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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.
Neural mechanisms of behavioral improvement induced by repeated transcranial direct current stimulation (tDCS) combined with cognitive training are yet unclear. Previously, we reported behavioral effects of a 3-day visuospatial memory training with concurrent anodal tDCS over the right temporoparietal cortex in older adults. To investigate intervention-induced neural alterations we here used functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) datasets available from 35 participants of this previous study, acquired before and after the intervention. To delineate changes in whole-brain functional network architecture, we employed eigenvector centrality mapping. Gray matter alterations were analyzed using DTI-derived mean diffusivity (MD). Network centrality in the bilateral posterior temporooccipital cortex was reduced after anodal compared to sham stimulation. This focal effect is indicative of decreased functional connectivity of the brain region underneath the anodal electrode and its left-hemispheric homolog with other “relevant” (i.e., highly connected) brain regions, thereby providing evidence for reorganizational processes within the brain's network architecture. Examining local MD changes in these clusters, an interaction between stimulation condition and training success indicated a decrease of MD in the right (stimulated) temporooccipital cluster in individuals who showed superior behavioral training benefits. Using a data-driven whole-brain network approach, we provide evidence for targeted neuromodulatory effects of a combined tDCS-and-training intervention. We show for the first time that gray matter alterations of microstructure (assessed by DTI-derived MD) may be involved in tDCS-enhanced cognitive training. Increased knowledge on how combined interventions modulate neural networks in older adults, will help the development of specific therapeutic interventions against age-associated cognitive decline.