After clinical trials end, continued follow-up of the assembled cohort often is desirable for additional research. Factors influencing participants’ decisions to consent to additional follow-up and how these shape post-trial cohorts have not been broadly studied.
We examined how two re-enrollment campaigns and the passage of time altered features of the post-trial cohorts compared with the original Women’s Health Initiative Hormone Therapy clinical trials.
We examined associations that markers of socio-demography, health, lifestyle and on-trial experiences had with re-enrollment and contrasted the characteristics of successive post-trial cohorts with those of the original enrollees.
The post-trial enrollment campaigns re-enrolled 81.1% and 82.5% of available women, respectively. Women who re-enrolled tended to have better health characteristics than those not re-enrolled. Compared to women of comparable age in the original cohort, women retained for the second post-trial follow-up less often had a history of cardiovascular disease [odds ratio OR=0.36], hypertension [OR=0.57], diabetes [OR=0.59], or measured cognitive deficit [OR=0.40]. These women more often had graduated from high school [OR=1.72] and had participated in other WHI trials [OR=1.76].
We have examined experience with creating follow-up cohorst from participants in a single study. Thus, our findings may not apply to other cohorts and protocols.
Post-trial enrollment in follow-up studies can be successful; however the characteristics of the resulting cohort may differ substantially from the originally assembled group of trial participants. Collection during the original trial of potential predictors of differential re-enrollment may facilitate re-enrollment.
Post-trial follow-up; Retention; Missing data
The Women’s Health Initiative Memory Study-Younger (WHIMS-Y) was designed to assess the effect of prior random assignment to hormone therapy (HT) (conjugated equine estrogen (CEE) alone or CEE plus medroxyprogesterone acetate (MPA)) on global cognitive function in younger middle-aged women relative to placebo. WHIMS-Y was an ancillary study to the Women’s Health Initiative (WHI) HT trial and enrolled 1361 women who were aged 50-54 years and postmenopausal at WHI enrollment. WHIMS-Y will examine whether an average of 5.4 years of HT during early menopause has longer term protective effects on global cognitive function and if these effects vary by regimen, time between menopause and study initiation, and prior use of HT. We present the study rationale and design. We describe enrollment, adherence to assigned WHI therapy, and compare risk factor characteristics of the WHIMS-Y cohort at the time of WHI enrollment to similar aged women in the WHI HT who did not enroll in WHIMS-Y. Challenges of WHIMS-Y include lower than expected and differential enrollment. Strengths of WHIMS-Y include balance in baseline risk factors between treatment groups, standardized and masked data collection, and high rates of retention and on-trial adherence and exposure. In addition, the telephone-administered cognitive battery showed adequate construct validity. WHIMS-Y provided an unprecedented chance to examine the hypothesis that HT may have protective effects on cognition in younger postmenopausal women aged 50-54 years. Integrated into the WHI, WHIMS-Y optimized the experience of WHI investigators to ensure high retention and excellent quality assurance across sites.
Postmenopausal hormone therapy; Cognitive function; Aging
To study the association of depressive symptoms or antidepressant medicine (ADM) use with subsequent cardiovascular disease (CVD) risk factor status in the Look AHEAD (Action for Health in Diabetes) trial of weight loss in type 2 diabetes.
RESEARCH DESIGN AND METHODS
Participants (n = 5,145; age [mean ± SD] 58.7 ± 6.8 years; BMI 35.8 ± 5.8 kg/m2) in two study arms (intensive lifestyle [ILI], diabetes support and education [DSE]) completed the Beck Depression Inventory (BDI), reported ADM use, and were assessed for CVD risk factors at baseline and annually for 4 years. Risk factor–positive status was defined as current smoking, obesity, HbA1c >7.0% or insulin use, and blood pressure or cholesterol not at levels recommended by expert consensus panel or medicine to achieve recommended levels. Generalized estimating equations assessed within-study arm relationships of elevated BDI score (≥11) or ADM use with subsequent year CVD risk status, controlled for demographic variables, CVD history, diabetes duration, and prior CVD risk status.
Prior year elevated BDI was associated with subsequent CVD risk factor–positive status for the DSE arm (A1C [odds ratio 1.30 (95% CI 1.09–1.56)]; total cholesterol [0.80 (0.65–1.00)]; i.e., protective from high total cholesterol) and the ILI arm (HDL [1.40 (1.12–1.75)], triglyceride [1.28 (1.00–1.64)]). Prior year ADM use predicted subsequent elevated CVD risk status for the DSE arm (HDL [1.24 (1.03–1.50)], total cholesterol [1.28 (1.05–1.57)], current smoking [1.73 (1.04–2.88)]) and for the ILI arm (A1C [1.25 (1.08–1.46)], HDL [1.32 (1.11–1.58)], triglycerides [1.75 (1.43–2.14)], systolic blood pressure [1.39 (1.11–1.74)], and obesity [1.46 (1.22–2.18)]).
Aggressive monitoring of CVD risk in diabetic patients with depressive symptoms or who are treated with ADM may be warranted.
Research has shown that several types of erythrocyte fatty acids (i.e., omega-3, omega-6, and trans) are associated with risk for cardiovascular diseases. However, there are complex metabolic and dietary relations among fatty acids, which induce correlations that are typically ignored when using them as risk predictors. A latent variable approach could summarize these complex relations into a few latent variable scores for use in statistical models. Twenty-two red blood cell (RBC) fatty acids were measured in Framingham (N = 3196). The correlation matrix of the fatty acids was modeled using structural equation modeling; the model was tested for goodness-of-fit and gender invariance. Thirteen fatty acids were summarized by three latent variables, and gender invariance was rejected so separate models were developed for men and women. A score was developed for the polyunsaturated fatty acid (PUFA) latent variable, which explained about 30% of the variance in the data. The PUFA score included loadings in opposing directions among three omega-3 and three omega-6 fatty acids, and incorporated the biosynthetic and dietary relations among them. Whether the PUFA factor score can improve the performance of risk prediction in cardiovascular diseases remains to be tested.
To study how type 2 diabetes adversely affects brain volumes, changes in volume, and cognitive function.
RESEARCH DESIGN AND METHODS
Regional brain volumes and ischemic lesion volumes in 1,366 women, aged 72–89 years, were measured with structural brain magnetic resonance imaging (MRI). Repeat scans were collected an average of 4.7 years later in 698 women. Cross-sectional differences and changes with time between women with and without diabetes were compared. Relationships that cognitive function test scores had with these measures and diabetes were examined.
The 145 women with diabetes (10.6%) at the first MRI had smaller total brain volumes (0.6% less; P = 0.05) and smaller gray matter volumes (1.5% less; P = 0.01) but not white matter volumes, both overall and within major lobes. They also had larger ischemic lesion volumes (21.8% greater; P = 0.02), both overall and in gray matter (27.5% greater; P = 0.06), in white matter (18.8% greater; P = 0.02), and across major lobes. Overall, women with diabetes had slightly (nonsignificant) greater loss of total brain volumes (3.02 cc; P = 0.11) and significant increases in total ischemic lesion volumes (9.7% more; P = 0.05) with time relative to those without diabetes. Diabetes was associated with lower scores in global cognitive function and its subdomains. These relative deficits were only partially accounted for by brain volumes and risk factors for cognitive deficits.
Diabetes is associated with smaller brain volumes in gray but not white matter and increasing ischemic lesion volumes throughout the brain. These markers are associated with but do not fully account for diabetes-related deficits in cognitive function.
Intraindividual variability among cognitive domains may predict dementia independently of interindividual differences in cognition. A multidomain cognitive battery was administered to 2305 older adult women (mean age 74 years) enrolled in an ancillary study of the Women's Health Initiative. Women were evaluated annually for probable dementia and mild cognitive impairment (MCI) for an average of 5.3 years using a standardized protocol. Proportional hazards regression showed that lower baseline domain-specific cognitive scores significantly predicted MCI (N = 74), probable dementia (N = 45), and MCI or probable dementia combined (N = 101) and that verbal and figural memory predicted each outcome independently of all other cognitive domains. The baseline intraindividual standard deviation across test scores (IAV Cognitive Domains) significantly predicted probable dementia and this effect was attenuated by interindividual differences in verbal episodic memory. Slope increases in IAV Cognitive Domains across measurement occasions (IAV Time) explained additional risk for MCI and MCI or probable dementia, beyond that accounted for by interindividual differences in multiple cognitive measures, but risk for probable dementia was attenuated by mean decreases in verbal episodic memory slope. These findings demonstrate that within-person variability across cognitive domains both at baseline and longitudinally independently accounts for risk of cognitive impairment and dementia in support of the predictive utility of within-person variability.
Calcium and vitamin D are thought to play important roles in neuronal functioning. Studies have found associations between low serum vitamin D levels and reduced cognitive functioning, as well as high serum calcium levels and reduced cognitive functioning.
To examine the effects of vitamin D and calcium on cognitive outcomes in elderly women.
Post-hoc analysis of a randomized double-blinded placebo-controlled trial.
40 Women’s Health Initiative clinical centers across the U.S.
4143 women aged 65 years and older without probable dementia at baseline who participated in the WHI Calcium and Vitamin D trial and the Women’s Health Initiative Memory Study.
2034 women were randomized to 1000 mg of calcium carbonate combined with 400 IU of vitamin D3; 2109 women were randomized to placebo.
Primary: classifications of probable dementia or mild cognitive impairment via a 4-phase protocol that included central adjudication. Secondary: global cognitive function and individual cognitive subtests.
Mean age of participants was 71 years. During mean follow-up of 7.8 years, there were 39 cases of incident dementia among calcium plus vitamin D subjects compared to 37 cases among placebo subjects (hazard ratio=1.11, 95% CI: 0.71–1.74, p=0.64). Likewise, there were 98 cases of incident mild cognitive impairment among calcium plus vitamin D subjects compared to 108 cases among placebo subjects (hazard ratio=0.95, 95% CI: 0.72–1.25, p=0.72). There were no significant differences in incident dementia or mild cognitive impairment, or in global or domain-specific cognitive function between groups.
There was no association between treatment assignment and incident cognitive impairment. Further studies are needed to investigate the effects of vitamin D and calcium separately, on men and in other age and ethnic groups, and with other doses.
Vitamin D; Calcium; Dementia; Cognition; Mild Cognitive Impairment
The prevalence and significance of low normal and abnormal ankle brachial index (ABI) values in a community‐dwelling population of sedentary, older individuals is unknown. We describe the prevalence of categories of definite peripheral artery disease (PAD), borderline ABI, low normal ABI, and no PAD and their association with lower‐extremity functional performance in the LIFE Study population.
Methods and Results
Participants age 70 to 89 in the LIFE Study underwent baseline measurement of the ABI, 400‐m walk, and 4‐m walking velocity. Participants were classified as follows: definite PAD (ABI <0.90), borderline PAD (ABI 0.90 to 0.99), low normal ABI (ABI 1.00 to 1.09), and no PAD (ABI 1.10 to 1.40). Of 1566 participants, 220 (14%) had definite PAD, 250 (16%) had borderline PAD, 509 (33%) had low normal ABI, and 587 (37%) had no PAD. Among those with definite PAD, 65% were asymptomatic. Adjusting for age, sex, race, body mass index, smoking, and comorbidities, lower ABI was associated with longer mean 400‐m walk time: (definite PAD=533 seconds; borderline PAD=514 seconds; low normal ABI=503 seconds; and no PAD=498 seconds [P<0.001]). Among asymptomatic participants with and without PAD, lower ABI values were also associated with longer 400‐m walk time (P<0.001) and slower walking velocity (P=0.042).
Among older community‐dwelling men and women, 14% had PAD and 49% had borderline or low normal ABI values. Lower ABI values were associated with greater functional impairment, suggesting that lower extremity atherosclerosis may be a common preventable cause of functional limitations in older people.
Clinical Trial Registration
URL: http://clinicaltrials.gov/ Unique identifier: NCT01072500.
aging; exercise; peripheral vascular disease
Many factors have been identified that influence the recruitment of African Americans into clinical trials; however, the influence of eligibility criteria may not be widely appreciated. We used the experience from the Look AHEAD (Action for Health in Diabetes) trial screening process to examine the differential impact eligibility criteria had on the enrollment of African Americans compared to other volunteers.
Look AHEAD is a large randomized clinical trial to examine whether assignment to an intensive lifestyle intervention designed to produce and maintain weight loss reduces the long-term risk of major cardiovascular events in adults with type 2 diabetes. Differences in the screening, eligibility, and enrollment rates between African Americans and members of other racial/ethnic groups were examined to identify possible reasons.
Look AHEAD screened 28,735 individuals for enrollment, including 6226 (21.7%) who were self-identified African Americans. Of these volunteers, 12.9% of the African Americans compared to 19.3% of all other screenees ultimately enrolled (p < 0.001). African Americans no more often than others were lost to follow-up or refused to attend clinic visits to establish eligibility. Furthermore, the enrollment rates of individuals with histories of cardiovascular disease and diabetes therapy did not markedly differ between the ethnic groups. Higher prevalence of adverse levels of blood pressure, heart rate, HbA1c, and serum creatinine among African American screenees accounted for the greater proportions excluded (all p < 0.001).
Compared to non-African Americans, African American were more often ineligible for the Look AHEAD trial due to comorbid conditions. Monitoring trial eligibility criteria for differential impact, and modifying them when appropriate, may ensure greater enrollment yields.
To examine the performance of the Telephone Interview for Cognitive Status (TICS) for identifying participants appropriate for trials of physical activity and cognitive training interventions.
Volunteers (N = 343), ages 70–85 years, who were being recruited for a pilot clinical trial on approaches to prevent cognitive decline, were administered TICS and required to score ≥31 prior to an invitation to attend clinic-based assessments. The frequencies of contraindications for physical activity and cognitive training interventions were tallied for individuals grouped by TICS scores. Relationships between TICS scores and other measures of cognitive function were described by scatterplots and correlation coefficients.
Eligibility criteria to identify candidates who were appropriate candidates for the trial interventions excluded 51.7% of the volunteers with TICS<31. TICS scores above this range were not strongly related to cognition or attendance at screening visits, however overall enrollment yields were approximately half for participants with TICS = 31 versus TICS = 41, and increased in a graded fashion throughout the range of scores.
Use of TICS to define eligibility criteria in trials of physical activity and cognitive training interventions may not be worthwhile in that many individuals with low scores would already be eliminated by intervention-specific criteria and the relationship of TICS with clinic-based tests of cognitive function among appropriate candidates for these interventions may be weak. TICS may be most useful in these trials to identify candidates for oversampling in order to obtain a balanced cohort of participants at risk for cognitive decline.
clinical trial design; cognitive interventions; eligibility criteria
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.
To develop a positive aging phenotype, we undertook analyses to describe multiple dimensions of positive aging and their relationships to one another in women 65 years of age and older and evaluate the performance of individual indicators and composite factors of this phenotype as predictors of time to death, years of healthy living, and years of independent living.
Data from Women’s Health Initiative clinical trial and observational study participants ages 65 years and older at baseline, including follow-up observations up to 8 years later, were analyzed using descriptive statistics and principal components analysis to identify the factor structure of a positive aging phenotype. The factors were used to predict time to death, years of healthy living (without hospitalization or diagnosis of a serious health condition), and years of independent living (without nursing home admission or use of special services).
We identified a multidimensional phenotype of positive aging that included two factors: Physical–Social Functioning and Emotional Functioning. Both factors were predictive of each of the outcomes, but Physical–Social Functioning was the strongest predictor. Each standard deviation of increase in Physical–Social Functioning was accompanied by a 23.7% reduction in mortality risk, a 19.4% reduction in risk of major health conditions or hospitalizations, and a 26.3% reduction in risk of dependent living.
Physical–Social Functioning and Emotional Functioning constitute important components of a positive aging phenotype. Physical–Social Functioning was the strongest predictor of outcomes related to positive aging, including years of healthy living, years of independent living, and time to mortality.
Positive aging; Phenotypes; Women's health; Healthy life span
The liver is an insulin-responsive organ that contributes significantly to both whole body insulin sensitivity and availability of sex steroids through the production of sex hormone binding globulin (SHBG). Our objective was to explore whether lower SHBG was associated with ectopic liver fat and mediated its effect on insulin resistance in The Study of Women’s Health Across the Nation (SWAN). A subset of midlife African American and Caucasian women from SWAN (n=208; 50.9±0.18 yrs; 71% Caucasian) had computed tomography scans to quantify visceral, subcutaneous and liver fat. Blood samples were collected and assayed for hormonal and metabolic markers. The cohort, while overweight, was generally healthy, and both liver fat and SHBG were unaffected by menopausal stage or race. Both higher liver fat and lower SHBG levels were significantly associated with higher insulin concentrations after adjustment for adiposity (r=−0.25, p<0.001 and r=−0.18, p=0.01). SHBG and liver fat had additive effects on insulin concentrations such that women with the lowest SHBG and the highest fat levels had the highest values (interaction p=0.09). The association between SHBG and insulin was more apparent among women with fattier livers. SHBG and liver fat appear to have independent effects on insulin levels as adjustment for each other did not diminish the strength of either association (p=0.023 and 0.001 respectively). These results confirmed the strong independent associations between increased liver fat and decreased SHBG with increased metabolic risk in midlife women. Further these data underscore the need for additional research into the role of liver fat in modifying SHBG’s influence on insulin levels.
liver fat; sex hormone binding globulin; perimenopause; ectopic fat; insulin resistance
This paper provides an assessment of the associations that weight loss patterns during the first year of an intensive lifestyle intervention have with four year maintenance and health outcomes. Two components described patterns of weight change during the first year of intervention: one reflected the typical pattern of weight loss over the 12 months, but distinguished those who lost larger amounts across the monthly intervals from those who lost less. The second component reflected the weight change trajectory, and distinguished a pattern of initial weight loss followed by regain versus a more sustained pattern of weight loss 2,438 individuals aged 45–76 years with type 2 diabetes mellitus, who enrolled in the weight loss intervention of a randomized clinical trial, were assigned scores according to how their weight losses reflected these patterns. Relationships these scores had with weight losses and health outcomes (glycosolated hemoglobin – HbA1c; systolic blood pressure, HDL-cholesterol, and triglycerides) over four years were described. Both individuals who had larger month-to-month weight losses in year 1 and whose weight loss was more sustained during the first year had better maintenance of weight loss over four years, independent of characteristics traditionally linked to weight loss success (p<0.001). While relationships with year 4 weight loss were stronger, the pattern of larger monthly weight loss during year 1 was also independently predictive of year 4 levels of HbA1c, HDL-cholesterol, and systolic blood pressure.
weight loss; type 2 diabetes mellitus; principal components analysis
While the gold standard method of cognitive assessment is a face-to-face administration, telephone-based assessments offer several advantages if they demonstrate reliability and validity.
Observational study; 110 participants randomly assigned to receive two administrations of the same cognitive test battery 6 months apart in one of four combinations (1st administration/2nd administration): telephone/telephone; telephone/face-to-face; face-to-face/telephone; or face-to-face/face-to-face.
Academic medical center
110 non-demented women between the ages of 65 and 90 years.
The battery included tests of attention, verbal learning and memory, verbal fluency, executive function, working memory and global cognitive functioning plus self-report measures of perceived memory problems, depressive symptoms, sleep disturbance and health-related quality of life. Test-retest reliability, concurrent validity, relative bias associated with telephone administration, and change scores were evaluated.
There were no statistically significant differences in scores on any of the cognitive tests or questionnaires between randomly assigned modes of administration at baseline indicating equivalence across modes. There was no significant bias for tests or questionnaires administered by telephone (ps>0.01). Nor was there a difference in mean change scores between administration modes except for the Category Fluency (p = 0.01) and the California Verbal Learning Test long delay-free recall (p < 0.01). Mean test-retest coefficients for the battery were not significantly different across groups though individual test-retest correlation coefficients were generally higher within mode than across mode.
Telephone administration of cognitive tests and questionnaires to older women is both reliable and valid. Use of telephone batteries can substantially reduce the economic cost and burden of cognitive assessments and increase enrollment, retention and data completeness thereby improving study validity.
cognition; assessment; telephone; validation; tests
Weight gain during young adulthood is common and is associated with increased cardiovascular risk. Preventing this weight gain from occurring may be critical to improving long-term health. Few studies have focused on weight gain prevention, and these studies have had limited success. SNAP (Study of Novel Approaches to Weight Gain Prevention) is an NIH-funded randomized clinical trial examining the efficacy of two novel self-regulation approaches to weight gain prevention in young adults compared to a minimal treatment control. The interventions focus on either small, consistent changes in eating and exercise behaviors, or larger, periodic changes to buffer against expected weight gains.
SNAP targets recruitment of six hundred young adults (18–35 years) with a body mass index between 21.0-30.0 kg/m2, who will be randomly assigned with equal probability to: (1) minimal intervention control; (2) self-regulation with Small Changes; or (3) self-regulation with Large Changes. Both interventions receive 8 weekly face-to-face group sessions, followed by 2 monthly sessions, with two 4-week refresher courses in each of subsequent years. Participants are instructed to report weight via web at least monthly thereafter, and receive monthly email feedback. Participants in Small Changes are taught to make small daily changes (~100 calorie changes) in how much or what they eat and to accumulate 2000 additional steps per day. Participants in Large Changes are taught to create a weight loss buffer of 5–10 pounds once per year to protect against anticipated weight gains. Both groups are encouraged to self-weigh daily and taught a self-regulation color zone system that specifies action depending on weight gain prevention success. Individualized treatment contact is offered to participants who report weight gains. Participants are assessed at baseline, 4 months, and then annually. The primary outcome is weight gain over an average of 3 years of follow-up; secondary outcomes include diet and physical activity behaviors, psychosocial measures, and cardiovascular disease risk factors.
SNAP is unique in its focus on weight gain prevention in young adulthood. The trial will provide important information about whether either or both of these novel interventions are effective in preventing weight gain.
Weight gain prevention; Young adults; Obesity; Self-regulation; Self-weighing
Muscle weakness and obesity are two significant threats to mobility facing the increasing number of older adults. To date, there are no studies that have examined the association of strength and body mass index (BMI) on event rates on a widely used performance measure of major mobility disability.
This study was a secondary analysis of a randomized controlled trial in which sedentary functionally limited participants (70–89 years, Short Physical Performance Battery ≤ 9) who were able to complete a 400-m walk test at baseline were randomized to a physical activity or health education intervention and reassessed for major mobility disability every 6 months for up to 18 months. We evaluated whether baseline grip strength and BMI predicted failure to complete the 400-m walk test in 15 minutes or less (major mobility disability).
Among N = 406 participants with baseline measures, lower grip strength was associated with an increased risk for developing major mobility disability, with and without covariate adjustment (p < .01): The hazard ratio (95% confidence interval) for the lowest versus high sex-specific quartile of grip strength was 6.11 (2.24–16.66). We observed a U-shaped relationship between baseline BMI and the risk of developing major mobility disability, such that the risk for participants with a BMI of 25–29 kg/m2 was approximately half that of participants with BMI less than 25 or 30 kg/m2 or more (p = .04 in fully adjusted analyses).
Our data highlight the importance of muscle weakness, low BMI, and obesity as risk factors for major mobility disability in older adults. Being overweight may be protective for major mobility disability.
Physical disability; Physical activity; Older adults
Look AHEAD is a randomized trial determining whether intensive lifestyle intervention (ILI) aimed at long-term weight loss and increased physical fitness reduces cardiovascular morbidity and mortality in overweight and obese individuals with type 2 diabetes compared to control (diabetes support and education, DSE). We investigated the correlates of NT-proBNP, a biomarker associated with heart failure risk, in a subsample from 15 of 16 participating centers and tested the hypothesis that ILI decreased NT-proBNP levels. Baseline and one-year blood samples were assayed for NT-proBNP in a random sample of 1500 without, and all 628 with, self-reported baseline CVD (N=2128). Linear models were used to assess relationships that logtransformed NT-proBNP had with CVD risk factors at baseline and that 1-year changes in NT-proBNP had with intervention assignment. At baseline, the mean (SD) age, BMI, and hemoglobin A1c were 59.6 (6.8) years, 36.0 kg/m2 (5.8), and 7.2% (1.1), respectively. Baseline geometric mean NT-proBNP was not different by condition (ILI 53.3 vs DSE 51.5, p=0.45), was not associated with BMI, and was inversely associated with hemoglobin A1c. At 1 year, ILI participants achieved an average weight loss of 8.3% compared to 0.7% in DSE. At 1 year, NT-proBNP levels increased to a greater extent in the intervention arm (ILI +21.3% vs. DSE +14.2%, p=0.046). The increased NT-proBNP associated with ILI was correlated with changes in A1c, BMI, and body composition. In conclusion, among overweight and obese persons with diabetes, an intensive lifestyle intervention that reduced weight was associated with an increased NT-proBNP.
natriuretic peptides; diabetes mellitus; obesity
We sought to determine if type 2 diabetes mellitus (T2DM) was associated with accelerated decline in domain-specific measures of cognitive function and fine motor speed.
Women aged 65–80 years who were enrolled in a clinical trial of postmenopausal hormone therapy were grouped as having T2DM (n=179) or not (n=1984) and followed for an average of 5 years with annual standardized assessments of domain-specific cognitive function. Mean patterns of cognitive measures over time were contrasted between groups using general linear models and Wald tests, with varying levels of covariate adjustment. The influences of age at onset, use of oral medications, and use of insulin were also examined.
T2DM was associated with mean deficits of 0.2–0.4 standard deviations (SD) across follow-up in most cognitive domains. Consistent evidence that rates of decline were accelerated among women with T2DM was evident only for verbal knowledge and verbal memory (p<0.05). Decrements in fine motor speed, but no measure of cognitive function, were greater for women with earlier onset T2DM. Use of oral diabetes medications was associated with better relative cognitive function.
In these women, T2DM was associated with cognitive deficits in most domains. Relative deficits in verbal knowledge and verbal memory may continue to increase after deficits in other domains have stabilized. Relative deficits in fine motor speed may be greater among women with earlier onsets of T2DM. Use of insulin, which may reflect greater T2DM severity, was associated with relatively greater cognitive deficits.
Although studies exploring relationships between obesity and cognitive impairment in the elderly are conflicting, literature suggests that overweight and obesity may be protective against cognitive impairment and dementia in older women. We examine the associations between changes in weight and waist circumference with global and domain-specific cognitive function in a large, well-defined cohort of 2283 older, post-menopausal women (age 65-79) prospectively followed through the Women's Health Initiative (WHI) Study of Cognitive Aging (WHISCA). We assessed the associations between changes in weight and waist circumference collected up to 5 years prior to WHISCA enrollment and mean levels of global and domain-specific cognitive performance across an average of 5.4 years of subsequent follow-up. There was a lack of associations between weight and cognition in women who remained stable or gained weight. The only significant relationships observed were in association with weight loss (p≤0.05), most likely signaling incipient disease. Moreover, cognition was not related to changes in waist circumference. Relationships were largely independent of initial BMI, self-reported caloric intake or dieting. The lack of associations between weight gain and cognition in women is consistent with the existent literature.
Late-life depressive symptoms (DS) increase the risk of incident mild cognitive impairment and probable dementia in the elderly. Our objectives were to examine the relationship between elevated DS and regional brain volumes including frontal lobe subregions, hippocampus and amygdala, and to determine whether elevated DS were associated with increased subclinical cerebrovascular disease in postmenopausal women.
DS were assessed an average of 8 years prior to structural brain MRI in 1372 women. The 8-item Burnam regression algorithm was used to define DS with a cut-point of 0.009. Adjusting for potential confounders, mean differences in total brain, frontal lobe subregions, hippocampus and amygdala volumes and total ischemic lesion volumes in the basal ganglia and the cerebral white and gray matter outside the basal ganglia were compared between women with and without DS.
Depressed women had lower baseline global cognition and were more likely to have prior hormone therapy history. After full adjustment, DS at baseline were associated with smaller superior and middle frontal gyral volumes. Hippocampal and amygdala volumes, and ischemic lesion volumes were similar in depressed and non-depressed women.
Depression was not assessed based on semi-structured interview, and we were unable to determine the temporal relationships between DS and frontal lobe volume differences due to the availability of only one MRI scan.
Elevated DS were associated with lower volumes in certain frontal lobe subregions but not in the medial temporal lobe structures. Our findings support the role of frontal lobe structures in late-life DS among women.
Late-life Depression; regional brain volumes; subclinical cerebrovascular disease; structural magnetic resonance imaging
Comparing findings from separate trials is necessary to choose among treatment options, however differences among study cohorts may impede these comparisons.
As a case study, to examine the overlap of study cohorts in two large randomized controlled clinical trials that assess interventions to reduce risk of major cardiovascular disease events in adults with type 2 diabetes in order to explore the feasibility of cross-trial comparisons
The Action for Health in Diabetes (Look AHEAD) and The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trials enrolled 5,145 and 10,251 adults with type 2 diabetes, respectively. Look AHEAD assesses the efficacy of an intensive lifestyle intervention designed to produce weight loss; ACCORD tests pharmacological therapies for control of glycemia, hyperlipidemia, and hypertension. Incidence of major cardiovascular disease events is the primary outcome for both trials. A sample was constructed to include participants from each trial who appeared to meet eligibility criteria and be appropriate candidates for the other trial’s interventions. Demographic characteristics, health status, and outcomes of members and non-members of this constructed sample were compared.
Nearly 80% of Look AHEAD participants were projected to be ineligible for ACCORD; ineligibility was primarily due to better glycemic control or no early history of cardiovascular disease. Approximately 30% of ACCORD participants were projected to be ineligible for Look AHEAD, often for reasons linked to poorer health. The characteristics of participants projected to be jointly eligible for both trials continued to reflect differences between trials according to factors likely linked to retention, adherence, and study outcomes.
Accurate ascertainment of cross-trial eligibility was hampered by differences between protocols.
Despite several similarities, the Look AHEAD and ACCORD cohorts represent distinct populations. Even within the subsets of participants who appear to be eligible and appropriate candidates for trials of both modes of intervention, differences remained. Direct comparisons of results from separate trials of lifestyle and pharmacologic interventions are compromised by marked differences in enrolled cohorts.
Randomized clinical trials; Cross-trial comparisons; Type 2 diabetes
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.
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.
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.
Results of this study are expected to have important public health implications for the large and growing population of older sedentary men and women.
Disability; Physical activity; Exercise; Geriatrics; Physical function
To determine if body weight (BMI) is independently associated with cognitive function in postmenopausal women and the relationship between body fat distribution as estimated by waist-hip-ratio (WHR) and cognitive function.
Cross-sectional data analysis
Baseline data from the Women's Health Initiative (WHI) hormone trials.
8745 postmenopausal women aged 65–79 years, free of clinical evidence of dementia and completed baseline evaluation in the Women's Health Initiative (WHI) hormone trials.
Participants completed a Modified Mini-Mental State Examination (3MSE), health and lifestyle questionnaires, and standardized measurements of height, weight, body circumferences and blood pressure. Statistical analysis of associations between 3MSE scores, BMI and WHR after controlling for known confounders.
With the exception of smoking and exercise, vascular disease risk factors, including hypertension, waist measurement, heart disease and diabetes, were significantly associated with 3MSE score and were included as co-variables in subsequent analyses. BMI was inversely related to 3MSE scores, for every 1 unit increase in BMI, 3MSE decrease 0.988 (p=.0001) after adjusting for age, education and vascular disease risk factors. BMI had the most pronounced association with poorer cognitive functioning scores among women with smaller waist measurements. Among women with the highest WHR, cognitive scores increased with BMI.
Increasing BMI is associated with poorer cognitive function in women with smaller WHR. Higher WHR, estimating central fat mass, is associated with higher cognitive function in this cross-sectional study. Further research is needed to clarify the mechanism for this association.
obesity; cognition; dementia; waist-hip ratio; women
Conjugated equine estrogen (CEE) therapies when initiated among older women have been shown to produce small decrements in global cognitive function. We are interested whether these persist after cessation and extend to specific cognitive domains.
Randomized controlled clinical trial
Fourteen clinical centers of the Women's Health Initiative
2,304 women aged 65-80 years and free of probable dementia at enrollment
0.625 mg/day of CEE, with or without medroxyprogesterone acetate (MPA, 10 mg/day), and matching placebos
Annual administrations of a battery of cognitive tests during and following the trial
General linear models were used to compare on-trial and post-trial mean standardized test scores between treatment groups, with adjustment for baseline risk factors for cognitive impairment.
Assignment to CEE-based therapies was associated with small mean relative decrements in global and several domain-specific cognitive functions on-trial, which largely persisted through up to 4 years post-trial. The strongest statistical evidence was for global cognitive function: 0.07 standard deviation decrements both on-trial (p=0.007) and post-trial (p=0.01). Among domain specific scores, the mean relative decrements were slightly smaller, were less significant, and tended to be larger for CEE-alone therapy.
CEE-based therapies, when initiated after age 65 years, produce a small broad-based decrement in cognitive function that persists after their use is stopped. The differences in cognitive function however are small and would not be detectable or have clinical significance for an individual woman. Differences in effects among cognitive domains suggest that more than one mechanism may be involved.
Postmenopausal hormone therapy; Cognitive function; Women's health