Design and baseline characteristics of the cocoa supplement and multivitamin outcomes study for the Mind: COSMOS-Mind.

BACKGROUND: Large simple trials are potentially efficient and cost-effective approaches to assess interventions to preserve cognitive function in older adults. High-dose cocoa flavanols supplementation is a promising intervention that warrants additional testing. We describe the design, recruitment success, and baseline characteristics of the Cocoa Supplement and Multivitamin Outcomes Study for the Mind (COSMOS-Mind) trial. METHODS: COSMOS-Mind is an ancillary study to the large-scale and predominantly mail-based COSMOS randomized controlled clinical trial. COSMOS is assessing whether cocoa extract (including 600 mg/d cocoa flavanols) and a multivitamin reduce risks for major cardiovascular events and total invasive cancer. COSMOS-Mind uses telephone-based interviews to assess cognitive function and impairment to determine whether cocoa flavanols benefit cognitive function in adults aged 65 years or older, targeting the enrollment of 2000 participants to provide >90% statistical power across 3 years of annual follow-up. RESULTS: Of the 3224 COSMOS screenees who expressed interest in COSMOS-Mind, 2350 (76%) successfully completed baseline cognitive assessments and 2262 (96%) geographically diverse, eligible individuals were ultimately enrolled over one year. At baseline, the primary outcome, a composite of cognitive test scores, was inversely associated with age in a manner consistent with assumptions used in projections of statistical power. CONCLUSIONS: Older adults are willing to enroll in large simple trials that include telephone-based cognitive assessments. Embedding these trials in large studies of other health outcomes is efficient and expands the scientific knowledge gained from the research. ClinicalTrials.gov Identifiers: NCT03035201 (COSMOS-Mind); NCT102422745 (parent COSMOS).

End-of-Trial Health Outcomes in Look AHEAD Participants who Elected to have Bariatric Surgery.

OBJECTIVE: This study examined end-of-trial health outcomes in participants in the Action for Health in Diabetes (Look AHEAD) trial who had bariatric surgery during the approximately 10-year randomized intervention. METHODS: Data were obtained from the Look AHEAD public access database of 4,901 individuals with type 2 diabetes and overweight/obesity who were assigned to intensive lifestyle intervention (ILI) or a diabetes support and education (DSE) control group. Changes in outcomes in participants who had bariatric surgery were compared with those in participants with BMI ≥ 30 kg/m2 who remained in the ILI and DSE groups. RESULTS: A total of 99 DSE and 97 ILI participants had bariatric surgery. At randomization, these 196 participants were significantly younger and more likely to be female and to have higher BMI than the remaining ILI (N = 1,972) and DSE (N = 2,009) participants. At trial's end, surgically treated participants lost 19.3% of baseline weight, compared with 5.8% and 3.3% for the ILI and DSE groups, respectively, and were more likely to achieve partial or full remission of their diabetes. CONCLUSIONS: The large, sustained improvements in weight and diabetes observed in this self-selected sample of surgically treated participants are consistent with results of multiple randomized trials.

Four-year analysis of cardiovascular disease risk factors, depression symptoms, and antidepressant medicine use in the Look AHEAD (Action for Health in Diabetes) clinical trial of weight loss in diabetes.

OBJECTIVE: 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/m(2)) 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. RESULTS: 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)]). CONCLUSIONS: Aggressive monitoring of CVD risk in diabetic patients with depressive symptoms or who are treated with ADM may be warranted.

Four-year change in cardiorespiratory fitness and influence on glycemic control in adults with type 2 diabetes in a randomized trial: the Look AHEAD Trial.

OBJECTIVE: To examine an intensive lifestyle intervention (ILI) compared with diabetes support and education (DSE) on 4-year change in fitness and physical activity (PA), and to examine the effect of change in fitness and PA, adjusting for potential confounders, on glycemic control in the Look AHEAD Trial. RESEARCH DESIGN AND METHODS: Subjects were overweight/obese adults with type 2 diabetes mellitus (T2DM) with available fitness data at 4 years (n = 3,942).This clinical trial randomized subjects to DSE or ILI. DSE subjects received standard care plus information related to diet, PA, and social support three times per year. ILI subjects received weekly intervention contact for 6 months, which was reduced over the 4-year period, and were prescribed diet and PA. Measures included weight, fitness, PA, and HbA1c. RESULTS: The difference in percent fitness change between ILI and DSE at 4 years was significant after adjustment for baseline fitness and change in weight (3.70 vs. 0.94%; P < 0.01). At 4 years, PA increased by 348 (1,562) kcal/week in ILI vs. 105 (1,309) kcal/week in DSE (P < 0.01). Fitness change at 4 years was inversely related to change in HbA1c after adjustment for clinical site, treatment, baseline HbA1c, prescribed diabetes medication, baseline fitness, and weight change (P < 0.01). Change in PA was not related to change in HbA1c. CONCLUSIONS: A 4-year ILI increased fitness and PA in overweight/obese individuals with T2DM. Change in fitness was associated with improvements in glycemic control, which provides support for interventions to improve fitness in adults with T2DM.

Ascertaining dementia-related outcomes for deceased or proxy-dependent participants: an overview of the Women's Health Initiative Memory Study supplemental case ascertainment protocol.

OBJECTIVE: The aim of the study was to compare a two-staged clinic-based standardized protocol with a supplemental proxy-based protocol. METHODS: The Women's Health Initiative Memory Study enrolled 7479 women, aged 65-79 years and free of dementia, in a clinical trial of postmenopausal hormone therapy who were followed for up to 13 years with annual two-staged clinic-based standardized protocols to identify incidence of probable dementia. A supplemental proxy-based protocol, involving telephone administration of the dementia questionnaire, was designed to assess the cognitive status of women who could no longer attend clinic visits because they died (n = 1058) or became dependent (n = 228). Chi-squared tests were used to compare characteristics of women eligible for proxy-based versus clinic-based assessment. Risk factor relationships were described using proportional hazards regression. RESULTS: Women who were eligible for proxy-based assessments tended to have worse cognitive impairment risk factor profiles and had higher rates of probable dementia (15.2% vs 3.5%) than clinic-assessed participants. Augmenting the clinic-based cases with those identified from proxy interviews reduced undercounting and materially altered observed relationships that years since menopause, smoking status, diabetes, and prior use of hormone therapy had with incidence of probable dementia. CONCLUSIONS: Although proxy interviews were successful in reducing biases in estimated incidence rates and risk factor relationships, it is unlikely that they will fully eliminate many biases. Proxy-based assessments are necessary in longer term studies to reduce undercounting of dementia cases and to characterize risk factor relationships.

Application of machine learning methods to describe the effects of conjugated equine estrogens therapy on region-specific brain volumes.

Use of conjugated equine estrogens (CEE) has been linked to smaller regional brain volumes in women aged ≥65 years; however, it is unknown whether this results in a broad-based characteristic pattern of effects. Structural magnetic resonance imaging was used to assess regional volumes of normal tissue and ischemic lesions among 513 women who had been enrolled in a randomized clinical trial of CEE therapy for an average of 6.6 years, beginning at ages 65-80 years. A multivariate pattern analysis, based on a machine learning technique that combined Random Forest and logistic regression with L(1) penalty, was applied to identify patterns among regional volumes associated with therapy and whether patterns discriminate between treatment groups. The multivariate pattern analysis detected smaller regional volumes of normal tissue within the limbic and temporal lobes among women that had been assigned to CEE therapy. Mean decrements ranged as high as 7% in the left entorhinal cortex and 5% in the left perirhinal cortex, which exceeded the effect sizes reported previously in frontal lobe and hippocampus. Overall accuracy of classification based on these patterns, however, was projected to be only 54.5%. Prescription of CEE therapy for an average of 6.6 years is associated with lower regional brain volumes, but it does not induce a characteristic spatial pattern of changes in brain volumes of sufficient magnitude to discriminate users and nonusers.

Telephone interview for cognitive status (TICS) screening for clinical trials of physical activity and cognitive training: the seniors health and activity research program pilot (SHARP-P) study.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Relative effects of tamoxifen, raloxifene, and conjugated equine estrogens on cognition.

OBJECTIVE: To compare the relative effects of conjugated equine estrogens (CEE), raloxifene, and tamoxifen therapies on cognition among women aged > or =65 years. METHODS: Annual Modified Mini-Mental State (3MS) examinations were used to assess global cognitive function in the two randomized placebo-controlled clinical trials of CEE therapies of the Women's Health Initiative Memory Study (WHIMS) and the Cognition in the Study of Tamoxifen and Raloxifene (CoSTAR). Analyses were limited to women who had 3MS testing at baseline and the first 3 years of follow-up and, because of potential ethnic-related differences between studies, to Caucasian women (WHIMS n = 6211, CoSTAR n = 250). Covariate adjustment was used to compare the postrandomization mean 3MS scores among the three active therapies with placebo therapy while controlling for differences between groups with respect to dementia risk factors. RESULTS: At baseline, the average (SD) 3MS scores by group were 95.24 (4.28) for placebo, 95.19 (4.33) for CEE, 94.60 (4.76) for raloxifene, and 95.02 (4.03) for tamoxifen. Compared with placebo, each active therapy was associated with a small mean relative deficit in 3MS scores of < or =0.5 units, which was fairly consistent between women with and without prior hysterectomy. Relative deficits were slightly greater for tamoxifen (p = 0.001) and less marked for raloxifene (p = 0.06) and CEE (p = 0.02) therapies. Relative deficits appeared to be greater among women with lower baseline 3MS scores: p = 0.009 (tamoxifen), p = 0.08 (raloxifene), and p = 0.03 (CEE). CONCLUSIONS: Although unmeasured differences between trials may have confounded analyses, these findings raise the possibility that both tamoxifen and raloxifene adversely affect cognitive function in older women; however, the magnitude of the effect is small, and the long-term consequences are unknown.

A uniform approach to modeling risk factor relationships for ischemic lesion prevalence and extent: the Women's Health Initiative Magnetic Resonance Imaging study.

BACKGROUND: Both the prevalence and extent of brain magnetic resonance imaging (MRI) abnormalities are related to risk factors for dementia. Typically these associations have been explored separately, but an integrated modeling approach would allow the separate relationships to be consistently described and contrasted. METHODS: Region-specific measures of ischemic lesion volumes were obtained from standardized brain MRI from 1,403 women enrolled in the Women's Health Initiative hormone therapy trials. Mixed-effects mixed-distribution models were fitted to explore jointly the relationships that the region-specific prevalence of ischemic lesions and region-specific ischemic lesion volumes had with risk factors and scores from tests of cognitive function. RESULTS: Women with greater probabilities (prevalence) of having ischemic lesions in brain regions also tended to have larger volumes (extent) of ischemic lesions within the affected regions (p < 0.001). Across the 5 regions included in analyses (frontal, limbic, occipital, parietal and temporal), prevalence and extent varied (p < 0.001). Each was increased among women who were older, had hypertension or who had previously been classified as cognitively impaired (p < 0.01). Additionally, extent was significantly increased among women with a history of smoking (p = 0.02). Cognitive function tests were more strongly related to the extent than prevalence of ischemic lesions and relationships varied among cognitive domains (p < 0.001). CONCLUSIONS: Mixed-effects mixed-distribution models provide a coherent basis for examining relationships involving the prevalence and extent of ischemic brain lesions. Across the cohort and regions we examined, relationships with risk factors and cognitive function appeared to be stronger for extent than for prevalence.