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

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.

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.

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.