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

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 (ANOVARM p = 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 (ANOVARM p = 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.

Pattern of polyphenol intake and the long-term risk of dementia in older persons

“…Most of the polyphenols constituting our pattern have documented clinical effects in cognitive aging and AD. For example, in moderately-sized trials (N<150), moderate to high doses of resveratrol (ie, 200-2000 mg/day) increased hippocampal connectivity and memory in older adults, 30,31 and decreased plasma and cerebrospinal fluid amyloid-β levels in AD patients. 32 Moreover, a few small trials demonstrated efficacy of flavanols in increasing hippocampal vascular plasticity, 33 and of both citrus flavanones and soy isoflavonoids in improving cognition in older persons.…”

Resveratrol, pterostilbene, and dementia

“…Moreover, hippocampus volume, microstructure, and resting‐state functional connectivity were analyzed using cerebral magnetic resonance imaging ( n = 14 vs. 16), and neuropsychological tests assessing learning and memory were performed . Compared with controls, the group receiving resveratrol supplementation showed a decrease in glycated hemoglobin A1c concentration, a statistically significant increase in resting‐state functional connectivity between right anterior hippocampus and right angular cortex, and a moderate preservation of left anterior hippocampus volume (Cohen's d = 0.68) . This proof‐of‐concept study indicates that resveratrol supplementation may reduce glycated hemoglobin A1c, preserve hippocampus volume, and improve resting‐state functional connectivity of the hippocampus in individuals at risk for dementia.…”

“…In healthy elderly adults, resveratrol supplementation (200 mg daily for 26 weeks) has been shown to enhance verbal episodic memory performance, long‐term glucose control, and resting‐state functional connectivity between the hippocampus and neocortical brain areas . A further study examined whether these favorable effects could also be observed in patients with mild cognitive impairment . In a randomized, double‐blind interventional study, 40 mildly cognitively impaired individuals (aged 50–80 years, 21 females, 19 males) were administered either resveratrol (200 mg/d; n = 18) or placebo (1,015 mg/d olive oil; n = 22) for 26 weeks.…”

“…Serum levels of glucose, glycated hemoglobin A1c, and insulin were measured before and after intervention. Moreover, hippocampus volume, microstructure, and resting‐state functional connectivity were analyzed using cerebral magnetic resonance imaging ( n = 14 vs. 16), and neuropsychological tests assessing learning and memory were performed . Compared with controls, the group receiving resveratrol supplementation showed a decrease in glycated hemoglobin A1c concentration, a statistically significant increase in resting‐state functional connectivity between right anterior hippocampus and right angular cortex, and a moderate preservation of left anterior hippocampus volume (Cohen's d = 0.68) .…”

Reduction of Cognitive Decline in Patients with or at High Risk for Diabetes

“…In humans, conflicting results [57, 58] and the lack of confirmation of several mechanisms involved in its activity in ‘preclinical’ models [52] preclude its current pharmacological use in patients with or at high risk of diabetes, or at high risk for development of cognitive impairment. However, recent clinical trials support the notion that resveratrol is capable of increasing cerebral blood flow during task performance [59, 49, 60] and enhancing oxygen extraction [49], reducing glycated hemoglobin A1c, preserving hippocampus volume, and improving hippocampus resting state functional connectivity in at-risk patients for dementia [61]. A randomized, double-blind clinical trial phase 1 (NCT02502253) will evaluate the effects of a Bioactive Dietary Polyphenol Preparation (BDPP), a combination of two nutraceutical preparations (grape seed polyphenolic extract, and resveratrol) in mood and cognition of patients with MCI and prediabetes or type 2 diabetes.…”