Diet is established among the most relevant adjustable variables of human health in modern societies. The recognition by the World Health Organization of cognitive impairment and dementia associated with aging as one of the major public health challenges of our time, highlights the imperative need for a more comprehensive understanding of how different aspects of lifestyle, in particular diet, affect neural function and consequent cognitive performance throughout lifespan. 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). Mounting evidence from preclinical and human studies demonstrate that NVC dysfunction is a key early factor contributing to the pathogenesis of cognitive decline and vascular cognitive impairment (VCI) in aging and conditions associated with accelerated microvascular aging, such as cerebral small vessel disease (cSVD). Failure at any part of the NVC pathway disrupts CBF resulting in catastrophic depletion of oxygenation and energy supply to brain cells, and, in the long run, to neuronal dysfunction and cognitive impairment. The investigators have shown that nitric oxide (NO) synthesized by 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. Shortly after the identification of nNOS as a source of NO for vasodilation in the brain, an alternative pathway for NO production independent of nNOS, relying on the sequential reduction of nitrate, the nitrate:nitrite:NO pathway, was unveiled. Nitrate consumed in green leafy vegetables as part of a normal diet is bioactivated to nitrite and both compounds are permanent constituents of blood/tissues in animal species, influencing CBF and resulting in improvements in learning and memory in rodents and VCI patients. However, a critical question remains on whether NO produced from nitrite is functionally linked to neuronal activation. This is key to understanding whether dietary nitrate can be linked to neuronal-dependent CBF increases and cognitive performance. The investigators and others have shown that upon excitatory stimulation, ascorbate is released from neurons being available for nitrite reduction and our preliminary data supports that NO bioavailability and CBF might be maintained independently of nNOS by the reduction of nitrite to NO in the brain extracellular space upon neuronal activation (unpublish data). This innovative mechanism functionally links the production of NO from nitrite to neuronal activation, triggering CBF increases and maintaining an operative NVC. A further facet is that, bridging diet and cognitive performance, this mechanism incorporates modulatory elements which is open to adjustment by diet via nitrate. Thus, in this pilot trial a proof of concept study will be conducted to investigate the clinical impact of a dietary nitrate supplementation intervention in a clinical population with VCI due to small vessel disease, as measured by changes on NVC and cognitive performance. The investigators hypothesise that functional NVC is maintained operative in VCI patients by increasing NO bioavailability in the extracellular space of the brain through a nitrate -rich diet that, in turn, supports an adequate CBF in response to neuronal activation, modulating the molecular mechanisms and cognitive performance of disease-related physiological and cognitive markers.
Professor João Laranjinha (CNC-UC) is the lead scientific contributor of the study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
QUADRUPLE
Enrollment
25
140 ml beetroot juice/day, corresponding to approximately 0.8 g of nitrate that will constitute a period of 2 weeks with a nitrate-diet (beetroot).
140 ml nitrate-depleted beetroot juice/day, that will constitute a period of 2 weeks with a nitrate-depleted diet (beetroot).
Institute for Nuclear Sciences Applied to Health (ICNAS), University of Coimbra
Coimbra, Portugal
RECRUITINGUnidade de Saúde Local de Coimbra (ULS Coimbra)
Coimbra, Portugal
RECRUITINGMemory retrieval cognitive task (d prime)
Comparing changes from baseline after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Memory encoding Blood Oxigenation Level Dependent (BOLD) signal amplitude
Comparing changes from baseline after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Ascorbate concentration in the posterior cingulate cortex
Comparing changes in ascorbate concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Score on the Visual Analogue Scale of the health-related quality of life EQ-5D-5L questionnaire
Comparing changes from baseline after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition on the score of the Visual Analogue Scale of EQ-5D-5L questionnaire, ranging from 0 to 100, where higher values mean better health related quality of life.
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Nitrate concentration in the blood
Comparing changes in nitrate concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Time frame: From baseline to the end of treatment up to Week 4 and from Week 7 to the end of placebo up to Week 11.
Glutathione concentration in the posterior cingulate cortex
Comparing changes in glutathione concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
N-acetylaspartate concentration in the posterior cingulate cortex
Comparing changes in n-acetylaspartate concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Glutamate concentration in the posterior cingulate cortex
Comparing changes in glutamate concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Gamma-aminobutyric acid (GABA) concentration in the posterior cingulate cortex
Comparing changes in gamma-aminobutyric acid (GABA) concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Lactate concentration in the posterior cingulate cortex
Comparing changes in lactate concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Creatine concentration in the posterior cingulate cortex
Comparing changes in creatine concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Time frame: From baseline to the end of treatment up to Week 4 and from baseline to the end of placebo up to Week 11.
Nitrite concentration in the blood
Comparing changes in nitrite concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Time frame: From baseline to the end of treatment up to Week 4 and from Week 7 to the end of placebo up to Week 11.
S-nitrosothiols concentration in the blood
Comparing changes in S-nitrosothiols concentration from baseline to after dietary nitrate supplementation (standardised beetroot juice) during 14 days versus the placebo condition.
Time frame: From baseline to the end of treatment up to Week 4 and from Week 7 to the end of placebo up to Week 11.
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