Dietary flavanols improve cerebral cortical oxygenation and cognition in healthy adults

 Does your stroke hospital have enough intelligence to read between the lines and recognize that greater brain oxygenation is what is needed immediately post stroke?  Even if this research was done in healthy adults?  Of course your stroke hospital will have to contact the researchers to get the protocol. Not doing any of that and your board of directors needs to be fired for not setting proper goals for the stroke unit. 100% RECOVERY FOR ALL!

Dietary flavanols improve cerebral cortical oxygenation and cognition in healthy adults

• Gabriele Gratton,
• Samuel R. Weaver,
• Claire V. Burley,
• Kathy A. Low,
• Edward L. Maclin,
• Paul W. Johns,
• Quang S. Pham,
• Samuel J. E. Lucas,
• Monica Fabiani &
• Catarina Rendeiro 

Scientific Reports volume 10, Article number: 19409 (2020) Cite this article

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Abstract

Cocoa flavanols protect humans against vascular disease, as evidenced by improvements in peripheral endothelial function, likely through nitric oxide signalling. Emerging evidence also suggests that flavanol-rich diets protect against cognitive aging, but mechanisms remain elusive. In a randomized double-blind within-subject acute study in healthy young adults, we link these two lines of research by showing, for the first time, that flavanol intake leads to faster and greater brain oxygenation responses to hypercapnia, as well as higher performance only when cognitive demand is high. Individual difference analyses further show that participants who benefit from flavanols intake during hypercapnia are also those who do so in the cognitive challenge. These data support the hypothesis that similar vascular mechanisms underlie both the peripheral and cerebral effects of flavanols. They further show the importance of studies combining physiological and graded cognitive challenges in young adults to investigate the actions of dietary flavanols on brain function.

Introduction

Lifespan wear and tear of the vascular system due to poor nutrition and lack of fitness, among other factors, can accelerate cognitive aging and lead to dementia. There is epidemiological evidence suggesting that flavonoids, a group of small molecules present in fruits and vegetables, can protect against vascular disease and cardiovascular-related mortality^1,2,3,4. In particular, cocoa flavanols, a sub-group of flavonoids (also present in berries, grapes, apples and tea) have been shown to improve endothelial function in humans quite rapidly (within 1–2 h) by enhancing vasodilatory properties of peripheral arteries^5,6. Acute benefits translate effectively into short-term (2–8 weeks) clinically relevant improvements in blood pressure and endothelial function (as measured by brachial flow-mediated dilatation, FMD)^7,8, comparable to those of drugs, such as statins^9,10. Mechanistically, the beneficial effects of cocoa flavanols on endothelial function have been linked to increases in bioavailability of nitric oxide (NO)⁶, which is known to be affected in the earliest stages of vascular disease¹¹.Whilst the acute effects of flavanols have been mainly attributed to phase I/II-derived (−)-epicatechin metabolites, the short to long term benefits may be also driven by gut-derived metabolites^12,13, although this remains to be established. Another emerging line of research further suggests that this class of plant-derived compounds may protect against cognitive decline in aging^14,15,16 and cognitive resilience to neuropsychiatric disorders and stress^17,18. Yet, the extent to which increases in circulatory levels of NO by flavanols can translate into benefits in the brain vasculature, and effectively influence cognitive performance in humans, is poorly understood.

Cerebral blood flow is controlled by neuronal activity but also by levels of arterial blood gases, in particular carbon dioxide (CO₂)¹⁹. Relevant to our hypothesis is the fact that NO is known to contribute to CO₂-dependent increases in cerebral blood flow in humans (hypercapnia)²⁰. Furthermore, cerebrovascular reactivity to CO₂ is widely accepted as a key biomarker of cerebrovascular health, and has been closely associated with cognitive function in health and disease states^{21,22,23,24,25}. Hence, hypercapnia represents a robust model to test whether flavanol-mediated increases in endothelial function (as assessed by gold-standard FMD) mediate benefits in cerebrovascular and cognitive function.

Only a handful of studies have previously reported effects of flavanols on the human cerebral vasculature, both in a resting state^26,27,28,29 and in response to cognitive challenges^30,31,32, albeit in opposite directions (increase/decrease in blood flow/velocity). Further, modulation of cerebral physiological outcomes by flavanols in the context of neuronal/cognitive challenges frequently and surprisingly fail to translate into cognitive benefits^26,30,31,32. A possibility is that the benefits of flavanols may only be visible at high levels of task difficulty. This highlights that, whilst some of these studies could provide ecological validity (as they target aging adults with cognitive and/or vascular problems), they were not designed in a manner that allows for an evaluation of the underlying physiological effects of these compounds in the human brain. This leaves some uncertainty about whether flavanols’ benefits in peripheral vascular function are reflected by similar effects on cerebrovascular reactivity, and whether the cognitive and vascular benefits are related.

There is a need to determine whether the peripheral vascular benefits of flavanols extend to the cerebral vasculature. This requires well-controlled experiments to demonstrate that flavanols (a) can modulate the brain’s vasculature; (b) that these effects, similarly to those found in the periphery, are revealed during physiological challenges likely involving the NO pathway; (c) that they affect cognitive performance, at least in challenging conditions; and (d) that cerebrovascular and cognitive benefits are linked.

In the current study, we employed separate physiological and cognitive challenges in a double-blind, within-subject, placebo-controlled acute (2 h) study to assess the underlying physiological actions of cocoa flavanols on cerebral and peripheral vascular and cognitive function. To measure cerebrovascular reactivity, we employed a CO₂-breathing challenge (hypercapnia) before and after intake of either a high- or low-flavanol intervention. During hypercapnia, we measured cortical haemoglobin concentration using functional near-infrared spectroscopy (fNIRS)³³, which allowed us to finely quantify the dynamics of cerebrovascular reactivity, providing information not only about the amplitude of this response, but also about its time course. Similar to peripheral measures, cerebral CO₂-reactivity has been shown to be mediated by the NO pathway²⁰, which is the hypothesized mechanism underlying the beneficial effects of flavanols on peripheral endothelial function⁶. To measure the cognitive effects of flavanols, we employed tasks with escalating levels of difficulty³⁴, which could inform us of the level at which the cognitive benefits of flavanols may emerge.