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1.  Implementing frailty into clinical practice: a cautionary tale 
Background
Little is known about the contribution of frailty in improving patient-level prediction beyond readily available clinical information. The objective of this study is to compare the predictive ability of 129 combinations of 7 frailty markers (cognition, energy, mobility, mood, nutrition, physical activity, and strength) and quantify their contribution to predictive accuracy beyond age, sex and number of chronic diseases.
Methods
Two cohorts from the Established Populations for Epidemiologic Studies of the Elderly were used. The model with the best predictive fit in predicting 6-year incidence of disability was determined using the Akaike Information Criterion. Predictive accuracy was measured by the C statistic.
Results
Incident disability was 23% in one cohort and 20% in the other cohort. The “best model” in each cohort was found to be a model including between 5 and 7 frailty markers including cognition, mobility, nutrition, physical activity and strength. Predictive accuracy of the 129 models ranged from 0.73 to 0.77 across both cohorts. Adding frailty markers to age, sex and chronic disease increased predictive accuracy by up to 3% in both cohorts (P< .001). The contribution of frailty increased up to 9% in the oldest age group.
Conclusions
Adding frailty markers provided a modest increase in patient-level prediction of disability. Such a modest increase may still be worthwhile because while age, sex and the number of chronic diseases are not modifiable, frailty may be. Further studies examining the contribution of frailty in improving prediction are needed before adopting frailty as a prognostic tool.
doi:10.1093/gerona/glt053
PMCID: PMC3806754  PMID: 23640761 CAMSID: cams2968
2.  The Association of Race, Gender, and Comorbidity With Mortality and Function After Hip Fracture 
Background
Few studies of hip fracture have large enough samples of men, minorities, and persons with specific comorbidities to examine differences in their mortality and functional outcomes. To address this problem, we combined three cohorts of hip fracture patients to produce a sample of 2692 patients followed for 6 months.
Method
Data on mortality, mobility, and other activities of daily living (ADLs) were available from all three cohorts. We used multiple regression to examine the association of race, gender, and comorbidity with 6-month survival and function, controlling for prefracture mobility and ADLs, age, fracture type, cohort, and admission year.
Results
The mortality rate at 6 months was 12%: 9% for women and 19% for men. Whites and women were more likely than were nonwhites and men to survive to 6 months, after adjusting for age, comorbidities, and prefracture mobility and function. Whites were more likely than were nonwhites to walk independently or with help at 6 months compared to not walking, after adjusting for age, comorbidities, and prefracture mobility and function. Dementia had a negative impact on survival, mobility, and ADLs at 6 months. The odds of survival to 6 months were significantly lower for people with chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), and/or cancer. Parkinson’s disease and stroke had negative impacts on mobility and ADLs, respectively, among survivors at 6 months.
Conclusions
The finding of higher mortality and worse mobility for nonwhite patients with hip fractures highlights the need for more research on race/ethnicity disparities in hip fracture care.
PMCID: PMC3807236  PMID: 18772476
Hip fracture; Mobility; Activities of daily living; Mortality
3.  PREVALENCE OF SLEEP DISTURBANCES IN A COHORT OF OLDER DRIVERS 
Background
Lower levels of driving capacity in older persons are typically attributed to cognitive, visual, and/or physical impairments, with sleep disturbances rarely considered. This is in contrast to the general adult population for whom sleep disturbances are established risk factors for crashes. We thus set out to determine the prevalence of sleep disturbances in the form of insomnia symptoms, daytime drowsiness, and sleep apnea risk in a cohort of older drivers, and assess how these relate to self-reported driving capacity.
Methods
Participants included 430 active drivers aged ≥ 70 years. Questionnaires measured self-reported insomnia symptoms (Insomnia Severity Index [ISI]), drowsiness (Epworth Sleepiness Scale [ESS]), apnea risk (Sleep Apnea Clinical Score [SACS]), driving mileage, driver self-ratings (overall and nighttime), and prior adverse driving events.
Results
Mean age was 78.5 years, with 85% being male. Overall, 64% were dissatisfied with sleep patterns and 26% had an abnormal ISI (≥ 8). A large proportion (60%) reported a moderate-to-high chance of dozing in the afternoon, and 19% had an abnormal ESS (≥ 10). Habitual snoring was noted by 43%, with 20% at risk for sleep apnea (SACS > 15). Regarding driving, the most consistent finding was for lower levels of nighttime driver self-ratings in participants with insomnia symptoms or drowsiness. Lower levels of driving mileage were also noted but only with difficulty falling asleep. Otherwise, sleep disturbances were not associated with prior adverse driving events.
Conclusion
In our cohort of older drivers, insomnia symptoms and daytime drowsiness were prevalent and associated with lower levels of nighttime driver self-ratings. Although sleep apnea risk was also prevalent, it was not associated with self-reported driving capacity. These preliminary findings suggest that insomnia symptoms and drowsiness merit continued consideration as risk factors for lower levels of driving capacity in older persons, particularly given that effective interventions are available.
PMCID: PMC3719852  PMID: 18693226
Insomnia; drowsiness; sleep apnea risk; drivers
4.  [No title available] 
PMCID: PMC3644955  PMID: 16339339
5.  Prevalence and Factors Associated With Thriving in Older Adulthood: A 10-Year Population-Based Study 
Background
Interest in the determinants of “successful aging” is growing. Nonetheless, successful aging remains ill defined, and its appropriate measurement is hotly contested. Most studies have focused on the absence of disability or deficits in physical performance as outcomes. The present study extends this research by using the Health Utilities Index Mark 3 (HUI3), a multidimensional measure of health status, to examine the maintenance of exceptionally good health among older participants in the Canadian National Population Health Survey (1994–2004).
Methods
The maintenance of exceptionally good health in old age was examined prospectively among 2432 individuals (65–85 years old at baseline) who met the inclusion criteria. The participants were classified into one of four health trajectories: thrivers (who maintained exceptional health with no or only mild disability), nonthrivers (who experienced a moderate or severe disability), the deceased, and the institutionalized.
Results
In 10 years of follow-up, 190 (8%) were thrivers (HUI3 score ≥ 0.89 at all interviews), 1076 (47%) were nonthrivers, 893 (36%) died, and 273 (9%) were institutionalized. The maintenance of exceptionally good health among the elderly participants was related to younger age at baseline, socioeconomic status (higher income), psychosocial factors (including lower psychological distress), and behavioral factors (never smoked and moderate alcohol use).
Conclusions
The maintenance of exceptionally good health in old age is related, at least in part, to modifiable lifestyle factors. However, elevated socioeconomic status also distinguishes those who are able to maintain exceptionally good health.
PMCID: PMC3544549  PMID: 18948561
Aging; Epidemiology; Longitudinal; Population health
6.  Survival of Parents and Siblings of Supercentenarians 
Background
Given previous evidence of familial predisposition for longevity, we hypothesized that siblings and parents of supercentenarians (age ≥ 110 years) were predisposed to survival to very old age and that, relative to their birth cohorts, their relative survival probabilities (RSPs) are even higher than what has been observed for the siblings of centenarians.
Methods
Mean age at death conditional upon survival to ages 20 and 50 and survival probabilities from ages 20 and 50 to higher ages were determined for 50 male and 56 female siblings and 54 parents of 29 supercentenarians. These estimates were contrasted with comparable estimates based on birth cohort-specific mortality experience for the United States and Sweden.
Results
Conditional on survival to age 20 years, mean age at death of supercentenarians’ siblings was ~81 years for men and women. Compared with respective Swedish and U.S. birth cohorts, these estimates were 17%–20% (12–14 years) higher for the brothers and 11%–14% (8–10 years) higher for the sisters. Sisters had a 2.9 times greater probability and brothers had a 4.3 times greater probability of survival from age 20 to age 90. Mothers of supercentenarians had a 5.8 times greater probability of surviving from age 50 to age 90. Fathers also experienced an increased survival probability from age 50 to age 90 of 2.7, but it failed to attain statistical significance.
Conclusions
The RSPs of siblings and mothers of supercentenarians revealed a substantial survival advantage and were most pronounced at the oldest ages. The RSP to age 90 for siblings of supercentenarians was approximately the same as that reported for siblings of centenarians. It is possible that greater RSPs are observed for reaching even higher ages such as 100 years, but a larger sample of supercentenarians and their siblings and parents is needed to investigate this possibility.
PMCID: PMC3258444  PMID: 17895443
7.  Longevity and Correlated Frailty in Multigenerational Families 
Multigenerational pedigrees provide an opportunity for assessing the effects of unobserved environmental and genetic effects on longevity (i.e., frailty). This article applies Cox proportional hazards models to data from three-generation pedigrees in the Utah Population Database using two different frailty specification schemes that account for common environments (shared frailty) and genetic effects (correlated frailty). In a model that includes measures of familial history of longevity and both frailty effects, we find that the variance component due to genetic factors is comparable to the one attributable to shared environments: Standard deviations of the correlated and the shared frailty distributions are 0.143 and 0.186, respectively. Through simulations, we also show a greater reduction in the bias of parameter estimates for fixed covariates through the use of the correlated frailty model.
PMCID: PMC3245842  PMID: 17234818
8.  Sleep in Assisted Living Facility Residents Versus Home-Dwelling Older Adults 
Background
Sleep problems among assisted living facility (ALF) residents are not well understood, and sleep-related differences between ALF residents and home-dwelling older adults have not been examined.
Methods
We compared sleep patterns in 19 ALF residents to sleep patterns in 19 matched home-dwelling older people (age ≥65 years). All were participating in the follow-up portion of a longitudinal study of sleep and functional outcomes following post-acute rehabilitation. Sleep was assessed with the Pittsburgh Sleep Quality Index and 1 week of wrist actigraphy.
Results
By actigraphy, ALF residents awoke earlier in the morning and exhibited more nighttime awakenings compared to home-dwelling participants (06:50 hours ± 1:29 hours vs 07:51 hours ± 1:19 hours and 19.5 ± 8.5 vs 12.9 ± 11.4 awakenings, respectively).
Conclusions
Larger studies are needed to confirm these initial findings that ALF residents have more disrupted sleep than do home-dwelling older persons, and to examine the functional and health consequences of poor sleep among ALF residents.
PMCID: PMC3184036  PMID: 19126856
Sleep; Aging; Circadian rhythms; Assisted living
9.  Dual Task Decrements in Gait among Healthy Older Adults: Contributing Factors 
Background
The factors that contribute to the dual task (DT) changes in performance that occur when older adults walk while simultaneously performing other tasks are not well-known. We hypothesized that cognitive and motor reserve (e.g., executive function, EF, postural control, and walking abilities) and affect (e.g., anxiety, depressive symptoms) influence the DT decrements (DTDs) in gait.
Methods
228 community-living, healthy older adults (mean: 76.2±4.2 yrs; 59% women) walked with and without dual tasking, e.g., subtracting 7’s, phoneme monitoring. Mobility (e.g., the Dynamic Gait Index), cognitive function (e.g., memory, EF), and affect (e.g., Geriatric Depression Scale) were quantified. Bivariate and multivariate analyses identified factors associated with the DTD in gait speed (a general measure of locomotor function), swing time, (reflecting balance during gait), and swing time variability (a measure of stride-to-stride consistency).
Results
Gait speed and swing time decreased (p<0.001) and swing time variability increased (became worse) (p<0.001) during all DTs. The DTD in gait speed was correlated with comfortable-walking gait speed, but not with tests of mobility or cognitive function. The DTD in swing time variability was correlated with EF, mobility and affect (e.g., depressive symptoms). Much of the variance in the DTDs was unexplained.
Conclusions
Usual-walking abilities and cognitive function contribute to the DT effects on gait, but these relationships depend on specifics of the DT, the gait feature being studied, and the particulars of the cognitive domain. Meeting the everyday challenges of walking while dual tasking apparently relies on multiple factors including a consistent gait pattern and EF.
PMCID: PMC3181497  PMID: 19126846
dual task; cognitive function; executive function; gait; variability
10.  Persistent Infection, Inflammation, and Functional Impairment in Older Latinos 
Background
The objective of this study was to examine whether cytomegalovirus (CMV), herpes simplex virus type-1 (HSV-1), and C-reactive protein (CRP) are associated with functional impairment in older Latinos.
Methods
A cross-sectional analysis of a cohort study conducted with a community dwelling elderly population. The sample was a subset (N = 1507/1789) of participants in the Sacramento Area Latino Study on Aging (SALSA) ages 60–101 with available serum samples and functional impairment measures. Baseline serum samples were assayed for levels of immunoglobulin G antibodies to CMV and HSV-1 and for levels of CRP. Several measures were used to assess functional impairment, including activities of daily living (ADL), instrumental activities of daily living (IADL), and walking pace.
Results
CMV and CRP showed statistically significant graded associations with ADL functional impairment, even after controlling for age and gender. The relationship between CMV and ADL was slightly attenuated, and the confidence interval contained the null value when adjusted for total number of health conditions, body mass index, and household income. Only high levels of CRP were significantly related to ADL and IADL impairment even after adjusting for all other covariates.
Conclusion
Inflammation is clearly linked to physical functioning among aging Latinos. This study also suggests a role for CMV infection in relation to ADL impairment. Further research examining the influence of infection, immune response, and inflammation on longitudinal trajectories of physical functioning is warranted.
PMCID: PMC3178457  PMID: 18559636
Cytomegalovirus (CMV); CRP; Latinos; Physical function; Community
11.  Type 2 Diabetes Is Negatively Associated With Alzheimer’s Disease Neuropathology 
Background
In cross-sectional and longitudinal studies, type 2 diabetes has been positively associated with the risk of Alzheimer’s disease (AD). The present descriptive study compared diabetic and nondiabetic subjects on the severity of neuritic plaques and neurofibrillary tangles (NFTs) in the cerebral cortex and in the hippocampus.
Methods
The study included specimens from 385 consecutive autopsies of residents of a nursing home (15.8% diabetics). Mean age at death = 84 years [standard deviation (SD) = 10], 66% were female, Clinical Dementia Rating mean = 3.0 (SD = 1.6), and 32.5% had an APOE4 allele. Additional analyses limited the sample to 268 subjects (14.1% diabetics) without neuropathology other than AD.
Results
Analyses of covariance controlling for age at death, dementia severity (Clinical Dementia Rating score), and APOE4 allele indicated that diabetics had significantly fewer neuritic plaques (p = .008) and NFTs (p = .047) in the cerebral cortex than did nondiabetics. In the hippocampus, diabetics had significantly lower plaque ratings than did nondiabetics (p = .019), but the lower ratings of NFTs did not achieve statistical significance (p = .082). In the entire sample, diabetics had significantly less AD-associated neuropathology in all four analyses.
Conclusions
These results raise the possibility that the varied associations observed between diabetes and AD may be specific to as yet ill-defined subgroups of dementia and diabetic patients or may be more characteristic of younger patients than of those who survive to a mean age of 84 years. Future studies are encouraged to examine a variety of other characteristics such as age that may interact with diabetes affecting the incidence of AD.
PMCID: PMC3163091  PMID: 15933386
12.  Does Inability to Allocate Attention Contribute to Balance Constraints during Gait in Older Adults? 
Background
Recent research has explored dual-task deficits during locomotion in older adults, yet the mechanisms underlying these deficits are poorly understood. In the current study, we examined one possible factor contributing to these deficits, the inability to flexibly allocate attention between two tasks.
Methods
Twelve healthy young adults and 12 healthy elderly adults performed obstacle avoidance while walking and an auditory Stroop task either alone or simultaneously.
Results
Using an attentional allocation index (AAI) to compare performance of healthy young and older adults and to measure the flexibility of allocation of attention, results showed a tendency in older adults toward a decreased ability to flexibly allocate their attention between the two tasks, with small AAI values. The decreased ability to allocate attention in older adults was found to be more prominent in the auditory Stroop task performance than in the obstacle avoidance task.
Conclusion
This study suggests that an important factor contributing to decreased dual-task performance in older adults when simultaneously performing a postural and secondary cognitive task is a reduced ability to flexibly allocate attention between the two tasks, with the general ability to switch attention flexibly being predictive of the ability to adhere to a prioritized focus.
PMCID: PMC3133738  PMID: 19126850
Gait; Attention; Aging
13.  The Development of Fear of Falling Among Community-Living Older Women: Predisposing Factors and Subsequent Fall Events 
Background
Fear of falling is a common and potentially modifiable health problem among older persons. However, relatively little is known about who develops fear of falling or why.
Methods
From a representative cohort of community-living persons aged 72 years or older, we evaluated 313 women who had no fear of falling. These participants underwent a comprehensive in-home assessment and were reassessed for fear of falling 1 year later. Fall events were ascertained monthly using a validated fall calendar.
Results
84 (27%) participants developed fear of falling at 1 year and 77 (25%) participants experienced at least one fall event. The predisposing factors for developing fear of falling included age 80 years or older (adjusted relative risk 1.48; 95% confidence intervals 1.04–2.12), visual impairment (1.42; 1.01–2.00), a sedentary lifestyle (1.96; 1.35–2.84), and no available emotional support (2.64; 1.57–4.41). The occurrence of a subsequent fall event was also significantly associated with developing fear of falling (unadjusted relative risk 1.70; 1.18–2.45), although this effect was observed only among participants who had at least one predisposing factor.
Conclusions
Among community-living older women, fear of falling develops due to a combination of predisposing factors and subsequent fall events. Since many of the predisposing factors are related to fall risk, preventive efforts to reduce fear of falling may also decrease the likelihood of falling.
PMCID: PMC3050034  PMID: 14570863
14.  Principal Component Analysis Reveals Age-Related and Muscle-Type-Related Differences in Protein Carbonyl Profiles of Muscle Mitochondria 
Carbonyl-modified proteins are considered markers of oxidative damage caused by oxidative stress, aging, and disease. Here we use a previously developed capillary electrophoretic method for detecting femtomole (10−15 mole) carbonyl levels in mitochondrial proteins that are size separated and profiled. For protein labeling, carbonyls were tagged with Alexa 488 hydrazine and amine groups in proteins with 3-(2-furoyl)quinoline-2-carboxaldehyde. Total mitochondrial protein carbonyl levels were statistically higher in fast- than in slow-twitch muscle of young Fischer 344 rats, and statistically higher in old than in young slow-twitch muscle. Even when some statistical comparisons of the total protein carbonyl levels would not reveal differences, principal component analysis (PCA) classified the carbonyl profiles into four distinct sample groups of different age and muscle types. In addition, PCA was used to predict that most age-related or muscle-type-related changes in carbonyl levels occur in proteins with a molecular weight between 9.8 and 11.7 kD.
PMCID: PMC3038117  PMID: 19126840
Mitochondria; Carbonyl; Principal component analysis; Fluorescence; Capillary electrophoresis
15.  Glutathione Peroxidase Enzyme Activity in Aging 
Background
It is hypothesized that free radical damage contributes to aging. Age-related decline in activity of the antioxidant enzyme glutathione peroxidase (GPx) may contribute to increased free radicals. We hypothesized that GPx activity decreases with age in a population of older women with disability.
Methods
Whole blood GPx activity was measured in baseline stored samples from participants in the Women's Health and Aging Study I, a cohort of disabled community-dwelling older women. Linear regression was used to determine cross-sectional associations between GPx activity and age, adjusting for hemoglobin, coronary disease, diabetes, selenium, and body mass index.
Results
Six hundred one participants had complete demographic, disease, and laboratory information. An inverse association was observed between GPx and age (regression coefficient = −2.9, p < .001), indicating that for each 1-year increase in age, GPx activity decreased by 2.9 μmol/min/L. This finding remained significant after adjustment for hemoglobin, coronary disease, diabetes, and selenium, but not after adjustment for body mass index and weight loss.
Conclusion
This is the first study to examine the association between age and GPx activity in an older adult cohort with disability and chronic disease. These findings suggest that, after age 65, GPx activity declines with age in older women with disability. This decline does not appear to be related to diseases that have been previously reported to alter GPx activity. Longitudinal examination of GPx activity and other antioxidant enzymes in diverse populations of older adults will provide additional insight into age- and disease-related changes in these systems.
PMCID: PMC2964084  PMID: 18511755
Glutathione peroxidase; Oxidative stress; Aging; Older adult
16.  Inflammation and Rate of Cognitive Change in High-Functioning Older Adults 
Background
Inflammatory proteins including interleukin-6 (IL-6) and C-reactive protein (CRP) have been associated with incident cognitive impairment, but little research has addressed their effects on the rate of cognitive change, and findings are mixed. The purpose of this study was to examine the relationship between serum levels of IL-6 and CRP and the rate of cognitive change across a range of cognitive domains in a sample of healthy older persons.
Methods
Growth curve analysis was performed on data from the MacArthur Study of Successful Aging, a longitudinal cohort study of high-functioning older adults aged 70–79 years at baseline in 1988 and reinterviewed in 1991 and 1995 (N = 851). Individual growth curve parameters were derived from baseline and follow-up performance in abstraction, language, spatial ability, verbal recall, spatial recognition, and global cognitive function based on age, IL-6, CRP, and covariates.
Results
Cross-sectionally, there is a generally linear negative relationship between inflammation and cognition, such that higher levels of inflammation are associated with lower levels of baseline cognitive function. After controlling for potential confounders, there was no effect of inflammation on baseline cognitive function or the rate of longitudinal cognitive change. However, persons in the top tertile on IL-6 were at an increased risk of incident declines on the Short Portable Mental Status Questionnaire (SPMSQ).
Conclusions
Although high levels of inflammation are associated with incident cognitive impairment, these results do not generalize to the full range of cognitive changes, where the role of inflammation appears to be marginal.
PMCID: PMC2952346  PMID: 18245760
Cognitive impairment; Interleukin-6; C-reactive protein
17.  Aging and Inflammation in Two Epidemiological Worlds 
Humans evolved in a world with high levels of infection resulting in high mortality across the life span and few survivors to advanced ages. Under such conditions, a strong acute-phase inflammatory response was required for survival; however, inflammatory responses can also promote chronic diseases of aging. We hypothesize that global historical increases in life span at older ages are partly explained by reduced lifetime exposure to infection and subsequent inflammation. To begin a test of this hypothesis, we compare C-reactive protein (CRP); levels in two populations with different epidemiological environments: the Tsimane of Bolivia and persons in the United States. High CRP is significantly more prevalent among the Tsimane up through middle age; by age 35, the Tsimane have spent more years with high CRP than have Americans at age 55. Further testing of the links among infection, inflammation, and chronic diseases of aging among the Tsimane requires collection of age-specific indicators of atherosclerosis and cardiac function.
PMCID: PMC2952348  PMID: 18314457
Inflammation; Infection; C-reactive protein
18.  A Twin-Study of Genetic Contributions to Hearing Acuity in Late Middle Age 
Background
Declines in hearing acuity, especially in the high frequency range, often appear in middle age. The objective of this study was to characterize genetic and environmental influences that may underlie this pattern.
Methods
One hundred seventy-nine monozygotic and 150 dizygotic twin pairs, ranging in age from 52 to 60 years, were selected from the Vietnam Era Twin Registry and individually tested for hearing acuity in the frequency range from 500 to 8000 Hz. Biometrical modeling was used to quantify genetic and environmental influences.
Results
For individuals’ better ears, approximately two-thirds (65%–70%, 95% confidence interval [CI], 46%–75%) of the variance in hearing acuity in the middle and high frequency ranges could be accounted for by genetic factors. For the individuals’ poorer ear, which would be expected to show lower heritability, approximately one-half (41%–54%, 95% CI, 11%–67%) of the variance in the middle and high frequency ranges could be accounted for by genetic influences. Within a given frequency range, the same genetic factors influenced both the better and poorer ears. In contrast, although there was some overlap of genetic influences on the middle and high frequencies within a given ear, there were also some genetic influences that were specific to each frequency.
Conclusions
Results suggest that genetic effects play an important role in the level of hearing loss that often appears in late middle age. These data have important implications for identifying persons who may be especially vulnerable to environmental risk factors such as noise exposure and medications with ototoxic properties.
PMCID: PMC2945698  PMID: 18000151
19.  Additive Effects of Cognitive Function and Depressive Symptoms on Mortality in Elderly Community-Living Adults 
Background
Poor cognitive function and depressive symptoms are common in the elderly, frequently coexist, and are interrelated. Both risk factors are independently associated with mortality. Few studies have comprehensively described how the combination of poor cognitive function and depressive symptoms affect the risk for mortality. Our aim was to examine whether the combination of varying levels of cognitive function and depressive symptoms affect the risk of mortality in community-living elderly adults.
Methods
We studied 6301 elderly adults (mean age, 77 years; 62% women; 81% white) enrolled in the Asset and Health Dynamics Among the Oldest Old (AHEAD) study, a prospective study of community-living participants conducted from 1993 to 1995. Cognitive function and depressive symptoms were measured using two validated measures developed for the AHEAD study. On each measure, participants were divided into tertiles representing the best, middle, and worst scores, and then placed into one of nine mutually exclusive groups ranging from best functioning on both measures to worst functioning on both measures. Mortality rates were assessed in each of the nine groups. Cox proportional hazards models were used to control for potentially confounding characteristics such as demographics, education, income, smoking, alcohol consumption, comorbidity, and baseline functional impairment.
Results
During 2 years of follow-up, 9% (548) of the participants died. Together, cognitive function and depressive symptoms differentiated between elderly adults at markedly different risk for mortality, ranging from 3% in those with the best function on both measures to 16% in those with the worst function on both measures (p < .001). Furthermore, for each level of cognitive function, more depressive symptoms were associated with higher mortality rates, and for each level of depressive symptoms, worse cognitive function was associated with higher mortality rates. In participants with the best cognitive function, mortality rates were 3%, 5%, and 9% in participants with low, middle, and high depressive symptoms, respectively (p < .001 for trend). The corresponding rates were 6%, 7%, and 12% in participants with the middle level of cognitive function (p < .001 for trend), and 10%, 13%, and 16% in participants with the worst level of cognitive function (p < .001 for trend). After adjustment for confounders, participants with the worst function on both measures remained at considerably higher risk for death than participants with the best function on both measures (adjusted hazard ratio, 3.1; 95% confidence interval, 2.0–4.7).
Conclusions
Cognitive function and depressive symptoms can be used together to stratify elderly adults into groups that have significantly different rates of death. These two risk factors are associated with an increased risk in mortality in a progressive, additive manner.
PMCID: PMC2939722  PMID: 12730257
20.  Hormone-Treated Snell Dwarf Mice Regain Fertility But Remain Long Lived and Disease Resistant 
Snell dwarf mice have multiple hormonal deficits, but the way in which these deficits postpone aging are still uncertain. In this study, Snell dwarf mice received 11 weeks of growth hormone and thyroxine injections that increased their weight by approximately 45%, although they remained much smaller than controls. The hormone treatment also restored fertility to male dwarf mice. Despite these effects on growth and maturation, the hormone treatments did not diminish life span or lower the resistance of dwarf mice to cataracts and kidney disease. Administration of thyroxine in food throughout adult life did diminish longevity of Snell dwarf mice, although these mice remain longer lived than control animals. These results show that a 45% increase in body size does not impair longevity or disease resistance for dwarf mice of either sex, and that the exceptional longevity of Snell dwarf mice does not, at least for males, depend on prepubertal immaturity.
PMCID: PMC2924623  PMID: 15699523
21.  Emergency Department Utilization Patterns Among Older Adults 
Background
We identified 4-year (2 years before and 2 years after the index [baseline] interview) ED use patterns in older adults and the factors associated with them.
Methods
A secondary analysis of baseline interview data from the nationally representative Survey on Assets and Health Dynamics Among the Oldest Old linked to Medicare claims data. Participants were 4310 self-respondents 70 years old or older. Current Procedural Terminology (CPT) codes 99281 and 99282 identified low-intensity use, and CPT codes 99283–99285 identified high-intensity use. Exploratory factor analysis and multivariable multinomial logistic regression were used.
Results
The majority (56.6%) of participants had no ED visits during the 4-year period. Just 5.7% had only low-intensity ED use patterns, whereas 28.9% used the ED only for high-intensity visits, and 8.7% had a mixture of low-intensity and high-intensity use. Participants with lower immediate word recall scores and those who did not live in major metropolitan areas were more likely to be low-intensity-only ED users. Older individuals, those who did not live in rural counties, had greater morbidity and functional status burdens, and lower immediate word recall scores were more likely to be high-intensity-only ED users. Participants who were older, did not live in major cities, had lower education levels, had greater morbidity and functional status burdens, and lower immediate word recall scores were more likely to have mixed ED use patterns.
Conclusions
Nearly half of these older adults used the ED at least once over a 4-year period, with a mean annual ED use percentage of 18.4. Few, however, used the ED only for visits that may have been avoidable. This finding suggests that triaging Medicare patients would not decrease ED overcrowding, although continued surveillance is necessary to detect potential changes in ED use patterns among older adults.
PMCID: PMC2923576  PMID: 18314459
Emergency department; Utilization patterns; Medicare, Claims data
22.  Cholinergic Deficiency Hypothesis in Delirium: A Synthesis of Current Evidence 
Deficits in cholinergic function have been postulated to cause delirium and cognitive decline. This review examines current understanding of the cholinergic deficiency hypothesis in delirium by synthesizing evidence on potential pathophysiological pathways. Acetylcholine synthesis involves various precursors, enzymes, and receptors, and dysfunction in these components can lead to delirium. Insults to the brain, like ischemia and immunological stressors, can precipitously alter acetylcholine levels. Imbalances between cholinergic and other neurotransmitter pathways may result in delirium. Furthermore, genetic, enzymatic, and immunological overlaps exist between delirium and dementia related to the cholinergic pathway. Important areas for future research include identifying biomarkers, determining genetic contributions, and evaluating response to cholinergic drugs in delirium. Understanding how the cholinergic pathway relates to delirium may yield innovative approaches in the diagnosis, prevention, and treatment of this common, costly, and morbid condition.
PMCID: PMC2917793  PMID: 18693233
Acetylcholine; Delirium; Delirium in older persons; Dementia; Cholinergic deficiency
23.  Sarcopenia Accelerates at Advanced Ages in Fisher 344×Brown Norway Rats 
Although the age-dependent loss of muscle mass and strength, sarcopenia, is an inevitable process, its onset and progression are not well established. Here we defined the onset and the progression of sarcopenia in a healthy aging animal model, Fisher 344×Brown Norway rats. Vastus lateralis, rectus femoris, and vastus medialis muscles (three of the quadriceps muscles) were analyzed at 5 months of age and at 3-month intervals between 12 and 39 months of age. We found an age-dependent decline in muscle mass and fiber number and an increase in fiber atrophy and nonmuscle tissue. Significant changes of fiber number and muscle mass were not observed until very late in life (30–33 months) and were concurrent, whereas fiber cross-sectional area (CSA) gradually declined from maximum CSA (24 months). Sarcopenic declines identified between 30 and 36 months did not continue to 39 months, possibly due to the increased proportion of type I fibers.
PMCID: PMC2902273  PMID: 18840796
Sarcopenia; Fisher Brown Norway rats; Quadriceps muscles; Aging
24.  Association of Longer Telomeres With Better Health in Centenarians 
Prior animal model studies have demonstrated an association between telomere length and longevity. Our study examines telomere length in centenarians in good health versus poor health. Using DNA from blood lymphocytes, telomere length was measured by quantitative polymerase chain reaction in 38 sex- and age-matched centenarians (ages 97–108). “Healthy” centenarians (n = 19) with physical function in the independent range and the absence of hypertension, congestive heart failure, myocardial infarction, peripheral vascular disease, dementia, cancer, stroke, chronic obstructive pulmonary disease, and diabetes were compared to centenarians with physical function limitations and ≥2 of the above conditions (n = 19). Healthy centenarians had significantly longer telomeres than did unhealthy centenarians (p = .0475). Our study demonstrated that investigations of the association between telomere length and exceptional longevity must take into account the health status of the individuals. This raises the possibility that perhaps it is not exceptional longevity but one's function and health that may be associated with telomere length.
PMCID: PMC2892727  PMID: 18772468
Telomere length; Centenarian; Longevity; Morbidity
25.  GAIT VARIABILITY AND THE RISK OF INCIDENT MOBILITY DISABILITY IN COMMUNITY-DWELLING OLDER ADULTS 
Background
Gait speed is a strong predictor of incident walking disability. The objective was to determine if gait variability adds to the prediction of incident mobility disability independent of gait speed.
Methods
Participants included 379 older adults (mean age= 79 years; 78% Caucasian, and 40% men) in the Cardiovascular Health Study at the Pittsburgh site. All could ambulate independently and reported no difficulty walking a half mile. Gait characteristics were determined from a 4 meter computerized walkway. For each gait parameter, variability was defined as the standard deviation from the individual steps from two passes. Incident walking disability was obtained by phone interview every 6 months for 54 months and was defined as new difficulty walking a half mile or inability to walk a half mile.
Results
Of the 379 participants, 222 (58.6%) developed incident mobility disability. In unadjusted Cox proportional hazards models gait speed, mean step length, mean stance time, and stance time variability were associated with incident mobility disability. After adjusting for gait speed, demographics, chronic conditions, prescription medications, health status, and physical activity level, only stance time variability remained an important indicator of disability. In the adjusted model, an increase in stance time variability of 0.01 seconds was associated with a 13% higher incidence of mobility disability (hazard ratio 1.13, 95% confidence interval 1.01 to 1.27).
Conclusions
Stance time variability is an independent predictor of future mobility disability. Future efforts are needed to determine whether interventions that decrease stance time variability will also delay mobility disability.
PMCID: PMC2858390  PMID: 17895436

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