The Combined Effect of Dietary Nitrate and Caloric Restriction on Cognitive and Vascular Function. (CRNitrateMRI)

Testing the Combined Effect of Dietary Nitrate and Caloric Restriction on Cognitive and Vascular Function in Older Adults Living With Overweight or Obesity: A 28-Day Pilot Randomised Trial

This pilot study will compare the effect of combining dietary nitrate and caloric restriction versus dietary nitrate alone. The participant will be contacted, having responded to an advertisement on social media and posters, to attend the screening visit. They will be asked about their health status, suitability for MRI and availability. The investigators will use physical activity and eating attitude questionnaires. The investigators will also measure their height, weight, body mass index (BMI), and blood pressure (BP) and undertake blood tests. If they are eligible, they will be randomised to one of the two arms. The first group will consume nitrate-rich beetroot juice with a calorie-restricted diet for 28 days. The second group will drink the same juice with a weight-maintenance diet for the same period. The food and drinks will be provided. The outcome measures will be measured twice (at the baseline and end visits) to evaluate the change. The primary outcome is the cognitive function. The secondary outcomes are peripheral vascular health (BP and microvascular perfusion), cerebral vascular health (brain blood flow), anthropometry, body composition, and exhaled NO and nitrate concentrations. Also, the feasibility and accessibility of the study will be assessed.

Study Overview

• Status: Not yet recruiting
• Conditions: Healthy; Overweight and Obesity; Older Adults
• Intervention / Treatment: Other: Nitrate-rich beetroot juice plus calorie-restricted diet; Other: Nitrate-rich beetroot juice plus weight-maintenance diet

Detailed Description

Twenty healthy males and females, aged 60-70 years, non-smokers, and living with overweight or obesity (BMI 25-40 kg/m2) will be recruited to a 28-day pilot, randomised, parallel trial to follow one of the interventions (dietary nitrate with calorie-restricted diet or dietary nitrate with weight-maintenance diet) if they are eligible. Their energy requirement will be calculated using the Mifflin-St Jeor Equation, and the participant will be instructed to follow a healthy diet ( pre-diet standardisation) for three days before the intervention to minimise the effect of the sudden change of their habitual diet (during which their energy requirement will be met). At the Baseline Visit (Day 0), they will be randomised to one of the two arms, and the outcome measurements will be taken. Cognitive function will be measured via a pen-and-paper test (TMT) and a cognitive battery of tests (COMPASS). Clinic and home resting blood pressure (BP) will be measured using an automated BP monitor. Microvascular perfusion will be measured by a Laser Doppler monitor. Cerebral blood flow will be measured using a brain MRI scan. Height, weight, BMI, skinfold thickness, and waist circumference will be measured via a wall-mounted stadiometer, calibrated scale, BMI equation, calipers, and a tape measure, respectively. Body composition will be measured by a bioelectrical impedance analysis (BIA). Exhaled NO will be measured using a fractional exhaled nitric oxide analyser (FeNO). Blood samples will be taken to measure plasma nitrate concentrations. Physical activity will be monitored through a wearable smartwatch with an integrated accelerometer. The participants will be provided with 14 bottles of nitrate-rich beetroot juice (70 ml, which provides 6.5mmol of nitrate/day) with their allocated diet to be consumed in the next 14 days, starting from the next day (Day 1), and the remaining 14 days' supply will be delivered on Day 13. There will be an energy deficit of 1,000 kcal/day if they are allocated to the caloric restriction group. Otherwise, the energy requirement will be met. After completing the 28-day intervention, the participant will attend the End Visit (Day 29), to repeat the same study measurements they have done in the Baseline Visit. An exit feedback questionnaire will be given to collect information on the acceptability and compliance with the measurement protocols and intervention.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Moira A Taylor, PhD RD; Phone Number: +44 (0)115 823 0141; Email: Moira.Taylor@nottingham.ac.uk
• Study Contact Backup: Name: Mushari Alharbi, MBBS, MSc; Phone Number: +44 (0)115 823 0141; Email: Mushari.Alharbi@nottingham.ac.uk

Study Locations

• United Kingdom
  • Nottinghamshire
    • Nottingham, Nottinghamshire, United Kingdom, NG7 2RD
      • The University of Nottingham
      • Contact: Moira A Taylor, PhD RD; Phone Number: +44 (0)115 823 0141; Email: Moira.Taylor@nottingham.ac.uk
      • Contact: Mushari Alharbi, MBBS, MSc; Phone Number: +44 (0)115 823 0141; Email: Mushari.Alharbi@nottingham.ac.uk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Participant is able to give written informed consent for their participation in the study.
• Healthy.
• Non-smoking adults.
• Male or female.
• Aged 60 to 75 years.
• BMI between 25 and 40 kg/m2.

Exclusion Criteria:

• Systolic BP > 180mmHg and/or diastolic BP >110mmHg at the Clinic Screening Visit.
• Contraindication for MRI.
• Does not have adequate understanding of verbal and written information in English, sufficient to complete an MRI safety screening and to give informed consent.
• Any existing or previous medical condition that may affect the study outcomes (i.e., diabetes, kidney dysfunction, malignant cancer, brain surgery, stroke).
• Any medical treatment that may affect the study outcomes (i.e., diuretics, anti-acids, organic nitrates, anti-pyschotics or neuro-stimulants).
• Evidence of an eating disorder as indicated by the Three-factor eating questionnaire (Eating Attitudes Tests-26).
• Blood donation within the last 3 months of the anticipated intervention beginnings.
• Having taken part in a research study in the last 3 months involving invasive procedures or an inconvenience allowance.
• High-alcohol consumers (≥ 14 units/week for females, and ≥ 22 units/week for males).
• Vegetarianism (likely to have very high nitrate intake and food provided during the dietary intervention unsuitable).
• Weight change over 3.0kg in the last 2 months (important influence on vascular function).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dietary nitrate plus caloric restriction; Participants will drink beetroot juice with a calorie-restricted diet for 28 days.	Other: Nitrate-rich beetroot juice plus calorie-restricted diet; One daily bottle (70ml) of nitrate-rich beetroot juice with a calorie-restricted diet (1,000kcal deficit).
Active Comparator: Dietary nitrate alone; Participants will drink beetroot juice with a weight-maintenance diet for 28 days.	Other: Nitrate-rich beetroot juice plus weight-maintenance diet; One daily bottle (70ml) of nitrate-rich beetroot juice with a weight-maintenance diet (energy will be met).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cognitive function (TMT-B)	Change in cognitive function from the baseline after 28 days intervention using a pen-and-paper cognitive test (TMT-B) compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite score of cognitive function	Change in the composite score of cognitive function from the baseline after 28 days intervention using a computerised cognitive battery (COMPASS) compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Cognitive function individual tasks (alphabetic working memory)	Change in the cognitive function of individual task (alphabetic working memory) from the baseline after 28 days of intervention using a computerised cognitive battery (COMPASS) compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Cognitive function individual task (serial subtraction)	Change in the cognitive function of individual task (serial subtraction) from the baseline after 28 days of intervention using a computerised cognitive battery (COMPASS) compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Cognitive function individual task (stroop)	Change in the cognitive function of individual task (stroop) from the baseline after 28 days of intervention using a computerised cognitive battery (COMPASS) compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Cognitive function individual task (peg and ball)	Change in the cognitive function of individual task (peg and ball) from the baseline after 28 days of intervention using a computerised cognitive battery (COMPASS) compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Cognitive function individual task (simple reaction time)	Change in the cognitive function of individual task (simple reaction time) from the baseline after 28 days of intervention using a computerised cognitive battery (COMPASS) compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Cognitive function (TMT-A)	Change in cognitive function from the baseline after 28 days intervention using a pen-and-paper cognitive test (TMT-A) compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Clinic blood pressure for systolic and diastolic pressure	Change in clinic blood pressure (systolic and diastolic pressure) from the baseline after 28 days intervention using automated blood pressure device compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Continuous home blood pressure for systolic and diastolic pressure	Changes in home blood pressure (systolic and diastolic pressure) from the first day of the intervention until last day using an automated blood pressure device compared to the comparator.	Every three days starting from Day 1 until Day 28 of the intervention.
Microvascular perfusion	Change in microvascular perfusion from the baseline after 28 days intervention using a Laser Doppler monitor compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Cerebral blood flow	Change in cerebral blood flow from the baseline after 28 days intervention using a brain MRI scan compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Anthropometry (weight)	Change in weight in kilograms from the baseline after 28 days intervention using a calibrated scale compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Anthropometry (BMI)	Change in BMI in kg/m^2 from the baseline after 28 days intervention using the BMI equation (weight and height will be combined to report BMI in kg/m^2) compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Anthropometry (skinfold thickness)	Change in skinfold thickness in millimetre from the baseline after 28 days intervention using a skinfold calipers, compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Anthropometry (waist circumference)	Change in waist circumference from the baseline after 28 days intervention using a tape measure compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Body composition (fat mass)	Change in body composition (fat mass in kg) from the baseline after 28 days intervention using a bioelectrical impedance analysis (BIA) compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Body composition (fat-free mass)	Change in body composition (fat-free mass in kg) from the baseline after 28 days intervention using a bioelectrical impedance analysis (BIA) compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Exhaled nitric oxide	Change in nitric oxide from the baseline after 28 days intervention using a fractional exhaled nitric oxide analyser (FeNO) compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Nitrate concentrations	Change in plasma nitrate concentrations from the baseline after 28 days intervention using an Ozone-based chemiluminescence compared to the comparator.	Baseline Visit (Day 0)-one day before intervention, and End Visit (Day 29)-one day after intervention.
Feasibility and accessibility	A paper exit feedback questionnaire will be administered at the end of the study to collect information on the acceptability and compliance with the measurement protocols and intervention.	End Visit (Day 29).

Collaborators and Investigators

• Sponsor: Moira Taylor
• Collaborators: King Abdulaziz University
• Investigators: Principal Investigator: Moira A Taylor, PhD RD, University of Nottingham

Publications and helpful links

General Publications

• Alharbi M, Stephan BC, Shannon OM, Siervo M. Does dietary nitrate boost the effects of caloric restriction on brain health? Potential physiological mechanisms and implications for future research. Nutr Metab (Lond). 2023 Oct 25;20(1):45. doi: 10.1186/s12986-023-00766-9.
• Alharbi M, Chiurazzi M, Nasti G, Muscariello E, Mastantuono T, Koechl C, Stephan BC, Shannon OM, Colantuoni A, Siervo M. Caloric Restriction (CR) Plus High-Nitrate Beetroot Juice Does Not Amplify CR-Induced Metabolic Adaptation and Improves Vascular and Cognitive Functions in Overweight Adults: A 14-Day Pilot Randomised Trial. Nutrients. 2023 Feb 10;15(4):890. doi: 10.3390/nu15040890.
• Babateen AM, Shannon OM, O'Brien GM, Olgacer D, Koehl C, Fostier W, Mathers JC, Siervo M. Moderate doses of dietary nitrate elicit greater effects on blood pressure and endothelial function than a high dose: A 13-week pilot study. Nutr Metab Cardiovasc Dis. 2023 Jun;33(6):1263-1267. doi: 10.1016/j.numecd.2023.02.024. Epub 2023 Mar 2.
• Shannon OM, Gregory S, Siervo M. Dietary nitrate, aging and brain health: the latest evidence. Curr Opin Clin Nutr Metab Care. 2022 Nov 1;25(6):393-400. doi: 10.1097/MCO.0000000000000866. Epub 2022 Aug 9.
• Siervo M, Babateen A, Alharbi M, Stephan B, Shannon O. Dietary nitrate and brain health. Too much ado about nothing or a solution for dementia prevention? Br J Nutr. 2022 Sep 28;128(6):1130-1136. doi: 10.1017/S0007114522002434.
• Babateen AM, Shannon OM, O'Brien GM, Okello E, Smith E, Olgacer D, Koehl C, Fostier W, Wightman E, Kennedy D, Mathers JC, Siervo M. Incremental Doses of Nitrate-Rich Beetroot Juice Do Not Modify Cognitive Function and Cerebral Blood Flow in Overweight and Obese Older Adults: A 13-Week Pilot Randomised Clinical Trial. Nutrients. 2022 Mar 2;14(5):1052. doi: 10.3390/nu14051052.
• Siervo M, Arnold R, Wells JC, Tagliabue A, Colantuoni A, Albanese E, Brayne C, Stephan BC. Intentional weight loss in overweight and obese individuals and cognitive function: a systematic review and meta-analysis. Obes Rev. 2011 Nov;12(11):968-83. doi: 10.1111/j.1467-789X.2011.00903.x. Epub 2011 Jul 18.

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2024
• Primary Completion (Estimated): August 31, 2024
• Study Completion (Estimated): August 31, 2024

Study Registration Dates

• First Submitted: November 6, 2023
• First Submitted That Met QC Criteria: November 27, 2023
• First Posted (Actual): November 30, 2023

Study Record Updates

• Last Update Posted (Actual): November 30, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Body Weight; Obesity; Overweight
• Other Study ID Numbers: 323-0723

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Only anonymised individual personal data will be shared, upon specific request from other researchers, for example, in order to undertake a meta analysis.
• IPD Sharing Time Frame: When requested.
• IPD Sharing Access Criteria: On receipt of requests, data will be made accessible if agreed by the University of Nottingham.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No