Protocol and recruitment results from a 13-week randomized controlled trial comparing the effects of different doses of nitrate-rich beetroot juice on cognition, cerebral blood flow and peripheral vascular function in overweight and obese older people

Babateen, Abrar; Rubele, Sofia; Shannon, Oliver M.; Okello, Edward; Smith, Ellen M. Lavoie; McMahon, Nicholas; O’Brien, Gerard; Wightman, Emma L.; Kennedy, David O.; Mathers, John C.; Siervo, Mario

doi:10.1016/j.conctc.2020.100571

Cited by 10 publications

(16 citation statements)

References 29 publications

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“…The randomization pattern was generated using the RAND function in Excel (Excel Microsoft software, Version 16.46, Microsoft corp., Redmond, WA, USA). Further details on participants recruitment, selection, and screening have been described elsewhere [15].…”

Section: Participants and Study Designmentioning

confidence: 99%

“…In addition, measurements of cognitive, vascular and pulmonary functions were performed. The measurement protocols have been described [15] and the results of the secondary outcome measures will be published in due course.…”

Section: Data Collection Proceduresmentioning

confidence: 99%

“…Participants returned the following day for the second baseline visit at Northumbria University between 15:00 and 16:00 to perform the cerebral blood flow measurement as described elsewhere [15]. Biological samples including salivary NO 2 − strips, saliva and urine samples were collected in the morning at home after an overnight fast (~12 h).…”

Section: Data Collection Proceduresmentioning

confidence: 99%

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Acceptability and Feasibility of a 13-Week Pilot Randomised Controlled Trial Testing the Effects of Incremental Doses of Beetroot Juice in Overweight and Obese Older Adults

et al. 2021

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Nitrate-rich food can increase nitric oxide production and improve vascular and brain functions. This study examines the feasibility of a randomised controlled trial (RCT) testing the effects of prolonged consumption of different doses of dietary nitrate (NO3-) in the form of beetroot juice (BJ) in overweight and obese older participants. A single-blind, four-arm parallel pilot RCT was conducted in 62 overweight and obese (30.4 ± 4 kg/m2) older participants (mean ± standard deviation (SD), 66 ± 4 years). Participants were randomized to: (1) high-NO3- (HN: 2 × 70 mL BJ/day) (2) medium-NO3- (MN: 70 mL BJ/day), (3) low-NO3- (LN: 70 mL BJ on alternate days) or (4) Placebo (PL: 70 mL of NO3--depleted BJ on alternate days), for 13 weeks. Compliance was checked by a daily log of consumed BJ, NO3- intake, and by measuring NO3- and NO2- concentrations in plasma, saliva, and urine samples. Fifty participants completed the study. Self-reported compliance to the interventions was >90%. There were significant positive linear relationships between NO3- dose and the increase in plasma and urinary NO3- concentration (R2 = 0.71, P < 0.001 and R2 = 0.46 P < 0.001, respectively), but relationships between NO3- dose and changes in salivary NO3- and NO2- were non-linear (R2 = 0.35, P = 0.002 and R2 = 0.23, P = 0.007, respectively). The results confirm the feasibility of prolonged BJ supplementation in older overweight and obese adults.

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Section: Participants and Study Designmentioning

confidence: 99%

Section: Data Collection Proceduresmentioning

confidence: 99%

Section: Data Collection Proceduresmentioning

confidence: 99%

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Acceptability and Feasibility of a 13-Week Pilot Randomised Controlled Trial Testing the Effects of Incremental Doses of Beetroot Juice in Overweight and Obese Older Adults

et al. 2021

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“…More and larger studies are needed to delineate the potential benefits and risks associated with nitrate and/or nitrite treatment on CBF, mood, and cognitive function, particularly in populations of people with differing ages and underlying health status. Importantly, a study in humans is underway to look at the effect of increasing doses of nitrate on cognition-related outcomes [ 83 ]. We also cannot differentiate between the direct effects of nitrate or nitrite in the fish, or indirect effects that could be generated by increased NO availability.…”

Section: Discussionmentioning

confidence: 99%

Nitrate and nitrite exposure leads to mild anxiogenic-like behavior and alters brain metabolomic profile in zebrafish

et al. 2020

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Dietary nitrate lowers blood pressure and improves athletic performance in humans, yet data supporting observations that it may increase cerebral blood flow and improve cognitive performance are mixed. We tested the hypothesis that nitrate and nitrite treatment would improve indicators of learning and cognitive performance in a zebrafish (Danio rerio) model. We utilized targeted and untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis to examine the extent to which treatment resulted in changes in nitrate or nitrite concentrations in the brain and altered the brain metabolome. Fish were exposed to sodium nitrate (606.9 mg/L), sodium nitrite (19.5 mg/L), or control water for 2–4 weeks and free swim, startle response, and shuttle box assays were performed. Nitrate and nitrite treatment did not change fish weight, length, predator avoidance, or distance and velocity traveled in an unstressed environment. Nitrate- and nitrite-treated fish initially experienced more negative reinforcement and increased time to decision in the shuttle box assay, which is consistent with a decrease in associative learning or executive function however, over multiple trials, all treatment groups demonstrated behaviors associated with learning. Nitrate and nitrite treatment was associated with mild anxiogenic-like behavior but did not alter epinephrine, norepinephrine or dopamine levels. Targeted metabolomics analysis revealed no significant increase in brain nitrate or nitrite concentrations with treatment. Untargeted metabolomics analysis found 47 metabolites whose abundance was significantly altered in the brain with nitrate and nitrite treatment. Overall, the depletion in brain metabolites is plausibly associated with the regulation of neuronal activity including statistically significant reductions in the inhibitory neurotransmitter γ-aminobutyric acid (GABA; 18–19%), and its precursor, glutamine (17–22%). Nitrate treatment caused significant depletion in the brain concentration of fatty acids including linoleic acid (LA) by 50% and arachidonic acid (ARA) by 80%; nitrite treatment caused depletion of LA by ~90% and ARA by 60%, change which could alter the function of dopaminergic neurons and affect behavior. Nitrate and nitrite treatment did not adversely affect multiple parameters of zebrafish health. It is plausible that indirect NO-mediated mechanisms may be responsible for the nitrate and nitrite-mediated effects on the brain metabolome and behavior in zebrafish.

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“…More and larger studies are needed to delineate the potential benefits and risks associated with nitrate and/or nitrite treatment on CBF, mood, and cognitive function, particularly in populations of people with differing ages and underlying health status. Importantly, a study in humans is underway to look at the effect of increasing doses of nitrate on cognition-related outcomes 86 . We also cannot differentiate between the direct effects of nitrate or nitrite in the fish, or indirect effects that could be generated by increased NO availability.…”

Section: Discussionmentioning

confidence: 99%

Nitrate and nitrite exposure increases anxiety-like behavior and alters brain metabolomic profile in zebrafish

García-Jaramillo

Beaver

Truong

et al. 2020

Preprint

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IntroductionDietary nitrate lowers blood pressure and improves athletic performance in humans, yet data supporting observations that it may increase cerebral blood flow and improve cognitive performance are mixed. Here we tested the hypothesis that nitrate and nitrite treatment would improve indicators of learning and cognitive performance in a zebrafish (Danio rerio) model. We also explored the extent to which nitrate and nitrite treatment affected the brain metabolome in order to understand how nitrate and nitrite supplementation may affect indices of cognitive function.MethodsFish were exposed to sodium nitrate (606.9 mg/L), sodium nitrite (19.5 mg/L), or control water for 2-4 weeks and free swim, startle response, innate predator avoidance, social cohesion, and shuttle box assays were performed.ResultsNitrate and nitrite treatment did not change fish weight, length, predator avoidance, or distance and velocity traveled in an unstressed environment. Nitrate- and nitrite-treated fish initially experienced more negative reinforcement and increased time to decision in the shuttle box assay, which is consistent with a decrease in associative learning or executive function however, over multiple trials, all treatment groups demonstrated behaviors associated with learning. Nitrate and nitrite treatment significantly increased anxiety-like behavior but did not alter epinephrine, norepinephrine or dopamine levels. Targeted LC-MS/MS analysis revealed no significant increase in brain nitrate or nitrite concentrations with treatment. An untargeted metabolomics analysis found 47 metabolites whose abundance was significantly altered in the brain with nitrate and nitrite treatment including an 18-19% reduction in the neurotransmitter γ-aminobutyric acid (GABA), and 17-22% reduction in its precursor, glutamine, which may contribute to the increased anxiety-like behavior.ConclusionNitrate and nitrite treatment did not adversely affect multiple parameters of zebrafish health but was associated with mild anxiety-like behavior, changes in the brain metabolome, and caused a short-term decrease in executive function or associative learning.

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Protocol and recruitment results from a 13-week randomized controlled trial comparing the effects of different doses of nitrate-rich beetroot juice on cognition, cerebral blood flow and peripheral vascular function in overweight and obese older people

Cited by 10 publications

References 29 publications

Acceptability and Feasibility of a 13-Week Pilot Randomised Controlled Trial Testing the Effects of Incremental Doses of Beetroot Juice in Overweight and Obese Older Adults

Acceptability and Feasibility of a 13-Week Pilot Randomised Controlled Trial Testing the Effects of Incremental Doses of Beetroot Juice in Overweight and Obese Older Adults

Nitrate and nitrite exposure leads to mild anxiogenic-like behavior and alters brain metabolomic profile in zebrafish

Nitrate and nitrite exposure increases anxiety-like behavior and alters brain metabolomic profile in zebrafish

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