Impact of Resveratrol on Glucose Control, Hippocampal Structure and Connectivity, and Memory Performance in Patients with Mild Cognitive Impairment

Theresa Köbe, A Veronica Witte, Ariane Schnelle, Valentina A Tesky, Johannes Pantel, Jan-Philipp Schuchardt, Andreas Hahn, Jens Bohlken, Ulrike Grittner, Agnes Flöel, Theresa Köbe, A Veronica Witte, Ariane Schnelle, Valentina A Tesky, Johannes Pantel, Jan-Philipp Schuchardt, Andreas Hahn, Jens Bohlken, Ulrike Grittner, Agnes Flöel

Abstract

In healthy older adults, resveratrol supplementation has been shown to improve long-term glucose control, resting-state functional connectivity (RSFC) of the hippocampus, and memory function. Here, we aimed to investigate if these beneficial effects extend to individuals at high-risk for dementia, i.e., patients with mild cognitive impairment (MCI). In a randomized, double-blind interventional study, 40 well-characterized patients with MCI (21 females; 50-80 years) completed 26 weeks of resveratrol (200 mg/d; n = 18) or placebo (1,015 mg/d olive oil; n = 22) intake. Serum levels of glucose, glycated hemoglobin A1c and insulin were determined before and after intervention. Moreover, cerebral magnetic resonance imaging (MRI) (3T) (n = 14 vs. 16) was conducted to analyze hippocampus volume, microstructure and RSFC, and neuropsychological testing was conducted to assess learning and memory (primary endpoint) at both time points. In comparison to the control group, resveratrol supplementation resulted in lower glycated hemoglobin A1c concentration with a moderate effect size (ANOVARMp = 0.059, Cohen's d = 0.66), higher RSFC between right anterior hippocampus and right angular cortex (p < 0.001), and led to a moderate preservation of left anterior hippocampus volume (ANOVARMp = 0.061, Cohen's d = 0.68). No significant differences in memory performance emerged between groups. This proof-of-concept study indicates for the first-time that resveratrol intake may reduce glycated hemoglobin A1c, preserves hippocampus volume, and improves hippocampus RSFC in at-risk patients for dementia. Larger trials with longer intervention time should now determine if these benefits can be validated and extended to cognitive function.

Keywords: MCI; hippocampus; memory performance; resting-state functional connectivity; resveratrol.

Figures

Figure 1
Figure 1
Study flow chart. In total, 110 MCI patients were screened on telephone, of which 88 were invited for baseline assessment. Forty-two patients met the inclusion criteria and were randomized to the resveratrol intervention group (n = 19) or to the placebo intervention group (n = 23). Two patients did not complete participation due to time constraints. Thus, 40 patients successfully completed the intervention over 26 weeks (resveratrol n = 18; placebo n = 22). Before and after the intervention period, patients underwent a standardized medical examination, including neuropsychological testing, cerebral magnetic resonance imaging (MRI), anthropometry, and fasting blood draw for detection of serum parameters and APOE e4 status. MRI scans from both time points baseline and follow-up were not available for 10 patients (scheduling problems at follow-up), leaving 30 patients for longitudinal MRI analysis (resveratrol n = 14; placebo n = 16).
Figure 2
Figure 2
A moderate, but non-significant decrease in the long-term glucose marker HbA1c after 26 weeks resveratrol intervention (n = 18) compared to placebo intervention (n = 19) (ANCOVARMp = 0.059, d = 0.66). The decrease reached statistical significance when analyzing the resveratrol group separately (paired t-test p = 0.005). HbA1c, glycated hemoglobin A1c.
Figure 3
Figure 3
Significant increase in resting-state functional connectivity between the right HC and the right angular cortex after 26 weeks resveratrol intervention (n = 14) compared to placebo intervention (n = 16). Color bar indicate t-values of significant voxels (resveratrol intervention > placebo intervention; cluster-based thresholding, p < 0.05). Individual masks of the left and right HC were used as seeds in the analysis. No group differences were observed for the opposite contrast (placebo intervention > resveratrol intervention), and when using the left HC as seed. For better visualization we superimposed the t-map on the MNI-template. Images are displayed in neurological convention, coordinates in mm according to MNI space. A, anterior; H, hippocampus; L, left; R, right; P, posterior.
Figure 4
Figure 4
A moderate, but non-significant, preservation of gray matter atrophy of the left, particularly anterior, hippocampus after 26 weeks resveratrol supplementation (n = 14) compared to placebo (n = 16) (ANCOVARM; left Hippocampus, p = 0.084, d = 0.68; left anterior Hippocampus, p = 0.061, d = 0.74). Error bars indicate standard error.

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