Effects of resveratrol on memory performance, hippocampus connectivity and microstructure in older adults – A randomized controlled trial☆
Introduction
Food-derived polyphenols, common in the Mediterranean diet, have been suggested to exert beneficial effects on brain health (reviewed e.g. in Davinelli et al., 2012; Bastianetto et al., 2015; Huhn et al., 2015). One of the most extensively studied polyphenols is resveratrol, which occurs in various natural sources such as blueberries, peanuts, red grapes and red wine (Baur et al., 2006; Baur, 2010). In vitro as well as in vivo rodent and primate studies provided evidence for antioxidative, anti-inflammatory and calorie-restriction mimicking characteristics of resveratrol (Baur, 2010; Bastianetto et al., 2015; Kulkarni and Canto, 2015). These effects have been discussed to contribute to improvements in glucose-metabolism and cardiovascular factors (reviewed in Liu et al., 2014; Kakoti et al., 2015; Huang et al., 2016), and eventually to preserved brain structure and neuronal function (discussed in Davinelli et al., 2012; Huhn et al., 2015; Tellone et al., 2015; Wong and Howe, 2018).
While preclinical studies yielded exciting results, data from interventional human studies on the effect of polyphenols on brain structure and cognition is scarce. Using small- to moderate sample sizes, few randomized controlled trials (RCTs) in older adults reported improved memory performance after supplementary intake of berry juice or formulas with cocoa-flavonol or other polyphenol-containing ingredients (Krikorian et al., 2010; Brickman et al., 2014; Small et al., 2014). A memory-enhancing effect in older adults has also been reported in two RCTs for the intake of isolated resveratrol (150–200 mg/day for 3 or 6 months) (Witte et al., 2014; Evans et al., 2017). In contrast, studies in younger age or patient groups did not detect significant effects of resveratrol on cognitive functions (Turner et al., 2015; Wightman et al., 2015; Zortea et al., 2016; Kobe et al., 2017). Also, a recent meta-analysis (Farzaei et al., 2017) including 255 participants of four studies (Witte et al., 2014; Wightman et al., 2015; Evans et al., 2017; Kobe et al., 2017) concluded that resveratrol has no significant impact on cognitive performance.
Only few human studies so far included measures that could yield underlying mechanistic insights. Two studies led by Kennedy and colleagues suggested that acute doses of 250 mg or 500 mg resveratrol enhance cerebral blood flow (Kennedy et al., 2010; Wightman et al., 2015). Studies with a longer duration of resveratrol supplementation (3–6 months) reported improvements in cerebrovascular responsiveness to hypercapnia (Evans et al., 2017) and changes in magnetic resonance imaging (MRI)-based measures of functional connectivity (FC) of the hippocampus, a key region involved in memory processes (Witte et al., 2014; Kobe et al., 2017). Witte et al. (2014) could also observe decreased levels of glycated hemoglobin (HbA1c), a long-term marker of glucose control, after resveratrol supplementation, which in turn correlated with resveratrol-induced improvements in functional connectivity and verbal memory. However, the hypothesis that resveratrol enhances human memory performance via improvements or maintenance of hippocampus functioning in aging remains to be established, and potentially related mechanistic pathways are still debated (Huhn et al., 2015; Dias et al., 2016; Figueira et al., 2017). Notably, so far only few longitudinal studies in healthy elderly were able to show plastic changes in either regional hippocampus blood volume (Pereira et al., 2007; Brickman et al., 2014) or functional connectivity and volume (Erickson et al., 2011; Witte et al., 2014) that followed a dose-response relationship with memory improvements after plasticity-enhancing interventions such as physical exercise or polyphenol diets. Similarly, in longitudinal studies, systemic changes such as improvements in physical activity or glucose metabolism have only occasionally been linked to selective changes in the hippocampus (Erickson et al., 2011; Cherbuin et al., 2012; Maass et al., 2015; Prehn et al., 2016).
This might be explained in part by the regional complexity of the hippocampus and its sub-structures that have distinct morphological and functional properties, as indicated by preclinical and post-mortem studies (Mueller et al., 2011; Robinson et al., 2016). Using ultra-high field (UHF) MRI, though, it is now possible to delineate hippocampus subfields in vivo with higher signal-to-noise ratio and higher spatial resolution. This also enables to identify plastic changes at the subfield level more reliably (Iglesias et al., 2016; Giuliano et al., 2017). Implementing 7 Tesla (7T) UHF MRI in interventional studies would thus help to better understand if and how the hippocampus translates potential plasticity-enhancing effects of a systemic factor, such as diet, into specific improvements in cognition (in this case memory). Therefore, we aimed to examine the effects of resveratrol on memory performance in an independent sample of older adults by employing sensitive memory tests, state-of-the-art 7T UHF MRI, and a broad array of blood-based biomarkers. We hypothesized that 6 months of resveratrol supplementation leads to improvements in memory performance, assessed with the California Verbal Learning Task (CVLT; Niemann et al., 2008). Secondary hypotheses included an improvement in glucose metabolism, reflected in lower HbA1c levels after resveratrol supplementation, and improvements in pattern recognition memory (Brickman et al., 2014). In addition, we hypothesized resveratrol-induced improvements in functional connectivity of the hippocampus within the default-mode network, and in measures of regional hippocampus volume and microstructure, assessed using 7T UHF MRI.
Section snippets
Participants and study design
Sixty healthy elderly participants (60–78 years) were recruited via the Max Planck Institute’s database and local advertisements in Leipzig, Germany. The research protocol was approved by the Ethics Committee of the University of Leipzig and was conducted in accordance with the Declaration of Helsinki. All subjects gave written informed consent and received reimbursement for participation. The trial was registered and a study protocol was uploaded at ClinicalTrials.gov with the identifier
Baseline characteristics
At baseline, the intervention and placebo group did not differ significantly in sex, age, years of education, MMSE, ApoE-status, SCD, depressive symptoms, verbal intelligence (measured with a vocabulary test), perceived stress, sleep quality, and BMI (see Table 1 for details). All participants met the MMSE inclusion criterion.
Compliance and change in mood and lifestyle factors
According to self-reported diaries and capsule counts, adherence to the capsule intake instructions was overall high in both groups (mean pill intake of > 94% ± 0.06;
Discussion
In this randomized controlled interventional study we did not detect significant effects of 26 weeks resveratrol intake compared to placebo on verbal memory performance measured using the CVLT in healthy elderly. In exploratory analyses, we observed a non-significant trend for stable performance in a pattern recognition task in the resveratrol group, while performance decreased in the placebo group. HbA1c levels as well as hippocampus volume, microstructure and functional connectivity did not
Declarations and conflict of interests
Our research was supported by grants of the German Research Foundation, contract grant number CRC 1052 “Obesity mechanisms” Project A1, A. Villringer/M. Stumvoll; Project B3, P. Kovacs and WI 3342/3–1, A.V. Witte. S.H. received a stipend from the Max Planck International Network for Aging (MaxNetAging). J.B. was funded by the IFB Adiposity Diseases which is supported by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1501 (AD2-06E99). Supplements (resveratrol and
Acknowledgements
The authors would first and foremost like to thank all participants for their invaluable contribution. Our gratitude is extended to Dr. Luigi Silvestro (3S-Pharmacological Serve International SRL, Bukarest, Romania and 3S-Pharmacological Consultation and Research GmbH, Harpstedt, Germany) for a timely measurement of blood resveratrol. Furthermore to be acknowledged is the supportive staff helping with administrative tasks, recruitment, general study organization, blood draw and data handling.
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General Theme: Cognition and Aging.