Mechanistic assessment of the acute and chronic cognitive effects of flavanol/anthocyanin intervention in humans

Lead Research Organisation: University of Reading
Department Name: Food and Nutritional Sciences

Abstract

Representing one of the most important lifestyle factors, diet can strongly influence the incidence of cardiovascular disease and neurodegenerative diseases and thus a healthy diet is crucial for healthy ageing. Various bioactive constituents of certain foods and beverages, in particular a class of compounds called flavonoids, have generated interest over the last few years. Recent dietary intervention studies, in particular those using wine, tea, cocoa or blueberries, have begun to demonstrate beneficial effects on the function of blood vessels and on mental performance (cognition). While such foods and beverages differ greatly in chemical composition, nutrient content and calories per serving, they have in common that they are amongst the major dietary sources of two flavonoids known as anthocyanins and flavanols. Dietary supplementation studies in humans using foods or extracts rich in these flavonoids have indicated that they possess an ability to enhance human cognition, memory and learning. It is thought that they may do this by increasing the flow of blood to specific regions of the brain, which control these vital processes.

Building on existing human work conducted in our laboratory, this multidisciplinary study is designed to determine how specific flavonoids may enhance human cognitive function by focussing on how they enhance blood vessel function thus increasing the amount of blood flow to the brain. The proposal, which is multidisciplinary in nature, will provide crucial information on the ability of flavonoid-rich foods to produce improvements in cognition by using optimised cognitive testing, along with state-of-the-art brain imaging (fMRI) techniques and blow flow measures (FMD). Importantly, this proposal will shed the first light on how flavonoids improve cognition in humans by examining their precise pathways of action in the body. The outcomes of this proposal have implications for exploiting the potential beneficial health effects of flavonoid components of the diet, particularly with relation to counteracting the decline in human cognitive function associated with normal and abnormal ageing. Although the study findings have most relevance to those at greatest risk of cognitive decline, notably older adults, the changes studied and the mechanisms involved hold relevance for all people. Indeed the concept of healthy brain ageing is rooted at the core of this proposal through the application of sound dietary recommendations. As the average-life span of humans increases this proposal becomes more relevant.

Data emanating from the proposal are necessary before academia/industry may work to exploit such biological activity in future. There has been a large growth in the desire for such functional foods (21% market growth in the USA) and cause-and-effect data are essential for the development of European Food Standards Agency health claims on specific flavonoid containing products. Such products would appeal to those wishing to temporarily boost their cognitive performance as well as those most at risk of cognitive impairment (i.e. 50-80 year olds). Indeed, the requirement for novel dietary approaches designed to improve cognitive health has never been greater, particularly given the increased incidence of age-related cognitive decline. Health care costs run as high as £23 billion per annum for all forms of dementia and is continuing to grow as the mean population life expectancy increases. Such a preventative strategy for the treatment of dementia is essential if the number of sufferers and the cost of their treatment are to be reduced. Understanding more about how specific diets may promote healthy brain aging and modulate cognitive losses will help us to define more effective public health advice and encourage the population to make more informed healthy food choices.

Technical Summary

Dietary-derived flavanols and anthocyanins have been shown to enhance cognition in humans and animals. These beneficial effects have been attributed to their potential to influence peripheral and cerebral blood flow. This proposal is designed to test the hypothesis that the impact of (-)-epicatechin and delphinidin at dietary levels (1mg/kg body weight) on neuro-cognitive function is mediated by eNOS/nNOS derived NO production and resultant changes in regional brain blood delivery.

Acute and chronic changes in cerebral blood flow in response to intervention will be assessed using a Siemens MAGNETOM Trio 3.T scanner to investigate the regional selectivity of cerebral blood flow during cognitive testing. Concurrently, the involvement of prolonged, augmented NO synthesis on cognitive improvements induced by flavanol/anthocyanin intake will be investigated as follows: 1) by testing neuro-cognitive outcomes and brain fMRI following flavanol/anthocyanin administration with or without systemic NOS-inhibition, via by i.v. infusion of L-N G-mono-methyl-arginine (L-NMMA; 1 mg.kg-1 per min-1 over 3 min); 2) by multivariate regression analysis, to assess correlations between behavioural parameters, peripheral (FMD) and cerebral (MRI) blood perfusion and circulating flavanol/anthocyanin metabolites using HPLC with electrochemical and MS detection; 3) by measurement of the circulating NO pool using gas-phase chemiluminescence and the activity of NAPDPH oxidase (enzymatically), as markers of NO status (production: eNOS/nNOS; destruction: NOX generated superoxide); and 4) by assessment of acute temporal nature of cognitive improvements following NOS inhibition (NOS inhibition should not affect cognitive improvements between 4-6h. Lastly, the longer term effects of flavonoid supplementation and the sustained effects of such an intervention will be addressed by examining whether cognitive improvements are maintained after a 12 week secession of treatment.

Planned Impact

Impact: This proposal will further our understanding of the impact of diet on human cognitive function. The proposal has strong academic and industrial relevance, as it will provide the first mechanistic understanding of the effects of flavonoids on cognitive health. The proposal addresses one of the long-term health issues of our generation: understanding and preventing the onset of cognitive decline throughout life and has strategic relevance to the strategic grand challenge 3 within the BBSRC delivery plan (2012-2015): "Fundamental bioscience enhancing lives and improving wellbeing". The proposal will also impact on the BBSRCs Food Security focus area in that it will provide underpinning science for the development of a variety of new, sustainable foods/beverages relevant to the UK market.

Industry: There is a huge, and growing, demand for novel foods/beverages that provide health benefits and this is particularly the case with those designed for brain health. Flavonoid-containing products would appeal to those wishing to temporarily boost their memory/cognitive performance as well as those most at risk of cognitive impairment (i.e. 50-80 year olds). In the US alone (the largest market for functional foods) a 21% growth in the functional foods market is expected in the coming years owing to the growing demand for functional foods, expected to reach $8.62 billion by 2015. Cause-and-effect data relating to flavonoid intake and cognitive efficacy will provide industry with the confidence to invest in new flavonoid-containing products aimed at cognitive enhancement and will provide a foundation for the development of EFSA/FDA health claims on specific flavonoid containing products. Thus, the proposal will be applicable to a variety of companies manufacturing plant-based products, such as tea, cocoa, apple, berries and coffee. To support this, the proposal will test pure flavonoids to allow the data to be applicable to as many companies as possible and not restricted to individual, existing products. Rather, it will provide fundamental data to aid in the development of a wide array of novel products over the next 5-10 years. The requirement for novel dietary approaches designed to improve cognitive health has never been greater given the increased incidence of age-related cognitive decline and neurodegenerative diseases. This proposal will provide the scientific basis for the design, and manufacture of novel flavonoid containing products for future exploitation.

General Public: The ability of flavonoids to enhance human cognition function has the potential to benefit the whole population. There is wide support for this type of research, as previous BBSRC surveys have shown. Although the study findings have most relevance to those at greatest risk of cognitive decline, notably older adults, cognition, and the mechanisms involved, have relevance for all individuals. Indeed, the concept of healthy brain ageing forms the core of this proposal. In addition to this, health care costs run as high as £23 billion per annum (Alzheimer's Society) for all forms of dementia, a figure that continues to grow as mean life expectancy increases. Preventative strategies for the treatment of dementia are essential if the number of sufferers and the cost of their treatment are to be reduced. Lastly, the public interest in such science is high, thus the proposal will be highly applicable for wide dissemination through public engagement events.

Government agencies involved in promotion of public health (FSA, DOH, and DEFRA): Understanding more about how specific diets may promote healthy aging and modulate disease progression will help agencies inform the public and encourage them to make more informed and healthy food choices. We anticipate being able to make recommendations about which foods may be most beneficial against declines in cognitive function.

Publications

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Cifuentes-Gomez T (2015) Factors Affecting the Absorption, Metabolism, and Excretion of Cocoa Flavanols in Humans. in Journal of agricultural and food chemistry

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Lamport DJ (2014) Fruits, vegetables, 100% juices, and cognitive function. in Nutrition reviews

 
Description We have established a direct link between flavanol intake and cognitive improvements which are mediated by activation (changes in blood flow) to 3 specific brain processing centres. Most notably, flavanol intake causes an activation of the Anterior Cingulate Cortex, an area of the brain know to be critical in both cognitive processing (notably executive function) and blood pressure control. Flavanol intake, including intake of pure (-)-epicatechin leads to temporal changes in peripheral and cerebral blood flow. Together these observation enhance the mechanistic case for flavanols as functional bioactives. Further Key Findings relating to chronic intake and physiological outcomes are predicted later this year.
Exploitation Route Research impact predominantly. Will inform better clinical trial design in future and gives further confidence in development of novel flavanol containing functional products (foods, supplements etc).
Sectors Education,Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description The findings emanating from our work have led to the development of various flavanol/anthocyanin related products aimed at improving cognitive health in both older adults and in younger adults.
First Year Of Impact 2019
Sector Agriculture, Food and Drink,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Economic

 
Description BBSRC Bioscience for Health Strategy Committee
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
 
Description Berries and brain function study 
Organisation Activ'Inside
PI Contribution We are conducting a RCT investigating the effect of a berry beverage on cognition, glucose response and cortisol levels in healthy older adults.
Collaborator Contribution They provided the berry intervention and matched placebo.
Impact Data collection is on-going so no output as yet but this relationship has led to discussion regarding further collaborations. This collaborative project spans nutrition and psychology and is therefore multi-disciplinary.
Start Year 2015
 
Description PepsiCo Quaker oats 
Organisation PepsiCo
Country United States 
Sector Private 
PI Contribution Provided data on phenolics in different commercial oat varieties and designed intervention and control diets for acute and chronic intervention trials
Collaborator Contribution Sourced high phenolic oat varieties and blended these to achieve the desired phenolic intake on the two clinical trials. Packaged all oat interventions and controls for participants.
Impact Interventions utalised in two clinical trials with great success.
Start Year 2015
 
Description The effects of flavanols on brain and vascular health 
Organisation Mars Incorporated UK
Country United Kingdom 
Sector Private 
PI Contribution Wrote successful grant application and hosted PhD student
Collaborator Contribution Supply of research intervention diets for human clinical trial (£60,000). Fully funded PhD studenship (stipend + fees + runing costs). Enhances my groups work in the flavonoid vascular area.
Impact Greatly expands the flavonoid brain and vascular research programme.
Start Year 2007
 
Description 5th Internation Conference on Polyphenols and Health 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact 1h Plenary session with round table discussion (1h). Discussion was wide ranging and set targets for research over the next 2-5 years

requests for Industry projects and manuscript requests
Year(s) Of Engagement Activity 2013
 
Description Alternatives to Medicine Event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Pupils attended the University to learn more about possible subjects to study as an alternative to medicine, such as Nutrition.
Year(s) Of Engagement Activity 2015,2017
 
Description Berkshire County Show 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Attendance and engagement with the general public at the Berkshire County show representing the University of Reading's Hugh Sinclair Unit of Human Nutrition. It was an opportunity to raise awareness and interest in our human trial in the hope that we would recruit volunteers to take part in the study.
Year(s) Of Engagement Activity 2016
 
Description Big Band Big Lunch Event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Spoke to the general public about our research and used the opportunity to try and recruit volunteers.
Year(s) Of Engagement Activity 2016
 
Description Careers Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Gave a careers talk at the University of Reading for Psychology Undergraduate students.
Year(s) Of Engagement Activity 2015
 
Description Dissemination conference 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Public engagement event run by the Department of Food and Nutritional Sciences targeted primarily at the public but with literature reaching a wider audience.

After session I received 18 emails requesting further information, publications and advice
Year(s) Of Engagement Activity 2013,2014
 
Description European Nutrition Leadership Platform Essentials Seminar 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Dr Manuel Schar was selected to participate at the 2017 European Nutrition Leadership Platform Essentials Seminar. This 10 day seminar was a great opportunity for Manuel to develop his leadership and team work skills together with 29 other prospective research leaders in the field of nutrition.
Year(s) Of Engagement Activity 2017
 
Description Hugh Sinclair 20th Anniversary Public lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Public lecture on research findings and public debate on the future of nutrition. Huge debate which changed many attitudes to nutrition as a preventative health strategy.
Year(s) Of Engagement Activity 2016
 
Description Hugh Sinclair Unit 20th Anniversary Celebrations - Video 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Helped to produce a video which was played at the event to celebrate the 20th anniversary of the Hugh Sinclair Unit of Human Nutrition at the University of Reading. The video contained testimonials of academics and content related to the research themes within the Unit. Also attended and helped out at the event.
Year(s) Of Engagement Activity 2015
 
Description International Conference on Polyphenols and Health 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Invited plenary talk at an International conference
Year(s) Of Engagement Activity 2015
 
Description Invited talk at local learned society 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact A research talk was given to members of a local learned society. There was a question and answer session following the talk as well as some promotional activity for research currently being undertaken at the University of Reading in relation to diet and health.
Year(s) Of Engagement Activity 2018
 
Description PepsiCo global internal science strategy meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Invited to participate in, and advise on, PepsiCo global science strategy over the next 5 years. Notably in areas of novel food and beverage design. What consumers want and what motivates them with respect to diet and health.
Year(s) Of Engagement Activity 2016
 
Description Pharmacy Practicals 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Assisting Pharmacy undergraduate students in completing a practical workshop which involved conducting health and lifestyle assessments on members of the general public.
Year(s) Of Engagement Activity 2018
 
Description Poster presentation at International Conference on Polyphenols and Health - 2017 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Presented a research poster at an international conference and answered questions in relation to the work.
Year(s) Of Engagement Activity 2017
 
Description Seminar to the Reading University for the Third Age 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Dr Manuel Schar gave a seminar to the Reading U3A outlining the BBSRC research on oat phenolic acids and cardiovascular health that Professor Jeremy Spencer and his group is conducting at the University of Reading. Around 20 U3A members attended the seminar and engaged through many questions in a meaningful discussion.
Year(s) Of Engagement Activity 2017
 
Description Summer School Event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Demonstrated a clinical technique used to measure endothelial function to local 6 form students.
Year(s) Of Engagement Activity 2015
 
Description Talk at British Feeding and Drinking Group Conference 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Gave a research talk at the British Feeding and Drinking Group Conference held in Wageningen, The Netherlands and answered questions related to the work.
Year(s) Of Engagement Activity 2015
 
Description Talk at International Conference on Polyphenols and Health - 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Research talk at conference.
Year(s) Of Engagement Activity 2015