Effect of multivitamin-mineral supplementation versus placebo on cognitive function: results from the clinic subcohort of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial and meta-analysis of 3 cognitive studies within COSMOS.

BACKGROUND: Longer effects of multivitamin-mineral (MVM) supplementation on late-life cognitive function remain untested using in-person, detailed neuropsychological assessments. Furthermore, insufficient evidence exists for healthcare providers to recommend daily MVM supplements to prevent cognitive decline. OBJECTIVES: This study aimed to test MVM effects on cognitive change using in-person, detailed neuropsychological assessments and conduct a meta-analysis within COSMOS (COcoa Supplement and Multivitamin Outcomes Study) cognitive substudies for a robust evaluation of MVM effects on cognition. METHODS: COSMOS is a 2 × 2 factorial trial of cocoa extract (500 mg flavanols/d) and/or a daily MVM supplement for cardiovascular disease and cancer prevention among 21,442 United States adults aged ≥60 y. There were 573 participants in the clinic subcohort of COSMOS (that is, COSMOS-Clinic) who completed all cognitive tests administered at baseline. For the meta-analysis, we included nonoverlapping participants across 3 COSMOS cognitive substudies: COSMOS-Clinic (n = 573); COSMOS-Mind (n = 2158); COSMOS-Web (n = 2472). RESULTS: In COSMOS-Clinic, we observed a modest benefit of MVM compared with placebo on global cognition over 2 y {mean difference [95% confidence interval (CI)] = 0.06 SD units (SU) (-0.003, 0.13)}, with a significantly more favorable change in episodic memory [mean difference (95% CI) = 0.12 SU (0.002, 0.23)] but not in executive function or attention [mean difference (95% CI) = 0.04 SU (-0.04, 0.11)]. The meta-analysis of COSMOS substudies showed clear evidence of MVM benefits on global cognition [mean difference (95% CI) = 0.07 SU (0.03, 0.11); P = 0.0009] and episodic memory [mean difference (95% CI) = 0.06 SU (0.03, 0.10); P = 0.0007]; the magnitude of effect on global cognition was equivalent to reducing cognitive aging by 2 y. CONCLUSIONS: In COSMOS-Clinic, daily MVM supplementation leads to a significantly more favorable 2-y change in episodic memory. The meta-analysis within COSMOS cognitive substudies indicates that daily MVM significantly benefits both global cognition and episodic memory. These findings within the COSMOS trial support the benefits of a daily MVM in preventing cognitive decline among older adults. This trial was registered at COSMOS-clinicaltrials.gov as NCT02422745, at COSMOS-Mind-clinicaltrials.gov as NCT03035201, and at COSMOS-Web-clinicaltrials.gov as NCT04582617.

Impact of multivitamin-mineral and cocoa extract on incidence of mild cognitive impairment and dementia: Results from the COcoa Supplement and Multivitamin Outcomes Study for the Mind (COSMOS-Mind).

INTRODUCTION: We assessed the effects of multivitamin-mineral and cocoa extract supplementation on incident mild cognitive impairment (MCI) and all-cause probable dementia. METHODS: COSMOS-Mind (N = 2262), a 2 × 2 factorial, randomized-controlled clinical trial administered a telephone-based cognitive battery at baseline and annually for 3 years. Incidence rates of MCI, and separately dementia, were compared among treatment arms with proportional hazards regression. RESULTS: Over 3 years, 110 incident MCI and 14 incident dementia cases were adjudicated. Incidence rates did not vary by assignment to multivitamin-mineral or cocoa extract (all p's ≥ 0.05); however, statistical power was low. When participants assigned to multivitamin-mineral versus placebo converted to MCI, their scores for global cognition (p = 0.03) and executive function (p < 0.001) were higher and had declined less relative to the previous year (p = 0.03 for global cognition; p = 0.004 for executive function). DISCUSSION: Multivitamin-mineral therapy may provide cognitive resilience, countering conversion to MCI, but not significantly reduce its incidence over 3 years. HIGHLIGHTS: Multivitamin-mineral supplementation did not reduce risks for cognitive impairment. Cocoa extract supplementation did not reduce risks for cognitive impairment. Multivitamin-mineral supplementation slowed cognitive declines for incident mild cognitive impairment.

Effects of cocoa extract and a multivitamin on cognitive function: A randomized clinical trial.

INTRODUCTION: Dietary supplements are touted for cognitive protection, but supporting evidence is mixed. COSMOS-Mind tested whether daily administration of cocoa extract (containing 500 mg/day flavanols) versus placebo and a commercial multivitamin-mineral (MVM) versus placebo improved cognition in older women and men. METHODS: COSMOS-Mind, a large randomized two-by-two factorial 3-year trial, assessed cognition by telephone at baseline and annually. The primary outcome was a global cognition composite formed from mean standardized (z) scores (relative to baseline) from individual tests, including the Telephone Interview of Cognitive Status, Word List and Story Recall, Oral Trail-Making, Verbal Fluency, Number Span, and Digit Ordering. Using intention-to-treat, the primary endpoint was change in this composite with 3 years of cocoa extract use. The pre-specified secondary endpoint was change in the composite with 3 years of MVM supplementation. Treatment effects were also examined for executive function and memory composite scores, and in pre-specified subgroups at higher risk for cognitive decline. RESULTS: A total of 2262 participants were enrolled (mean age = 73y; 60% women; 89% non-Hispanic White), and 92% completed the baseline and at least one annual assessment. Cocoa extract had no effect on global cognition (mean z-score = 0.03, 95% CI: -0.02 to 0.08; P = .28). Daily MVM supplementation, relative to placebo, resulted in a statistically significant benefit on global cognition (mean z = 0.07, 95% CI 0.02 to 0.12; P = .007), and this effect was most pronounced in participants with a history of cardiovascular disease (no history: 0.06, 95% CI 0.01 to 0.11; history: 0.14, 95% CI -0.02 to 0.31; interaction, nominal P = .01). Multivitamin-mineral benefits were also observed for memory and executive function. The cocoa extract by MVM group interaction was not significant for any of the cognitive composites. DISCUSSION: Cocoa extract did not benefit cognition. However, COSMOS-Mind provides the first evidence from a large, long-term, pragmatic trial to support the potential efficacy of a MVM to improve cognition in older adults. Additional work is needed to confirm these findings in a more diverse cohort and to identify mechanisms to account for MVM effects. HIGHLIGHTS: COSMOS-Mind was a large simple pragmatic randomized clinical trial in older adults conducted by mail and telephone. The trial used a two-by-two factorial design to assess treatment effects of two different interventions within a single large study. We found no cognitive benefit of daily cocoa extract administration (containing 500 mg flavanols) for 3 years. Daily multivitamin-mineral (MVM) supplementation for 3 years improved global cognition, episodic memory, and executive function in older adults. The MVM benefit appeared to be greater for adults with cardiovascular disease.

Contributions of the Women's Health Initiative to Cardiovascular Research: JACC State-of-the-Art Review.

The WHI (Women's Health Initiative) enrolled 161,808 racially and ethnically diverse postmenopausal women, ages 50-79 years, from 1993 to 1998 at 40 clinical centers across the United States. In its clinical trial component, WHI evaluated 3 randomized interventions (menopausal hormone therapy; diet modification; and calcium/vitamin D supplementation) for the primary prevention of major chronic diseases, including cardiovascular disease, in older women. In the WHI observational study, numerous clinical, behavioral, and social factors have been evaluated as predictors of incident chronic disease and mortality. Although the original interventions have been completed, the WHI data and biomarker resources continue to be leveraged and expanded through ancillary studies to yield novel insights regarding cardiovascular disease prevention and healthy aging in women.

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).

Growth hormone-releasing hormone effects on brain γ-aminobutyric acid levels in mild cognitive impairment and healthy aging.

IMPORTANCE: Growth hormone-releasing hormone (GHRH) has been previously shown to have cognition-enhancing effects. The role of neurotransmitter changes, measured by proton magnetic resonance spectroscopy, may inform the mechanisms for this response. OBJECTIVE: To examine the neurochemical effects of GHRH in a subset of participants from the parent trial. DESIGN: Randomized, double-blind, placebo-controlled substudy of a larger trial. SETTING: Clinical research unit at the University of Washington School of Medicine. PARTICIPANTS: Thirty adults (17 with mild cognitive impairment [MCI]), ranging in age from 55 to 87 years, were enrolled and successfully completed the study. INTERVENTIONS: Participants self-administered daily subcutaneous injections of tesamorelin (Theratechnologies Inc), a stabilized analogue of human GHRH (1 mg/d), or placebo 30 minutes before bedtime for 20 weeks. At baseline and weeks 10 and 20, participants underwent brain magnetic resonance imaging and spectroscopy protocols and cognitive testing and provided blood samples after fasting. Participants also underwent glucose tolerance tests before and after intervention. MAIN OUTCOMES AND MEASURES: Brain levels of glutamate, inhibitory transmitters γ-aminobutyric acid (GABA) and N-acetylaspartylglutamate (NAAG), and myo-inositol (MI), an osmolyte linked to Alzheimer disease in humans, were measured in three 2 × 2 × 2-cm3 left-sided brain regions (dorsolateral frontal, posterior cingulate, and posterior parietal). Glutamate, GABA, and MI levels were expressed as ratios to creatine plus phosphocreatine, and NAAG was expressed as a ratio to N-acetylaspartate. RESULTS: After 20 weeks of GHRH administration, GABA levels were increased in all brain regions (P < .04), NAAG levels were increased (P = .03) in the dorsolateral frontal cortex, and MI levels were decreased in the posterior cingulate (P = .002). These effects were similar in adults with MCI and older adults with normal cognitive function. No changes in the brain levels of glutamate were observed. In the posterior cingulate, treatment-related changes in serum insulin-like growth factor 1 were positively correlated with changes in GABA (r = 0.47; P = .001) and tended to be negatively correlated with MI (r = -0.34; P = .06). Consistent with the results of the parent trial, a favorable treatment effect on cognition was observed in substudy participants (P = .03). No significant associations were observed between treatment-related changes in neurochemical and cognitive outcomes. Glucose homeostasis in the periphery was not reliably affected by GHRH administration and did not account for treatment neurochemical effects. CONCLUSIONS: Twenty weeks of GHRH administration increased GABA levels in all 3 brain regions, increased NAAG levels in the frontal cortex, and decreased MI levels in the posterior cingulate. To our knowledge, this is the first evidence that 20 weeks of somatotropic supplementation modulates inhibitory neurotransmitter and brain metabolite levels in a clinical trial, and it provides preliminary support for one possible mechanism to explain favorable GHRH effects on cognition in adults with MCI and in healthy older adults. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00257712.