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

Abstract

Key Aspects

• Study Objective: The primary aim of the COSMOS-Mind study was to investigate the effects of daily administration of cocoa extract (containing 500 mg/day flavanols) versus placebo, and a commercial multivitamin-mineral (MVM) versus placebo on cognitive function in older adults.
• Study Design: COSMOS-Mind employed a large, randomized, two-by-two factorial, 3-year trial design. This design allowed for the simultaneous assessment of two interventions within a single study. Cognition was assessed annually via telephone using a battery of standardized tests.
• Primary Outcome: The primary outcome was a global cognition composite score. This composite was derived from the mean of standardized (z) scores from individual cognitive tests, including the Telephone Interview of Cognitive Status, Word List and Story Recall, Oral Trail-Making, Verbal Fluency, Number Span, and Digit Ordering. The primary endpoint was the change in this composite after 3 years of cocoa extract use.
• Secondary Outcome: The pre-specified secondary endpoint was the change in the global cognition composite score after 3 years of MVM supplementation. The study also examined treatment effects on executive function and memory composite scores.
• Participant Characteristics: The study enrolled 2262 participants with a mean age of 73 years. The cohort was predominantly female (60%) and non-Hispanic White (89%). A significant portion (92%) completed the baseline and at least one annual assessment.
• Main Findings: Cocoa Extract: Cocoa extract had no significant effect on global cognition. The mean z-score change was 0.03 (95% CI: -0.02 to 0.08; P = .28), indicating no statistically significant difference between the cocoa extract and placebo groups.
• Main Findings: MVM Supplementation: Daily MVM supplementation resulted in a statistically significant improvement in global cognition compared to placebo. The mean z-score change was 0.07 (95% CI: 0.02 to 0.12; P = .007). This positive effect was particularly pronounced in participants with a history of cardiovascular disease.
• Subgroup Analyses: The study found that the beneficial effect of MVM supplementation was more pronounced in participants with a history of cardiovascular disease. The interaction was nominally significant (P = .01). No significant interaction was found between cocoa extract and MVM for any cognitive composite scores.
• Conclusions: The study concluded that cocoa extract did not provide cognitive benefits in this population. However, MVM supplementation showed a statistically significant positive effect on global cognition, particularly in individuals with a history of cardiovascular disease. This provides the first evidence from a large, long-term trial supporting the potential of MVMs to improve cognition in older adults.

Strengths

• Clear Study Design and Outcomes

  The abstract clearly outlines the study's randomized, two-by-two factorial design and specifies the primary and secondary outcomes, providing a concise overview of the methodological approach.

  "COSMOS-Mind, a large randomized two-by-two factorial 3-year trial, assessed cognition by telephone at baseline and annually." (Page 1)
• Comprehensive Cognitive Assessment

  The study employed a comprehensive battery of cognitive tests, enhancing the robustness of the cognitive assessment and allowing for a detailed evaluation of different cognitive domains.

  "The primary outcome was a global cognition composite formed from mean standardized (z) scores (relative to baseline) from individual tests" (Page 1)
• Statistically Significant Findings

  The abstract reports statistically significant findings for the effect of MVM supplementation on global cognition, providing quantitative data with confidence intervals and p-values.

  "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)" (Page 1)
• Large Sample Size and Follow-up

  The study included a large sample size with a high follow-up rate, increasing the statistical power and generalizability of the findings.

  "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 assess- ment." (Page 1)

Suggestions for Improvement

• Clarify MVM Composition

  This medium-impact improvement would enhance the study's transparency and allow for better comparison with other studies. The Abstract section particularly needs this detail as it provides the initial overview of the intervention being tested. Providing specific details about the MVM composition would strengthen the paper by allowing readers to understand precisely what intervention was tested and facilitating comparisons with other studies that may have used different MVM formulations. This would also aid in interpreting the findings and understanding the potential mechanisms underlying the observed effects. Ultimately, specifying the MVM composition would significantly improve the study's scientific contribution by ensuring its findings can be properly contextualized and compared with the broader literature.

  "a commercial multivitamin-mineral (MVM) versus placebo improved cognition in older women and men." (Page 1)

  Implementation: Include a brief phrase indicating the type of MVM used (e.g., "a standard commercial multivitamin-mineral supplement") and mention key components or refer to a table in the main text where the full composition is detailed (e.g., "Centrum Silver; see Table S6 for full composition").

• Elaborate on Cardiovascular Disease Subgroup

  This medium-impact improvement would provide a more nuanced understanding of the findings and their potential clinical implications. The Abstract section is the appropriate place for this detail as it highlights key findings and potential target populations. Elaborating on the cardiovascular disease subgroup finding would strengthen the paper by providing more context for interpreting the results and highlighting a specific population that may benefit most from MVM supplementation. This would also stimulate further research into the mechanisms underlying this subgroup difference. Ultimately, providing more detail on this subgroup would significantly improve the study's scientific contribution by highlighting a potentially important clinical implication of the findings.

  "this effect was most pronounced in participants with a history of cardiovascular disease" (Page 1)

  Implementation: Add a sentence specifying how cardiovascular disease history was defined (e.g., "self-reported history of myocardial infarction, stroke, or other cardiovascular events") and briefly explain the potential reasons for the observed difference (e.g., "potentially due to improved micronutrient status in individuals with cardiovascular disease").

• Mention Limitations Briefly

  This low-impact improvement would provide a more balanced overview of the study's findings and their limitations. While the Abstract should primarily focus on the key findings, briefly acknowledging limitations enhances the study's credibility. Briefly mentioning limitations would strengthen the paper by providing a more realistic perspective on the findings and acknowledging potential areas for future research. This would also help readers interpret the results in the context of these limitations. Ultimately, acknowledging limitations would improve the study's scientific contribution by presenting a more balanced and transparent overview of the research.

  "Additional work is needed to confirm these findings in a more diverse cohort" (Page 1)

  Implementation: Add a short phrase at the end of the abstract, such as "Limitations include the predominantly non-Hispanic White cohort and reliance on self-reported data." or "Further research is needed to confirm these findings in a more diverse population and to elucidate the underlying mechanisms."

Highlights

Key Aspects

• Study Design: The COSMOS-Mind study employed a large, simple, pragmatic, randomized clinical trial design. This approach, conducted via mail and telephone, allowed for efficient enrollment and assessment of a substantial number of participants, enhancing the study's statistical power and generalizability.
• Two-by-Two Factorial Design: This study utilized a two-by-two factorial design. This design allows researchers to simultaneously evaluate the effects of two different interventions—cocoa extract and a multivitamin-mineral (MVM) supplement—within a single study, optimizing resources and time.
• Cocoa Extract Findings: The study found no significant cognitive benefit from daily administration of cocoa extract containing 500 mg of flavanols over a 3-year period. This suggests that cocoa extract, at least at this dosage and duration, may not be an effective intervention for improving cognitive function in older adults.
• MVM Supplementation Findings: Daily MVM supplementation demonstrated a statistically significant improvement in global cognition, episodic memory, and executive function in older adults over 3 years. This indicates that MVM supplementation may be a promising intervention for enhancing cognitive performance in this population. Episodic memory, the ability to recall specific events and experiences, and executive function, a set of mental skills that include planning, focusing attention, and juggling multiple tasks, are crucial for daily functioning and independence in older adults.
• Cardiovascular Disease Subgroup: The positive effects of MVM supplementation appeared to be more pronounced in individuals with a history of cardiovascular disease. This suggests that individuals with cardiovascular conditions might derive greater cognitive benefits from MVM supplementation, potentially due to addressing underlying vascular-related cognitive impairments or micronutrient deficiencies.

Strengths

• Concise Summary of Findings

  The Highlights section effectively summarizes the key findings of the study in a clear and concise manner, providing a quick overview of the main results.

  "We found no cognitive benefit of daily cocoa extract administration" (Page 2)
• Clear Presentation of Interventions

  The section clearly presents the two interventions tested (cocoa extract and MVM) and their respective dosages, allowing for a straightforward understanding of the study's focus.

  "COSMOS-Mind was a large simple pragmatic randomized clinical trial in older adults" (Page 2)
• Highlighting of Key Populations

  The section effectively highlights the key population that showed a more pronounced benefit from MVM supplementation (adults with cardiovascular disease), providing valuable information for targeted interventions.

  "The MVM benefit appeared to be greater for adults with cardiovascular disease." (Page 2)

Suggestions for Improvement

• Expand on Study Design Implications

  This medium-impact improvement would provide a more comprehensive understanding of the study's methodological strengths and their implications for interpreting the findings. The Highlights section is an appropriate place for this detail as it sets the stage for understanding the significance of the results. Expanding on the study design implications would strengthen the paper by emphasizing the robustness of the study's approach and how it contributes to the reliability of the findings. This would also help readers appreciate the study's contribution to the field in terms of methodological advancements. Ultimately, providing more context on the study design would significantly improve the Highlights section by highlighting the study's methodological rigor and its contribution to research methodology.

  "COSMOS-Mind was a large simple pragmatic randomized clinical trial in older adults conducted by mail and telephone." (Page 2)

  Implementation: Add a sentence or two explaining the advantages of the large, pragmatic, randomized trial design, such as its ability to assess real-world effectiveness and its increased generalizability. For example: "The large, simple, pragmatic design, conducted via mail and telephone, enhanced enrollment and ensured broader applicability of findings. The two-by-two factorial design efficiently assessed two interventions simultaneously."

• Clarify the Significance of Negative Findings

  This medium-impact improvement would provide a more nuanced understanding of the study's findings regarding cocoa extract. The Highlights section is the ideal place to address this as it presents the main results. Clarifying the significance of the negative findings for cocoa extract would strengthen the paper by providing a more complete picture of the study's implications. This would also help readers understand that the lack of effect for cocoa extract is still a valuable finding that contributes to the field's knowledge. Ultimately, elaborating on the negative findings would significantly improve the Highlights section by providing a more balanced and informative overview of the study's results.

  "We found no cognitive benefit of daily cocoa extract administration (containing 500 mg flavanols) for 3 years." (Page 2)

  Implementation: Add a sentence explaining the implications of the lack of cognitive benefit from cocoa extract. For example: "While cocoa extract showed no cognitive benefits in this study, this finding contributes to the growing body of literature on the effects of cocoa flavanols and helps refine our understanding of their potential as cognitive enhancers."

• Provide Context for MVM Findings

  This high-impact improvement would enhance the reader's understanding of the significance of the MVM findings by placing them within the broader context of existing research. The Highlights section is the appropriate place for this context as it introduces the key findings. Providing context for the MVM findings would strengthen the paper by highlighting the novelty and importance of these results in relation to previous studies. This would also help readers appreciate the study's contribution to the field and its potential implications for public health. Ultimately, contextualizing the MVM findings would significantly improve the Highlights section by emphasizing the study's contribution to the existing body of knowledge on MVM supplementation and cognitive health.

  "Daily multivitamin-mineral (MVM) supplementation for 3 years improved global cognition, episodic memory, and executive function in older adults." (Page 2)

  Implementation: Add a sentence or two comparing the MVM findings to previous research, highlighting any consistencies or discrepancies. For example: "These findings provide the first evidence from a large, long-term trial that MVM supplementation can improve cognition in older adults, contrasting with some previous studies that showed mixed results. This supports the potential of MVMs as a widely accessible intervention for cognitive health."

1 BACKGROUND

Key Aspects

• Urgent Need for Cognitive Preservation Strategies: The rapidly increasing prevalence of Alzheimer's disease and related dementias, affecting over 46 million people globally, necessitates the urgent development of effective strategies to preserve cognitive function. This highlights a critical public health challenge, as the societal burden of these conditions is substantial and growing.
• Lack of FDA-Approved Interventions: Currently, there are no interventions approved by the United States Food and Drug Administration (FDA) to prevent cognitive decline in asymptomatic older adults. Furthermore, existing pharmacological treatments for individuals with mild cognitive impairment due to Alzheimer's disease have not demonstrated sufficient evidence of clinical benefit. This underscores the gap in available treatments and emphasizes the need for novel approaches.
• Cocoa Flavanols and Cognitive Function: Cocoa, in its unprocessed form, contains high quantities of catechins and epicatechins, which are flavanols, a subclass of flavonoids. These compounds, along with modest amounts of theobromine and caffeine, have been suggested to potentially slow cognitive decline. The proposed mechanism involves improved cerebral vasodilation, blood flow, perfusion, and angiogenesis. Epicatechin, the most common flavanol in cocoa, is able to cross the blood-brain barrier and may accumulate in the brain, potentially leading to physiological effects at higher levels. However, the evidence supporting the cognition-enhancing effects of cocoa flavanols primarily comes from epidemiological studies and a limited number of small clinical trials, with a recent review suggesting that memory and executive function might benefit most from higher doses (500-750 mg/day).
• Micronutrients, Minerals, and Cognitive Health: Individual micronutrients and minerals play essential roles in various biological pathways that maintain normal bodily and brain functions. Deficiencies in these micronutrients among older adults may elevate the risk of cognitive decline and dementia. However, trials investigating the effects of single nutrients, such as folic acid, B vitamins, omega-3 fatty acids, and vitamin D, on cognition have produced mixed results. These inconsistencies could be attributed to variations in study designs, including differences in the specific micronutrients tested, cognitive tests administered, outcome measures, participant demographics, and nutritional status. While meta-analytic reviews have not found sufficient evidence to recommend individual nutrient supplements for brain health, the potential of a comprehensive approach remains to be fully explored.
• Multivitamin-Mineral (MVM) Supplementation: The potential benefits of longer-term daily intake of a multivitamin-mineral (MVM) supplement, either alone or in combination with other dietary supplements, for enhancing global cognitive function in older adults (aged 65 years and above) have been investigated in only one large randomized controlled trial (RCT), which exclusively involved male physicians. Given the widespread use of MVMs in the general population, further research is crucial to determine their efficacy in protecting cognitive function in a broader population of older adults.
• Study Objective: This study aims to investigate whether daily treatment with cocoa extract (CE) and/or a multivitamin-mineral (MVM) supplement over a 3-year period can protect cognitive function in older adults. This research seeks to address the pressing need for accessible interventions to mitigate cognitive decline in an aging population.

Strengths

• Clear Identification of Research Gap

  The section effectively establishes the urgent need for interventions to address cognitive decline and highlights the lack of FDA-approved treatments, setting a strong rationale for the study.

  "There is an urgent need to identify effective strategies to preserve cognitive function" (Page 2)
• Comprehensive Background on Cocoa Flavanols

  The section provides a thorough overview of the current knowledge on cocoa flavanols, including their potential mechanisms of action and the existing evidence from epidemiological and clinical studies.

  "Dietary consumption of cocoa flavanols may slow cognitive decline through improved cerebral vasodilation" (Page 2)
• Well-Explained Rationale for Studying MVMs

  The section clearly articulates the rationale for investigating the effects of MVM supplementation, emphasizing the limited existing research and the widespread use of MVMs in the general population.

  "Further study is needed given their widespread use in the general population" (Page 2)

Suggestions for Improvement

• Strengthen Connection to Subsequent Sections

  This medium-impact improvement would enhance the flow and coherence of the paper by explicitly linking the background information to the study's specific design and methodology. The Background section is the appropriate place for this connection as it lays the foundation for the research. Explicitly connecting the background to the subsequent sections would strengthen the paper by providing a clearer rationale for the chosen methods and highlighting how the study builds upon existing knowledge. This would also help readers understand the study's contribution to the field in a more comprehensive way. Ultimately, strengthening this connection would significantly improve the paper's overall narrative and impact by demonstrating how the study's design directly addresses the research gaps identified in the Background.

  "Here we tested whether daily treatment with cocoa extract (CE) and/or a MVM for 3 years protected cognitive function in older adults." (Page 2)

  Implementation: Add a paragraph at the end of the section that briefly summarizes how the study's design, including the two-by-two factorial approach and the focus on both cocoa extract and MVM supplementation, directly addresses the gaps and limitations identified in the existing literature. For example: "To address the limitations of previous studies and further investigate the potential of both cocoa extract and MVM supplementation for cognitive protection, the present study, COSMOS-Mind, employs a large, randomized, two-by-two factorial design. This approach allows for the simultaneous assessment of both interventions and builds upon the existing knowledge base by..."

• Elaborate on the Public Health Implications

  This high-impact improvement would further emphasize the significance of the study by providing a more detailed discussion of the potential public health implications of the research. The Background section is ideal for this as it establishes the broader context and importance of the work. Elaborating on the public health implications would strengthen the paper by highlighting the potential impact of the findings on population health, particularly in relation to the aging population and the growing burden of cognitive decline. This would also help readers understand the study's contribution to addressing a major public health challenge. Ultimately, providing a more comprehensive discussion of the public health implications would significantly improve the paper's impact and relevance by emphasizing the potential of the research to inform public health strategies and interventions.

  "Identifying a safe, affordable, and accessible intervention to protect cognitive function against decline in older adults is a pressing public health priority." (Page 2)

  Implementation: Expand the discussion of the societal burden of Alzheimer's disease and related dementias, including specific statistics on the economic and social costs. Add a paragraph that explores the potential of accessible interventions, such as MVM supplementation, to mitigate this burden at a population level. For example: "Given the substantial economic and social costs associated with cognitive decline, identifying accessible and affordable interventions, such as MVM supplementation, could have significant public health implications. If proven effective, such interventions could be implemented broadly to potentially reduce the incidence and impact of cognitive impairment in older adults."

• Clarify the Controversy Surrounding B Vitamins

  This medium-impact improvement would provide a more balanced and nuanced perspective on the existing literature regarding B vitamins and cognitive function. The Background section is the appropriate place for this clarification as it presents the current state of knowledge in the field. Clarifying the controversy surrounding B vitamins would strengthen the paper by acknowledging the complexities and uncertainties in the existing research and providing a more complete picture of the scientific debate. This would also help readers understand the need for further research in this area. Ultimately, providing a more nuanced discussion of the B vitamin controversy would significantly improve the paper's scientific rigor and credibility by presenting a more balanced and comprehensive overview of the existing literature.

  "Although not without controversy, particularly with respect to potential cognition-enhancing effects of B vitamins" (Page 2)

  Implementation: Add a sentence or two that briefly explains the nature of the controversy surrounding B vitamins and cognitive function, mentioning the conflicting findings and potential reasons for the discrepancies. For example: "While some studies have suggested a potential benefit of B vitamins for cognitive health, others have found no significant effect, leading to ongoing debate about their efficacy. This controversy may be partly due to differences in study populations, dosages, and outcome measures."

2 METHODS

Key Aspects

• Study Design: The COSMOS-Mind study was an ancillary study to the larger COSMOS trial, which investigated the effects of cocoa extract (CE) and a multivitamin-mineral (MVM) supplement on cardiovascular and cancer outcomes. It employed a 2x2 factorial design, a method where participants are randomly assigned to one of four groups: CE with MVM-placebo, CE-placebo with MVM, CE with MVM, or CE-placebo with MVM-placebo. This design allowed for the simultaneous assessment of the independent and combined effects of CE and MVM on cognitive function. The study was conducted in accordance with ethical guidelines and approved by the Institutional Review Board of Wake Forest University School of Medicine.
• Supplement Details: The cocoa extract (CE) used in the study was provided by Mars Edge and contained 500 mg of cocoa flavanols, including 80 mg of (-)-epicatechins, along with small amounts of theobromine (approximately 50 mg/day) and caffeine (approximately 15 mg/day). The multivitamin-mineral (MVM) supplement used was Centrum Silver, manufactured by Pfizer Consumer Healthcare (now Haleon). The specific nutrient composition of the MVM is detailed in Table S6 of the supplementary materials.
• Participant Eligibility: The study targeted the enrollment of 2000 participants from the parent COSMOS trial. Eligibility criteria for the parent trial included individuals with no history of myocardial infarction or stroke, no history of cancer within the past 2 years (excluding non-melanoma skin cancer), no serious illness that would preclude participation, no current use of cocoa or vitamin/mineral supplements (or willingness to abstain during the trial), no reported extreme sensitivity to cocoa products or caffeine, successful completion of a placebo run-in period with at least 75% adherence, and no current participation in another clinical trial. Additional eligibility criteria for COSMOS-Mind included being 65 years of age or older, not taking insulin for diabetes, and being able to complete a telephone-based cognitive assessment.
• Randomization and Masking: Participants were randomly assigned to one of the four treatment groups using a computer-generated sequence, stratified by sex, age (in 5-year bins), and recruitment source. All investigators, examiners, and participants were masked to treatment group assignments, meaning they were unaware of who was receiving which intervention. This blinding helps to minimize bias in the study results.
• Recruitment Procedures: Participants were recruited from the Women's Health Initiative Extension Study, individuals contacted by Brigham and Women's Hospital for the vitamin D and OmegA-3 TriaL, and through commercial mailing lists and media campaigns. Individuals from traditionally underrepresented groups in research were prioritized in the initial contact queue to increase their representation in the sample. Participants provided demographic information, anthropometric measurements (height and weight), and medical history through questionnaires.
• Cognitive Assessment: Cognitive function was assessed using a standardized telephone-based battery administered at baseline and annually for 3 years. The battery included tests of general cognitive status (Telephone Interview for Cognitive Status [TICSm]), episodic memory (Word List Recall, Story Recall), executive function (Oral Trail-Making Test Part B, Verbal Fluency, Number Span, Digit Ordering Test). These tests are commonly used to evaluate different aspects of cognitive performance in older adults. The primary outcome was a global cognition composite score, calculated as the mean of standardized scores from the individual cognitive tests.
• Statistical Analysis: The primary and secondary endpoints were pre-specified in the study protocol. The researchers used an intention-to-treat approach, meaning that all participants were analyzed according to their original treatment assignment, regardless of whether they completed all assessments. Linear mixed effects models were used to analyze the data, with time as a categorical factor. The primary analysis compared the mean change in cognitive scores from baseline across the follow-up assessments between the CE and CE-placebo groups (primary endpoint) and between the MVM and MVM-placebo groups (key secondary endpoint). Interactions between CE and MVM treatments and consistency of effects among subgroups were also examined.

Strengths

• Comprehensive Methodological Details

  The section provides a thorough description of the study design, participant recruitment, randomization, cognitive assessments, and statistical analyses, offering a clear and detailed account of the methods employed.

  "COSMOS-Mind examined the effects of these supplements on cognitive function, and the details of study design, participant demo- graphics, and baseline characteristics are published." (Page 2)
• Rigorous Study Design

  The use of a 2x2 factorial design, randomization, and masking procedures demonstrates a commitment to rigorous methodology, minimizing bias and enhancing the internal validity of the study.

  "Given that no additive or synergistic effects were expected with CE and MVM supplementation, the 2 × 2 factorial design provided an efficient strategy" (Page 2)
• Clear Eligibility Criteria

  The section clearly outlines the eligibility criteria for both the parent COSMOS trial and the COSMOS-Mind ancillary study, ensuring a well-defined study population.

  "Parent trial eligibility criteria included: (1) no history of myocardial infarction (MI) or stroke" (Page 3)
• Detailed Cognitive Assessment Battery

  The description of the standardized telephone cognitive battery is comprehensive, providing specific details about the tests used and the cognitive domains assessed.

  "Tests included the 50-point modi- fied Telephone Interview for Cognitive Status (TICSm with 10-minute short delay word list recall), an additional 40-minute Long Delay Word List Recall" (Page 3)
• Appropriate Statistical Analysis

  The use of linear mixed effects models and an intention-to-treat approach are appropriate statistical methods for analyzing longitudinal data in clinical trials.

  "We followed the intention-to-treat approach: all par- ticipants were grouped as originally randomly assigned and scores from all cognitive assessments (baseline and Years 1, 2 and 3) for all participants were included in analyses." (Page 4)

Suggestions for Improvement

• Provide More Detail on Cognitive Test Scoring

  This medium-impact improvement would enhance the reproducibility and transparency of the study's cognitive assessment procedures. The Methods section is the appropriate place for this detail as it provides the foundation for understanding how cognitive function was measured and quantified. Providing more detail on cognitive test scoring would strengthen the paper by allowing other researchers to more accurately replicate the study's methods and compare their findings to those of COSMOS-Mind. This would also facilitate meta-analyses and systematic reviews that synthesize data across multiple studies. Ultimately, clarifying the scoring procedures would significantly improve the study's scientific contribution by ensuring that the cognitive assessment methods are fully transparent and replicable.

  "A standardized telephone cognitive battery was administered at base- line and annually for 3 years" (Page 3)

  Implementation: Include a more detailed description of the scoring procedures for each cognitive test, specifying the range of possible scores, the direction of scoring (i.e., higher scores indicate better or worse performance), and any specific rules or adjustments used in the scoring process. For example: "The TICSm has a maximum score of 50 points, with higher scores indicating better cognitive function. The Word List Recall test involves recalling a list of 10 words, with one point awarded for each word correctly recalled. The Oral Trail-Making Test Part B is scored in seconds, with lower times indicating better performance. Raw scores were log-transformed to reduce skewness."

• Justify the Choice of Cognitive Tests

  This medium-impact improvement would provide a stronger rationale for the selection of specific cognitive tests and enhance the reader's understanding of how these tests relate to the study's overall goals. The Methods section is the ideal place for this justification as it explains the reasoning behind the chosen methodological approach. Justifying the choice of cognitive tests would strengthen the paper by demonstrating the link between the study's objectives and the specific cognitive domains assessed. This would also help readers evaluate the appropriateness of the chosen tests for measuring the effects of cocoa extract and MVM supplementation on cognitive function. Ultimately, providing a clear rationale for the cognitive tests would significantly improve the study's scientific rigor and interpretability by ensuring that the chosen methods are well-aligned with the research questions.

  "A standardized telephone cognitive battery was administered at base- line and annually for 3 years to assess general cognitive status, episodic memory and executive function." (Page 3)

  Implementation: Add a paragraph that explains the rationale for selecting the specific cognitive tests included in the battery. Briefly discuss the cognitive domains assessed by each test and how they relate to the study's hypotheses about the potential effects of cocoa extract and MVM supplementation. For example: "The cognitive battery was designed to assess a range of cognitive domains relevant to aging and potentially modifiable by the interventions. The TICSm was chosen as a measure of global cognitive function. Word List Recall and Story Recall were selected to assess episodic memory, a domain particularly vulnerable to age-related decline. The Oral Trail-Making Test, Verbal Fluency, Number Span, and Digit Ordering Test were included to measure executive function, a set of cognitive skills important for daily functioning."

• Clarify the Handling of Missing Data

  This high-impact improvement would enhance the transparency and rigor of the statistical analysis by providing a more detailed explanation of how missing data were addressed. The Methods section is the appropriate place for this clarification as it describes the statistical procedures used in the study. Clarifying the handling of missing data would strengthen the paper by allowing readers to better understand the potential impact of missing data on the study's findings and evaluate the appropriateness of the chosen imputation method. This would also increase confidence in the robustness of the results. Ultimately, providing a more detailed explanation of the missing data handling would significantly improve the study's scientific rigor and credibility by ensuring that the statistical analysis is transparent and appropriately addresses potential biases.

  "Multiple imputation by fully conditional specification was used to examine the influence of missing data." (Page 4)

  Implementation: Expand the description of the statistical analysis to include more specific details about the handling of missing data. Specify the percentage of missing data for each cognitive test at each time point. Explain the multiple imputation procedure in more detail, including the number of imputations performed, the variables included in the imputation model, and any sensitivity analyses conducted to assess the impact of different imputation methods. For example: "Missing data ranged from 8% at Year 1 to 21% at Year 3. Multiple imputation by fully conditional specification was used to address missing data. Fifty imputed datasets were created, including all cognitive test scores, treatment assignment, and baseline covariates in the imputation model. Sensitivity analyses using different imputation models showed similar results."

3 RESULTS

Key Aspects

• Enrollment and Baseline Characteristics: The study enrolled 2262 participants between August 2, 2016, and August 17, 2017. Participants were well-balanced across the four treatment groups in terms of baseline characteristics and cognitive test scores. The majority of participants completed the cognitive assessments throughout the 3-year follow-up period. Those who missed at least one assessment differed slightly from those who completed all assessments, primarily in terms of race/ethnicity, physical activity, smoking, education, baseline cognitive scores, and prevalence of type 2 diabetes.
• Primary Endpoint: Cocoa Extract and Global Cognition: Cocoa extract (CE) had no significant effect on global cognition over the 3-year study period. The mean change in global cognition z-score for the CE group compared to the CE-placebo group was 0.03 (95% CI: -0.02 to 0.08; P = .28), indicating no statistically significant difference between the groups. This finding suggests that daily consumption of cocoa extract containing 500 mg of flavanols does not improve global cognitive function in older adults over a 3-year period.
• Secondary Endpoint: MVM and Global Cognition: Daily multivitamin-mineral (MVM) supplementation resulted in a statistically significant improvement in global cognition compared to placebo. The mean change in global cognition z-score for the MVM group compared to the MVM-placebo group was 0.07 (95% CI: 0.02 to 0.12; P = .007). This finding provides evidence that daily MVM use can enhance global cognitive function in older adults over a 3-year period. Baseline MVM use did not significantly affect the treatment response.
• Subgroup Analysis: MVM and Cardiovascular Disease History: A pre-specified subgroup analysis revealed that the positive effect of MVM supplementation on global cognition was more pronounced in participants with a history of cardiovascular disease (CVD). The interaction between MVM treatment and CVD history was statistically significant (P = .01). Participants with CVD history who received MVM showed a greater improvement in global cognition compared to those without CVD history. This suggests that individuals with CVD may derive greater cognitive benefits from MVM supplementation.
• Other Cognitive Outcomes: CE had no significant effects on episodic memory or executive function. However, MVM supplementation led to significant improvements in both episodic memory (mean change z-score = 0.06, 95% CI: 0.002 to 0.13; P = .04) and executive function (mean change z-score = 0.06, 95% CI: 0.01 to 0.11; P = .02). These findings further support the potential of MVM supplementation to enhance specific cognitive domains in older adults.
• Interaction between CE and MVM: There was no significant interaction between CE and MVM supplementation for any of the cognitive outcomes. This indicates that the addition of CE did not alter the beneficial effect of MVM on cognition. In simpler terms, cocoa extract neither enhanced nor diminished the positive effects of the multivitamin on cognitive function.
• Attrition and Safety: Multiple imputation analyses indicated that differential attrition (i.e., participants dropping out of the study) did not significantly bias the results. Additionally, there were no safety concerns associated with the use of either CE or MVM supplements during the trial.

Strengths

• Clear Presentation of Results

  The section clearly presents the main findings of the study, including the effects of cocoa extract and MVM supplementation on global cognition and other cognitive outcomes. The use of mean change z-scores, confidence intervals, and p-values allows for a straightforward interpretation of the results.

  "Cocoa extract had no effect on global cognition (mean z-score = 0.03, 95% CI: -0.02 to 0.08; P = .28)." (Page 4)
• Well-Defined Statistical Analyses

  The section provides a concise description of the statistical analyses performed, including the use of linear mixed effects models, intention-to-treat approach, and pre-specified primary and secondary endpoints. This demonstrates a rigorous analytical approach.

  "We followed the intention-to-treat approach: all par- ticipants were grouped as originally randomly assigned" (Page 4)
• Comprehensive Subgroup Analyses

  The section includes pre-specified subgroup analyses, which provide valuable insights into the potential heterogeneity of treatment effects. The finding that MVM supplementation had a more pronounced effect in participants with a history of cardiovascular disease is particularly noteworthy.

  "forest plots show a relative benefit of MVM versus MVM-placebo for participants with a CVD history" (Page 4)
• Inclusion of Relevant Figures

  The section refers to figures that visually depict the main findings, such as the change in global cognition over time for the different treatment groups. These figures enhance the reader's understanding of the results.

  "Figure 2A shows change in global cognition, relative to baseline, for participants assigned to CE" (Page 4)

Suggestions for Improvement

• Provide More Context for Findings

  This medium-impact improvement would enhance the reader's understanding of the results by placing them within the broader context of the study's design and objectives. The Results section is the appropriate place for this context as it allows readers to connect the findings back to the initial research questions. Providing more context would strengthen the paper by explicitly linking the results to the study's rationale and highlighting how the findings contribute to the overall goals of the research. This would also help readers appreciate the significance of the results in relation to the study's design and methodology. Ultimately, adding more context would significantly improve the Results section by providing a more comprehensive and meaningful interpretation of the findings.

  "COSMOS-Mind participants were enrolled from August 2, 2016 to August 17, 2017." (Page 4)

  Implementation: Begin the section with a brief paragraph that reiterates the study's primary and secondary objectives and the overall design. Briefly mention the key interventions (cocoa extract and MVM) and the primary outcome (global cognition). For example: "This section presents the results of the COSMOS-Mind trial, which aimed to investigate the effects of daily cocoa extract (CE) and multivitamin-mineral (MVM) supplementation on cognitive function in older adults. Using a 2x2 factorial design, participants were randomized to receive CE, MVM, both, or placebo. The primary outcome was the change in global cognition composite score after 3 years."

• Expand on the Clinical Significance

  This high-impact improvement would provide a more meaningful interpretation of the study's findings by discussing their potential clinical implications. The Results section is an appropriate place for this discussion as it allows readers to understand the practical relevance of the observed effects. Expanding on the clinical significance would strengthen the paper by highlighting the potential impact of the findings on clinical practice and public health. This would also help readers appreciate the study's contribution to the field in terms of its potential to inform interventions for cognitive health. Ultimately, discussing the clinical significance would significantly improve the Results section by providing a more impactful and relevant interpretation of the findings.

  "Daily MVM supplementation, relative to placebo, resulted in a statistically significant benefit on global cognition" (Page 4)

  Implementation: Include a paragraph that discusses the potential clinical significance of the observed effects, particularly the positive effect of MVM supplementation on global cognition. Consider discussing the magnitude of the effect size, the potential implications for cognitive aging, and the potential benefits for specific populations (e.g., individuals with cardiovascular disease). For example: "The statistically significant improvement in global cognition observed with MVM supplementation, while modest in magnitude (0.07 z-score units), may have clinical relevance for older adults, particularly those with a history of cardiovascular disease. This effect size could potentially translate to a meaningful difference in cognitive function over time. Further research is needed to determine the long-term clinical impact and to identify the optimal duration and dosage of MVM supplementation."

• Clarify the Rationale for Subgroup Analyses

  This medium-impact improvement would provide a stronger justification for the chosen subgroup analyses and enhance the reader's understanding of their relevance to the study's overall goals. The Results section is the ideal place for this clarification as it presents the findings of these analyses. Clarifying the rationale for subgroup analyses would strengthen the paper by demonstrating the link between the study's hypotheses and the specific subgroups examined. This would also help readers evaluate the appropriateness of the chosen subgroups and their potential to inform targeted interventions. Ultimately, providing a clear rationale for the subgroup analyses would significantly improve the study's scientific rigor and interpretability by ensuring that the chosen analyses are well-aligned with the research questions.

  "Subgroups were pre-specified given their possible associations with cognitive and/or cardiovascular response to the interventions." (Page 4)

  Implementation: Add a brief explanation of why the specific subgroups (e.g., age, sex, BMI, cognitive function, CVD history) were chosen for analysis. Briefly discuss the potential relevance of each subgroup to the study's hypotheses about the effects of cocoa extract and MVM supplementation. For example: "Pre-specified subgroup analyses were conducted to explore potential heterogeneity of treatment effects across different populations. These subgroups were chosen based on their potential associations with cognitive function and/or cardiovascular health, as well as their relevance to the study's hypotheses. For instance, the subgroup analysis based on CVD history was conducted because individuals with CVD may be more likely to benefit from MVM supplementation due to potential micronutrient deficiencies or other underlying factors."

Non-Text Elements

FIGURE 1 Consort diagram showing flow of participants from first approach...

Full Caption

FIGURE 1 Consort diagram showing flow of participants from first approach through randomization to each of the four treatment combinations in the two-by-two factorial design. Abbreviations: CE, cocoa extract; MVM, multivitamin-mineral

Figure/Table Image (Page 5)

First Reference in Text

Figure 2A shows change in global cognition, relative to baseline, for participants assigned to CE (Figure 1, Groups 2 & 4) versus CE-placebo (Figure 1, Groups 1 & 3).

Description

• Flow of Participants: The diagram is a flow chart that illustrates the journey of participants in the study, starting from when they were first approached to take part in the research. It shows how many people were initially contacted, how many were excluded at different stages, and for what reasons. For example, some people might not have been contactable, some might have declined to participate, and others might have been excluded for not meeting specific criteria.
• Randomization: The diagram outlines the process of 'randomization,' which is a method used to fairly assign participants to different treatment groups. This is like drawing names out of a hat to decide who gets which treatment, ensuring no bias in how people are assigned. In this study, randomization ensures that each participant has an equal chance of being assigned to any of the treatment groups, which is crucial for the scientific validity of the results because it helps to ensure that any differences observed between the groups are due to the treatment itself, and not some other factor.
• Two-by-Two Factorial Design: The study uses a 'two-by-two factorial design.' This is a type of experimental setup where two different treatments are tested both separately and together. It's like testing whether a plant grows better with fertilizer A, fertilizer B, both, or neither. Here, the treatments are cocoa extract (CE) and a multivitamin-mineral (MVM) supplement. This design allows researchers to see not only if each treatment works on its own but also if they have a combined effect when given together.
• Four Treatment Combinations: The diagram shows that participants are divided into four groups, each receiving a different combination of treatments: (1) CE-Placebo and MVM-Placebo, meaning they get neither the cocoa extract nor the multivitamin; (2) CE and MVM-Placebo, meaning they get the cocoa extract but not the multivitamin; (3) CE-Placebo and MVM, meaning they get the multivitamin but not the cocoa extract; and (4) CE and MVM, meaning they get both treatments. 'Placebo' is a dummy treatment that has no active effect, used as a control to compare against the actual treatments.
• Completion of Assessments: The chart indicates how many participants completed each stage of the study, specifically the baseline cognitive assessment and subsequent annual assessments. 'Cognitive assessment' refers to tests that measure mental functions like memory and thinking skills. The numbers show how many people dropped out or were unable to complete the assessments each year. For example, it shows that out of 587 participants in the CE-Placebo, MVM-Placebo group, 462 completed the Year 3 assessment, while 125 did not.

Scientific Validity

• Comprehensive Participant Tracking: The CONSORT diagram meticulously tracks participant flow, which is crucial for assessing the study's internal validity. It provides a clear account of attrition rates and reasons for withdrawal, which are essential for evaluating potential biases. However, the reasons for non-contactability and refusal are not detailed, which could be important for understanding selection bias.
• Randomization Integrity: The diagram confirms that participants were randomized, which is a strength of the study design. However, it does not detail the method of randomization or allocation concealment, which are important for ensuring the integrity of the randomization process.
• Factorial Design Appropriateness: The use of a two-by-two factorial design is appropriate for the research question, allowing for the assessment of both main effects and interactions between CE and MVM. This design is well-suited to investigate the independent and combined effects of the interventions.

Communication

• Clarity of Group Labeling: The diagram clearly labels each of the four treatment groups, aiding in the understanding of the study's design. The use of abbreviations is defined in the caption, which is helpful.
• Visual Presentation of Attrition: The diagram effectively uses a visual format to present the flow of participants, making it easy to follow the progression and attrition at each stage. However, the lack of specific reasons for withdrawal or non-completion at each stage limits the depth of information conveyed.
• Accessibility of Information: While the diagram is informative, it could be improved by providing more context within the figure itself, such as brief explanations of the exclusion criteria or reasons for dropout. This would enhance the stand-alone interpretability of the figure without needing to refer to the main text.

FIGURE 2 Three-year change in global cognition composite by assignment to (A)...

Full Caption

FIGURE 2 Three-year change in global cognition composite by assignment to (A) daily cocoa extract supplementation, and (B) daily multivitamin-mineral supplementation (plotted values: mean standardized (z) scores (relative to baseline) and 95% confidence intervals). Forest plot marginal differences by baseline subgroups for (C) cocoa extract and (D) multivitamin-mineral treatment groups

Figure/Table Image (Page 8)

First Reference in Text

As seen in Figure 3, at base- line, participants without CVD history outperformed those with CVD history on the global cognition composite (mean difference = 0.22, 95% CI: 0.08 to 0.37; P = .003); after Year 1, the MVM-placebo declined while the MVM group showed relative improvement (or pro- tection against decline).

Description

• Change in Global Cognition Over Three Years: The figure illustrates how participants' thinking and memory skills, referred to as 'global cognition,' changed over a three-year period. This change is measured using a 'global cognition composite,' which is a combined score from various tests that assess different aspects of brain function, like memory, attention, and problem-solving abilities. The results are shown separately for two different treatments: daily cocoa extract supplementation and daily multivitamin-mineral supplementation.
• Standardized (z) Scores: The changes in cognition are presented as 'standardized (z) scores.' A z-score is a way of representing data that shows how far a particular data point is from the average (mean), measured in terms of standard deviations. Think of it like a common yardstick that allows for comparison across different tests or measurements. Here, it indicates how much each participant's cognitive performance changed from their own starting point (baseline).
• 95% Confidence Intervals: The '95% confidence intervals' provide a range within which we can be 95% certain the true average change in cognition lies. It's like saying, 'We're pretty sure the real answer is between this number and that number.' In a graph, these intervals are often shown as bars extending from the plotted points, indicating the precision of the estimate.
• Forest Plots for Subgroup Differences: The figure includes 'forest plots,' which are a way of graphically representing the results of different studies or subgroups within a study. In this case, they show how the effects of cocoa extract and multivitamin-mineral supplementation differ across various subgroups of participants. These subgroups are defined by characteristics like age, sex, body mass index, and medical history. A forest plot typically displays the effect size (here, the difference in cognitive change) for each subgroup, along with its confidence interval, allowing for a visual comparison of treatment effects across different groups.
• Marginal Differences: The term 'marginal differences' refers to the average difference in the outcome (change in global cognition) between the treatment groups (active vs. placebo) within each subgroup. It's a way of looking at the treatment effect separately for each group, like comparing the effect of a medicine on men versus women or younger versus older adults. This helps to see if the treatment works differently for different types of people.

Scientific Validity

• Appropriateness of Outcome Measure: The use of a global cognition composite is appropriate for assessing overall cognitive change. However, the specific tests contributing to this composite should be scrutinized for their relevance and sensitivity to the interventions being studied. The reliance on z-scores is standard practice, but it assumes that the cognitive measures are normally distributed.
• Confidence Interval Interpretation: The 95% confidence intervals are correctly applied, providing an estimate of the precision of the observed effects. However, the interpretation of these intervals should be cautious, particularly when making inferences about the efficacy of the interventions in the absence of p-values.
• Subgroup Analysis Validity: The subgroup analyses via forest plots are a valuable addition, allowing for the exploration of heterogeneity of treatment effects. However, these analyses should be interpreted with caution due to the potential for increased Type I error when conducting multiple comparisons. The rationale for choosing these specific subgroups should be clearly justified.
• Control for Confounders: It is not immediately clear from the figure whether the analyses have been adjusted for potential confounders. While the caption mentions 'baseline subgroups,' it is important that the analyses account for other factors that could influence cognitive change.

Communication

• Clarity of Graphical Presentation: The graphical presentation is generally clear, with separate panels for each intervention and clear labeling of axes. However, the use of z-scores may be difficult for some readers to interpret, and the figure could benefit from a more explicit explanation of what a z-score represents in this context.
• Forest Plot Readability: The forest plots are relatively standard in their presentation, but the sheer number of subgroups presented could be overwhelming. It may be beneficial to highlight the most relevant or statistically significant subgroups to aid in interpretation.
• Caption Completeness: The caption provides a good overview of the figure's content but could be improved by briefly explaining the rationale for the subgroup analyses and the implications of the findings. Additionally, defining 'marginal differences' within the caption would enhance understanding.
• Visual Clutter: There is a risk of visual clutter due to the amount of information presented. Simplifying the figure by focusing on fewer, key subgroups or using supplementary materials for less critical analyses could improve readability.

FIGURE 4 Three-year change in the episodic memory composite (A) and executive...

Full Caption

FIGURE 4 Three-year change in the episodic memory composite (A) and executive function composite (B) for the active and placebo multivitamin-mineral groups (plotted values: mean standardized (z) scores and 95% confidence intervals).

Figure/Table Image (Page 9)

First Reference in Text

MVM supplementation led to relative improvements both for memory (mean change z-score = 0.06, 95% CI: 0.002 to 0.13; P = .04) and for executive function (mean change z-score = 0.06, 95% CI: 0.01 to 0.11; P = .02) (Figure 4).

Description

Scientific Validity

Communication

TABLE 1 Distribution of baseline characteristics for COSMOS-Mind participants...

Full Caption

TABLE 1 Distribution of baseline characteristics for COSMOS-Mind participants by cocoa extract (CE) and multivitamin-mineral (MVM) treatment assignment

Figure/Table Image (Page 6)

First Reference in Text

Baseline characteristics and baseline cognitive test scores were well balanced across treatment groups (Table 1 and Table S1).

Description

• Purpose of the Table: This table shows the characteristics of the participants at the start of the study, called 'baseline characteristics.' These characteristics include things like age, sex, race, education, health status, and lifestyle factors. The purpose of showing this information is to demonstrate that the different treatment groups were similar to each other at the beginning of the study. This is important because if the groups were very different at the start, it would be hard to tell if any changes seen later were due to the treatments or just because of these initial differences.
• Treatment Groups: The participants were divided into four groups based on whether they received cocoa extract (CE), a multivitamin-mineral supplement (MVM), both, or neither. The table compares these groups to see if they were similar in terms of their baseline characteristics. For example, it checks if the average age or the proportion of men and women was roughly the same in each group. A 'placebo' is a dummy treatment that has no active effect, used here as a control to compare against the actual treatments. So, 'CE-Placebo, MVM-Placebo' means participants in this group got neither the cocoa extract nor the multivitamin.
• Types of Characteristics Shown: The table includes a variety of characteristics, such as demographic information (age, sex, race, education), health measurements (body mass index, blood pressure), medical history (diabetes, cardiovascular disease), medication use, lifestyle factors (exercise, smoking, alcohol, chocolate intake), and cognitive function scores. These characteristics are important because they could potentially influence how a person responds to the treatments.
• Statistical Measures: The table uses different statistical measures to describe the characteristics. For continuous variables like age or body mass index, it shows the 'mean (SD),' which stands for the average value and the standard deviation (a measure of how spread out the values are around the mean). For categorical variables like sex or smoking status, it shows the number and percentage of participants in each category (e.g., '914 (40.4)' for males, meaning 914 participants, or 40.4% of the total, were male). 'Median (IQR)' is used for variables that might not be normally distributed, where the median is the middle value, and the IQR (interquartile range) is the range between the 25th and 75th percentiles, giving an idea of the spread of the middle 50% of the data.
• Importance of Balance: The table is meant to show that the treatment groups were 'well balanced,' meaning there were no major differences between the groups in any of the baseline characteristics. This balance is crucial for the validity of the study because it means that any differences in outcomes observed later are more likely to be due to the treatments themselves rather than pre-existing differences between the groups.

Scientific Validity

• Comprehensive Baseline Assessment: The table provides a comprehensive assessment of a wide range of baseline characteristics, which is crucial for evaluating the comparability of the treatment groups. This thoroughness enhances the internal validity of the study by ensuring that potential confounders are identified and can be accounted for in the analysis.
• Appropriate Statistical Reporting: The use of means, standard deviations, medians, and interquartile ranges, as well as counts and percentages, is appropriate for the types of data presented. However, the table lacks p-values, which would typically be used to formally assess the statistical significance of any differences between groups.
• Relevance of Variables: The variables included in the table are relevant to the study's research questions and potential confounding factors. However, the rationale for including each variable could be more explicitly stated, particularly for those that may not be immediately obvious to the reader.
• Potential for Residual Confounding: While the table demonstrates a good balance across many variables, there is always the potential for residual confounding due to unmeasured or unknown factors. The authors should acknowledge this limitation and discuss its potential impact on the study's findings.

Communication

• Organization and Clarity: The table is well-organized, with clear headings and logical grouping of variables. The use of abbreviations is consistent, and the caption provides a good overview of the table's content. However, the table is quite dense, and the sheer amount of information presented could be overwhelming for some readers. It may be helpful to use bolding or shading to highlight key findings or to separate different categories of variables more distinctly.
• Readability: The font size and formatting are generally readable, but the table spans multiple pages, which can make it difficult to follow. It might be beneficial to present the table as a supplementary file or to split it into smaller, more focused tables.
• Accessibility for Non-Experts: The table is primarily aimed at a scientific audience and uses technical terms that may not be familiar to non-experts. While some terms are explained in the footnotes, others are not. Providing a brief glossary of terms or expanding the footnotes could improve accessibility.
• Inclusion of Statistical Significance: The table would be strengthened by the inclusion of p-values to indicate the statistical significance of any differences between groups. This would provide a more objective assessment of the balance achieved by randomization and help readers interpret the importance of any observed differences.

4 DISCUSSION

Key Aspects

• First Large-Scale Trial of CE and MVM on Cognition: COSMOS-Mind represents the first large-scale, long-term randomized controlled trial (RCT) to investigate the effects of both cocoa extract (CE) and a multivitamin-mineral (MVM) supplement on global cognition in a general population of older adults. This distinguishes it from previous studies that were typically smaller, shorter in duration, or focused on specific populations like male physicians.
• No Cognitive Benefit from Cocoa Extract: The study found no significant positive effect of daily cocoa extract (CE) supplementation, containing 500 mg of flavanols, on global cognition over a 3-year period. This finding contrasts with some previous smaller, shorter-term trials that suggested potential cognitive benefits of cocoa flavanols, particularly at higher doses. The lack of effect in COSMOS-Mind could be due to several factors, including the specific dose used, the study's duration, or the annual assessment schedule, which might have missed acute effects.
• Cognitive Benefits of MVM Supplementation: Daily MVM supplementation demonstrated a statistically significant improvement in global cognition compared to placebo over 3 years. This finding provides the first evidence from a large, long-term trial supporting the potential of MVMs to enhance cognitive function in older adults. The study also found improvements in episodic memory and executive function with MVM use, suggesting benefits across multiple cognitive domains.
• Enhanced MVM Benefit in Individuals with CVD History: Pre-planned subgroup analyses indicated that the positive effect of MVM supplementation on global cognition was more pronounced in participants with a baseline history of cardiovascular disease (CVD). This suggests that individuals with CVD may experience greater relative improvement or protection from CVD-related cognitive decline, potentially due to the correction of underlying micronutrient deficiencies or other vascular-related factors. This finding highlights a specific population that may derive particular benefit from MVM supplementation.
• Comparison with Previous Research: The discussion compares the findings of COSMOS-Mind with previous research on cocoa flavanols and MVM supplementation. It highlights the discrepancies between the negative CE findings and some earlier studies, suggesting potential explanations such as differences in dosage, study duration, and the inclusion of theobromine and caffeine in the CE supplement. It also contrasts the positive MVM findings with the lack of effect observed in the Physicians' Health Study II (PHS II), a previous large trial of MVMs in male physicians, attributing the differences to factors such as study population, cognitive assessment methods, and the timing of cognitive assessments relative to the intervention period.
• Potential Mechanisms and Clinical Significance: The discussion explores potential mechanisms underlying the observed cognitive benefits of MVM supplementation, particularly in individuals with CVD history. It suggests that MVMs may improve cognition by addressing micronutrient deficiencies, which are more common in older adults and those with CVD. The authors also attempt to estimate the clinical significance of the MVM effect, suggesting that it may correspond to a slowing of cognitive aging by 1.8 years, although they acknowledge the limitations of this estimation.
• Study Strengths and Limitations: The discussion acknowledges the strengths of the COSMOS-Mind study, including its large sample size, long-term follow-up, pragmatic design, and the use of a 2x2 factorial approach. It also addresses the limitations, such as the lack of racial and ethnic diversity in the study population, the reliance on self-reported data for some measures, the inability to pinpoint the specific components of the MVM responsible for the cognitive benefits, and the lack of biomarker data. These limitations affect the generalizability of the findings and the ability to fully understand the underlying mechanisms.
• Future Research Directions: The authors emphasize the need for further research to confirm the findings in a more diverse population, to identify the optimal duration and dosage of MVM supplementation, and to elucidate the mechanisms underlying the observed cognitive benefits. They also suggest that future studies should investigate the potential role of specific micronutrients and explore the interaction between MVM supplementation and other factors, such as diet and lifestyle.

Strengths

• Comprehensive Overview of Findings

  The section effectively summarizes the main findings of the study, highlighting the lack of effect of cocoa extract and the positive effects of MVM supplementation on global cognition, particularly in individuals with a history of cardiovascular disease.

  "Although our findings did not support a positive effect of CE (primary endpoint), cognition significantly benefited from 3 years of daily MVM use" (Page 5)
• Appropriate Comparison with Previous Research

  The section thoughtfully compares the study's findings with previous research on cocoa flavanols and MVM supplementation, providing context and highlighting potential reasons for discrepancies.

  "Only a handful of controlled, shorter-term trials have examined the potential benefits of cocoa flavanols on cognition in older adults." (Page 5)
• Balanced Discussion of Study Strengths and Limitations

  The section acknowledges both the strengths and limitations of the study, providing a balanced perspective on the findings and their implications.

  "COSMOS-Mind had several strengths." (Page 10)
• Clear Articulation of Future Research Directions

  The section clearly outlines the need for further research to confirm the findings, explore mechanisms, and investigate the optimal use of MVM supplementation for cognitive health.

  "An additional trial is needed to confirm these findings in a more representative cohort and to explore potential mechanisms for cognitive benefit." (Page 10)

Suggestions for Improvement

• Strengthen Discussion of Mechanisms

  This medium-impact improvement would provide a more in-depth understanding of the potential pathways through which MVM supplementation may improve cognitive function. The Discussion section is the appropriate place for this more detailed exploration of mechanisms, as it allows for a deeper interpretation of the findings and their implications. Expanding the discussion of mechanisms would strengthen the paper by providing a more comprehensive theoretical framework for understanding the observed effects and by generating more specific hypotheses for future research. This would also enhance the paper's contribution to the field by advancing the understanding of the complex interplay between nutrition and cognitive health. Ultimately, a more thorough discussion of mechanisms would significantly improve the Discussion section by providing a more nuanced and insightful interpretation of the study's findings and their potential implications for the prevention and treatment of cognitive decline.

  "One account for this finding relates to the potential treatment-related improvement in micronutrient levels in CVD-compromised individuals" (Page 9)

  Implementation: Expand the discussion of potential mechanisms beyond the brief mention of micronutrient deficiencies. Consider discussing other potential pathways, such as the role of MVMs in reducing oxidative stress, inflammation, or improving vascular health. Explore the potential role of specific micronutrients, such as B vitamins, vitamin D, and antioxidants, in more detail. For example: "While the current study did not directly assess biomarkers of oxidative stress or inflammation, it is plausible that MVM supplementation may improve cognitive function by reducing oxidative damage and inflammation in the brain, both of which are implicated in age-related cognitive decline. Specific micronutrients within the MVM, such as vitamin E and vitamin C, are known to have antioxidant properties, while others, such as omega-3 fatty acids (not included in this MVM), have been shown to reduce inflammation. Furthermore, B vitamins, which were included in the MVM, play a crucial role in homocysteine metabolism, and elevated homocysteine levels have been linked to both cardiovascular disease and cognitive impairment."

• Elaborate on Clinical Significance and Public Health Implications

  This high-impact improvement would provide a more comprehensive and impactful discussion of the study's findings by further exploring their potential clinical significance and public health implications. The Discussion section is the ideal place for this elaboration, as it allows for a broader interpretation of the results and their potential impact on practice and policy. Expanding on the clinical significance and public health implications would strengthen the paper by highlighting the potential of MVM supplementation as a widely accessible and affordable intervention for promoting cognitive health in older adults. This would also enhance the paper's contribution to the field by emphasizing the potential of the findings to inform public health strategies and interventions aimed at reducing the burden of age-related cognitive decline. Ultimately, a more detailed discussion of clinical significance and public health implications would significantly improve the Discussion section by providing a more impactful and relevant interpretation of the study's findings and their potential to improve the lives of older adults.

  "This work may ultimately have important public health implications for standard of care to improve or protect cognitive function in older adults." (Page 10)

  Implementation: Expand the discussion of the potential clinical significance of the findings by providing more context for the observed effect sizes. Discuss the potential impact of MVM supplementation on the trajectory of cognitive aging in more detail, considering the potential for delaying the onset of cognitive impairment or dementia. Explore the potential public health implications of the findings, considering the widespread use of MVMs and their potential to improve cognitive health at a population level. For example: "While the observed effect size for MVM supplementation on global cognition may appear modest, it is important to consider the potential impact of this effect over time. Given the progressive nature of age-related cognitive decline, even a small improvement in cognitive function could potentially translate into a significant delay in the onset of cognitive impairment or dementia. Furthermore, given the widespread availability and relatively low cost of MVMs, even a modest effect could have significant public health implications if applied broadly to the aging population. MVM supplementation could potentially represent a simple, scalable, and affordable intervention for promoting cognitive health and reducing the societal burden of age-related cognitive decline."

• Provide More Nuanced Interpretation of Negative Cocoa Extract Findings

  This medium-impact improvement would provide a more balanced and insightful interpretation of the study's findings by further exploring the potential reasons for the lack of effect of cocoa extract on cognition. The Discussion section is the appropriate place for this more nuanced interpretation, as it allows for a deeper consideration of the factors that may have influenced the results. Expanding the discussion of the negative cocoa extract findings would strengthen the paper by providing a more complete picture of the study's implications and by highlighting the complexities of research on cocoa flavanols and cognitive function. This would also enhance the paper's contribution to the field by informing future research on cocoa flavanols and helping to refine the understanding of their potential as cognitive enhancers. Ultimately, a more nuanced interpretation of the negative cocoa extract findings would significantly improve the Discussion section by providing a more balanced and comprehensive understanding of the study's results and their implications for the field.

  "Daily CE supplementation for 3 years did not affect cognitive function in our trial." (Page 5)

  Implementation: Expand the discussion of the potential reasons for the lack of effect of cocoa extract on cognition. Consider discussing the possibility that the specific dose or formulation of cocoa extract used in the study may not have been optimal for cognitive benefits. Explore the potential role of individual differences in response to cocoa flavanols, such as genetic factors or variations in gut microbiota. Discuss the limitations of relying solely on annual cognitive assessments, which may have missed potential short-term or fluctuating effects. For example: "While the current study found no significant effect of cocoa extract on cognition, it is important to consider several factors that may have influenced this result. The dose of cocoa flavanols used in the study (500 mg/day) may have been too low to produce significant cognitive benefits, particularly in light of previous studies that suggested potential benefits at higher doses. Additionally, the specific formulation of the cocoa extract, which included theobromine and caffeine, may have influenced the results. It is also possible that individual differences in response to cocoa flavanols, such as genetic variations or differences in gut microbiota composition, may have played a role. Future research should explore these factors in more detail to better understand the potential of cocoa flavanols as cognitive enhancers."

Non-Text Elements

FIGURE 3 Three-year change in global cognition composite for the active and...

Full Caption

FIGURE 3 Three-year change in global cognition composite for the active and placebo multivitamin-mineral groups by history of cardiovascular disease, which was based on self-report of transient ischemic attack, congestive heart failure, coronary artery bypass graft, angioplasty, or stent (plotted values: mean standardized (z) scores and 95% confidence intervals).

Figure/Table Image (Page 9)

First Reference in Text

The MVM-treated CVD history subgroup had sustained increases in cognitive function after 2 years (Figure 3), while the placebo-treated CVD history subgroup showed cognitive decline after Year 1.

Description

• Focus on Cognitive Change: This figure shows how a person's overall thinking and memory abilities, called 'global cognition,' changed over three years. It specifically looks at these changes in two groups of people: those who took a multivitamin-mineral supplement (active group) and those who took a pill with no active ingredients (placebo group).
• Comparison Based on Cardiovascular Disease History: The figure divides each group (active and placebo) further into two subgroups based on whether they had a history of cardiovascular disease (CVD). Cardiovascular disease refers to conditions affecting the heart and blood vessels. The history is determined by participants' self-reporting of specific events like a transient ischemic attack (often called a 'mini-stroke'), congestive heart failure, or procedures like coronary artery bypass graft, angioplasty, or stent placement.
• Standardized (z) Scores: The changes in cognition are shown using 'standardized (z) scores.' A z-score is a statistical measure that describes a value's relationship to the mean (average) of a group of values, measured in terms of standard deviations from the mean. If a z-score is zero, it indicates the data point's score is identical to the mean score. A positive z-score indicates the value is above the mean, while a negative z-score indicates it is below the mean. Here, it's used to show how much each individual's cognitive performance changed relative to their own starting point (baseline).
• 95% Confidence Intervals: The '95% confidence intervals' indicate a range within which we are 95% certain that the true average change in cognition lies for each group. It's like saying, 'We're pretty sure the real average change is somewhere between these two values.' These are usually represented graphically as bars or lines extending from a plotted point, giving a visual sense of the precision of the estimate.
• Plotted Values: The figure plots the average (mean) change in cognitive scores for each group over the three years. This allows for a visual comparison of how cognition changed in the active group versus the placebo group, and how this differed between those with and without a history of cardiovascular disease.

Scientific Validity

• Self-Reported CVD History: The reliance on self-reported cardiovascular disease history is a potential limitation. Self-reports can be subject to recall bias or misinterpretation, which could affect the accuracy of subgroup categorization. It would be preferable to have this confirmed by medical records.
• Appropriateness of Outcome Measure: Using a global cognition composite is suitable for a broad assessment of cognitive function. However, the specific domains of cognition most affected by MVM supplementation in those with CVD history are not discernible from this figure alone. Further breakdown into domain-specific scores could provide more nuanced insights.
• Statistical Analysis: The use of z-scores and 95% confidence intervals is appropriate for presenting the data. However, without p-values or tests for statistical significance, it is difficult to determine the certainty of the observed differences between groups.
• Potential Confounding Factors: While the study attempts to isolate the effect of CVD history, other factors could confound the relationship between MVM supplementation, CVD history, and cognitive change. These potential confounders should be addressed in the statistical analysis.

Communication

• Clarity of Grouping: The figure clearly distinguishes between active and placebo groups and further stratifies by CVD history, which is crucial for understanding the study's findings. However, the specific criteria for 'CVD history' could be more prominently displayed on the figure itself for better clarity.
• Visual Representation: The use of a line graph to depict changes over time is effective for showing trends. However, the figure could be enhanced by including markers for each year to clearly indicate the time points at which measurements were taken.
• Caption Detail: The caption adequately describes the figure but could benefit from a brief explanation of why CVD history was chosen as a stratifying variable. Additionally, including a statement about the statistical significance of the observed differences would strengthen the interpretation.
• Accessibility for Non-Experts: While the figure is generally understandable, the concept of z-scores might be challenging for some readers. Providing a lay-friendly explanation of z-scores in the caption or a supplementary note could improve accessibility.

RESEARCH IN CONTEXT

Key Aspects

• Systematic Literature Review: The authors conducted a systematic review of the existing literature using PubMed and MEDLINE databases. This review highlighted that much of the evidence supporting the potential cognitive benefits of cocoa flavanols in older adults is derived from observational studies. Furthermore, it revealed that only a limited number of controlled trials have investigated the effects of multivitamin-mineral (MVM) supplementation on cognitive function in older adults. This demonstrates a gap in the current research, particularly regarding rigorous, interventional studies on the impact of MVMs on cognition in this population.
• Interpretation of Findings: The authors interpret their findings, indicating no significant cognitive improvement with daily intake of cocoa extract containing 500 mg/day of cocoa flavanols over a 3-year period. However, they provide the first evidence from a long-term, randomized controlled trial involving older men and women that daily use of a safe, readily accessible, and low-cost MVM can improve cognition. This finding is significant as it suggests a potential avenue for enhancing cognitive health in older adults through a widely available intervention.
• Public Health Implications: The authors suggest that the finding regarding MVM's positive effect on cognition could have important public health implications for brain health and resilience against future cognitive decline. This is particularly relevant given the aging global population and the increasing prevalence of age-related cognitive impairment. The potential of a readily available and affordable intervention like MVM supplementation to improve cognitive function on a large scale is a noteworthy contribution to the field.
• Future Research Directions: The authors outline future research directions based on their findings. They propose that the results challenge the current understanding of the efficacy of MVM supplementation in improving cognitive function. They also set the stage for new avenues of research aimed at identifying the mechanisms underlying the observed cognitive benefits and exploring alternative approaches, such as combination therapy, to enhance cognitive health in older adults.

Strengths

• Clear and Concise Summary

  The section provides a clear and concise summary of the study's findings and their implications, effectively encapsulating the main takeaways for the reader.

  "There was no cognitive improvement with daily intake for 3 years of cocoa extract" (Page 3)
• Appropriate Contextualization

  The section effectively places the study within the broader context of existing research by referencing the systematic review and highlighting the novelty of the findings.

  "The literature was reviewed using PubMed and MEDLINE." (Page 3)
• Well-Defined Future Directions

  The section clearly outlines future research directions, providing a roadmap for further investigation in this area.

  "Our results challenge the current status quo regarding the efficacy of MVM supplementation" (Page 3)

Suggestions for Improvement

• Expand on the Systematic Review Methodology

  This medium-impact improvement would enhance the transparency and reproducibility of the literature review process. The Research in Context section is the appropriate place for this detail as it provides the foundation for understanding how the current study fits within the existing body of knowledge. Expanding on the systematic review methodology would strengthen the paper by providing a more detailed account of how the literature was searched, selected, and synthesized. This would also allow readers to better evaluate the comprehensiveness and rigor of the review. Ultimately, clarifying the review methodology would significantly improve the study's scientific contribution by ensuring that the contextualization of the findings is based on a transparent and robust review process.

  "The literature was reviewed using PubMed and MEDLINE." (Page 3)

  Implementation: Provide more details about the search strategy, including the specific search terms used, the databases searched, the date range of the search, and the inclusion/exclusion criteria for selecting studies. For example: "The systematic review was conducted using PubMed and MEDLINE databases. The search terms included 'cocoa flavanols,' 'multivitamin-mineral,' 'cognition,' 'older adults,' and related terms. Studies published between January 2000 and March 2022 were considered. Only randomized controlled trials involving adults aged 65 years or older and assessing the effects of cocoa extract or MVM supplementation on cognitive outcomes were included."

• Discuss Limitations of Existing Research

  This medium-impact improvement would provide a more critical assessment of the existing literature and highlight the specific gaps that the current study addresses. The Research in Context section is the ideal place for this discussion as it sets the stage for justifying the need for the current study. Discussing the limitations of existing research would strengthen the paper by providing a more nuanced understanding of the state of the field and by emphasizing the unique contribution of the current study. This would also help readers appreciate the study's significance in advancing the understanding of the relationship between cocoa flavanols, MVM supplementation, and cognitive function. Ultimately, providing a more critical assessment of the existing literature would significantly improve the Research in Context section by highlighting the study's contribution to addressing the limitations of previous research.

  "Much of the support for potential cognitive benefits of cocoa flavanols in older adults is based on observational studies." (Page 3)

  Implementation: Briefly discuss the limitations of the existing research on cocoa flavanols and MVM supplementation, such as the prevalence of observational studies, the small sample sizes and short durations of many controlled trials, and the heterogeneity of study populations and outcome measures. For example: "While observational studies have suggested potential cognitive benefits of cocoa flavanols, these studies are limited by potential confounding factors. Furthermore, many of the existing controlled trials on cocoa flavanols and MVM supplementation have been limited by small sample sizes, short durations, and a reliance on specific populations, such as male physicians. The heterogeneity of outcome measures across studies also makes it difficult to compare findings and draw definitive conclusions."

• Elaborate on the Implications for Clinical Practice

  This high-impact improvement would provide a more direct link between the study's findings and their potential impact on clinical practice. The Research in Context section is the appropriate place for this discussion as it connects the research to its broader implications. Elaborating on the implications for clinical practice would strengthen the paper by highlighting the potential of MVM supplementation as a safe, accessible, and low-cost intervention to improve cognition in older adults. This would also help readers understand the study's contribution to the field in terms of its potential to inform clinical guidelines and recommendations. Ultimately, providing a more detailed discussion of the clinical implications would significantly improve the Research in Context section by emphasizing the study's potential to translate research findings into practical applications that can benefit the health and well-being of older adults.

  "This finding could have important public health implications for brain health and resilience against future cognitive decline." (Page 3)

  Implementation: Discuss the potential implications of the findings for clinical practice, considering the need for further research to confirm the results and establish optimal dosages and durations of MVM supplementation. For example: "While further research is needed to confirm these findings and establish optimal dosages and durations, the results suggest that daily MVM supplementation may be a safe, accessible, and low-cost intervention to improve cognition in older adults. This finding could potentially inform clinical guidelines and recommendations for cognitive health, particularly in individuals with a history of cardiovascular disease. However, it is important to emphasize that MVM supplementation should not be considered a replacement for a healthy lifestyle, including a balanced diet and regular physical activity."