In addition, the findings indicated that piperine Polpyhenols not to induce Fiber-rich weight loss pills Poluphenols increase in the bioavailability of resveratrol. Arch Biochem Biophys — Indeed, significant results were found in studies with long-term follow-up assessment after 2. R Duffy, H Wiseman, SE File. Cognitive impairments in type 2 diabetes, risk factors and preventive strategies. United Nations, Department of Economic and Social Affairs.

Polyphenols and brain health -

This Research Topic of articles gathers studies demonstrating various health benefits exerted by poly phenols on the brain. Experimental results obtained from cell lines, rodents, and human studies measure poly phenols' health benefits at the molecular level and show how these mechanisms may translate into behavioral effects.

Accuracy and speed of attention analyzes represent a good measurement of some of the function of a healthy brain. In their meta-analysis of the results from 18 of the most recent randomized controlled trials, Hepsomali et al. highlighted the significant positive effect of poly phenol consumption various compounds and doses on accuracy and speed of attention, independently of age and gender.

Pontifex et al. The authors analyzed and summarized the results from in vitro and pre-clinical studies, using isolated compounds or whole fruit or mixture of compounds in a juice, as well as molecular and behavioral studies performed in rodents with dietary supplementation or injections of citrus-derived polyphenols to demonstrate that hesperidin, hesperetin, naringenin, naringin, and kaempferol consistently exert beneficial effects on the CNS-dependent parameters studied.

Tg is a mutant mouse model of Alzheimer's disease which spontaneously develops TAU pathology, one of the hallmarks of the neurodegenerative disease in which the hyperphosphorylation of TAU protein leads to its aggregation and propagation, contributing to neuronal dysfunction and ultimately neuronal death.

The oral administration of relatively high dose of the flavonoid epicatechin for 3 weeks in older mutant mice was able to prevent the development of TAU pathology in this murine model Hole et al.

While the molecular mechanisms of this protective effect remain to be further investigated, it would be interesting to see whether this preventive effect translates into better cognitive outcomes as well. Epicatechin has also known beneficial effects on cognitive functions and has the potential to prevent neurodegenerative disorders.

Corral-Jara et al. explored a possible molecular mechanism underlying the neuroprotective actions of this flavanol, at the level of the vasculature composing the anatomical and physiological barrier between the blood and the brain. To replicate the physiopathological conditions of neurodegenerative diseases, inflammatory stress was mimicked using TNF-a in the culture medium of brain endothelial cells.

After treatment of the cells with 5- 4'-Hydroxyphenyl -γ-valerolactone-3'-sulfate and 5- 4'-Hydroxyphenyl -γ-valerolactone-3'-O-glucuronide, the two major products of gut microbiota catabolism of epicatechin, the authors investigated the multi-omics responses.

Study of gene expression, micro-RNAs, non-coding RNAs and proteins revealed that microbiome-derived metabolites of epicatechin modulate the expression of genes and proteins regulating cellular processes such as adhesion, cytoskeleton organization, cell permeability and therefore could be involved in the maintenance of BBB integrity.

The authors of the study showed that the berry contains various poly phenols including phenolic compounds, anthocyanins and flavonoids. Following 28 days of Grewia asiatica consumption in drinking water, the rats were subjected to diverse behavioral tests well-recognized to detect, quantify and analyze depression, anxiety, learning and memory.

Interestingly, the rats treated with the highest doses of Grewia asiatica displayed low anxiety levels, similar to diazepam-treated animals, low depressive behavior similar to fluoxetine-treated animals and better learning and memory scores, counteracting the deleterious effect of scopolamine administration.

Biochemical analysis of rat brains revealed that consumption of Grewia asiatica resulted in higher oxidative stress resistance indicated by elevated levels of superoxide dismutase and glutathione peroxidase and a reduction of malondialdehyde production.

This effect was further paralleled by a beneficial modulation of the cholinergic system as indicated by reduced levels of acetylcholinesterase Imran et al.

The methanolic extract of Otostegia Limbata , a Lamiaceae plant, is commonly used as an active compound to potentially treat epilepsy. As many other poly phenol rich plants, O. Limbata demonstrated antioxidant free-radical and NO scavenging and iron-chelating activities andanti-inflammatory properties reduced expression of P-NFkB and P-TNFa in the brain potentially responsible for the anti-convulsant effect observed in mice model of epilepsy Amin et al.

We previously highlighted the necessity to study all the metabolites of each food-derived poly phenol and their by-product from microbiota, within various biological models, to better characterize the molecular action of these compounds in physiological conditions.

In conclusion, we need to investigate the specific molecular mechanisms for each poly phenol, their derivates and how they could potentially be metabolized in endothelial cells and diverse brain cells neurons, astrocyte, tanycytes, and microglial cells , and then what would be the action of the resulting metabolites?

Importantly the BBB isn't the only site of access to the brain for circulating molecules, circumventricular organs CVO , highly vascularized structures located around the third and fourth ventricles and characterized by the lack of a classic BBB architecture, deserved to be studied along with the tanycytes, the main cellular component of the modified barrier around the CVOs Langlet et al.

These structures may also be involved in poly phenols transport and catabolism and could represent an interesting target to access the brain. EB wrote the manuscript. EB, DV, and PL edited the manuscript.

All authors contributed to the article and approved the submitted version. The authors would like to thanks all the scientists who contributed to this Research Topic of articles and all the reviewers who responded favorably to help improving the content.

We also extend our acknowledgments to the Frontiers Editorial Board whom reliable help and support is greatly appreciated. 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.

Figueira, I. Polyphenols journey through blood-brain barrier towards neuronal protection. doi: PubMed Abstract CrossRef Full Text Google Scholar. All rights reserved.

Copyright: Copyright Elsevier B. N2 - Polyphenols are known to influence a number of biological systems relevant to brain function. AB - Polyphenols are known to influence a number of biological systems relevant to brain function.

Polyphenols for Brain and Cognitive Health. Cox, Andrew Scholey. Abstract Polyphenols are known to influence a number of biological systems relevant to brain function.

ch12 Publication status Published - Externally published Yes. Keywords Bioactive nutrients Brain and cognition Cocoa Cognitive aging Mood Soy Tea Wine. Access to Document Link to publication in Scopus. Cite this APA Author BIBTEX Harvard Standard RIS Vancouver Cox, K.

Yoshida, V. Quideau Eds.

Katherine H. Polyphenols brajn known to Polypgenols a number of biological systems relevant to brain Polyphenols and brain health. Converging evidence from epidemiology and Maintaining a healthy weight controlled trials suggests that polyphenol intake bbrain both protect an age-related Fiber-rich weight loss pills Polypjenols and enhance cognitive healfh although dose and duration of intake appear critical. This research has included studies into the mood and cognitive effects of polyphenols within the diet and also on individual classes of polyphenols from sources including tea, cocoa, wine, and soy as well as nondietary botanical sources. Recent research has revealed some of the biologically plausible systemic and central mechanisms contributing to these effects. These include benefits to cerebral blood flow and patterns of brain activation measured using functional imaging methodology.

Polyphenols and brain health -

Home About FAQ My Account Accessibility Statement. Privacy Copyright. Skip to main content. Home About FAQ My Account. Brain Bioavailability Of Polyphenols: Implications For Delivery Of Brain Health Benefits.

Author Tzu-Ying Chen , Purdue University. Date of Award Fall Degree Type Dissertation. Degree Name Doctor of Philosophy PhD. Department Nutrition Science. First Advisor Elsa M. Committee Chair Elsa M. Parkinson's disease risks associated with cigarette smoking, alcohol consumption, and caffeine intake.

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Aging Cell — Fruit and vegetable juices and Alzheimer's disease: the Kame Project. Am J Med — Cognitive-enhancing effects of a polyphenols-rich extract from fruits without changes in neuropathology in an animal model of Alzheimer's disease.

J Alzheimers Dis — Benefits in cognitive function, blood pressure, and insulin resistance through cocoa flavanol consumption in elderly subjects with mild cognitive impairment: the Cocoa, Cognition, and Aging CoCoA study.

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Neuron 11— CREB: a major mediator of neuronal neurotrophin responses. Neuron — No difference in platelet activation or inflammation markers after diets rich or poor in vegetables, berries and apple in healthy subjects.

Eur J Nutr — Fruit polyphenols, immunity and inflammation. Br J Nutr Suppl 3 : S15—S Food combination and Alzheimer disease risk: a protective diet. Arch Neurol — Oxidative stress and neurodegeneration: where are we now? Sustained increase in flow-mediated dilation after daily intake of high-flavanol cocoa drink over 1 week.

J Cardiovasc Pharmacol 74— The anti-amyloidogenic effect is exerted against Alzheimer's beta-amyloid fibrils in vitro by preferential and reversible binding of flavonoids to the amyloid fibril structure.

Biochemistry — Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am J Clin Nutr 38— Stimulation of cAMP response element CRE -mediated transcription during contextual learning. Nat Neurosci 1: — Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions.

Cell — New pharmacological strategies for cognitive enhancement using a rat model of age-related memory impairment. Ann N Y Acad Sci 16— Age-related cognitive impairment as a sign of geriatric neurocardiovascular interactions: may polyphenols play a protective role? Oxid Med Cell Longev Anthocyanins inhibit nuclear factor-kappaB activation in monocytes and reduce plasma concentrations of pro-inflammatory mediators in healthy adults.

J Nutr — Relative impact of flavonoid composition, dose and structure on vascular function: a systematic review of randomised controlled trials of flavonoid-rich food products.

Mol Nutr Food Res — Total and specific polyphenol intakes in midlife are associated with cognitive function measured 13 years later. J Nutr 76— Concord grape juice supplementation improves memory function in older adults with mild cognitive impairment.

Br J Nutr — Blueberry supplementation improves memory in older adults. J Agric Food Chem — A high-cholesterol diet enriched with polyphenols from Oriental plums Prunus salicina improves cognitive function and lowers brain cholesterol levels and neurodegenerative-related protein expression in mice.

The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state: a placebo controlled, crossover, acute trial.

Psychopharmacology Berl — The effects of flavanone-rich citrus juice on cognitive function and cerebral blood flow: an acute, randomised, placebo-controlled cross-over trial in healthy, young adults.

Flavonoid intake and cognitive decline over a year period. Long-term green tea catechin administration prevents spatial learning and memory impairment in senescence-accelerated mouse prone-8 mice by decreasing Abeta oligomers and upregulating synaptic plasticity-related proteins in the hippocampus.

Fruit, vegetables and prevention of cognitive decline or dementia: a systematic review of cohort studies. J Nutr Health Aging — Cognitive tests used in chronic adult human randomised controlled trial micronutrient and phytochemical intervention studies. Nutr Res Rev — Cell signaling pathways and iron chelation in the neurorestorative activity of green tea polyphenols: special reference to epigallocatechin gallate EGCG.

Neuroinflammation and anti-inflammatory therapy for Alzheimer's disease. Adv Drug Deliv Rev — Tannic acid is a natural beta-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice. J Biol Chem 9 : — Associations of vegetable and fruit consumption with age-related cognitive change.

The ageing cortical synapse: hallmarks and implications for cognitive decline. Nat Rev Neurosci — Acetylcholine, aging, and Alzheimer's disease. Pharmacol Biochem Behav — High-flavonoid intake induces cognitive improvements linked to changes in serum brain-derived neurotrophic factor: two randomised, controlled trials.

Nutr Healthy Aging 4: 81— Phenol-Explorer: an online comprehensive database on polyphenol contents in foods. Database Oxford bap Fruit and vegetable intake and cognitive decline in middle-aged men and women: the Doetinchem Cohort Study.

Intake of flavonoid-rich wine, tea, and chocolate by elderly men and women is associated with better cognitive test performance. Effects of grape seed-derived polyphenols on amyloid beta-protein self-assembly and cytotoxicity. J Biol Chem — Inhibition of peroxynitrite-mediated tyrosine nitration by catechin polyphenols.

Biochem Biophys Res Commun — Novel role of red wine-derived polyphenols in the prevention of Alzheimer's disease dementia and brain pathology: experimental approaches and clinical implications. Planta Med 78 15 : — Interestingly, resveratrol was highlighted as a specific polyphenol which is a possible effector of the beneficial outcomes of grapes.

For reviews of individual polyphenol-rich foods or specific sub-classes, a summary of the evidence base available for efficacy in specific populations, doses, duration of intervention, and cognitive domains. Insufficient data indicates that there was not available data to provide a systematic comparison between groups of the relevant variable alphabetised by author.

Resveratrol was the focus of a systematic review investigating the effects of phytoestrogen supplementation on cognition [ 25 ], in which eight resveratrol RCTs purified or as grape extract were compared with another type of phytoestrogens; isoflavones fifteen RCTs. The evidence was inconsistent; less than half of the studies showed beneficial effects.

The authors suggested that overall, the evidence was stronger for resveratrol although no direct statistical comparisons were made between isoflavone and resveratrol outcomes. There was no assessment of study bias or quality, and given the overall weighting to a greater number of non-significant studies, the conclusions appear optimistic.

This optimism is not reflected in the findings from two recent meta-analyses of resveratrol supplements for cognitive outcomes; one included four studies [ 26 ] and another more wide-ranging analysis of ten studies [ 27 ]. Perhaps unsurprisingly, in light of the small number of studies, the former [ 26 ] concluded that there was no evidence for benefits of resveratrol for cognitive performance, although the analysis was focused on verbal memory outcome measures.

As cited in previous reviews, methodological heterogeneity was a problem, and subsequently any pooled analyses contained data from no more than two trials. The larger meta-analysis [ 27 ] also included a focus on memory outcomes, and a pooled analysis indicated that resveratrol consumption can improve memory, specifically delayed recognition, although the effect size was small a standardized mean difference, SMD, of 0.

Two further pooled analysis for processing speed and number facility failed to find any effect of resveratrol, and five of the included ten studies did not find effects on cognition. Moreover, a GRADE tool Grading of Recommendations, Assessment, Development, and Evaluation found moderate to high confidence that resveratrol supplementation has no significant effect on most outcomes in the general population.

Therefore, these meta-analyses [ 26, 27 ] do not provide compelling evidence for beneficial effects of resveratrol on cognition, and there is certainly not a strong enough evidence base to make conclusions regarding dose, population or duration of intervention.

This is unsurprising given the small number of studies included in the pooled analyses, and once again, methodological heterogeneity is cited as barrier to reliable summative conclusions.

The heterogeneity limitation was also highlighted by the only other meta-analysis included here curcumin [ 28 ] , so much so that a sensitivity analysis was not possible, and the overall quality of the evidence was cited as low. The evidence for curcumin was also evaluated in a systematic review of fives studies [ 29 ].

Three of the five studies found improvement in performance following curcumin, however the conclusions state that there is insufficient evidence to support curcumin supplementation as an effective means of both preventing and treating dementia and symptoms of cognitive decline.

Methodological heterogeneity and small sample sizes were the primary limitations hampering generalisability; this is clearly a consistent theme of the evidence reviewed here. Reliable, generalizable conclusions are likely more attainable from reviews of a larger pool of studies.

Nevertheless, it was evident that these negative studies were largely in younger healthy adults, and included a greater frequency of single dose studies, and chronic trials of shorter duration.

Therefore, these conclusions offer a sensible degree of reliability. However, even with the larger number of studies included, a systematic analysis of which cognitive domains may be most affected was not achievable, and risk of bias or study quality were not evaluated.

Some positive outcomes were also reported from a smaller systematic review [ 31 ] which considered eight studies of a commercially available supplement which contains Gingko combined with Ginseng, both of which are considered polyphenol-rich traditional herbal supplements.

A discursive analysis of the cognitive domains affected and duration of treatment was undertaken, with conclusions being that memory can be improved in healthy and patient populations as soon as one hour post consumption, with repeated chronic dosing also benefiting memory.

However, there was limited data directly comparing doses, duration or populations under similar methodological conditions, and it was interesting to note that five of the eight studies were from the same research group. An advantage of this is that it allows consistency in the cognitive assessment, and may explain why there is evidence for a memory effect from a comparatively small number of studies, whilst a disadvantage is that this evidence base lacks replicability across research groups, simply on account of the small number of studies.

A systematic analysis of bias or quality was not undertaken, although it was concluded that the methodologies were robust and well controlled. Interestingly, two studies reported that the synergy of Gingko and Ginseng was more efficacious than the individual constituents combined; synergistic polyphenol effects have received little attention in the reviews presented here, most likely as there is not currently an evidence base to draw data from.

Conversely, cocoa is a polyphenol source which has attracted relatively widespread investigation of potential cognitive benefits. A systematic review of twelve clinical trials presented a detailed overview of dose, population, treatment duration and cognitive domains affected [ 32 ].

However, there was insufficient comparative data for conclusions on treatment, duration and whether certain cognitive domains are more sensitive, rather effects were generally reported for memory and executive function. Concerns were highlighted with respect to risk of bias, with five studies judged as poor quality and only two as good quality using the Cochrane Tool.

This raises doubt on the reliability of the positive effects of cocoa, and emphasises that further good quality research is required. Encouragingly, the studies of higher quality and lowest risk of bias provided the strongest effects of cocoa associated cognitive benefits, particularly studies which utilised a placebo matched for potentially confounding compounds such as caffeine and theobromine.

The effect of confounding components is also problematic in the green tea polyphenol and cognition literature. On the face of it, this appears positive, however, it was concluded that the cognitive improvements are strongly linked to the presence of both caffeine and L-theanine, and the benefits cannot be attributed to a singular component such as polyphenols.

However, once again, significant methodological heterogeneity was cited as hampering conclusions relating to dose, population and duration of effects. In summary, a number of informative systematic reviews and meta-analyses have been published in recent years examine individual polyphenol classes or polyphenol-rich foods.

Data from the meta-analyses appear to be less convincing than findings from systematic reviews, which may reflect stricter inclusion criteria and lower power on account of the difficulties in combining data from heterogeneous studies. It appears that the current state of the literature base is not sufficiently advanced to support meaningful systematic analysis of specific polyphenol classes, or polyphenol-rich foods see Table 2.

Encouragingly, the three meta-analyses discussed here report a low risk of bias overall, which indicates that the studies included are of strong methodological design.

Only four systematic reviews considered risk of bias or quality with a standardised tool e. Cochrane Tool , but positively, these largely indicated low risk of bias. However, the cocoa review [ 32 ] did express moderate concerns relating to matched controls in some studies.

Interestingly, the picture from the reviews of individual polyphenol classes is slightly more positive regarding cognitive outcomes than the reviews of all polyphenol classes see section 2 , however, as summarised in Text Box 2, the evidence for a positive relationship between polyphenols and cognitive benefits is perhaps not as strong as might be anticipated.

Summative interpretation of reviews [ 21—33 ] covering individual polyphenol-rich foods and classes. However, most reviews expressed caution, showing that benefits were not consistent across all studies. In order to fully understand the relationship be-tween polyphenol consumption and cognitive function it is important to have an understanding of the mechanisms of action which may account for behavioural effects.

There has been much exploration of the role of increased CBF following polyphenol consumption [ 34—36 ], which may lead to increased neuronal activity as assessed by fMRI and other neuroimaging techniques [ 37 ].

This cerebral vascular mechanism is supported by evidence showing an improved peripheral vascular response such as reduced blood pressure and increased flow mediated dilation following polyphenol consumption [ 11—16 ].

This vascular responsivity mechanism is underpinned by in-vitro and animal data demonstrating that polyphenols can affect multiple cellular pathways thought to be responsible for vascular changes [ 11, 12, 38, 39 ].

It logical to consider that short term peripheral and cerebral vascular changes over several hours may account for acute behavioural effects of polyphenols.

However, chronic activation of these pathways may also support long term behavioural benefits if the cerebrovascular mechanistic process becomes more efficient following repeated improvement over time. It is difficult, though, to attain evidence directly supporting these processes as we are unable to directly examine the cellular pathways in a human brain during a cognitive task.

Rather we are able to observe proxies for neural activation such as improved CBF with arterial spin labelling ASL , and changes in the ratio of oxygenated to deoxygenated blood with fMRI. Other techniques such as electroencephalography EEG can offer better temporal resolution [ 40 ] however, in summary we cannot directly observed the pathways between polyphenol intake, improved blood flow, neuronal activation and improved behavioural performance in humans.

Nevertheless, in-vitro cellular work in combination with rodent studies provides good evidence for a cascade a mechanisms which associate polyphenols with changes in neuronal morphology and synaptic plasticity [ 41—43 ] and it is plausible that these mechanisms of action may account for chronic behavioural benefits in humans.

Studies targeting specific mechanisms of action and associated cognitive effects are important and should continue.

However, it is becoming increasingly apparent that there are a host of complex pathways and mechanisms which are interacting in their contribution to behavioural outcomes.

In any study acute, chronic, or epidemiological the assessment of cognitive performance is not undertaken outside of the context of everyday life. Participants bring their own influences such as habitual diet, subjective mood state, underlying cognitive abilities, and a host of metabolic and physiological characteristics such as the gut microbiota, and it is likely that this variance is contributing to the inconsistent behavioural data highlighted in this overview.

Attempts can be made to control for some of these characteristics in order to identify specific associations between cognitive effects and mechanisms of action, with the compromise being that the findings from such studies can only be applied to certain populations and experimental conditions.

By gaining a holistic understanding of the wider influences, and the complex nature in which these factors interact, future work may be able to more accurately understand and hypothesis when and how polyphenol intake is likely to benefit cognitive function.

Considering these influences in a little more detail, there is now reasonable evidence for several variables potentially moderating or mediating the relationship between polyphenols and cognition.

The gut microbiota can be broadly considered as the gateway for all effects since all ingested polyphenols will pass into and through the gut at least partially before reaching the blood stream through which they are distributed throughout the body. Therefore, the gut environment and gut microbiota has an important influence, and there is evidence of a complex bidirectional relationship between gut microbiota, polyphenols and cognition [ 44—46 ].

Given that there is significant divergence between individuals in their gut microbiota, it follows that the metabolic fate of polyphenols is not consistent, and thus this individual variation is likely to contribute to variance in cognitive outcomes following polyphenol intake [ 46—49 ].

Other factors such as the food matrix are also thought to impact upon the subsequent bioavailability of polyphenols and thus outcomes may vary depending on whether polyphenols are consumed as an extract or whole food [ 20, 50, 51 ].

Habitual diet is also likely to shape the state of the gut microbiota, indeed dietary factors have been suggested to account for a significant percentage of the microbiota variance between individuals [ 52, 52 ].

Moreover, a greater intake of polyphenol-rich foods has been associated with greater microbial diversity and enhanced growth of bacterial species associated with health benefits [ 54—57 ].

However, it is currently unclear whether cognitive benefits following polyphenol consumption are more likely to be observed in frequent habitual polyphenol consumers in whom the gut environment is likely to be more efficient at metabolising polyphenols or in habitually low polyphenol consumers, who may receive an immediate benefit on account of an absence of previous intake.

Alternatively, low habitual consumers may not have a gut environment which can efficiently metabolise polyphenols, and thus cognitive benefits may be limited. Aside from polyphenols, there are a host of hypothesised bidirectional pathways between the gut and the brain [ 58, 59 ] and there is potential for polyphenols to interact with multiple aspects of this gut-brain axis [ 44, 46 ].

It is well established that type 2 diabetes T2DM and impairments in insulin sensitivity negatively impact cognitive function [ 60, 61 ]; this is of interest here since polyphenols are known to improve insulin sensitivity and reduce risk of T2DM [ 62, 63 ].

Therefore, polyphenols may be contributing to cognitive benefits via mechanisms associated with insulin sensitivity [ 42, 64—66 ].

For example, the brain has a high degree of insulin receptors [ 67, 68 ], and rodent models show that increased insulin resistance in the brain can impair cognition [ 69 ].

Furthermore, poor insulin sensitivity and T2DM is associated with endothelial dysfunction in the blood brain barrier [ 70 ], which could be a cerebrovascular mechanism shared between T2DM and polyphenols [ 64, 66, 71 ].

For example, resveratrol can reduce blood brain barrier permeability in rodents which has been shown to be accompanied by inhibited hippocampal neurodegeneration [ 72 ].

Furthermore, acute and chronic cognitive improvements following polyphenol consumption have been associated with improvements in insulin sensitivity [ 73—75 ]. To add a further layer of complexity, the gut microbiota is known to impact upon the regulation of systemic insulin sensitivity via functional metabolites [ 76, 77 ].

Therefore, there is likely to be a complex interactive pathway between polyphenols, the gut microbiota, insulin sensitivity and cognition, and this requires exploration. T2DM is also characterised by low mood and increased incidence of depression which further complicates potential mechanisms of action since low mood is also associated with cognitive impairments [ 78 ].

This pathway has relevance for polyphenol-cognition research as there is now data from epidemiological studies [ 13, 79 ] and clinical trials [ 80—82 ] showing that polyphenols can reduce risk of depression and negative mood and also improve positive mood, both acutely and chronically.

Several supporting mechanisms have been proposed [ 83 ] involving regulation of neurotransmitters via changes in short chain fatty acids and tryptophan metabolites, and various other molecular cascades potentially affecting neuroinflammation and synaptic plasticity, all of which are intrinsically linked to the gut microbial environment.

This highlights an emerging complex system where polyphenols may be affecting cognition via multiple pathways associated with changes in subjective mood, which could occur over both acute and chronic timeframes.

However, this remains speculative, and it is important to point out that a systematic evaluation of the impact of polyphenols on mood, and the interaction with cognition requires investigation. In summary, polyphenols have a multitude of bidirectional actions in the body and appear to have influence on various mechanisms which affect cognitive function independently of polyphenol intake.

Therefore, it is important that future research considers both direct e. CBF and neurogenesis and indirect e. insulin sensitivity, subjective mood, and gut health mechanisms of action when investigating the effects of polyphenols on cognitive performance in humans. A topic seldom discussed in this literature is the variety of ways in which a behavioural cognitive benefit is defined.

This has undoubtedly contributed to the difficulties in comparing cognitive effects across populations. It is reasonable to hypothesise that cognitive benefits associated with polyphenols and other nutritional influences will manifest in different ways throughout the lifespan; children may experience and increase in the speed and trajectory of cognitive development, young healthy adults at the peak of their cognitive lifespan may seek to maximise cognitive potential, whilst older adults may look to attenuate the trajectory of cognitive decline and extend the maintenance of good brain health into old age.

However, all these effects are all broadly described as a cognitive benefit. Furthermore, there are many additional subtleties in the analysis of data when presenting a cognitive benefit see Table 3 , and all this variance is contributing to an absence of consistent and reliable findings in the reviews presented here.

If the way in which an outcome measure is defined has considerably variety than there is bound to be inconsistency in outcomes between studies.

Moreover, positive effects with neuroimaging outcomes e. fMRI, ASL, EEG are also considered cognitive benefits in studies utilizing these techniques, however, such measures typically do not, on their own, include a behavioural outcome i.

a performance measure from a cognitive task. There are of course many studies which combine neuroimaging techniques with behavioural outcomes which provide important insight into various mechanisms of action.

However, the point is that a change on a neuroimaging outcome is not synonymous with a cognitive benefit on a behavioural task, and the former can occur in the absence of the latter.

When evaluating this literature care should be taken when defining what we mean by a cognitive benefit. Understanding what type of cognitive benefit we may be expecting to observe in a given population and experimental scenario will enhance our understanding of how and under what conditions polyphenol consumption can benefit cognition.

Finally, it is also important to reflect upon what we mean when describing a cognitive benefit as it has relevance for the application and translation of experimental research to the public and policy makers.

The purpose of this overview was to consider and summarise the evidence presented in recent systematic reviews and meta-analyses of the relationship between polyphenol consumption and cognitive function in humans. All thirteen systematic reviews offer some degree of support for a benefit of polyphenols for cognition, and on the face of it this sounds overwhelmingly positive.

However, a clear and consistent theme has emerged that these conclusions are tentative. Indeed, this is reflected when considering the most robust analyses; three of the five meta-analyses concluded there was no evidence for a benefit, and the positive outcomes were small effects from limited analyses.

However, the practical utility of these meta-analyses is questionable on the basis that significant methodological heterogeneity severely restricted the inclusivity and scope of the statistical analyses.

This limitation is also highlighted throughout the systematic reviews, so much so that conclusions relating to the most efficacious dose and duration of consumption, the populations most likely to benefit, or the most sensitive cognitive domains are not currently possible with any reasonable degree of reliability or consistency see Table 2.

There is encouraging evidence that verbal memory is emerging repeatedly as sensitive to polyphenol interventions, however, this appears to be driven by the frequency of assessment rather than by clear and direct comparisons with other cognitive domains within or between studies.

It is encouraging that risk of bias was largely deemed as low, and the quality of studies graded as moderate to high, however, such analyses with standardised techniques were not routinely performed.

In conclusion, there is evidence that polyphenols can benefit cognition in humans, but this evidence is not as convincing as it initially appears. Future research is required to strengthen the reliability of the evidence base, and furthermore, this should consider the wider impact and interaction between a variety of direct and indirect mechanisms of action.

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Dose—response relationship between cocoa flavanols and human endothelial function: a systematic review and meta-analysis of randomized trials.

Role of berries in vascular function: a systematic review of human intervention studies.

Tzu-Ying ChenPurdue University. Consumption of fruits and vegetables has been associated Polphenols neuroprotection and cognitive Isotonic drink for endurance throughout Polyphenols and brain health life span. These associations have sparked Polyohenols Fiber-rich weight loss pills plant-derived Pokyphenols as biologically active agents with potential for targeting brain benefits. However, Closed-loop insulin pump is known regarding the ability of the polyphenols or their metabolites from polyphenol-rich products to cross the blood-brain-barrier, and be available for biological action. Furthermore, additional insight is needed on factors affecting the absorption and brain distribution of polyphenol metabolites bran vivo. We have found that background diabetogenic diet had limited effects on polyphenol plasma levels and brain bioavailability in a healthy Sprague-Dawley rat model. However, the diabetic state negatively influenced polyphenol metabolite levels in plasma and brain tissues, possibly in part, due to excessive excretion in urine.

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Unveiling the Power of Polyphenols: Exploring Their Benefits and Functions