doi:10.1212/WNL.0b013e318264e380
PMCID: PMC3414665  PMID: 22815558
21.  Modification of the Association Between Ambient Air Pollution and Lung Function by Frailty Status Among Older Adults in the Cardiovascular Health Study 
American Journal of Epidemiology  2012;176(3):214-223.
The susceptibility of older adults to the health effects of air pollution is well-recognized. Advanced age may act as a partial surrogate for conditions associated with aging. The authors investigated whether gerontologic frailty (a clinical health status metric) modified the association between ambient level of ozone or particulate matter with an aerodynamic diameter less than 10 µm and lung function in 3,382 older adults using 7 years of follow-up data (1990–1997) from the Cardiovascular Health Study and its Environmental Factors Ancillary Study. Monthly average pollution and annual frailty assessments were related to up to 3 repeated measurements of lung function using cumulative summaries of pollution and frailty histories that accounted for duration as well as concentration. Frailty history was found to modify long-term associations of pollutants with forced vital capacity. For example, the decrease in forced vital capacity associated with a 70-ppb/month greater cumulative sum of monthly average ozone exposure was 12.3 mL (95% confidence interval: 10.4, 14.2) for a woman who had spent the prior 7 years prefrail or frail as compared with 4.7 mL (95% confidence interval: 3.8, 5.6) for a similar woman who was robust during all 7 years (interaction P < 0.001).
doi:10.1093/aje/kws001
PMCID: PMC3491964  PMID: 22811494
aging; effect modifier, epidemiologic; environmental exposure; frail elderly; respiratory function tests
22.  Serum 25-Hydroxyvitamin D and Pulmonary Function in Older Disabled Community-Dwelling Women 
Background.
Recent studies have expanded the functions of vitamin D to a possible role in pulmonary function. Our objective was to examine the relationship between serum 25-hydroxyvitamin D (25[OH]D), serum parathyroid hormone, and pulmonary function in older women.
Methods.
We examined the relationship of serum 25(OH)D and parathyroid hormone with pulmonary function (forced expiratory volume in one second [FEV1], forced vital capacity [FVC], and FEV1/FVC ratio) in a cross-sectional study of 646 moderately to severely disabled women, 65 years or more, living in the community in Baltimore, Maryland, who participated in the Women’s Health and Aging Study I.
Results.
Overall, median (25th, 75th percentile) serum 25-hydroxyvitamin D concentrations were 19.9 (14.7, 26.7) ng/mL. Serum 25(OH)D was positively associated with FEV1 (p = .03), FVC (p = .18), and FEV1/FVC (p = .04) in multivariable linear regression models adjusting for age, race, education, smoking, height, physical activity, cognition, interleukin-6, chronic diseases, and other potential confounders. In the same models, serum parathyroid hormone was not significantly associated with FEV1, FVC, or FEV1/FVC.
Conclusions.
These findings support the idea that vitamin D deficiency is independently associated with poor pulmonary function in older disabled women.
doi:10.1093/gerona/glr213
PMCID: PMC3732158  PMID: 22156439
Aging; Lung function; Parathyroid hormone; Vitamin D; Women
23.  Incident Preclinical Mobility Disability Increases Future Risk of New Difficulty Walking and Reduction in Walking Activity 
Purpose
This study examines whether and how report of a change in walking behavior, incident preclinical mobility disability (PCMD), predicts subsequent reduction in walking activity.
Materials and Methods
Data are from a prospective study of 436 community-dwelling women age 70–79 years. Outcome measures include subjective and objective measures of walking ability at 3 years.
Principal Results
Incident PCMD is associated with loss of walking abilities at 3-years, regardless of baseline physical impairment. Compared to women without, women with incident PCMD at 1.5 years after baseline were 2.7 (95% CI 1.4–7.2) times more likely to report that they no longer walk outdoors at least 8 blocks and 4.9 (1.9–13.1) times more likely to report new difficulty walking. Incident PCMD was also associated with declines in objective outcomes. Incident PCMD is an independent marker of subsequent decreased walking activity.
Major conclusions
Incident PCMD appears to be a target for programs to prevent declines in walking activity in older adults.
doi:10.1016/j.archger.2011.08.018
PMCID: PMC3248983  PMID: 21944428
disability; geriatrics; epidemiology; prevention; physical activity
24.  Anemia and 9-Year Domain-Specific Cognitive Decline in Community-Dwelling Older Women: The Women’s Health and Aging Study II 
Objectives
To test the hypothesis that anemia (hemoglobin <12 g/dL) is associated with a faster rate of 9-year cognitive decline in a community-dwelling sample of women aged 70-80 years at baseline.
Design
A population-based, prospective cohort study
Setting
East Baltimore, Maryland
Participants
436 women sampled to be representative of the 2/3 least disabled women in, aged 70-80 years at baseline (1994-1996).
Measurements
9-year trajectories of cognitive decline, analyzed with linear random effects models, in the domains of immediate verbal recall, delayed verbal recall, psychomotor speed, and executive function.
Results
At baseline and after adjustment for demographic and disease covariates, women with anemia were slower to complete a test of executive function than women without anemia by - 0.43 SD (95% CI: −0.74, −0.13) on the Trail Making Test, Part B (TMTB). During follow-up, anemia was associated with a faster rate of decline in memory. Between baseline and year 3, women with anemia declined at a rate of 0.18 more SD/year (95% CI: −0.29, −0.06) than women without anemia on the Hopkins Verbal Learning Test (HVLT) and by .0.15 more SD/year (95% CI: −0.26. −0.04) on the Hopkins Verbal Learning Test-Delayed (HVLT-Delayed).
Conclusion
Anemia was associated with poorer baseline performance on a test of executive function and with faster rates of decline on tests of immediate and delayed verbal recall. If this relationship is causal, it is possible that treatment of anemia could prevent or postpone cognitive decline.
doi:10.1111/j.1532-5415.2009.02400.x
PMCID: PMC3560911  PMID: 19682133
anemia; elderly; executive function; longitudinal study; memory
25.  Association Between Inflammatory-related Disease Burden and Frailty: Results From the Women’s Health and Aging Studies (WHAS) I and II 
Frailty is associated with a pro-inflammatory state, which has been characterized by elevated levels of systemic inflammatory biomarkers, but has not been related to the number of co-existing chronic diseases associated with inflammation. We sought to determine the extent to which a higher number of inflammatory-related diseases is associated with frailty and to identify the most common disease patterns associated with being frail in older adults. We performed binomial regression analyses to assess whether a higher count of inflammatory-related diseases increases the probability of frailty using data from the Women's Health and Aging Studies I and II, companion cohorts composed of 70–79-year-old community-dwelling older women in Baltimore, Maryland (n=620). An increase of one inflammatory-related disease was associated log-linearly with frailty (Prevalence Ratio (PR)=2.32, 95% Confidence Interval (CI)=1.85–2.92). After adjusting for age, race, education, and smoking status, the probability of frailty remained significant (PR=1.97, 95%CI=1.52–2.55). In the frail population, chronic kidney disease (CKD) and depressive symptoms (Prevalence=22.9%, 95%CI=14.2–34.8%); CVD and depressive symptoms (21.7%, 95%CI=13.2–33.5%); CKD and anemia (18.7%, 95%CI=11.1–29.7%); cardiovascular disease (CVD), CKD, and pulmonary disease (10.7%, 95%CI=5.2–21.0%); CKD, anemia, and depressive symptoms (8.7%, 95%CI=3.9–18.2%); and CVD, anemia, pulmonary disease, and depressive symptoms (5.0%, 95%CI=1.6–14.4%) were among the most frequent disease combinations. Their prevalence percentages were significantly higher in the frail versus non-frail women. A higher inflammatory-related disease count, perhaps reflecting a greater pro-inflammatory burden, increases the likelihood of frailty. Shared mechanisms among specific disease combinations may further contribute to this risk.
doi:10.1016/j.archger.2011.05.020
PMCID: PMC3197795  PMID: 21763008
comorbidity; inflammation; frailty

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