Mars Flavanol Exercise and Cognitive Function Study

I. Background and Significance A. The epidemiology of cognitive aging. Encompassing multiple cognitive domains, higher order thinking includes memory, language, abstract reasoning, and visuospatial ability. A range of studies have established that memory is a cognitive domain differentially targeted by the normal aging process. With an increase in lifespan and a decrease in co-morbid diseases, aging individuals expect to lead cognitively-challenging lives. Even mild forgetfulness, therefore, is no longer considered 'benign'. Indeed, with the exponential growth of the aging population, and since memory decline will occur in all of us as we age, age-related memory decline has emerged as a major societal problem.

B. The anatomy of cognitive aging. A range of studies in humans, non-human primates and rodents have established that the hippocampal formation, a brain circuit vital for memory, is targeted by the aging process. Age-related hippocampal dysfunction is therefore a major contributor to age-related memory decline.

The hippocampal formation is organized as a circuit, made up of separate but interconnected regions, including the entorhinal cortex, the dentate gyrus, the CA subfields, and the subiculum. Because of hippocampal circuit properties, dysfunction in one subregion will affect the function of neighboring subregions and the hippocampal circuit as a whole. Thus, when confronted with any process that causes the hippocampal circuit to malfunction, pinpointing the subregion that is most effected becomes an important goal.

In the case of age-related memory decline, a range of studies in humans, non-human primates, and rodents, have suggested that normal aging causes hippocampal dysfunction by differentially targeting the dentate gyrus.

C. Imaging cognitive aging. The anatomical organization of the hippocampal circuit and the differential vulnerability of the dentate gyrus to cognitive aging imposes specific requirements on brain imaging techniques. Specifically, an imaging technique must be able to assess the functional integrity of the multiple hippocampal subregions, in particular the dentate gyrus. With this in mind, our lab has been dedicated to optimizing a functional brain imaging approach applicable to both the human and rodent hippocampal formation. We have recently achieved this goal, and have been applying our cross-species imaging capabilities to investigate a range of process that affect hippocampal function.

D. Flavanols, exercise, and cognitive aging. Previous studies have established that physical exercise improved hippocampal function. We have recently exploited our cross-species imaging techniques to show, that within the hippocampal circuit, exercise has a selective effect on dentate gyrus function, in humans and in mice. Independently, a recent study has shown that the flavanol epichatechin improves hippocampal function, and importantly, within the hippocampal circuit, epichatechin was found to differentially target the dentate gyrus. Moreover, this study showed that epichatechin coupled with exercise had its greatest effect on dentate gyrus function.

E. Summary. Starting at around 30 years of age, all of us will begin experiencing the insidious cognitive slide of age-related memory decline. With the expansion of aging, age-related memory decline is swelling to epidemic proportions, and ameliorating age-related memory decline has emerged as major societal goal.

This proposal is designed to test the following hypothesis: That flavanols with or without physical exercise will ameliorate age-related memory decline. This hypothesis is informed by two sets of interleaving findings: First, a range of studies have pinpointed dysfunction in the dentate gyrus as a specific brain region contributing to age-related memory decline; and second, flavanol consumption with or without physical exercise enhances memory performance by improving dentate gyrus function.

In order to experimentally test this hypothesis an imaging technique is required that can assess the functional integrity of the dentate gyrus, techniques that are now available. Importantly, these imaging techniques have been developed so that can they can be applied not only to humans but also to animal models, generating the same 'imaging readout'. Cross-species imaging is particularly important for translational studies.