Sebastian Huhn

Components of a Mediterranean diet and their impact on cognitive functions in aging

Background: Adhering to the Mediterranean diet (MeDi) is known to be beneficial with regard to many age-associated diseases including cardiovascular diseases and type 2 diabetes. Recent studies also suggest an impact on cognition and brain structure, and increasing effort is made to track effects down to single nutrients. Aims: We aimed to review whether two MeDi components, i.e., long-chain omega-3 fatty acids (LC-n3-FA) derived from sea-fish, and plant polyphenols including resveratrol (RSV), exert positive effects on brain health in aging. Content: We summarized health benefits associated with the MeDi and evaluated available studies on the effect of (1) fish-consumption and LC-n3-FA supplementation as well as (2) diet-derived or supplementary polyphenols such as RSV, on cognitive performance and brain structure in animal models and human studies. Also, we discussed possible underlying mechanisms. Conclusion: A majority of available studies suggest that consumption of LC-n3-FA with fish or fishoil-supplements exerts positive effects on brain health and cognition in older humans. However, more large-scale randomized controlled trials are needed to draw definite recommendations. Considering polyphenols and RSV, only few controlled studies are available to date, yet the evidence based on animal research and first interventional human trials is promising and warrants further investigation. In addition, the concept of food synergy within the MeDi encourages future trials that evaluate the impact of comprehensive lifestyle patterns to help maintaining cognitive functions into old age.

Effects of resveratrol on memory performance, hippocampus connectivity and microstructure in older adults: A randomized controlled trial

Introduction: The polyphenol resveratrol has been suggested to exert beneficial effects on memory and the aging hippocampus due to calorie‐restriction mimicking effects. However, the evidence based on human interventional studies is scarce. We therefore aimed to determine the effects of resveratrol on memory performance, and to identify potential underlying mechanisms using a broad array of blood‐based biomarkers as well as hippocampus connectivity and microstructure assessed with ultra‐high field magnetic resonance imaging (UHF‐MRI). Methods: In this double‐blind, randomized controlled trial, 60 elderly participants (60–79 years) with a wide body‐mass index (BMI) range of 21–37 kg/m2 were randomized to receive either resveratrol (200mg/day) or placebo for 26 weeks (registered at ClinicalTrials.gov: NCT02621554). Baseline and follow‐up assessments included the California Verbal Learning Task (CVLT, main outcome), the ModBent task, anthropometry, markers of glucose and lipid metabolism, inflammation and neurotrophins derived from fasting blood, multimodal neuroimaging at 3 and 7T, and questionnaires to assess confounding factors. Results: Multivariate repeated‐measures ANOVA did not detect significant time by group effects for CVLT performance. There was a trend for preserved pattern recognition memory after resveratrol, while performance decreased in the placebo group (n.s., p=0.07). Further exploratory analyses showed increases in both groups over time in body fat, cholesterol, fasting glucose, interleukin 6, high sensitive C‐reactive protein, tumor necrosis factor alpha and in mean diffusivity of the subiculum and presubiculum, as well as decreases in physical activity, brain‐derived neurotrophic factor and insulin‐like growth factor 1at follow‐up, which were partly more pronounced after resveratrol. Discussion: This interventional study failed to show significant improvements in verbal memory after 6 months of resveratrol in healthy elderly with a wide BMI range. A non‐significant trend emerged for positive effects on pattern recognition memory, while possible confounding effects of unfavorable changes in lifestyle behavior, neurotrophins and inflammatory markers occurred. Our findings also indicate the feasibility to detect (un)healthy aging‐related changes in measures of hippocampus microstructure after 6 months using 7T diffusion MRI. More studies incorporating a longer duration and larger sample size are needed to determine if resveratrol enhances memory performance in healthy older adults. HIGHLIGHTSIn this randomized clinical trial, 6 months resveratrol supplementation showed no significant effects on verbal memory compared to placebo.Unfavorable changes in lifestyle factors at follow‐up might have introduced confounding.Secondary analyses showed a trend towards preserved pattern recognition.We used multimodal ultra high field MRI to detect subtle changes in microstructure of hippocampus subfields.

EFFECTS OF LEPTIN ON HIPPOCAMPUS VOLUME AND COGNITIVE PERFORMANCE

VENs were the same in AD compared to controls. Interestingly, while the ratio of GABRQ-expressing neurons was significantly lower in bvFTD (p1⁄40.03) compared to controls, this ratio was significantly increased in AD compared to controls (p1⁄40.05). Conclusions:We show that GABRQ-expressing neurons are selectively vulnerable in bvFTD. Our data indicates that in AD cases this group of neurons is spared in the ACC, and suggests that other Layer 5 neurons are targeted by neurodegeneration in AD. The selective vulnerability of VENs in bvFTD is shared with the surrounding GABRQ-expressing neurons, implicating that a larger neuronal group specific to ACC and FI is linked to social-emotional behavior.

Effects of Resveratrol on Cognitive Functions

Resveratrol (RSV) is a naturally occurring polyphenol found in berries, grapes, red wine, and nuts. Based on numerous animal and human studies, it has been suggested as a possible candidate for the treatment of cardiovascular impairments, metabolic dysfunctions, and neurodegenerative diseases. Beyond that, research has started to focus on its influence on cognitive functions and animal studies have described RSV’s beneficial effects on brain structure and function. The first controlled studies in humans reported the beneficial effects of RSV administration with regard to cognitive functions, especially in older populations. Possible underlying mechanisms of RSV range from antioxidant and antiinflammatory actions to the activation of sirtuins and neuroprotective properties. Future studies should now address previous limitations such as flaws in the study design and focus on translating findings from animals to humans and eventually strengthen the hypothesis that RSV could help maintain cognitive health until old age. This chapter summarizes what is known about the effects of RSV on health outcomes with a focus on cognitive functions and possible underlying mechanisms. In addition, we discuss limitations and challenges of previous studies as well as future perspectives in RSV research.

ASSOCIATION OF HIPPOCAMPAL VOLUMES WITH COGNITIVE TASKS IN A LARGE POPULATION-BASED COHORT

Background:Volume loss in the hippocampus is thought to be a primary driver of verbal memory decline in aging. However, recent work highlights the role of small vessel cerebrovascular disease, operationally defined as white matter hyperintensities (WMH), in memory decline and dementia. The extent to which these two pathological features neurodegeneration and cerebrovascular disease are independent or interactive on their effect on memory is unclear. The purpose of this study was to examine whether WMH burden moderates the relationship between hippocampal volume and verbal memory in ethnically-diverse older adults without dementia. Methods:Ninety-one participants from the Einstein Aging Study (age mean (sd)1⁄479.8(4.9), 66% women, 56% Caucasian) received high-resolution magnetic resonance imaging (MRI). Hippocampal volume and total intracranial volume were derived using FreeSurfer. White matter hyperintensity volumes were computed with in-house developed software. Episodic memory was evaluated using the free recall score from the picture version of the Free and Cued Selective Reminding Test, a verbal memory test that is sensitive for the detection of clinical Alzheimer’s disease. Participants were adjudicated to be non-demented at a diagnostic consensus case conference. A series of separate linear regression analyses were used to examine the relationship of total hippocampal volume, total WMH volume, and the interaction between hippocampal volume and WMH with memory function, controlling for total intracranial volume. Results: In separate models, smaller hippocampal volume was associated with poorer verbal memory performance (b 1⁄40.23, p1⁄40.04), but WMH were not (b 1⁄40.03, p1⁄40.82). In a combined model, there was a significant interaction term (b 1⁄42.17, p1⁄40.01) such that smaller hippocampal volume was related to poorer memory function only among older adults with higher levels of WMH. Also in this combined model, there was a main effect of WMH (b1⁄4-2.11, p1⁄40.01) for the prediction of verbal memory, but not for hippocampal volume (b1⁄4-0.04, p1⁄40.79). Conclusions:These findings provide further evidence that cerebrovascular disease plays a role in the expression of verbal memory decline in aging. Small vessel cerebrovascular may be necessary for the impact of hippocampal volume loss on memory to manifest in older adults without dementia.

FTO IS NOT RELATED TO IMAGING PARAMETERS OF THE HIPPOCAMPUS: A VOLUMETRIC AND DIFFUSION TENSOR IMAGING STUDY

collected and aggregated together from GAAIN, and APOE genotype frequencies were calculated for different age, cognitive status, and race subject groups. Hippocampal radial profiles were computed from structural MRI scans of 383 e2 and 1616 e4 carriers and grouped by cognitive status. Results:Although the APOE e2 allele was found to be associated with a smaller risk of developing Alzheimer’s disease, it did not significantly protect the hippocampi of subjects from atrophy. Conclusions: GAAIN provides a useful foundation for discovering and aggregating data from over 20 research studies of Alzheimer’s disease around the world. This has the potential to reveal trends and correlations in data that are not apparent from small sample sizes.