The Neurovascular Coupling as a biomarker and a target for cognitive enhancement in aging and vascular dementia through an innovative dietary nitrate-driven nitric oxide redox cycle: a translational study

Overview

Project Summary

 
Diet is established among the most relevant adjustable variables of human health in modern societies. Vascular cognitive impairment (VCI) is a major cause of dementia in Western countries and all the conditions that lead to VCI have a contribution of neurovascular dysfunction.

Owing to its high energy needs, the brain is endowed with fine mechanisms for a precise spatial and temporal control of cerebral blood flow (CBF) according to neural activity, the neurovascular coupling (NVC). A chronic impairment of NVC leads to chronic injury associated with cognitive decline. Hence, studying NVC as a potential biomarker of cerebrovascular disease and targeting with therapeutic intent via diet is a novel and promising avenue for neural intervention in rescuing cognitive decline and dementia.
Failure at any part of the NVC pathway could cause disrupted CBF resulting in catastrophic depletion of oxygenation and energy supply. We have shown that nitric oxide (NO) synthesized by the neuronal nitric oxide synthase (nNOS) is a direct mediator of NVC and that decreased bioavailability of NO along aging compromised NVC and reduced local CBF. We have also shown that we consume metabolic precursors of NO in the diet.

Our hypothesis is that a functional NVC is maintained operative along aging by increasing NO bioavailability in the extracellular space of the brain through diet that, in turn, supports an adequate CBF in response to neuronal activation, reducing the progression of age-related cognitive decline and vascular dementia.
The ultimate goal is to support a dietetic intervention for cognition enhancement on basis of a well-defined molecular mechanism. This way a functional NVC may be modulated to avert VCI. Previously published evidence and the preliminary data we have generated support the feasibility of this hypothesis.

The utilization of state of the art in vivo recordings we have developed over the years will make possible to simultaneously follow the dynamics of metabolites from both, neuronal and a vascular origin in the rat brain. The detection of aberrant dynamic profiles of the messengers will permit to identify the primary sites of dysfunction along NVC pathway, representing early biomarkers of dysfunction. We anticipate that similar observations might be made in humans in terms of the profile of fMRIBold signals during the clinical trial.
 
We will follow a translational approach in which pre-clinical animal models of cerebral hypoperfusion and dementia will be used to establish the mechanisms that sustain NO bioavailability in the brain. Having answer to the question whether cognition improves via increasing NO bioavailability, sustaining a regular CBF, the results in the animal models will be translated to VCI patients submitted to dietary intervention and fMRIBold analysis via a clinical trial. For this we have assembled an international interdisciplinary and translational team, comprising basic research scientists and neurologists.

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