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

Abrar M Babateen, Oliver M Shannon, Gerard M O'Brien, Edward Okello, Ellen Smith, Dilara Olgacer, Christina Koehl, William Fostier, Emma Wightman, David Kennedy, John C Mathers, Mario Siervo, Abrar M Babateen, Oliver M Shannon, Gerard M O'Brien, Edward Okello, Ellen Smith, Dilara Olgacer, Christina Koehl, William Fostier, Emma Wightman, David Kennedy, John C Mathers, Mario Siervo

Abstract

Nitrate-rich food increases nitric oxide (NO) production and may have beneficial effects on vascular, metabolic, and brain function. This pilot study tested the effects of prolonged consumption of a range of doses of dietary nitrate (NO3-), provided as beetroot juice, on cognitive function and cerebral blood flow (CBF) in overweight and obese older participants. The study had a 13-week single-blind, randomised, parallel design, and 62 overweight and obese older participants (aged 60 to 75 years) received the following interventions: (1) high NO3- (2 × 70 mL beetroot juice/day) (2) medium NO3- (70 mL beetroot juice/day), (3) low NO3- (70 mL beetroot juice on alternate days), or (4) placebo (70 mL of NO3--depleted beetroot juice on alternate days). Cognitive functions were assessed using the Computerised Mental Performance Assessment System (COMPASS) assessment battery. CBF, monitored by concentration changes in oxygenated and deoxygenated haemoglobin, was assessed in the frontal cortex using near-infrared spectroscopy. The findings of this pilot study showed that cognitive function and CBF were not affected by supplementation with NO3--rich beetroot juice for 13 weeks, irrespective of the NO3- dose administered. These findings require confirmation in larger studies using more sophisticated imaging methods (i.e., MRI) to determine whether prolonged dietary NO3- supplementation influences brain function in older overweight people.

Keywords: beetroot juice; cerebral blood flow; cognition; inorganic nitrate; older adults.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cognitive task battery.
Figure 2
Figure 2
Protocol of the near-infrared spectroscopy (NIRS) assessment; 3S: serial subtraction 3, 7S: serial subtraction 7, P&B: peg and ball. * Stroop and peg and ball are not based on a fixed time, so the data were extracted based on the least time recorded by a participant.
Figure 3
Figure 3
Prolonged effect of incremental doses of supplemental NO3− in form of beetroot juice on cerebral oxygen saturation (A), total haemoglobin (B), oxyhaemoglobin (C), and deoxyhaemoglobin (D). HN, high nitrate; MN, medium nitrate; LN, low nitrate; PL, placebo. No significant differences between groups were found for any of the cerebral blood flow (CBF)-related parameters (p > 0.05). HN (high NO3−; two 70 mL shots of beetroot juice/day, morning and evening), MN (medium NO3−; 70 mL of beetroot juice/day), LN (low NO3−; 70 mL of beetroot juice every alternate days), and PL (placebo; 70 mL of NO3−-depleted beetroot juice every alternate days). Each shot of beetroot juice contains 400 mg of NO3−. Data represent the change of CBF parameters recorded when performing cognitive tasks at 13 weeks from the resting period at baseline and were analysed using a one-way ANOVA. Data are expressed as mean ± SEM, (n = 47).

References

    1. Deary I.J., Corley J., Gow A., Harris S.E., Houlihan L.M., Marioni R., Penke L., Rafnsson S.B., Starr J.M. Age-associated cognitive decline. Br. Med. Bull. 2009;92:135–152. doi: 10.1093/bmb/ldp033.
    1. Barzilai N., Huffman D.M., Muzumdar R.H., Bartke A. The critical role of metabolic pathways in aging. Diabetes. 2012;61:1315–1322. doi: 10.2337/db11-1300.
    1. Strait J.B., Lakatta E.G. Aging-associated cardiovascular changes and their relationship to heart failure. Heart Fail. Clin. 2012;8:143–164. doi: 10.1016/j.hfc.2011.08.011.
    1. Reitz C., Luchsinger A.J., Mayeux R. Vascular disease and cognitive impairment. Expert Rev. Neurother. 2008;8:1171–1174. doi: 10.1586/14737175.8.8.1171.
    1. Leeuwis A.E., Benedictus M.R., Kuijer J.P., Binnewijzend M.A., Hooghiemstra A.M., Verfaillie S.C., Koene T., Scheltens P., Barkhof F., Prins N.D., et al. Lower cerebral blood flow is associated with impairment in multiple cognitive domains in Alzheimer’s disease. Alzheimer’s Dement. 2017;13:531–540. doi: 10.1016/j.jalz.2016.08.013.
    1. Wolters F.J., de Bruijn R.F., Hofman A., Koudstaal P.J., Ikram M.A. Cerebral vasoreactivity, apolipoprotein E, and the risk of dementia: A population-based study. Arterioscler. Thromb. Vasc. Biol. 2016;36:204–210. doi: 10.1161/ATVBAHA.115.306768.
    1. Bangen K.J., Nation D.A., Clark L.R., Harmell A.L., Wierenga C.E., Dev S.I., Edelano-Wood L., Zlatar Z.Z., Salmon D.P., Liu T., et al. Interactive effects of vascular risk burden and advanced age on cerebral blood flow. Front. Aging Neurosci. 2014;6:159. doi: 10.3389/fnagi.2014.00159.
    1. Wolters F.J., Ikram M.A. Cerebral Perfusion and the Risk of Dementia: A Population-Based Study. Circulation. 2017;136:719–728. doi: 10.1161/CIRCULATIONAHA.117.027448.
    1. Mokhber N., Shariatzadeh A., Avan A., Saber H., Babaei G.S., Chaimowitz G., Azarpazhooh M.R. Cerebral blood flow changes during aging process and in cognitive disorders: A review. Neuroradiol. J. 2021;34:300–307. doi: 10.1177/19714009211002778.
    1. Ruitenberg A., den Heijer T., Bakker S.L., van Swieten J.C., Koudstaal P.J., Hofman A., Breteler M.M. Cerebral hypoperfusion and clinical onset of dementia: The Rotterdam Study. Ann. Neurol. Off. J. Am. Neurol. Assoc. Child Neurol. Soc. 2005;57:789–794. doi: 10.1002/ana.20493.
    1. Leeuwis A.E., Smith L.A., Melbourne A., Hughes A., Richards M., Prins N.D., Sokolska M., Atkinson D., Tillin T., Jäger H.R., et al. Cerebral blood flow and cognitive functioning in a community-based, multi-ethnic cohort: The SABRE Study. Front. Aging Neurosci. 2018;10:279. doi: 10.3389/fnagi.2018.00279.
    1. Picón-Pagès P., Garcia-Buendia J., Muñoz F.J. Functions and dysfunctions of nitric oxide in brain. Biochim. Biophys. Acta (BBA) Mol. Basis Dis. 2019;1865:1949–1967. doi: 10.1016/j.bbadis.2018.11.007.
    1. Weitzberg E., Lundberg J.O. Novel Aspects of Dietary Nitrate and Human Health. Annu. Rev. Nutr. 2013;33:129–159. doi: 10.1146/annurev-nutr-071812-161159.
    1. Venturelli M., Pedrinolla A., Boscolo Galazzo I., Fonte C., Smania N., Tamburin S., Muti E., Crispoltoni L., Stabile A., Pistilli A., et al. Impact of Nitric Oxide Bioavailability on the Progressive Cerebral and Peripheral Circulatory Impairments During Aging and Alzheimer’s Disease. Front. Physiol. 2018;9:169. doi: 10.3389/fphys.2018.00169.
    1. Torregrossa A.C., Aranke M., Bryan N.S. Nitric oxide and geriatrics: Implications in diagnostics and treatment of the elderly. J. Geriatr. Cardiol. JGC. 2011;8:230.
    1. Seals D.R., Jablonski K.L., Donato A.J. Aging and vascular endothelial function in humans. Clin. Sci. 2011;120:357–375. doi: 10.1042/CS20100476.
    1. Herrera M.D., Mingorance C., Rodriguez-Rodriguez R., Alvarez de Sotomayor M. Endothelial dysfunction and aging: An update. Ageing Res. Rev. 2010;9:142–152. doi: 10.1016/j.arr.2009.07.002.
    1. Van Der Loo B., Labugger R., Skepper J.N., Bachschmid M.M., Kilo J., Powell J.M., Palacios-Callender M., Erusalimsky J., Quaschning T., Malinski T., et al. Enhanced Peroxynitrite Formation Is Associated with Vascular Aging. J. Exp. Med. 2000;192:1731–1744. doi: 10.1084/jem.192.12.1731.
    1. Torreilles F., Salman-Tabcheh S., Guérin M.-C., Torreilles J. Neurodegenerative disorders: The role of peroxynitrite. Brain Res. Rev. 1999;30:153–163. doi: 10.1016/S0165-0173(99)00014-4.
    1. Gómez-Pinilla F. Brain foods: The effects of nutrients on brain function. Nat. Rev. Neurosci. 2008;9:568–578. doi: 10.1038/nrn2421.
    1. Adan R.A., van der Beek E.M., Buitelaar J.K., Cryan J.F., Hebebrand J., Higgs S., Schellekens H., Dickson S.L. Nutritional psychiatry: Towards improving mental health by what you eat. Eur. Neuropsychopharmacol. 2019;29:1321–1332. doi: 10.1016/j.euroneuro.2019.10.011.
    1. Siervo M., Scialò F., Shannon O.M., Stephan B.C., Ashor A.W. Does dietary nitrate say NO to cardiovascular ageing? Current evidence and implications for research. Proc. Nutr. Soc. 2018;77:112–123. doi: 10.1017/S0029665118000058.
    1. Samieri C., Perier M.-C., Gaye B., Proust-Lima C., Helmer C., Dartigues J.-F., Berr C., Tzourio C., Empana J.-P. Association of cardiovascular health level in older age with cognitive decline and incident dementia. JAMA. 2018;320:657–664. doi: 10.1001/jama.2018.11499.
    1. Joris P.J., Mensink R.P., Adam T.C., Liu T.T. Cerebral blood flow measurements in adults: A review on the effects of dietary factors and exercise. Nutrients. 2018;10:530. doi: 10.3390/nu10050530.
    1. Wightman E.L., Haskell-Ramsay C.F., Thompson K., Blackwell J.R., Winyard P., Forster J., Jones A.M., Kennedy D.O. Dietary nitrate modulates cerebral blood flow parameters and cognitive performance in humans: A double-blind, placebo-controlled, crossover investigation. Physiol. Behav. 2015;149:149–158.
    1. Presley T.D., Morgan A.R., Bechtold E., Clodfelter W., Dove R.W., Jennings J.M., Kraft R.A., King S.B., Laurienti P.J., Rejeski W.J., et al. Acute effect of a high nitrate diet on brain perfusion in older adults. Nitric Oxide. 2011;24:34–42.
    1. Clifford T., Babateen A., Shannon O.M., Capper T., Ashor A., Stephan B., Robinson L., O’Hara J.P., Mathers J.C., Stevenson E., et al. Effects of inorganic nitrate and nitrite consumption on cognitive function and cerebral blood flow: A systematic review and meta-analysis of randomised clinical trials. Crit. Rev. Food Sci. Nutr. 2019;59:2400–2410. doi: 10.1080/10408398.2018.1453779.
    1. Justice J.N., Johnson L.C., DeVan A., Cruickshank-Quinn C., Reisdorph N., Bassett C.J., Evans T.D., Brooks F.A., Bryan N.S., Chonchol M.B., et al. Improved motor and cognitive performance with sodium nitrite supplementation is related to small metabolite signatures: A pilot trial in middle-aged and older adults. Aging. 2015;7:1004. doi: 10.18632/aging.100842.
    1. Aliahmadi M., Amiri F., Bahrami L.S., Hosseini A.F., Abiri B., Vafa M. Effects of raw red beetroot consumption on metabolic markers and cognitive function in type 2 diabetes patients. J. Diabetes Metab. Disord. 2021;20:673–682. doi: 10.1007/s40200-021-00798-z.
    1. Williams I., Wheatcroft S., Shah A., Kearney M. Obesity, atherosclerosis and the vascular endothelium: Mechanisms of reduced nitric oxide bioavailability in obese humans. Int. J. Obes. 2002;26:754–764. doi: 10.1038/sj.ijo.0801995.
    1. Toda N., Okamura T. Obesity impairs vasodilatation and blood flow increase mediated by endothelial nitric oxide: An overview. J. Clin. Pharmacol. 2013;53:1228–1239. doi: 10.1002/jcph.179.
    1. Babateen A.M., Rubele S., Shannon O., Okello E., Smith E., McMahon N., O’Brien G., Wightman E., Kennedy D., Mathers J.C., et al. 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. Contemp. Clin. Trials Commun. 2020;18:100571. doi: 10.1016/j.conctc.2020.100571.
    1. Babateen A., Shannon O., O’Brien G., Okello E., Khan A., Rubele S., Wightman E., Smith E., McMahon N., Olgacer D., et al. 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. Nutrients. 2021;13:769. doi: 10.3390/nu13030769.
    1. Bescos R., Ashworth A., Cutler C., Brookes Z.L., Belfield L., Rodiles A., Casas-Agustench P., Farnham G., Liddle L., Burleigh M., et al. Effects of Chlorhexidine mouthwash on the oral microbiome. Sci. Rep. 2020;10:14336. doi: 10.1038/s41598-020-61912-4.
    1. Bell L., Lamport D.J., Field D.T., Butler L.T., Williams C.M. Practice effects in nutrition intervention studies with repeated cognitive testing. Nutr. Healthy Aging. 2018;4:309–322. doi: 10.3233/NHA-170038.
    1. Goldberg T.E., Harvey P.D., Wesnes K., Snyder P., Schneider L.S. Practice effects due to serial cognitive assessment: Implications for preclinical Alzheimer’s disease randomized controlled trials. Alzheimer’s Dement. Diagn. Assess. Dis. Monit. 2015;1:103–111. doi: 10.1016/j.dadm.2014.11.003.
    1. Haskell C.F., Robertson B., Jones E., Forster J., Jones R., Wilde A., Maggini S., Kennedy D.O. Effects of a multi-vitamin/mineral supplement on cognitive function and fatigue during extended multi-tasking. Hum. Psychopharmacol. Clin. Exp. 2010;25:448–461. doi: 10.1002/hup.1144.
    1. Kennedy D.O., Wightman E.L., Reay J.L., Lietz G., Okello E.J., Wilde A., Haskell C.F. Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: A double-blind, placebo-controlled, crossover investigation. Am. J. Clin. Nutr. 2010;91:1590–1597. doi: 10.3945/ajcn.2009.28641.
    1. Wightman E.L., Jackson P.A., Khan J., Forster J., Heiner F., Feistel B., Suarez C.G., Pischel I., Kennedy D.O. The Acute and Chronic Cognitive and Cerebral Blood Flow Effects of a Sideritis scardica (Greek Mountain Tea) Extract: A Double Blind, Randomized, Placebo Controlled, Parallel Groups Study in Healthy Humans. Nutrients. 2018;10:955. doi: 10.3390/nu10080955.
    1. Jackson P.A., Kennedy D.O. The application of near infrared spectroscopy in nutritional intervention studies. Front. Hum. Neurosci. 2013;7:473. doi: 10.3389/fnhum.2013.00473.
    1. Kazui H., Kitagaki H., Mori E. Cortical activation during retrieval of arithmetical facts and actual calculation: A functional magnetic resonance imaging study. Psychiatry Clin. Neurosci. 2000;54:479–485. doi: 10.1046/j.1440-1819.2000.00739.x.
    1. Grandjean J., D’Ostilio K., Phillips C., Balteau E., Degueldre C., Luxen A., Maquet P., Salmon E., Collette F. Modulation of brain activity during a Stroop inhibitory task by the kind of cognitive control required. PLoS ONE. 2012;7:e41513.
    1. Ruocco A.C., Rodrigo A.H., Lam J., Di Domenico S.I., Graves B., Ayaz H. A problem-solving task specialized for functional neuroimaging: Validation of the Scarborough adaptation of the Tower of London (S-TOL) using near-infrared spectroscopy. Front. Hum. Neurosci. 2014;8:185. doi: 10.3389/fnhum.2014.00185.
    1. Whitehead A.L., Julious S.A., Cooper C.L., Campbell M.J. Estimating the sample size for a pilot randomised trial to minimise the overall trial sample size for the external pilot and main trial for a continuous outcome variable. Stat. Methods Med. Res. 2016;25:1057–1073. doi: 10.1177/0962280215588241.
    1. Dormanns K., Brown R., David T. The role of nitric oxide in neurovascular coupling. J. Theor. Biol. 2016;394:1–17. doi: 10.1016/j.jtbi.2016.01.009.
    1. Toda N., Ayajiki K., Okamura T. Cerebral blood flow regulation by nitric oxide in neurological disorders. Can. J. Physiol. Pharmacol. 2009;87:581–594. doi: 10.1139/Y09-048.
    1. Bor-Seng-Shu E., Kita W.S., Figueiredo E.G., Paiva W., Fonoff E.T., Teixeira M.J., Panerai R.B. Cerebral hemodynamics: Concepts of clinical importance. Arq. Neuro-Psiquiatr. 2012;70:352–356. doi: 10.1590/S0004-282X2012000500010.
    1. Korte N., Nortley R., Attwell D. Cerebral blood flow decrease as an early pathological mechanism in Alzheimer’s disease. Acta Neuropathol. 2020;140:793–810.
    1. Bangen K.J., Werhane M.L., Weigand A.J., Edmonds E.C., Delano-Wood L., Thomas K., Nation D.A., Evangelista N.D., Clark A.L., Liu T.T., et al. Reduced regional cerebral blood flow relates to poorer cognition in older adults with type 2 diabetes. Front. Aging Neurosci. 2018;10:270. doi: 10.3389/fnagi.2018.00270.
    1. Kelly J., Fulford J., Vanhatalo A., Blackwell J.R., French O., Bailey S.J., Gilchrist M., Winyard P.G., Jones A.M. Effects of short-term dietary nitrate supplementation on blood pressure, O2 uptake kinetics, and muscle and cognitive function in older adults. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2013;304:R73–R83. doi: 10.1152/ajpregu.00406.2012.
    1. Taddei S., Virdis A., Ghiadoni L., Salvetti G., Bernini G., Magagna A., Salvetti A. Age-related reduction of NO availability and oxidative stress in humans. Hypertension. 2001;38:274–279. doi: 10.1161/01.HYP.38.2.274.
    1. Carlström M., Liu M., Yang T., Zollbrecht C., Huang L., Peleli M., Borniquel S., Kishikawa H., Hezel M., Persson A.E.G., et al. Cross-talk between nitrate-nitrite-NO and NO synthase pathways in control of vascular NO homeostasis. Antioxid. Redox Signal. 2015;23:295–306. doi: 10.1089/ars.2013.5481.
    1. Gilchrist M., Winyard P.G., Fulford J., Anning C., Shore A.C., Benjamin N. Dietary nitrate supplementation improves reaction time in type 2 diabetes: Development and application of a novel nitrate-depleted beetroot juice placebo. Nitric Oxide. 2015;40:67–74. doi: 10.1016/j.niox.2014.05.003.
    1. Hassing L.B., Dahl A.K., Pedersen N.L., Johansson B. Overweight in midlife is related to lower cognitive function 30 years later: A prospective study with longitudinal assessments. Dement. Geriatr. Cogn. Disord. 2010;29:543–552. doi: 10.1159/000314874.
    1. Elias M.F., Elias P.K., Sullivan L.M., Wolf P.A., D’Agostino R.B. Obesity, diabetes and cognitive deficit: The Framingham Heart Study. Neurobiol. Aging. 2005;26:11–16. doi: 10.1016/j.neurobiolaging.2005.08.019.
    1. Wightman E.L., Haskell-Ramsay C.F., Reay J.L., Williamson G., Dew T., Zhang W., Kennedy D.O. The effects of chronic trans-resveratrol supplementation on aspects of cognitive function, mood, sleep, health and cerebral blood flow in healthy, young humans. Br. J. Nutr. 2015;114:1427–1437. doi: 10.1017/S0007114515003037.

Source: PubMed

3
Subscribe