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1.  Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE Study randomized clinical trial 
JAMA  2014;311(23):2387-2396.
SUMMARY
Importance
In older adults reduced mobility is common and is an independent risk factor for morbidity, hospitalization, disability, and mortality. Limited evidence suggests that physical activity may help prevent mobility disability; however, there are no definitive clinical trials examining if physical activity prevents or delays mobility disability.
Objective
To test the hypothesis that a long-term structured physical activity program is more effective than a health education program (also referred to as a successful aging program) in reducing the risk of major mobility disability.
Design, Setting, and Participants
The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial that enrolled participants between February 2010 and December 2011, who participated for an average of 2.6 years. Follow-up ended in December 2013. Outcome assessors were blinded to the intervention assignment. Participants were recruited from urban, suburban and rural communities at 8 field centers throughout the US. We randomized a volunteer sample of 1,635 sedentary men and women aged 70–89 years who had physical limitations, defined as a score on the Short Physical Performance Battery of 9 or below, but were able to walk 400 m.
Interventions
Participants were randomized to a structured moderate intensity physical activity program (n=818) done in a center and at home that included including aerobic, resistance and flexibility training activities or to a health education program (n=817) consisting of workshops on topics relevant to older adults and upper extremity stretching exercises.
Main Outcomes and Measures
The primary outcome was major mobility disability objectively defined by loss of ability to walk 400 m.
Results
Incident major mobility disability occurred in 30.1% (n=246/818) of physical activity and 35.5% (n=290/817) of health education participants (HR=0.82, 95%CI=0.69–0.98, p=0.03). Persistent mobility disability was experienced by 120/818 (14.7%) physical activity and 162/817 (19.8%) health education participants (HR=0.72; 95%CI=0.57–0.91; p=0.006). Serious adverse events were reported by 404/818 (49.4%) of the physical activity and 373/817 (45.7%) of the health education participants (Risk Ratio=1.08; 95%CI=0.98–1.20).
Conclusions and Relevance
A structured moderate intensity physical activity program, compared with a health education program, reduced major mobility disability over 2.6 years among older adults at risk of disability. These findings suggest mobility benefit from such a program in vulnerable older adults.
Registration
ClinicalsTrials.gov identifier NCT01072500.
doi:10.1001/jama.2014.5616
PMCID: PMC4266388  PMID: 24866862
2.  PERFORMANCE OF A COMPUTER-BASED ASSESSMENT OF COGNITIVE FUNCTION MEASURES IN TWO COHORTS OF SENIORS 
International journal of geriatric psychiatry  2013;28(12):10.1002/gps.3949.
Background
Computer-administered assessment of cognitive function is being increasingly incorporated in clinical trials, however its performance in these settings has not been systematically evaluated.
Design
The Seniors Health and Activity Research Program (SHARP) pilot trial (N=73) developed a computer-based tool for assessing memory performance and executive functioning. The Lifestyle Interventions and Independence for Seniors (LIFE) investigators incorporated this battery in a full scale multicenter clinical trial (N=1635). We describe relationships that test scores have with those from interviewer-administered cognitive function tests and risk factors for cognitive deficits and describe performance measures (completeness, intra-class correlations).
Results
Computer-based assessments of cognitive function had consistent relationships across the pilot and full scale trial cohorts with interviewer-administered assessments of cognitive function, age, and a measure of physical function. In the LIFE cohort, their external validity was further demonstrated by associations with other risk factors for cognitive dysfunction: education, hypertension, diabetes, and physical function. Acceptable levels of data completeness (>83%) were achieved on all computer-based measures, however rates of missing data were higher among older participants (odds ratio=1.06 for each additional year; p<0.001) and those who reported no current computer use (odds ratio=2.71; p<0.001). Intra-class correlations among clinics were at least as low (ICC≤0.013) as for interviewer measures (ICC≤0.023), reflecting good standardization. All cognitive measures loaded onto the first principal component (global cognitive function), which accounted for 40% of the overall variance.
Conclusion
Our results support the use of computer-based tools for assessing cognitive function in multicenter clinical trials of older individuals.
doi:10.1002/gps.3949
PMCID: PMC3775886  PMID: 23589390
Cognitive function; Clinical trial; Performance measures
3.  Risk of Hospitalized Gastrointestinal Bleeding in Persons Randomized to Diuretic, ACE-Inhibitor, or Calcium-Channel Blocker in ALLHAT 
Calcium channel-blockers (CCB) are an important class of medication useful in the treatment of hypertension. Several observational studies have suggested an association between CCB therapy and gastrointestinal hemorrhage. Using administrative databases, we re-examined in a post-hoc analysis whether the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) participants randomized to the calcium-channel blocker amlodipine had a greater risk of hospitalized gastrointestinal bleeding (a pre-specified outcome) compared to those randomized to the diuretic chlorthalidone or the ACE-inhibitor lisinopril. Participants randomized to chlorthalidone did not have a reduced risk for gastrointestinal bleeding hospitalizations compared to participants randomized to amlodipine (HR, 1.09, 95% CI 0.92-1.28). Those randomized to lisinopril were at increased risk of gastrointestinal bleeding compared those randomized to chlorthalidone (HR, 1.16; 95% CI, 1.00-1.36). In a post-hoc comparison, participants assigned lisinopril therapy had a higher risk of hospitalized gastrointestinal hemorrhage (HR,1.27, 95% CI 1.06-1.51) versus those assigned to amlodipine. In-study use of atenolol prior to first gastrointestinal hemorrhage was related to a lower incidence of GI bleeding (HR, 0.69; 95% CI, 0.57-0.83). In conclusion, hypertensive patients on amlodipine do not have an increased risk of GI bleeding hospitalizations compared to those on either chlorthalidone or lisinopril.
doi:10.1111/jch.12180
PMCID: PMC3844932  PMID: 24283598
4.  The influence of subclinical cardiovascular disease and related risk factors on cognition in type 2 diabetes mellitus: The DHS-Mind study 
We hypothesized that measures of coronary artery calcified plaque (CAC) collected at baseline from the Diabetes Heart Study (DHS) would explain associations between cognition and diabetes collected at follow-up approximately 7 years later. The DHS is a sibling study of cardiovascular disease (CVD) in a cohort with a high prevalence of type 2 diabetes (~80%). Associations between baseline CAC and cognitive performance were tested using generalized estimating equations and mixed effects models to adjust for familial relationships. Diabetes status was associated (p<0.05) with poorer performance on tests of verbal memory, processing speed, and semantic fluency adjusting for age, sex, education, and hypertension status. As hypothesized, including CAC in the statistical model attenuated this association. Additionally, CAC and fasting glucose predicted performance in tasks not associated with diabetes status in this study (Stroop Task, Phonemic Fluency). These results confirm work attributing the heterogeneity of cognitive outcomes in type 2 diabetes to subclinical risk factors that combine to affect different aspects of brain function. Importantly, these results imply that risk factor intervention should begin before comorbidities, particularly CVD, become clinically apparent.
doi:10.1016/j.jdiacomp.2013.04.004
PMCID: PMC3770734  PMID: 23659774
type 2 diabetes; cardiovascular disease; atherosclerosis; cognition
5.  The LIFE Cognition Study: design and baseline characteristics 
Observational studies have shown beneficial relationships between exercise and cognitive function. Some clinical trials have also demonstrated improvements in cognitive function in response to moderate–high intensity aerobic exercise; however, these have been limited by relatively small sample sizes and short durations. The Lifestyle Interventions and Independence for Elders (LIFE) Study is the largest and longest randomized controlled clinical trial of physical activity with cognitive outcomes, in older sedentary adults at increased risk for incident mobility disability. One LIFE Study objective is to evaluate the effects of a structured physical activity program on changes in cognitive function and incident all-cause mild cognitive impairment or dementia. Here, we present the design and baseline cognitive data. At baseline, participants completed the modified Mini Mental Status Examination, Hopkins Verbal Learning Test, Digit Symbol Coding, Modified Rey–Osterrieth Complex Figure, and a computerized battery, selected to be sensitive to changes in speed of processing and executive functioning. During follow up, participants completed the same battery, along with the Category Fluency for Animals, Boston Naming, and Trail Making tests. The description of the mild cognitive impairment/dementia adjudication process is presented here. Participants with worse baseline Short Physical Performance Battery scores (prespecified at ≤7) had significantly lower median cognitive test scores compared with those having scores of 8 or 9 with modified Mini Mental Status Examination score of 91 versus (vs) 93, Hopkins Verbal Learning Test delayed recall score of 7.4 vs 7.9, and Digit Symbol Coding score of 45 vs 48, respectively (all P<0.001). The LIFE Study will contribute important information on the effects of a structured physical activity program on cognitive outcomes in sedentary older adults at particular risk for mobility impairment. In addition to its importance in the area of prevention of cognitive decline, the LIFE Study will also likely serve as a model for exercise and other behavioral intervention trials in older adults.
doi:10.2147/CIA.S65381
PMCID: PMC4154884  PMID: 25210447
exercise; physical activity; older adults; dementia
6.  The Demographic and Medical Correlates of Plasma Aβ40 and Aβ42 
Plasma amyloid beta-42 (Aβ42) and Aβ42/Aβ40 are increasingly recognized as biomarkers for dementia, with low levels indicating increased risk. Little is known about the demographic and medical correlates of plasma Aβ40 or Aβ42. In 997 community-dwelling, non-demented older adults from the Health, Aging and Body Composition Study, we determined the cross-sectional association between a wide range of demographic and medical variables with Aβ40 and Aβ42. In multivariate stepwise linear regression models, Aβ40 was significantly associated with race (β=−14.70, F=22.01, p<0.0001), age (β=1.34, F=6.39, p=0.01), creatinine (β=52.91, F=151.77, p<0.0001), and serum brain-derived neurotrophic factor (BDNF) (β=−0.0004, F=7.34, p=0.007); Aβ42 was significantly associated with race (β=−3.72, F=30.83, p<0.0001), sex (β=1.39, F=4.32, p=0.04), education (β=1.50, F=4.78, p=0.03), Apolipoprotein E (APOE) e4 allele status (β=−2.82, F=16.57, p<0.0001), and creatinine (β=9.32, F=120.09, p<0.0001). These correlates should be considered as potential confounders in future studies investigating plasma Aβ as a biomarker of dementia. Understanding fully how these correlates mediate or modify the association between plasma Aβ and dementia will be a fundamental step in determining the biological pathways through which plasma Aβ40 and Aβ42 are associated with dementia, and in determining their full potential as biomarkers.
doi:10.1097/WAD.0b013e318260a8cb
PMCID: PMC3473156  PMID: 22732677
Plasma amyloid beta; dementia; cognitive decline; biomarker; epidemiology
7.  Changes in Cognitive Function in a Randomized Trial of Physical Activity: Results of the Lifestyle Interventions and Independence for Elders Pilot Study 
Background
Cognitive impairment is an important contributor to disability. Limited clinical trial evidence exists regarding the impact of physical exercise on cognitive function (CF). We report results of a pilot study to provide estimates of the relative impact of physical activity (PA) on 1-year changes in cognitive outcomes and to characterize relationships between changes in mobility disability and changes in cognition in older adults at increased risk for disability.
Methods
Sedentary persons (102) at increased risk for disability (aged 70–89 years) were randomized to moderate-intensity PA or health education. Participants were administered the Digit Symbol Substitution Test (DSST), Rey Auditory Verbal Learning Test (RAVLT), modified Stroop test, and Modified Mini-Mental State Examination at baseline and 1 year.
Results
Group differences were not significant but improvements in cognitive scores were associated with improvements in physical function. Specifically, the DSST significantly correlated with change in the Short Physical Performance Battery score (r = .38, p = .0002), in chair stand score (r = .26, p = .012), in balance score (r = .21, p = .046), and in 400-m gait speed (r = .15, p = .147). Change recall on the RAVLT and in the Stroop test was also positively correlated with changes in chair stand and balance, respectively.
Conclusions
These results provide further support for the benefits of exercise on CF in older adults. An adequately powered clinical trial of PA involving older adults at increased risk for cognitive disability is needed to expand the indications for prescribing exercise for prevention of decline in brain function.
doi:10.1093/gerona/glp014
PMCID: PMC2679423  PMID: 19244157
Exercise; Cognition; Aging; Prevention; LIFE study
8.  Low 25-Hydroxyvitamin D Predicts the Onset of Mobility Limitation and Disability in Community-Dwelling Older Adults: The Health ABC Study 
Background.
Although low 25-hydroxyvitamin D (25(OH)D) is prevalent among older adults and is associated with poor physical function, longitudinal studies examining vitamin D status and physical function are lacking. We examined the association between 25(OH)D, parathyroid hormone (PTH), and the onset of mobility limitation and disability over 6 years of follow-up in community-dwelling, initially well-functioning older adults participating in the Health, Aging and Body Composition study (n = 2,099).
Methods.
Serum 25(OH)D and PTH were measured at the 12-month follow-up visit (1998–1999). Mobility limitation and disability (any/severe difficulty walking 1/4 mile or climbing 10 steps) was assessed semiannually over 6 years of follow-up. The association between 25(OH)D, PTH, and mobility limitation and disability was examined using Cox proportional hazard regression models adjusted for demographics, season, behavioral characteristics, and chronic conditions.
Results.
At baseline, 28.9% of the participants had 25(OH)D <50 nmol/L and 36.1% had 25(OH)D of 50 to <75 nmol/L. Participants with 25(OH)D <50 and 50 to <75 nmol/L were at greater risk of developing mobility limitation (HR (95% CI): 1.29 (1.04–1.61) and 1.27 (1.05–1.53), respectively) and mobility disability (HR (95% CI): 1.93 (1.32–2.81) and 1.30 (0.92–1.83), respectively) over 6 years of follow-up compared with participants with 25(OH)D ≥75 nmol/L. Elevated PTH, however, was not significantly associated with developing mobility limitation or disability.
Conclusions.
Low 25(OH)D was associated with an increased risk of mobility limitation and disability in community-dwelling, initially well-functioning black and white older adults. Prevention or treatment of low 25(OH)D may provide a pathway for reducing the burden of mobility disability in older adults.
doi:10.1093/gerona/gls136
PMCID: PMC3598356  PMID: 22573914
25-hydroxyvitamin D; Mobility limitation; Vitamin D; Parathyroid hormone
9.  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.
doi:10.1093/aje/kws147
PMCID: PMC3571245  PMID: 23118104
aged; 25-hydroxyvitamin D; muscle strength; physical performance
10.  Alzheimer's Disease Risk Assessment Using Large-Scale Machine Learning Methods 
PLoS ONE  2013;8(11):e77949.
The goal of this work is to introduce new metrics to assess risk of Alzheimer's disease (AD) which we call AD Pattern Similarity (AD-PS) scores. These metrics are the conditional probabilities modeled by large-scale regularized logistic regression. The AD-PS scores derived from structural MRI and cognitive test data were tested across different situations using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. The scores were computed across groups of participants stratified by cognitive status, age and functional status. Cox proportional hazards regression was used to evaluate associations with the distribution of conversion times from mild cognitive impairment to AD. The performances of classifiers developed using data from different types of brain tissue were systematically characterized across cognitive status groups. We also explored the performance of anatomical and cognitive-anatomical composite scores generated by combining the outputs of classifiers developed using different types of data. In addition, we provide the AD-PS scores performance relative to other metrics used in the field including the Spatial Pattern of Abnormalities for Recognition of Early AD (SPARE-AD) index and total hippocampal volume for the variables examined.
doi:10.1371/journal.pone.0077949
PMCID: PMC3826736  PMID: 24250789
11.  The Feasibility of Inpatient Geriatric Assessment for Older Adults Receiving Induction Chemotherapy for Acute Myelogenous Leukemia 
OBJECTIVES
To test the feasibility and utility of a bedside geriatric assessment (GA) to detect impairment in multiple geriatric domains in older adults initiating chemotherapy for acute myelogenous leukemia (AML).
DESIGN
Prospective observational cohort study.
SETTING
Single academic institution.
PARTICIPANTS
Individuals aged 60 and older with newly diagnosed AML and planned chemotherapy.
MEASUREMENTS
Bedside GA was performed during inpatient exmination for AML. GA measures included the modified Mini-Mental State Examination; Center for Epidemiologic Studies Depression Scale; Distress Thermometer, Pepper Assessment Tool for Disability (includes self- reported activities of daily living (ADLs), instrumental ADLs, and mobility questions); Short Physical Performance Battery (includes timed 4-m walk, chair stands, standing balance); grip strength, and Hematopoietic Cell Transplantation Comorbidity Index.
RESULTS
Of 54 participants (mean age 70.8 ± 6.4) eligible for this analysis, 92.6% completed the entire GA battery (mean time 44.0 ± 14 minutes). The following impairments were detected: cognitive impairment, 31.5%; depression, 38.9%; distress, 53.7%; impairment in ADLs, 48.2%; impaired physical performance, 53.7%; and comorbidity, 46.3%. Most were impaired in one (92.6%) or more (63%) functional domains. For the 38 participants rated as having good performance status according to standard oncologic assessment (Eastern Cooperative Oncology Performance Scale score ≤1), impairments in individual GA measures ranged from 23.7% to 50%. Significant variability in cognitive, emotional, and physical status was detected even after stratification according to tumor biology (cytogenetic risk group classification).
CONCLUSION
Inpatient GA was feasible and added new information to standard oncology assessment, which may be important for stratifying therapeutic risk in older adults with AML.
doi:10.1111/j.1532-5415.2011.03614.x
PMCID: PMC3782375  PMID: 22091497
geriatric assessment; acute myelogenous leukemia; cancer; functional status; elderly
12.  A Randomized Controlled Trial of Telephone-Delivered Cognitive-Behavioral Therapy for Late-life Anxiety Disorders 
Objectives
Older adults face a number of barriers to receiving psychotherapy, such as a lack of transportation and access to providers. One way to overcome such barriers is to provide treatment by telephone. The purpose of this study was to examine the effects of cognitive behavioral therapy delivered by telephone (CBT-T) to older adults diagnosed with an anxiety disorder.
Design
Randomized controlled trial.
Setting
Participants' homes.
Participants
Sixty participants ≥ 60 years of age with a diagnosis of Generalized Anxiety Disorder, Panic Disorder, or Anxiety Disorder Not Otherwise Specified.
Intervention
CBT-T vs. information-only comparison.
Measurements
Co-primary outcomes included worry (Penn State Worry Questionnaire) and general anxiety (State Trait Anxiety Inventory). Secondary outcomes included clinician-rated anxiety (Hamilton Anxiety Rating Scale), anxiety sensitivity (Anxiety Sensitivity Index), depressive symptoms (Beck Depression Inventory), quality of life (SF-36), and sleep (Insomnia Severity Index). Assessments were completed prior to randomization, immediately upon completion of treatment, and 6 months after completing treatment.
Results
CBT-T was superior to information-only in reducing general anxiety (ES = 0.71), worry (ES = 0.61), anxiety sensitivity (ES = 0.85), and insomnia (ES = 0.82) at the post-treatment assessment; however, only the reductions in worry were maintained by the 6 month follow-up assessment (ES = 0.80).
Conclusions
These results suggest that CBT-T may be efficacious in reducing anxiety and worry in older adults, but additional sessions may be needed to maintain these effects.
doi:10.1097/JGP.0b013e31822ccd3e
PMCID: PMC3407971  PMID: 22828172
anxiety; cognitive-behavioral therapy; elderly; Generalized Anxiety Disorder; Panic Disorder; telephone-delivered psychotherapy
13.  Strength Training for Arthritis Trial (START): design and rationale 
Background
Muscle loss and fat gain contribute to the disability, pain, and morbidity associated with knee osteoarthritis (OA), and thigh muscle weakness is an independent and modifiable risk factor for it. However, while all published treatment guidelines recommend muscle strengthening exercise to combat loss of muscle mass and strength in knee OA patients, previous strength training studies either used intensities or loads below recommended levels for healthy adults or were generally short, lasting only 6 to 24 weeks. The efficacy of high-intensity strength training in improving OA symptoms, slowing progression, and affecting the underlying mechanisms has not been examined due to the unsubstantiated belief that it might exacerbate symptoms. We hypothesize that in addition to short-term clinical benefits, combining greater duration with high-intensity strength training will alter thigh composition sufficiently to attain long-term reductions in knee-joint forces, lower pain levels, decrease inflammatory cytokines, and slow OA progression.
Methods/Design
This is an assessor-blind, randomized controlled trial. The study population consists of 372 older (age ≥ 55 yrs) ambulatory, community-dwelling persons with: (1) mild-to-moderate medial tibiofemoral OA (Kellgren-Lawrence (KL) = 2 or 3); (2) knee neutral or varus aligned knee ( -2° valgus ≤ angle ≤ 10° varus); (3) 20 kg.m-2 ≥ BMI ≤ 45 kg.m-2; and (3) no participation in a formal strength-training program for more than 30 minutes per week within the past 6 months. Participants are randomized to one of 3 groups: high-intensity strength training (75-90% 1Repetition Maximum (1RM)); low-intensity strength training (30-40%1RM); or healthy living education. The primary clinical aim is to compare the interventions’ effects on knee pain, and the primary mechanistic aim is to compare their effects on knee-joint compressive forces during walking, a mechanism that affects the OA disease pathway. Secondary aims will compare the interventions’ effects on additional clinical measures of disease severity (e.g., function, mobility); disease progression measured by x-ray; thigh muscle and fat volume, measured by computed tomography (CT); components of thigh muscle function, including hip abductor strength and quadriceps strength, and power; additional measures of knee-joint loading; inflammatory and OA biomarkers; and health-related quality of life.
Discussion
Test-retest reliability for the thigh CT scan was: total thigh volume, intra-class correlation coefficients (ICC) = 0.99; total fat volume, ICC = 0.99, and total muscle volume, ICC = 0.99. ICC for both isokinetic concentric knee flexion and extension strength was 0.93, and for hip-abductor concentric strength was 0.99. The reliability of our 1RM testing was: leg press, ICC = 0.95; leg curl, ICC = 0.99; and leg extension, ICC = 0.98. Results of this trial will provide critically needed guidance for clinicians in a variety of health professions who prescribe and oversee treatment and prevention of OA-related complications. Given the prevalence and impact of OA and the widespread availability of this intervention, assessing the efficacy of optimal strength training has the potential for immediate and vital clinical impact.
Trial registration
ClinicalTrials.gov, NCT01489462
doi:10.1186/1471-2474-14-208
PMCID: PMC3722013  PMID: 23855596
14.  Poor Cognitive Function and Risk of Severe Hypoglycemia in Type 2 Diabetes 
Diabetes Care  2012;35(4):787-793.
OBJECTIVE
Self-management of type 2 diabetes including avoidance of hypoglycemia is complex, but the impact of cognition on safe self-management is not well understood. This study aimed to assess the effect of baseline cognitive function and cognitive decline on subsequent risk of severe hypoglycemia and to assess the effect of different glycemic strategies on these relationships.
RESEARCH DESIGN AND METHODS
Prospective cohort analysis of data from the ACCORD trial included 2,956 adults aged ≥55 years with type 2 diabetes and additional cardiovascular risk factors. Cognitive tests (Digit Symbol Substitution Test [DSST], Rey Auditory Verbal Learning Test, Stroop Test, and Mini Mental Status Examination) were conducted at baseline and 20 months. Study outcomes were incident confirmed severe hypoglycemia requiring medical assistance (HMA) and hypoglycemia requiring any assistance (HAA).
RESULTS
After a median 3.25-year follow-up, a 5-point-poorer baseline score on the DSST was predictive of a first episode of HMA (hazard ratio 1.13 [95% CI 1.08–1.18]). Analyses of the other cognitive tests and of HAA were consistent with the DSST results. Cognitive decline over 20 months increased the risk of subsequent hypoglycemia to a greater extent in those with lower baseline cognitive function (Pinteraction = 0.037). Randomization to an intensive versus standard glycemic strategy had no impact on the relationship between cognitive function and the risk of severe hypoglycemia.
CONCLUSIONS
Poor cognitive function increases the risk of severe hypoglycemia in patients with type 2 diabetes. Clinicians should consider cognitive function in assessing and guiding their patients regarding safe diabetes self-management regardless of their glycemic targets.
doi:10.2337/dc11-1855
PMCID: PMC3308284  PMID: 22374637
15.  Effects of randomization to intensive glucose lowering on brain structure and function in type 2 diabetes ACCORD Memory in Diabetes Study 
Lancet Neurology  2011;10(11):969-977.
Background
Persons with type 2 diabetes (T2D) are at risk for cognitive impairment and brain atrophy. The ACCORD Memory in Diabetes (MIND) Study investigated whether persons randomized to an intensive glycaemic therapeutic strategy targeting HbA1c to <6% had better cognitive function and a larger brain volume at 40 months than persons randomized to a standard strategy targeting HbA1c to 7%–7.9%.
Methods
ACCORD MIND was a double 2×2 factorial parallel group randomised trial conducted in 52 clinical sites in North America. Participants [age 55 – <80 years] with T2D, high HbA1c concentrations (>7.5%), and at high risk for cardiovascular events were randomised to treatment groups using a centralized web-based system. Clinic staff and participants were not blinded to treatment arm. The cognitive primary outcome, the Digit Symbol Substitution Test (DSST) score, was assessed at baseline, 20 and 40 months. Total brain volume (TBV), the primary brain structure outcome, was assessed with MRI at baseline and 40 months in a sub-set of 632 participants. All participants with follow-up data were included in the primary analyses. In February, 2008, increased mortality risk led to the termination of the intensive therapy and transition of those participants to standard glycaemic treatment.
Results
Randomised patients (n=2977; mean age 62.3 years) were consecutively enrolled; the final analysis included 1358 intensive and 1416 standard arm participants with a 20 or 40 month DSST score. Of the 614 with a baseline MRI, 230 intensive and 273 standard therapy participants were included in the analysis. There was no treatment difference in the DSST score. The intensive group had a greater TBV than the standard group (difference, 4.62; 95% CI 2.0 to7.3 cm3; p=0.0007).
Interpretation
Although significant differences in TBV favored the intensive therapy, cognitive outcomes were not different. Combined with the unfavorable effects on other ACCORD outcomes, MIND findings do not support using intensive therapy to reduce the adverse effects of diabetes on the brain in patients similar to MIND participants. (ClinicalTrials.gov number, NCT00182910).
doi:10.1016/S1474-4422(11)70188-0
PMCID: PMC3333485  PMID: 21958949
16.  Subclinical Vascular Disease Burden and Risk for Death and Cardiovascular Events in Older Community Dwellers 
Background.
Individual measures and previous composite measures of subclinical vascular disease defined high risk for cardiovascular events, but did not detect low and modest risk. A different approach might better describe the spectrum from low to high risk.
Methods and Results.
In the Cardiovascular Health Study, 3,252 participants without history of clinical cardiovascular disease (M ± SD 74.3 years ± 5.1, 63% women, 17% African Americans) had noninvasive vascular assessments in 1992–1993. We assigned a score of 0, 1, or 2 (no, mild, or severe abnormalities) to ankle–arm index, electrocardiogram, and common carotid intima-media thickness, based on clinical cutoffs. A summary index (range 0–6, absent to severe disease) summed individual scores. Abdominal aortic ultrasound and brain magnetic resonance imaging were collected in a subsample. Mortality and incident cardiovascular events were identified through June 2008. Event and death rates increased across index grades. Comparing grades 1 to 5+ with absent disease, and adjusting for demographics, hazard ratios for cardiovascular events within 8 years ranged from 1.1 (95% confidence interval 0.8–1.6) to 4.7 (3.4–6.9) and, for mortality, from 1.5 (1.0–2.3) to 5.0 (3.3–7.7) (p for trend across grades <.001 for both outcomes). Adjustment for cardiovascular risk factors did not substantially change the associations. The index improved mortality risk classification over demographics and risk factors in participants who did not die during the follow-up. Including in the index the aortic ultrasound and the brain magnetic resonance imaging further improved risk classification.
Conclusions.
Older adults with minimal subclinical vascular disease had low cardiovascular events risk and mortality. This approach might more fully account for vascular burden.
doi:10.1093/gerona/glr069
PMCID: PMC3202905  PMID: 21705627
Epidemiology; Aging; Atherosclerosis; Cardiovascular disease; Mortality
17.  Biomarkers of Renal Function and Cognitive Impairment in Patients With Diabetes 
Diabetes Care  2011;34(8):1827-1832.
OBJECTIVE
Kidney disease is associated with cognitive impairment in studies of nondiabetic adults. We examined the cross-sectional relation between three measures of renal function and performance on four measures of cognitive function in the Action to Control Cardiovascular Risk in Diabetes Memory in Diabetes (ACCORD-MIND) study.
RESEARCH DESIGN AND METHODS
The relationships among estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (n = 2,968), albumin/creatinine ratio (ACR) ≥30 μg/mg (n = 2,957), and cystatin C level >1.0 mg/L (n = 532) with tertile of performance on the Mini-Mental State Examination, Rey Auditory Verbal Learning Test (RAVLT), Digit Symbol Substitution Test (DSST), and Stroop Test of executive function were measured.
RESULTS
In adjusted logistic regression models, ACR ≥30 μg/mg was associated with performance in the lowest tertile, compared with the highest two tertiles, on the RAVLT (odds ratio 1.30, 95% CI 1.09–1.56, P = 0.006), equivalent to 3.6 years of aging, and on the DSST (1.47, 1.20–1.80, P = 0.001), equivalent to 3.7 years of aging. Cystatin C >1.0 mg/L was borderline associated with the lowest tertile on the DSST (1.81, 0.93–3.55, P = 0.08) and Stroop (1.78, 0.97–3.23, P = 0.06) in adjusted models. eGFR was not associated with any measure of cognitive performance.
CONCLUSIONS
In diabetic people with HbA1c >7.5% at high risk for cardiovascular disease, decreased cognitive function was associated with kidney disease as measured by ACR, a measure of microvascular endothelial pathology, and cystatin C, a marker of eGFR.
doi:10.2337/dc11-0186
PMCID: PMC3142061  PMID: 21715519
18.  The Lifestyle Interventions and Independence for Elders Study: Design and Methods 
Background.
As the number of older adults in the United States rises, maintaining functional independence among older Americans has emerged as a major clinical and public health priority. Older people who lose mobility are less likely to remain in the community; demonstrate higher rates of morbidity, mortality, and hospitalizations; and experience a poorer quality of life. Several studies have shown that regular physical activity improves functional limitations and intermediate functional outcomes, but definitive evidence showing that major mobility disability can be prevented is lacking. A Phase 3 randomized controlled trial is needed to fill this evidence gap.
Methods.
The Lifestyle Interventions and Independence for Elders (LIFE) Study is a Phase 3 multicenter randomized controlled trial designed to compare a supervised moderate-intensity physical activity program with a successful aging health education program in 1,600 sedentary older persons followed for an average of 2.7 years.
Results.
LIFE's primary outcome is major mobility disability, defined as the inability to walk 400 m. Secondary outcomes include cognitive function, serious fall injuries, persistent mobility disability, the combined outcome of major mobility disability or death, disability in activities of daily living, and cost-effectiveness.
Conclusions.
Results of this study are expected to have important public health implications for the large and growing population of older sedentary men and women.
doi:10.1093/gerona/glr123
PMCID: PMC3193523  PMID: 21825283
Disability; Physical activity; Exercise; Geriatrics; Physical function
19.  The Relationship Between Cognitive Function and Physical Performance in Older Women: Results From the Women’s Health Initiative Memory Study 
Background
Cognitive function and physical performance are associated, but the common sequence of cognitive and physical decline remains unclear.
Methods
In the Women’s Health Initiative Memory Study (WHIMS) clinical trial, we examined associations at baseline and over a 6-year follow-up period between the Modified Mini-Mental State (3MS) Examination and three physical performance measures (PPMs): gait speed (meters/second), chair stands (number of stands in 15 seconds), and grip strength (kilograms). Using mixed models, we examined the baseline 3MS as predictor of change in PPM, change in the 3MS as predictor of change in PPM, and baseline PPM as predictors of 3MS change.
Results
Among 1,793 women (mean age = 70.3 years, 89% white, and mean 3MS score = 95.1), PPM were weakly correlated with 3MS—gait speed: r = .06, p = .02; chair stands: r = .09, p < .001; and grip strength: r = .10, p < .001. Baseline 3MS score was associated with subsequent PPM decline after adjustment for demographics, comorbid conditions, medications, and lifestyle factors. For every SD (4.2 points) higher 3MS score, 0.04 SD (0.04 m/s) less gait speed and 0.05 SD (0.29 kg) less grip strength decline is expected over 6 years (p ≤ .01 both). Changes in 3MS and PPM were associated, particularly with chair stands and grip strength (p < .003 both). Baseline PPMs were not associated with subsequent 3MS change.
Conclusions
Baseline global cognitive function and change in global cognitive function were associated with physical performance change, but baseline physical performance was not associated with cognitive change in this cohort. These analyses support the hypothesis that cognitive decline on average precedes or co-occurs with physical performance decline.
doi:10.1093/gerona/glp149
PMCID: PMC2822281  PMID: 19789197
Cognitive function; Physical performance; Cognition; Physical function
20.  Feasibility and Acceptability of Bibliotherapy and Telephone Sessions for the Treatment of Late-life Anxiety Disorders 
Clinical gerontologist  2010;33(1):62-68.
This article describes the development of Biblio and Telephone Therapy or BTT, a cognitive-behavioral treatment program for late-life anxiety disorders. Although studies have examined bibliotherapy for the treatment of late-life depression, none have studied it as a format for treating late-life anxiety. The application of this treatment to 4 older adults with Generalized Anxiety Disorder (GAD) and/or Panic Disorder (PD) is described and benefits, advantages and limitations are discussed.
doi:10.1080/07317110903344968
PMCID: PMC2909126  PMID: 20661315
21.  Coronary heart disease in moderately hypercholesterolemic, hypertensive black and non-black patients randomized to pravastatin vs. usual care: The Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial (ALLHAT-LLT) 
American heart journal  2009;158(6):948-955.
Background
In previous analyses in the Antihypertensive and Lipid-Lowering to Prevent Heart Attack Trial (ALLHAT), Blacks had a significantly lower risk of coronary heart disease (CHD) in the pravastatin compared to the usual care group, while non-Blacks had no benefit from pravastatin. No previous statin trial has enrolled enough minority participants to analyze the results separately in Blacks.
Objectives
To determine if apparent racial differences in CHD in ALLHAT are explained by differences in baseline characteristics, adherence during the trial, or achieved blood pressure and lipid lowering.
Methods
This was a pre-specified subgroup analysis of a randomized controlled trial. Hypertensive, moderately hypercholesterolemic participants were assigned to open-label pravastatin (40 mg/day) or usual care. The outcome was a composite of non-fatal myocardial infarction and fatal CHD. We performed intention-to-treat survival analyses using Cox proportional hazards models, adjusting for baseline covariates (age, sex, aspirin use, history of CHD and diabetes, and baseline hypertension treatment), and time-varying levels of blood pressure and total cholesterol.
Results
After adjustment for baseline characteristics, there remained a significant interaction between race and treatment group (p=0.02). In stratified models, Blacks in the pravastatin group had a 29% lower risk of CHD (HR 0.71, 95% CI 0.57 – 0.90, p=0.005) compared to usual care, while non-Blacks had no benefit (HR 1.00, 95% CI 0.85 – 1.19, p=0.95). With further adjustment for achieved blood pressure and total cholesterol, the HR in Blacks was 0.65 (95% CI 0.45 – 0.96, p=0.03) and in non-Blacks was 1.07 (95% CI 0.81 – 1.41, p=0.65).
Conclusions
Our results suggest that pravastatin is effective in preventing CHD in blacks.
doi:10.1016/j.ahj.2009.10.001
PMCID: PMC2904958  PMID: 19958861
22.  Effect of ginkgo biloba on blood pressure and incidence of hypertension in elderly men and women 
American journal of hypertension  2010;23(5):528-533.
Background
Accumulating evidence suggests that ginkgo biloba is cardioprotective, in part, through its vasodilatory and antihypertensive properties. However, definitive data on its blood pressure-lowering effects in humans is lacking.
Methods
We determined the effects of ginkgo biloba extract (240 mg/day) on blood pressure and incident hypertension in 3,069 participants (mean age, 79 yrs; 46% female; 96% White) from the Ginkgo Evaluation of Memory study. We also examined whether the treatment effects are modified by baseline hypertension status.
Results
At baseline 54% of the study participants were hypertensive, 28% were pre-hypertensive, and 17% were normotensive. Over a median follow-up of 6.1 years, there were similar changes in blood pressure and pulse pressure in the ginkgo biloba and placebo groups. Although baseline hypertension status did not modify the antihypertensive effects of ginkgo biloba, it did influence the changes in blood pressure variables observed during follow-up, with decreases in hypertensives, increases in normotensives, and no changes in pre-hypertensives. Among participants who were not on antihypertensive medications at baseline, there was no difference between treatment groups in medication use over time, as the OR (95% CI) for being a never-user in the ginkgo biloba group was 0.75 (0.48–1.16). The rate of incident hypertension also did not differ between participants assigned to ginkgo biloba vs. placebo (HR, 0.99, 95% CI, 0.84–1.15).
Conclusions
Our data indicate that ginkgo biloba does not reduce blood pressure or the incidence of hypertension in elderly men and women.
doi:10.1038/ajh.2010.14
PMCID: PMC2989407  PMID: 20168306
gingko biloba; blood pressure; hypertension; elderly
23.  Treatment of minor depression in older adults: A pilot study comparing sertraline and exercise 
Aging & mental health  2007;11(1):61-68.
The purpose of this study was to conduct a pilot clinical trial to test the feasibility and efficacy of an exercise program and anti-depressant treatment compared with usual care in improving the emotional and physical functioning of older adults with minor depression. Participants were 37 older adults with minor depression who were randomized to exercise, sertraline, or usual care; 32 participants completed the 16 week study. Outcomes included measures of both emotional (clinician and self-report) and physical (observed and self-report) functioning. There were trends for the superiority of the exercise and sertraline conditions over usual care in improving SF-36 mental health scores and clinician-rated depression scores. Individuals in the exercise condition showed greater improvements in physical functioning than individuals in the usual care condition. Both sertraline and exercise show promise as treatments for late-life minor depression. However, exercise has the added benefit of improving physical functioning as well.
doi:10.1080/13607860600736372
PMCID: PMC2885010  PMID: 17164159
24.  Insomnia in Older Adults with Generalized Anxiety Disorder 
Objectives
The purposes of this study are to determine the frequency and severity of insomnia symptoms and related complaints experienced by older adults with GAD and compare them with older adults without GAD; compare insomnia symptoms among older adults with GAD with and without comorbid depression; determine if there are age differences in insomnia severity among people with GAD; and determine if there are differences in insomnia severity between older adults with GAD and older adults diagnosed with insomnia.
Design
Cross-sectional.
Setting
Participants were recruited through primary care clinics, advertisements, and mass mailings.
Participants
110 older adults; 31 with GAD, 25 with GAD and depression, 33 worried well, and 21 with no psychiatric diagnosis.
Measurements
Psychiatric diagnosis, sleep disturbance, and health.
Results
Participants with GAD with and without comorbid depression reported significantly greater sleep disturbance severity than participants with no psychiatric diagnosis and the worried well. There were no differences in sleep disturbances between older adults with GAD only and older adults with comorbid GAD and depression. The severity of sleep disturbance reported by older participants with GAD was greater than reports by young and middle-aged participants with GAD, and comparable to reports by older adults with a diagnosis of insomnia.
Conclusions
Ninety percent of older adults with GAD report dissatisfaction with sleep and the majority report moderate to severe insomnia. These findings support the assessment of sleep disturbances within the context of late-life GAD.
PMCID: PMC2699110  PMID: 19472436
Anxiety; GAD; insomnia; sleep
25.  Ginkgo biloba for Prevention of Dementia: A Randomized Controlled Trial 
Context
Ginkgo biloba is widely used for its potential effects on memory and cognition. To date, adequately powered clinical trials testing the effect of G biloba on dementia incidence are lacking.
Objective
To determine effectiveness of G biloba vs placebo in reducing the incidence of all-cause dementia and Alzheimer disease (AD) in elderly individuals with normal cognition and those with mild cognitive impairment (MCI).
Design, Setting, and Participants
Randomized, double-blind, placebo-controlled clinical trial conducted in 5 academic medical centers in the United States between 2000 and 2008 with a median follow-up of 6.1 years. Three thousand sixty-nine community volunteers aged 75 years or older with normal cognition (n=2587) or MCI (n=482) at study entry were assessed every 6 months for incident dementia.
Intervention
Twice-daily dose of 120-mg extract of G biloba (n=1545) or placebo (n=1524).
Main Outcome Measures
Incident dementia and AD determined by expert panel consensus.
Results
Five hundred twenty-three individuals developed dementia (246 receiving placebo and 277 receiving G biloba) with 92% of the dementia cases classified as possible or probable AD, or AD with evidence of vascular disease of the brain. Rates of dropout and loss to follow-up were low (6.3%), and the adverse effect profiles were similar for both groups. The overall dementia rate was 3.3 per 100 person-years in participants assigned to G biloba and 2.9 per 100 person-years in the placebo group. The hazard ratio (HR) for G biloba compared with placebo for all-cause dementia was 1.12 (95% confidence interval [CI], 0.94–1.33; P=.21) and for AD, 1.16 (95% CI, 0.97–1.39; P=.11). G biloba also had no effect on the rate of progression to dementia in participants with MCI (HR, 1.13; 95% CI, 0.85–1.50; P=.39).
Conclusions
In this study, G biloba at 120 mg twice a day was not effective in reducing either the overall incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI.
doi:10.1001/jama.2008.683
PMCID: PMC2823569  PMID: 19017911

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