The predicted increase in the incidence of dementia worldwide highlights the imperative need for a more comprehensive understanding of how different aspects of lifestyle, in particular diet, may affect neural function and consequent cognitive performance throughout lifespan. Studies in humans demonstrated that deficient neurovascular- and cerebral blood flow (CBF) contribute to cognitive dysfunction. The brain is endowed with fine mechanisms for a precise spatial and temporal control of CBF according to cellular activity, named neurovascular coupling (NVC). Nitric oxide (NO) is a direct mediator of NVC and its bioavailability is diminished in aging and neurodegeneration, compromising the functionality of NVC. In addition to its synthesis by a family of synthases, NO can be produced in vivo along the nitrate-nitrite-NO redox pathway. In this regard, nitrate and nitrite, consumed in vegetables as part of a normal diet, are permanent constituents of blood/tissues in animal species, and act as NO metabolic precursors, influencing CBF, resulting in improvements in learning and memory in rodents and humans, including vascular dementia patients.
However, the lack of a convincing molecular mechanism for the action of nitrite as a bridge between active neurons and local increases of CBF raises uncertainties pertaining its potential therapeutic use. We have identified a mechanism occurring in the brain involving a redox interaction of ascorbate and nitrite ascorbate that, supporting NVC, maintains the functionality of functional CBF that is required to support cognitive functions.
In essence, to delay or prevent cognition deficits associated with aging/neurodegeneration by improving the efficiency of NVC, a molecular mechanism operative in the brain and influenced by diet (nitrate and ascorbic acid from fresh green vegetables) that is critical for cognition.
The ultimate goal of this research proposal is to implement a nitrate/ascorbic acid-based dietary approach to enhance cognition in individuals with cognitive deficits affected by brain aging and vascular dementia.  We will follow a translational research approach whereby multimodal molecular, mechanistic and functional data obtained in vivo in rodents, using state-of-the art in vivo recordings, will be translated into a population of vascular dementia patients submitted to a clinical trial. This proposal has also significance for reverse translation inasmuch as data obtained from patients will help formulate new avenues in mechanistic approaches. For that we have assembled an international interdisciplinary and translational team, comprising basic research scientists (from Portugal and abroad) and Clinical Neurologists from the Local University Hospital..