Polyphenols and memory enhancement -
The COMPASS groupings are consistent with other studies that have administered the COMPASS as an outcome measure Kennedy et al.
As an exploratory analysis, further analyses using GLMM were conducted on the BRIEF-A behavioral regulation index and metacognition index.
Random intercepts were utilized in each GLMM model, and covariates of age, sex, baseline BMI, educational level, average energy intake, and average dietary polyphenol intake were included as fixed effects.
Where applicable, gamma with log link function and normal with identity link function target distributions were used. Appropriate covariance structures were used to model correlation associated with repeated time measurements in gamma models.
Robust estimations were used to handle any violations of model assumptions. Intervention group differences at time points were assessed using simple contrasts. As a measure of visuospatial learning, a visit x trial x group, repeated-measures ANCOVA was performed on the displacement scores trials 1 to 5 on the location learning task covariates of age, sex, baseline BMI, educational level, average energy intake, and average dietary polyphenol intake.
Moreover, a trial x group, repeated-measures ANCOVA was conducted at each visit weeks 0, 12, and 24 to examine differences in visuospatial learning at each visit.
Data from participants were included in the location learning analyses if data were obtained at week 12 [last observation carried forward from week 12 for missing values]. As the location learning displacement scores were not normally distributed, the data were winsorized, where scores greater than 3 standard deviations from the mean were replaced with the highest score that fell below the criterion of 3 standard deviations from the mean.
Due to the exploratory nature of this trial, there was no adjustment to the value of p for multiple testing. As detailed in Figure 1 , from people who completed the initial online screening questionnaire, did not fulfill the eligibility criteria, and 13 withdrew consent to participate in the study.
Details of participant baseline scores and background information of the total sample are detailed in Table 1.
There were no other statistically significant time x group interactions on other COMPASS cognitive tasks. Capsule bottles with remaining capsules were returned at the week assessment, and participants completed a daily medication monitoring phone application.
To assess the effectiveness of condition concealment during the study, participants predicted at the end of the trial their condition allocation i. The frequency of self-reported adverse reactions is included in Table 5.
No serious adverse reactions were reported by participants, and a similar frequency of adverse reactions was reported in both groups. Five participants withdrew from the trial due to a moderate severity of self-reported adverse reactions associated with capsule intake.
However, there were no significant between-group differences in episodic memory, working memory, or accuracy in attention. This was specifically characterized by a greater improvement in the Metacognition index. However, there were no between-group differences in changes in other self-report measures of cognitive abilities or quality of life.
In fact, study dropouts were more common in the placebo group, with many participants citing adverse reactions from the capsules as the reason for withdrawal from the study. In recent systematic reviews examining the impact of grape Bird et al.
Moreover, in a systematic review of berry-based supplements and foods, it was reported that they may have beneficial effects on resting brain perfusion, cognitive function, memory performance, executive functioning, processing speed, and attention indices Bonyadi et al.
However, substantial differences in the clinical trials make robust conclusions difficult. Overall, these findings may have important implications for the progression of MCI.
In a meta-analysis of 7 studies, it was confirmed that reaction time is slower in people with MCI, and its slowing may be an early sign of AD Andriuta et al.
Moreover, it has been demonstrated that performance on the location learning task is worse in people with AD compared with MCI, indicating that this measure could discriminate between MCI and AD Kessels et al.
In a study on the BRIEF-A, adults with MCI and subjective cognitive complaints reported significant difficulties with selective aspects of executive functioning relative to healthy controls despite clinically normal performance on several neuropsychological tests of executive function.
These findings suggest that the BRIEF-A may be sensitive to subtle changes in executive function Rabin et al. Although not measured in this study, the informant-reported BRIEF-A also seems to provide a reliable indicator of cognitive deficits in older adults Scholz and Donders, It is important to note that in this study, several statistically significant improvements were identified in the placebo group over time.
This was demonstrated by improvements in immediate and delayed word recall, choice reaction time, and reaction time on the Stroop task. Moreover, there was a statistically significant reduction in the CFQ score over time in the placebo group, but no significant changes were observed in the remaining self-report measures BRIEF-A and CASP.
These results suggest that practice and placebo responses partly accounted for changes observed over time in participants, but this did not occur in all tasks. Some of the practice effects may have been minimized in the study as computer-based tasks were only completed on 3 occasions over a 6-month period.
Additionally, it is possible that the re-administration of the cognitive tasks masked some of the performance deteriorations that might be observed in people with MCI over time. How grapes and blueberries affect cognitive functioning requires further investigation, although several mechanisms are speculated.
In preclinical and in vitro trials, blueberry supplementation reversed neuronal aging attributed to a reduction in oxidative stress Joseph et al. Blueberries may also lower neuroinflammation Shukitt-Hale et al. Preclinical trials have also demonstrated that grapes can alleviate age-related reduction of hippocampal neurogenesis and synaptogenesis Rastegar-Moghaddam et al.
All in all, these studies demonstrate that blueberries and grapes may provide cognitive benefits via their antioxidant, anti-inflammatory, and neuroprotective effects; upregulation of neuronal signaling proteins; and stimulation of neurogenesis. However, as these biological actions were not investigated in this study, these mechanisms remain speculative.
Despite some positive results from the study, further research is required to validate and expand upon the current findings. Moreover, identifying populations that may realize greater benefits from supplementation will be important.
Possibilities include younger people, adults with early and mild MCI or subjective memory complaints, or people consuming a diet low in polyphenols. Even though in this study, the habitual intake of dietary polyphenols did not influence treatment outcomes, more comprehensive dietary assessments may be required to provide a more valid measure of long-term dietary intake.
Objective outcome measures and more comprehensive and sensitive neuropsychological assessments will also help to substantiate the results from self-report and computer-based cognitive tasks. These include measuring blood markers of oxidative stress, inflammation, and neurogenesis, and neural imaging to identify changes in brain centers associated with memory and cognitive performance.
A more comprehensive assessment of MCI will also be important, as MCI in this study was diagnosed using the telephone version of the MoCA. However, no between-group differences in other cognitive domains were identified, including episodic memory the primary outcome measure.
The preliminary positive results of this unique polyphenol-rich extract require further investigation in robust clinical trials. The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.
The studies involving human participants were reviewed and approved by National Institute of Integrative Medicine Human Research Ethics Committee.
DG, CP, LP, and AL designed the research. AL and SS conducted the research. AL and PD analyzed the data. AL, SS, CP, LP, DG, VP, and PD were involved in writing the paper. All authors contributed to the article and approved the submitted version.
The funder was not involved in data collection, interpretation of data, or the decision to submit it for publication. AL is the managing director of Clinical Research Australia, a contract research organization that has received research funding from nutraceutical companies.
AL has also received presentation honoraria from nutraceutical companies. SS is an employee of Clinical Research Australia and declares no other conflicts of interest. PD and VP declare no conflicts of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Andriuta, D. Is reaction time slowing an early sign of Alzheimer's disease?
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Bonyadi, N. Effect of berry-based supplements and foods on cognitive function: a systematic review. Bridger, R. Psychometric properties of the cognitive failures questionnaire. Ergonomics 56, — Broadbent, D.
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Colizzi, C. The protective effects of polyphenols on Alzheimer's disease: a systematic review. Future studies should harmonize control conditions and use memory tests with high construct validity and focus on the quality of the methods.
Methodological quality can be increased by for example concealment of allocation, using an intention-to-treat analysis, and measuring compliance as well as implementing memory tests that are insensitive to ceiling or test-retest effects, such as the computerized administration of the Mnemonic Similarity Task Moreover, future studies should include larger samples and longer follow-up to increase power.
Yet, the sample sizes and durations of the RCTs included in this review did not seem to affect the results. By including biological parameters, such as urine or blood samples, and functional and structural brain measures using e.
Performing longer longitudinal studies in the future could provide insight into whether the consumption of polyphenols decreases progression rates of patients with mild neurocognitive disorder to dementia.
Based on reviewing 66 short- to longer-duration daily polyphenol intervention RCTs with small to large sample sizes, a beneficial effect of polyphenols on WM and EM in middle-aged to older adults may be considered small on average, according to qualitative review and a pooled meta-analysis of all available outcomes of 49 studies.
The reported outcome measures largely varied and some studies of longer duration and larger sample sizes did not report any significant memory improvement after polyphenol administration.
We also noted strong evidence for reporting bias and the statistical heterogeneity was considerably large between studies. Thus interpretation warrants caution and needs to be confirmed by further research.
Future studies are encouraged to harmonize polyphenol formulas and doses as well as neuropsychological test methodology, and to increase sample sizes and follow-up periods.
Overall, dietary supplementation studies investigating diet-effects on memory of high quality do exist, however, suffer from known limitations in the field and the problem to investigate rather small expected effects. The original contributions presented in the study are included in the article as meta-data.
Further inquiries related to effect sizes per study or other queries can be directed to the corresponding author. KV, EM, and AVW: conceptualization and data analysis.
KV and AVW: conducted literature search. KV: first draft. EM and AVW: visualization. EM, AVW, and AK: review and correction. All authors contributed to the article and approved the submitted manuscript. This work was supported by grants of the German Research Foundation No.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. United Nations, Department of Economic and Social Affairs.
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Mazza M, Capuano A, Bria P, Mazza S. However, no phenolic metabolite was found to be significantly associated with improvement in the PALTEA in decliners. Overall, we could not identify significant association between the microbial metabolites of epi catechins, the valerolactones, β-type procyanidins dimers, or phenolic compounds present in PEGB and memory improvement.
Blueberry and grape have both been reported to improve memory performances in humans 21— In this study, we investigated the beneficial effects on memory of a polyphenol-rich combination of blueberry and grape extracts PEGB , which provides high amounts of monomeric flavanols, known to reduce cognitive decline in mice This combination offers a synergistic action between the two extracts Indeed, we previously demonstrated a potentiation of the absorption of blueberry polyphenols by grape polyphenols in mice, therefore indicating positive interactions occurring between phytochemicals in this specific formulation, resulting in their improved bioavailability While not showing significant improvement in episodic memory in the whole population after a 6-month supplementation with PEGB, the present study, clearly demonstrates a positive effect on episodic memory of a subset of this population, healthy elderly subjects presenting the highest memory decline.
Supplementing the participants for 6 months with PEGB did not result in a significant decrease in the primary outcome of this study, the PALTEA in the whole study population.
We observed a high variability in baseline PAL score, which may be explained by inter-center differences including educational level that was lower in French volunteers. Indeed, the incidence of cognitive decline has been found to be lower in more educated populations Moreover, we noticed that subjects in the placebo group had a lower PALTEA at the second visit than at baseline.
This observation may rely on a test-retest effect. Indeed, although, the protocol included a cognitive practice and a MOT, improvements in cognitive scores measured in the placebo group reveal that a test—retest effect subsisted in this study.
This has been previously described This practice effect reduced the chances to show a significant between-group difference thus the significant PEGB effects showed in the present study were probably underestimated.
Importantly, this practice effect probably accounts for the failure of showing a significant effect on the primary outcome in the whole study population. Indeed, it was more difficult to demonstrate a significant effect of PEGB in participants whose results were already quite good at baseline since margin of improvement was small.
Interestingly, we showed that the 6-month PEGB supplementation significantly protected verbal episodic memory, a secondary criteria of the trial, as measured by VRMFR.
However, this was not the case for working memory evaluated by SSP, although baseline span lengths were consistent with results previously published for subjects of the same age 60—year-old Our analysis revealed a significant interaction between the PEGB effect and baseline PALTEA.
In order to determine which subjects were responsive to the supplementation, we stratified the population into quartiles according to the baseline PALTEA, the main criteria of the study. Such a high number of errors was also reported by Junkilla et al. However, Q4 subjects did not display low MMSE score, as reported by Junkilla et al.
The decliners presented lower memory performances than people of the same age group. They exhibited global cognitive impairment, with lower results in various tests compared to subjects of other quartiles. It is noteworthy that these subjects also had a lower level of education. However, consistently with the inclusion criteria, they were generally healthy as confirmed by blood tests data not shown.
Interestingly, our results showed a beneficial effect of PEGB supplementation on episodic and recognition memory in decliners. This effect was significant despite the low number of subjects. Using the normative data of the CANTAB battery www.
com , the baseline cognitive age of the decliners was estimated at After 6 months, the cognitive age of the supplemented subjects was estimated at To our knowledge, the effect of polyphenols on episodic memory evaluated by PAL has never been shown to date.
Previous interventional studies with grape or blueberry juice, performed on MCI subjects, revealed no effect on PAL performance compared to placebo 22 , By contrast, a beneficial effect of the consumption of flavanols on verbal recognition memory has been highlighted by a longitudinal approach during aging Moreover, a small-sized effect of grape juice on verbal episodic memory was previously observed using Californian Verbal Learning Test More recently, tow randomized, double-blind, placebo-controlled trials, highlighted the effectiveness of blueberry consumption on verbal recognition memory and working memory in healthy elderly subjects 25 , The daily dose of PEGB is equivalent to a consumption of less than g of fresh fruits.
Our study therefore demonstrates that a nutritional amount of berry polyphenols improves the memory of healthy elderly people exhibiting an age-related cognitive decline, and restores the performances expected for their age. Urinary concentration of polyphenols is generally considered as a reliable marker of their consumption A recent epidemiological study showed that urinary polyphenol measurement was more suitable than dietary survey to associate polyphenol consumption with biological effects, and demonstrated an association between excreted concentrations of phenolic metabolites and the risk of cognitive decline measured by the MMSE 14 , In the present work, we found that changes in flavanols were strongly associated with memory improvement.
Indeed, increases in urine levels of epi catechins and especially their conjugated metabolites were positively and significantly correlated with memory performance at the VRMFR and the VRMR delayed.
This was not the case for PALTEA where no correlation was observed. We assumed that the lack of association between these factors and PALTEA in decliners might be attributed to the low number of subjects in this group.
Moreover, in contrast to what was observed in animals 36 , no significant correlation between urinary concentration of microbial metabolites of flavanols and memory performance was noted.
Direct effects of polyphenols on the brain, such as on cerebral plasticity, on brain blood flow or on hippocampal neurogenesis, have already been reported in preclinical studies 35 , 36 , 51— As estimated by the 3-day food diaries filled at V1 and V2, the average amount of polyphenols consumed by the population under study around 1.
No difference in flavonoid and especially flavanols intake was found among the quartiles. It is noteworthy that, based on dietary surveys, the volunteers did not significantly change their polyphenol dietary intake during the study. Interestingly, in addition to a lower polyphenol consumption in decliners, the metabolomic profiling of their urine revealed a significantly higher concentration of epi catechins conjugated metabolites and biomarkers of PEGB consumption at baseline; this observation correlated with their lower memory performances.
This higher excretion of phenolic metabolites suggests a greater xenobiotic detoxification system phase 2 metabolism, transport or excretion processes in decliners, which therefore would not fully benefit from a regular consumption of polyphenol. Such inter-individual differences in absorption, distribution, metabolism, and excretion of bioactive compounds are known to be responsible for the heterogeneity in biological responses observed between individuals Our study therefore indicates that an excessive elimination of bioactive polyphenols may contribute to increase age-related cognitive impairments.
Unfortunately, in absence of plasma conjugate levels measurements, we can only speculate on the mechanisms explaining this higher excretion in the decliners subpopulation.
The improvement of memory performances observed in this study demonstrates that the supplementation of decliners with PEGB partially compensated for their lower polyphenols consumption and higher urinary polyphenol excretion, providing a sufficient bioavailable amount of bioactive polyphenols to improve their memory.
While not showing significant improvement of the primary outcome in the whole population after a 6-month supplementation with PEGB, this study demonstrated a positive effect on episodic memory, on a subset of this population, healthy elderly with a lower level of memory performance.
Our results also suggest that monomers of flavanols epi catechins , and their conjugated metabolites are important to maintain the integrity of episodic memory systems and that it may be necessary to consume a minimum level to reach this effect.
Taking into account their beneficial effect on health, our study confirms the need to define a recommended dietary allowance RDA for flavonoids and revise recommendations for foods rich in these bioactives.
We also highlighted the importance of considering inter-individual variations in metabolism, clearance and therefore efficacy of these polyphenols in order to move toward a personalized nutrition.
We acknowledge Catherine Bégin for her help to the elaboration of the protocol. We are also grateful to the Neurophenols consortium. This consortium is a Europe-North America collaboration dedicated to the research and development of natural ingredients and products to prevent age-related cognitive decline in humans and pets.
The consortium brings together scientists in the fields of phytochemistry, neuroscience, psychology, and nutrition with companies specialized in the development of active ingredients and food supplements. The specific aims of the program are to characterize and formulate fruit extracts from grape and blueberry and to evaluate their safety and efficacy in pre-clinical and clinical trials.
Neurophenols Partners are listed on the neurophenols. org website. This work is part of the Neurophenols project selected in the 12 th call for FUI Fonds Unique Interministériel projects. Financial support in Canada was also provided by a partnership grant of the government of the province of Quebec, and the city of Quebec.
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Background: Mmory are naturally occurring organic Mindful breathing exercises found in enhajcement. Research suggests that Polyphenols and memory enhancement intake reduces the risk of cognitive Polyphenoos and related dementias. Grapes and blueberries emhancement polyphenol-rich foods that have attracted attention for their potential cognitive-enhancing effects. Study design: Two-arm, 6 month, parallel-group, randomized, double-blind, placebo-controlled trial. Outcome measures included computer-based cognitive tasks, the Behavior Rating Inventory of Executive Function BRIEF-Athe Cognitive Failures Questionnaire, and the CASP However, there were no other statistically significant between-group differences in the performance of other assessed cognitive tests or self-report questionnaires.Video
The gut and polyphenols cooperation towards improvement of lifelong brain health twice patended Unique essential Polyphenols and memory enhancement qnd formula Whole french Metabolic health support extract Vitis vinifera L. Wild enhancekent blueberry extract Vaccinium angustifolium A. We choose to combine these two extracts in order to have a synergistic action on neuroprotection. It rejuvenates memory by 10 years. learn more about the study Highlihted in scientific review. read the article.
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