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

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.

Figure 1

A bilateral map of the hippocampal circuit generated from the high-resolution acquisitions of CBV-fMRI. A three-dimensional rendering of the bilateral hippocampal circuit (top) derived from a group-wise template of multiple axial slices (illustrated at bottom), generated using the native sub-millimeter resolution of CBV maps (Supplementary Video 1). The EC is the main gateway into the hippocampal circuit, and over the long axis (top) the circuit is divided into the head (red), body (green) and tail (blue). In its transverse axis (bottom), taken through the body of the hippocampal long axis (indicated by arrows, top), the hippocampal circuit is divided into the dentate gyrus (brown), CA3 (yellow), CA1 (blue) and subiculum (green). All statistical analyses were performed only in the boundaries of the hippocampal circuit.

Figure 2

Mapping a differential pattern of age-related dysfunction in the hippocampal circuit. (a) A voxel-based analysis of 35 individuals ranging from 21–65 years of age revealed that the greatest age-related decline in CBV occurred in the body of the hippocampal circuit (top left; color coded by degree of significance). A transverse slice (bottom left), onto which the hippocampal circuit mask was applied, revealed that age-related CBV decline localized primarily to the dentate gyrus. A scatter plot (right) shows the association between age and mean CBV from all significantly correlated voxels (β = −0.844, r² = 0.678, P < 0.001). (b) A voxel-based analysis in subjects with preclinical Alzheimer’s disease compared with age-matched controls revealed CBV reductions in the EC (left, reprocessed from ref. 1). A scatter plot (right) shows individual-subject mean CBV values in those lateral EC voxels determined to be significantly different between patients with preclinical Alzheimer’s disease and healthy controls (t₉₄ = 7.265, P < 0.001).

Figure 3

Performance on the ModBent declines with age. (a) The ModBent task is divided into two parts. During the matching trials (top), participants were shown a complex stimulus for 10 s. Following a 1-s inter-trial interval, they were required to select, via a key press, which of two stimuli matched the one they had just studied, as quickly and as accurately as possible. Following 41 matching trials, participants were shown a series of 82 stimuli (bottom), 41 of which appeared on the initial study set during the matching trials and 41 of which were foils. They were required to indicate, as quickly as possible, whether each stimulus appeared earlier (yes response) or was new (no response). The primary variable of the ModBent task is the mean RT for correct rejections of foils during the recognition trials. (b) As part of the task development, the ModBent was administered to 62 undergraduate students (mean age = 21.1 ± 0.80 years). Performance was normally distributed (Kolmogorov-Smirnov test statistic (62) = 0.091, P = 0.20), as shown. A subset of participants were tested following a 3-month interval and good test–re-test reliability was achieved (ICC = 0.743). (c) When applied to 149 healthy subjects across the adult life span (ages 21–69 years), performance on the ModBent (reaction time in correctly rejecting foil items) worsened with age (β = 22.31, P < 0.001).

Figure 4

Performance on the ModBent overlaps with the anatomical site of hippocampal aging. (a) A voxel-based analysis of 35 individuals revealed that better performance on the ModBent task correlated with greater CBV in the body of the hippocampal circuit (top left). A transverse slice, onto which the hippocampal circuit mask was applied, shows that the correlation localized primarily to the dentate gyrus (bottom left; coronal section, color coded by degree of significance). A scatter plot (right) shows the association between ModBent performance and single-subject mean CBV from all significantly correlated voxels (β = −0.633, r² = 0.465, P < 0.001). (b) A voxel-based analysis in the same group showed that better performance on a delayed retention task correlated with greater CBV in the EC (left). A scatter plot (right) shows the association between performance on this delayed retention task and single-subject mean CBV from all significantly correlated voxels (β = 0.693, r² = 0.562, P < 0.001).

Figure 5

Flavanols enhance CBV-fMRI. (a) A voxel-based analysis of 37 individuals revealed that, compared with those in the low-flavanol condition, those in the high-flavanol condition showed a CBV increase in the body of the hippocampal circuit. A transverse slice, onto which the hippocampal circuit mask was applied, shows that the CBV increase localized primarily to the dentate gyrus and subiculum (bottom left; color coded for degree of significance). Single-subject line plots (right) show mean CBV in all voxels determined to have a significant group × time interaction (F_1,33 = 27.58, P < 0.0001). (b) A voxel-based analysis of 35 individuals revealed that better performance on the ModBent task correlated with greater CBV in the body of the right hippocampal circuit (top left). A transverse slice, onto which the hippocampal circuit mask was applied, shows that the correlation localized primarily to the dentate gyrus (bottom left; color coded for degree of significance). A scatter plot (right) shows the association between change in ModBent performance and single-subject mean change in CBV from all significantly correlated voxels (β = −0.554, r² = 0.307, P < 0.001).