Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults

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Abstract

The dentate gyrus (DG) is a region in the hippocampal formation whose function declines in association with human aging and is therefore considered to be a possible source of age-related memory decline. Causal evidence is needed, however, to show that DG-associated memory decline in otherwise healthy elders can be improved by interventions that enhance DG function. We addressed this issue by first using a high-resolution variant of functional magnetic resonance imaging (fMRI) to map the precise site of age-related DG dysfunction and to develop a cognitive task whose function localized to this anatomical site. Then, in a controlled randomized trial, we applied these tools to study healthy 50–69-year-old subjects who consumed either a high or low cocoa flavanol–containing diet for 3 months. A high-flavanol intervention was found to enhance DG function, as measured by fMRI and by cognitive testing. Our findings establish that DG dysfunction is a driver of age-related cognitive decline and suggest non-pharmacological means for its amelioration.

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Figure 1: A bilateral map of the hippocampal circuit generated from the high-resolution acquisitions of CBV-fMRI.
Figure 2: Mapping a differential pattern of age-related dysfunction in the hippocampal circuit.
Figure 3: Performance on the ModBent declines with age.
Figure 4: Performance on the ModBent overlaps with the anatomical site of hippocampal aging.
Figure 5: Flavanols enhance CBV-fMRI.

Change history

  • 02 November 2014

    In the version of this article initially published online, the abstract referred to a high or low cocoa–containing diet. It should have read high or low cocoa flavanol–containing diet. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank F. Gage for previous discussions and A. Glass for helping with the statistical analysis. This investigation was supported by US National Institutes of Health grants AG034618, AG035015, AG025161 and AG08702, the James S. McDonnell Foundation, and an unrestricted grant by MARS, Inc.

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Affiliations

Authors

Contributions

A.M.B. designed and implemented the ModBent task and help write the manuscript. U.A.K. and F.A.P. performed the imaging analyses and help write the manuscript. L.-K.Y. aided in designing the ModBent task. W.S. administered the ModBent task to college students. H.S. aided is establishing inclusionary/exclusionary criteria for the clinical trial. M.W. performed the statistical analysis on the cognitive variables. R.P.S. was responsible for subject recruitment and characterization and helped to write the manuscript. S.A.S. designed and evaluated all the studies and was the primary writer of the manuscript.

Corresponding author

Correspondence to Scott A Small.

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Competing interests

H.S. is employed by MARS, Inc., a company with long-term research and commercial interests in flavanols and procyanidins.

Integrated supplementary information

Supplementary Figure 1 Stimulus generation

(a) Lissajous figures parameterized by the equations X = sin(at+d), Y = sin(bt). a and b determined the vertical and horizontal frequency of the Lissajous loop, respectively. a was selected from the integer set [1-8,11] and b was selected from [1-6]. Only those a and b values were chosen that generated a non-integer quotient when b was divided by a(b) Lissajous figures belonging to a specific a/b pair were further modified by d=[1-5]. All figures were traced in the range t=[1-20pi] with a sampling step of pi/100.

Supplementary Figure 2 Study Protocol Flow Diagram

Supplementary Figure 3 Effect of flavanol and exercise on ModBent performance

a) Mean performance on the ModBent for the groups receiving the low (gray bars) and high (black bars) flavanol dietary supplements at baseline and follow up, analyzed with a between-group ANCOVA controlling for each individual’s baseline performance. The high dietary flavanol group improved cognitive performance by a mean time of 630ms.b) Mean performance on the ModBent for the no exercise (gray bars) and exercise (black bars) groups at baseline and follow up.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Tables 1 and 2 (PDF 2077 kb)

Supplementary Methods Checklist

(PDF 428 kb)

3D surface rendering of the hippocampal formation.

The hippocampal formations of subjects were masked and coregistered into a groupwise template. The resulting grayscale template image was thresholded and rendered in 3DSlicer using an adaptive marching cubes algorithm. The hippocampal formation is displayed in the left-anterior-oblique view and rotated clockwise. (MOV 6363 kb)

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Brickman, A., Khan, U., Provenzano, F. et al. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat Neurosci 17, 1798–1803 (2014). https://doi.org/10.1038/nn.3850

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