Chronic Consumption of Cranberries ( Vaccinium macrocarpon) for 12 Weeks Improves Episodic Memory and Regional Brain Perfusion in Healthy Older Adults: A Randomised, Placebo-Controlled, Parallel-Groups Feasibility Study

Emma Flanagan, Donnie Cameron, Rashed Sobhan, Chloe Wong, Matthew G Pontifex, Nicole Tosi, Pedro Mena, Daniele Del Rio, Saber Sami, Arjan Narbad, Michael Müller, Michael Hornberger, David Vauzour, Emma Flanagan, Donnie Cameron, Rashed Sobhan, Chloe Wong, Matthew G Pontifex, Nicole Tosi, Pedro Mena, Daniele Del Rio, Saber Sami, Arjan Narbad, Michael Müller, Michael Hornberger, David Vauzour

Abstract

Background: Ageing is highly associated with cognitive decline and modifiable risk factors such as diet are believed to protect against this process. Specific dietary components and in particular, (poly)phenol-rich fruits such as berries have been increasingly recognised for their protection against age-related neurodegeneration. However, the impact of cranberries on cognitive function and neural functioning in older adults remains unclear.

Design: A 12-week parallel randomised placebo-controlled trial of freeze-dried cranberry powder was conducted in 60 older adults aged between 50 and 80 years. Cognitive assessment, including memory and executive function, neuroimaging and blood sample collection were conducted before and after the intervention to assess the impact of daily cranberry consumption on cognition, brain function and biomarkers of neuronal signalling.

Results: Cranberry supplementation for 12 weeks was associated with improvements in visual episodic memory in aged participants when compared to placebo. Mechanisms of action may include increased regional perfusion in the right entorhinal cortex, the accumbens area and the caudate in the cranberry group. Significant decrease in low-density lipoprotein (LDL) cholesterol during the course of the intervention was also observed. No significant differences were, however, detected for BDNF levels between groups.

Conclusions: The results of this study indicate that daily cranberry supplementation (equivalent to 1 small cup of cranberries) over a 12-week period improves episodic memory performance and neural functioning, providing a basis for future investigations to determine efficacy in the context of neurological disease. This trial was registered at clinicaltrials.gov as NCT03679533 and at ISRCTN as ISRCTN76069316.

Keywords: BDNF; LDL-cholesterol; MRI; arterial spin labelling (ASL); brain; cerebral blood flow (CBF); cognition; flavonoids.

Conflict of interest statement

DV, MH, MM, and AN received funding from the Cranberry Institute. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Flanagan, Cameron, Sobhan, Wong, Pontifex, Tosi, Mena, Del Rio, Sami, Narbad, Müller, Hornberger and Vauzour.

Figures

FIGURE 1
FIGURE 1
Consolidated standards of reporting trials (CONSORT) flowchart diagram. ASL, arterial spin labelling; MRI, magnetic resonance imaging; VBM, voxel-based morphometry.
FIGURE 2
FIGURE 2
Representative magnetic resonance imaging data following 12-week consumption of a cranberry extract or a placebo. (A) Axial view of FastSurfer cortical and subcortical segmentations superimposed on a T1-weighted image; (B) axial T2-weighted fluid attenuated inversion recovery (FLAIR) image; (C) a coronal view of the T1-weighted image indicating regions that showed significantly increased perfusion after 12 weeks consumption of a cranberry extract—namely, from superior to inferior, the right caudate nucleus, accumbens area, and entorhinal cortex; (D) an axial cerebral blood flow (CBF) map, in the T1 space, derived from arterial spin labelling data; (E)t-value maps overlaid on a standard brain show trends to increased perfusion in the cranberry group as compared to the placebo group, in similar regions to those indicated in the ROI-wise analyses; and (F) differences in mean blood perfusion for the right caudate nucleus (rCN), right nucleus accumbens (rNAc), and right entorhinal cortex (rEC), with p-values represented for group × time interaction effects between cranberry and placebo groups from baseline to follow-up.

References

    1. Bloom DE, Boersch-Supan A, McGee P, Seike A. Population aging: facts, challenges, and responses. Benefits Compens Int. (2011) 41:22.
    1. Alzheimer’s Disease International. World Alzheimer Report 2019: Attitudes to Dementia. London: Alzheimer’s Disease International; (2019).
    1. Long JM, Holtzman DM. Alzheimer disease: an update on pathobiology and treatment strategies. Cell. (2019) 179:312–39. 10.1016/j.cell.2019.09.001
    1. Miquel S, Champ C, Day J, Aarts E, Bahr BA, Bakker M, et al. Poor cognitive ageing: vulnerabilities, mechanisms and the impact of nutritional interventions. Ageing Res Rev. (2018) 42:40–55. 10.1016/j.arr.2017.12.004
    1. Vauzour D, Camprubi-Robles M, Miquel-Kergoat S, Andres-Lacueva C, Bánáti D, Barberger-Gateau P, et al. Nutrition for the ageing brain: towards evidence for an optimal diet. Ageing Res Rev. (2017) 35:222–40. 10.1016/j.arr.2016.09.010
    1. Devore EE, Kang JH, Breteler MM, Grodstein F. Dietary intakes of berries and flavonoids in relation to cognitive decline. Ann Neurol. (2012) 72:135–43. 10.1002/ana.23594
    1. Letenneur L, Proust-Lima C, Le Gouge A, Dartigues J, Barberger-Gateau P. Flavonoid Intake and Cognitive Decline over a 10-Year Period. Am J Epidemiol. (2007) 165:1364–71. 10.1093/aje/kwm036
    1. Shishtar E, Rogers GT, Blumberg JB, Au R, Jacques PF. Long-term dietary flavonoid intake and change in cognitive function in the Framingham Offspring cohort. Public Health Nutrit. (2020) 23:1576–88. 10.1017/s136898001900394x
    1. Lefèvre-Arbogast S, Gaudout D, Bensalem J, Letenneur L, Dartigues J-F, Hejblum BP, et al. Pattern of polyphenol intake and the long-term risk of dementia in older persons. Neurology. (2018) 90:e1979–88. 10.1212/wnl.0000000000005607
    1. Bell L, Williams CM. Blueberry benefits to cognitive function across the lifespan. Int J Food Sci Nutr. (2021) 72:650–2. 10.1080/09637486.2020.1852192
    1. Jennings A, Steves CJ, Macgregor A, Spector T, Cassidy A. Increased habitual flavonoid intake predicts attenuation of cognitive ageing in twins. BMC Med. (2021) 19:185. 10.1186/s12916-021-02057-7
    1. Ahles S, Joris PJ, Plat J. Effects of berry anthocyanins on cognitive performance, vascular function and cardiometabolic risk markers: a systematic review of randomized placebo-controlled intervention studies in humans. Int J Mol Sci. (2021) 22:6482. 10.3390/ijms22126482
    1. Travica N, D’Cunha NM, Naumovski N, Kent K, Mellor DD, Firth J, et al. The effect of blueberry interventions on cognitive performance and mood: a systematic review of randomized controlled trials. Brain Behav Immun. (2020) 85:96–105. 10.1016/j.bbi.2019.04.001
    1. Gutierres JM, Carvalho FB, Schetinger MR, Marisco P, Agostinho P, Rodrigues M, et al. Anthocyanins restore behavioral and biochemical changes caused by streptozotocin-induced sporadic dementia of Alzheimer’s type. Life Sci. (2014) 96:7–17. 10.1016/j.lfs.2013.11.014
    1. Meireles M, Marques C, Norberto S, Fernandes I, Mateus N, Rendeiro C, et al. The impact of chronic blackberry intake on the neuroinflammatory status of rats fed a standard or high-fat diet. J Nutr Biochem. (2015) 26:1166–73. 10.1016/j.jnutbio.2015.05.008
    1. Zhang Y, Meng Q, Yin J, Zhang Z, Bao H, Wang X. Anthocyanins attenuate neuroinflammation through the suppression of MLK3 activation in a mouse model of perioperative neurocognitive disorders. Brain Res. (2020) 1726:146504. 10.1016/j.brainres.2019.146504
    1. Rendeiro C, Vauzour D, Kean RJ, Butler LT, Rattray M, Spencer JP, et al. Blueberry supplementation induces spatial memory improvements and region-specific regulation of hippocampal BDNF mRNA expression in young rats. Psychopharmacology. (2012) 223:319–30. 10.1007/s00213-012-2719-8
    1. Williams CM, El Mohsen MA, Vauzour D, Rendeiro C, Butler LT, Ellis JA, et al. Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free Radic Biol Med. (2008) 45:295–305. 10.1016/j.freeradbiomed.2008.04.008
    1. Vauzour D, Rendeiro C, D’Amato A, Waffo-Téguo P, Richard T, Mérillon JM, et al. Anthocyanins promote learning through modulation of synaptic plasticity related proteins in an animal model of ageing. Antioxidants. (2021) 10:10081235. 10.3390/antiox10081235
    1. Krikorian R, Shidler MD, Nash TA, Kalt W, Vinqvist-Tymchuk MR, Shukitt-Hale B, et al. Blueberry supplementation improves memory in older adults. J Agric Food Chem. (2010) 58:3996–4000. 10.1021/jf9029332
    1. Lamport DJ, Lawton CL, Merat N, Jamson H, Myrissa K, Hofman D, et al. Concord grape juice, cognitive function, and driving performance: a 12-wk, placebo-controlled, randomized crossover trial in mothers of preteen children. Am J Clin Nutr. (2016) 103:775–83. 10.3945/ajcn.115.114553
    1. Boespflug EL, Eliassen JC, Dudley JA, Shidler MD, Kalt W, Summer SS, et al. Enhanced neural activation with blueberry supplementation in mild cognitive impairment. Nutr Neurosci. (2018) 21:297–305. 10.1080/1028415x.2017.1287833
    1. Whyte AR, Rahman S, Bell L, Edirisinghe I, Krikorian R, Williams CM, et al. Improved metabolic function and cognitive performance in middle-aged adults following a single dose of wild blueberry. Eur J Nutr. (2021) 60:1521–36. 10.1007/s00394-020-02336-8
    1. Lee J, Torosyan N, Silverman DH. Examining the impact of grape consumption on brain metabolism and cognitive function in patients with mild decline in cognition: a double-blinded placebo controlled pilot study. Exp Gerontol. (2017) 87:121–8. 10.1016/j.exger.2016.10.004
    1. Vauzour D. Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects. Oxidat Med Cell Longev. (2012) 2012:1–16. 10.1155/2012/914273
    1. Seymour EM, Tanone II, Urcuyo-Llanes DE, Lewis SK, Kirakosyan A, Kondoleon MG, et al. Blueberry intake alters skeletal muscle and adipose tissue peroxisome proliferator-activated receptor activity and reduces insulin resistance in Obese Rats. J Med Food. (2011) 14:1511–8. 10.1089/jmf.2010.0292
    1. Stull AJ, Cash KC, Johnson WD, Champagne CM, Cefalu WT. Bioactives in blueberries improve insulin sensitivity in obese, insulin-resistant men and women. J Nutrit. (2010) 140:1764–8. 10.3945/jn.110.125336
    1. Kumar Singh A, Cabral C, Kumar R, Ganguly R, Kumar Rana H, Gupta A, et al. Beneficial effects of dietary polyphenols on gut microbiota and strategies to improve delivery efficiency. Nutrients. (2019) 11:11092216. 10.3390/nu11092216
    1. Rodríguez-Daza MC, Pulido-Mateos EC, Lupien-Meilleur J, Guyonnet D, Desjardins Y, Roy D. Polyphenol-mediated gut microbiota modulation: toward prebiotics and further. Front Nutrit. (2021) 8:689456. 10.3389/fnut.2021.689456
    1. Crispi S, Filosa S, Di Meo F. Polyphenols-gut microbiota interplay and brain neuromodulation. Neural Regenerat Res. (2018) 13:241429. 10.4103/1673-5374.241429
    1. Bowtell JL, Aboo-Bakkar Z, Conway ME, Adlam AR, Fulford J. Enhanced task-related brain activation and resting perfusion in healthy older adults after chronic blueberry supplementation. Appl Physiol Nutr Metab. (2017) 42:773–9. 10.1139/apnm-2016-0550
    1. Lamport DJ, Pal D, Moutsiana C, Field DT, Williams CM, Spencer JP, et al. The effect of flavanol-rich cocoa on cerebral perfusion in healthy older adults during conscious resting state: a placebo controlled, crossover, acute trial. Psychopharmacology. (2015) 232:3227–34. 10.1007/s00213-015-3972-4
    1. Haskell-Ramsay C, Schmitt J, Actis-Goretta L. The impact of epicatechin on human cognition: the role of cerebral blood Flow. Nutrients. (2018) 10:10080986. 10.3390/nu10080986
    1. Brickman AM, Khan UA, Provenzano FA, Yeung L-K, Suzuki W, Schroeter H, et al. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat Neurosci. (2014) 17:1798–803. 10.1038/nn.3850
    1. Zhao S, Liu H, Gu L. American cranberries and health benefits – an evolving story of 25 years. J Sci Food Agricult. (2018) 100:5111–6. 10.1002/jsfa.8882
    1. Bariexca T, Ezdebski J, Redan BW, Vinson J. Pure polyphenols and cranberry juice high in anthocyanins increase antioxidant capacity in animal organs. Foods. (2019) 8:8080340. 10.3390/foods8080340
    1. Shukitt-Hale B, Galli RL, Meterko V, Carey A, Bielinski DF, McGhie T, et al. Dietary supplementation with fruit polyphenolics ameliorates age-related deficits in behavior and neuronal markers of inflammation and oxidative stress. Age. (2005) 27:49–57. 10.1007/s11357-005-4004-9
    1. Basu A, Betts NM, Ortiz J, Simmons B, Wu M, Lyons TJ. Low-energy cranberry juice decreases lipid oxidation and increases plasma antioxidant capacity in women with metabolic syndrome. Nutrit Res. (2011) 31:190–6. 10.1016/j.nutres.2011.02.003
    1. Pourmasoumi M, Hadi A, Najafgholizadeh A, Joukar F, Mansour-Ghanaei F. The effects of cranberry on cardiovascular metabolic risk factors: a systematic review and meta-analysis. Clin Nutrit. (2020) 39:774–88. 10.1016/j.clnu.2019.04.003
    1. Rodriguez-Mateos A, Feliciano RP, Boeres A, Weber T, dos Santos CN, Ventura MR, et al. Cranberry (poly)phenol metabolites correlate with improvements in vascular function: a double-blind, randomized, controlled, dose-response, crossover study. Mol Nutrit Food Res. (2016) 60:2130–40. 10.1002/mnfr.201600250
    1. Crews WD, Harrison DW, Griffin ML, Addison K, Yount AM, Giovenco MA, et al. A double-blinded, placebo-controlled, randomized trial of the neuropsychologic efficacy of cranberry juice in a sample of cognitively intact older adults: pilot study findings. J Alternat Complement Med. (2005) 11:305–9. 10.1089/acm.2005.11.305
    1. Rattanabannakit C, Risacher SL, Gao S, Lane KA, Brown SA, McDonald BC, et al. The cognitive change index as a measure of self and informant perception of cognitive decline: relation to neuropsychological tests. J Alzheimer’s Dis. (2016) 51:1145–55. 10.3233/jad-150729
    1. Irvine MA, Scholey A, King R, Gillings R, Vauzour D, Demichele SJ, et al. The cognitive ageing, nutrition and neurogenesis (CANN) trial: design and progress. Alzheimers Dement. (2018) 4:591–601. 10.1016/j.trci.2018.08.001
    1. Rodriguez-Mateos A, Vauzour D, Krueger CG, Shanmuganayagam D, Reed J, Calani L, et al. Bioavailability, bioactivity and impact on health of dietary flavonoids and related compounds: an update. Arch Toxicol. (2014) 88:1803–53. 10.1007/s00204-014-1330-7
    1. Hollis JL, Craig LC, Whybrow S, Clark H, Kyle JA, McNeill G. Assessing the relative validity of the Scottish Collaborative Group FFQ for measuring dietary intake in adults. Public Health Nutr. (2017) 20:449–55. 10.1017/S1368980016002421
    1. Hsieh S, Schubert S, Hoon C, Mioshi E, Hodges JR. Validation of the addenbrooke’s cognitive examination III in frontotemporal dementia and Alzheimer’s disease. Dement Geriatr Cogn Disord. (2013) 36:242–50. 10.1159/000351671
    1. Reitan RM. Trail Making Test: Manual for Administration and Scoring. Reitan: Neuropsychology Laboratory; (1992).
    1. Tombaugh T. Trail Making Test A and B: normative data stratified by age and education. Arch Clin Neuropsychol. (2004) 19:203–14. 10.1016/s0887-6177(03)00039-8
    1. Meyers JE, Meyers KR. Rey Complex Figure Test and Recognition trial Professional Manual. Lutz, FL: Psychological Assessment Resources; (1995).
    1. Tu S, Wong S, Hodges JR, Irish M, Piguet O, Hornberger M. Lost in spatial translation - A novel tool to objectively assess spatial disorientation in Alzheimer’s disease and frontotemporal dementia. Cortex. (2015) 67:83–94. 10.1016/j.cortex.2015.03.016
    1. Zhang N, Gordon ML, Goldberg TE. Cerebral blood flow measured by arterial spin labeling MRI at resting state in normal aging and Alzheimer’s disease. Neurosci Biobehav Rev. (2017) 72:168–75. 10.1016/j.neubiorev.2016.11.023
    1. Sierra-Marcos A. Regional cerebral blood flow in mild cognitive impairment and Alzheimer’s Disease measured with arterial spin labeling magnetic resonance imaging. Int J Alzheimer’s Dis. (2017) 2017:1–10. 10.1155/2017/5479597
    1. Good CD, Johnsrude IS, Ashburner J, Henson RNA, Friston KJ, Frackowiak RSJ. A voxel-based morphometric study of ageing in 465 normal adult human brains. NeuroImage. (2001) 14:21–36. 10.1006/nimg.2001.0786
    1. Fazekas F, Chawluk JB, Alavi A, Hurtig HI, Zimmerman RA. MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. Am J Roentgenol. (1987) 149:351–6.
    1. Henschel L, Conjeti S, Estrada S, Diers K, Fischl B, Reuter M. FastSurfer - A fast and accurate deep learning based neuroimaging pipeline. NeuroImage. (2020) 219:117012. 10.1016/j.neuroimage.2020.117012
    1. Feliciano R, Mills C, Istas G, Heiss C, Rodriguez-Mateos A. Absorption, metabolism and excretion of cranberry (Poly)phenols in humans: a dose response study and assessment of inter-individual variability. Nutrients. (2017) 9:9030268. 10.3390/nu9030268
    1. Feliciano RP, Mecha E, Bronze MR, Rodriguez-Mateos A. Development and validation of a high-throughput micro solid-phase extraction method coupled with ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry for rapid identification and quantification of phenolic metabolites in human plasma and urine. J Chromatogr A. (2016) 1464:21–31. 10.1016/j.chroma.2016.08.027
    1. de Jager CA, Dye L, de Bruin EA, Butler L, Fletcher J, Lamport DJ, et al. Criteria for validation and selection of cognitive tests for investigating the effects of foods and nutrients. Nutrit Rev. (2014) 72:162–79. 10.1111/nure.12094
    1. Spencer JPE. The impact of flavonoids on memory: physiological and molecular considerations. Chem Soc Rev. (2009) 38:b800422f. 10.1039/b800422f
    1. Naiberg MR, Newton DF, Goldstein BI. Flow-mediated dilation and neurocognition: systematic review and future directions. Psychosom Med. (2016) 78:192–207. 10.1097/PSY.0000000000000266
    1. Foster TC. Biological markers of age-related memory deficits: treatment of senescent physiology. CNS Drugs. (2006) 20:153–66. 10.2165/00023210-200620020-00006
    1. Neshatdoust S, Saunders C, Castle SM, Vauzour D, Williams C, Butler L, et al. High-flavonoid intake induces cognitive improvements linked to changes in serum brain-derived neurotrophic factor: two randomised, controlled trials. Nutrit Healthy Aging. (2016) 4:81–93. 10.3233/nha-1615
    1. Lee IT, Chan YC, Lin CW, Lee WJ, Sheu WH. Effect of cranberry extracts on lipid profiles in subjects with Type 2 diabetes. Diabet Med. (2008) 25:1473–7. 10.1111/j.1464-5491.2008.02588.x
    1. Jiang H, Zhang W, Li X, Xu Y, Cao J, Jiang W. The anti-obesogenic effects of dietary berry fruits: a review. Food Res Int. (2021) 147:110539. 10.1016/j.foodres.2021.110539
    1. Mansoorian B, Combet E, Alkhaldy A, Garcia AL, Edwards CA. Impact of fermentable fibres on the colonic microbiota metabolism of dietary polyphenols rutin and quercetin. Int J Environ Res Public Health. (2019) 16:292. 10.3390/ijerph16020292
    1. Flanagan E, Muller M, Hornberger M, Vauzour D. Impact of flavonoids on cellular and molecular mechanisms underlying age-related cognitive decline and neurodegeneration. Curr Nutr Rep. (2018) 7:49–57. 10.1007/s13668-018-0226-1
    1. Lim SL, Rodriguez-Ortiz CJ, Kitazawa M. Infection, systemic inflammation, and Alzheimer’s disease. Microbes Infect. (2015) 17:549–56. 10.1016/j.micinf.2015.04.004
    1. Selby-Pham SNB, Miller RB, Howell K, Dunshea F, Bennett LE. Physicochemical properties of dietary phytochemicals can predict their passive absorption in the human small intestine. Sci Rep. (2017) 7:1888–w. 10.1038/s41598-017-01888-w

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