The effect of a high-polyphenol Mediterranean diet (Green-MED) combined with physical activity on age-related brain atrophy: the Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study (DIRECT PLUS)

Alon Kaplan, Hila Zelicha, Anat Yaskolka Meir, Ehud Rinott, Gal Tsaban, Gidon Levakov, Ofer Prager, Moti Salti, Yoram Yovell, Jonathan Ofer, Sebastian Huhn, Frauke Beyer, Veronica Witte, Arno Villringer, Nachshon Meiran, Tamar B Emesh, Peter Kovacs, Martin von Bergen, Uta Ceglarek, Matthias Blüher, Michael Stumvoll, Frank B Hu, Meir J Stampfer, Alon Friedman, Ilan Shelef, Galia Avidan, Iris Shai, Alon Kaplan, Hila Zelicha, Anat Yaskolka Meir, Ehud Rinott, Gal Tsaban, Gidon Levakov, Ofer Prager, Moti Salti, Yoram Yovell, Jonathan Ofer, Sebastian Huhn, Frauke Beyer, Veronica Witte, Arno Villringer, Nachshon Meiran, Tamar B Emesh, Peter Kovacs, Martin von Bergen, Uta Ceglarek, Matthias Blüher, Michael Stumvoll, Frank B Hu, Meir J Stampfer, Alon Friedman, Ilan Shelef, Galia Avidan, Iris Shai

Abstract

Background: The effect of diet on age-related brain atrophy is largely unproven.

Objectives: We aimed to explore the effect of a Mediterranean diet (MED) higher in polyphenols and lower in red/processed meat (Green-MED diet) on age-related brain atrophy.

Methods: This 18-mo clinical trial longitudinally measured brain structure volumes by MRI using hippocampal occupancy score (HOC) and lateral ventricle volume (LVV) expansion score as neurodegeneration markers. Abdominally obese/dyslipidemic participants were randomly assigned to follow 1) healthy dietary guidelines (HDG), 2) MED, or 3) Green-MED diet. All subjects received free gym memberships and physical activity guidance. Both MED groups consumed 28 g walnuts/d (+440 mg/d polyphenols). The Green-MED group consumed green tea (3-4 cups/d) and Mankai (Wolffia-globosa strain, 100 g frozen cubes/d) green shake (+800 mg/d polyphenols).

Results: Among 284 participants (88% men; mean age: 51 y; BMI: 31.2 kg/m2; APOE-ε4 genotype = 15.7%), 224 (79%) completed the trial with eligible whole-brain MRIs. The pallidum (-4.2%), third ventricle (+3.9%), and LVV (+2.2%) disclosed the largest volume changes. Compared with younger participants, atrophy was accelerated among those ≥50 y old (HOC change: -1.0% ± 1.4% compared with -0.06% ± 1.1%; 95% CI: 0.6%, 1.3%; P < 0.001; LVV change: 3.2% ± 4.5% compared with 1.3% ± 4.1%; 95% CI: -3.1%, -0.8%; P = 0.001). In subjects ≥ 50 y old, HOC decline and LVV expansion were attenuated in both MED groups, with the best outcomes among Green-MED diet participants, as compared with HDG (HOC: -0.8% ± 1.6% compared with -1.3% ± 1.4%; 95% CI: -1.5%, -0.02%; P = 0.042; LVV: 2.3% ± 4.7% compared with 4.3% ± 4.5%; 95% CI: 0.3%, 5.2%; P = 0.021). Similar patterns were observed among younger subjects. Improved insulin sensitivity over the trial was the parameter most strongly associated with brain atrophy attenuation (P < 0.05). Greater Mankai, green tea, and walnut intake and less red and processed meat were significantly and independently associated with reduced HOC decline (P < 0.05). Elevated urinary concentrations of the polyphenols urolithin-A (r = 0.24; P = 0.013) and tyrosol (r = 0.26; P = 0.007) were significantly associated with lower HOC decline.

Conclusions: A Green-MED (high-polyphenol) diet, rich in Mankai, green tea, and walnuts and low in red/processed meat, is potentially neuroprotective for age-related brain atrophy.This trial was registered at clinicaltrials.gov as NCT03020186.

Keywords: Green Mediterranean diet; age-related atrophy; aging; dietary intervention; hippocampal occupancy score; neurodegeneration; polyphenols.

© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.

Figures

FIGURE 1
FIGURE 1
Flowchart of Brain DIRECT PLUS (Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study). Green-MED diet, Mediterranean diet higher in polyphenols and lower in red/processed meat; HDG, healthy dietary guidelines; MED, Mediterranean diet.
FIGURE 2
FIGURE 2
LVV and HOC across age at baseline. n = 284. Brain MRI-derived data were quantified and segmented in a fully automated manner using NeuroQuant. A change in slope was significant at age 50 y (P-nonlinear trend < 0.0001 for both, analyzed by spline regression). HOC, hippocampal occupancy score; LVV, lateral ventricle volume.
FIGURE 3
FIGURE 3
Dynamics in volume of different brain structures after 18 mo of lifestyle intervention [DIRECT-PLUS (Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study), n = 224]. (A) Individual response of change in HOC (% of change). A decrease in HOC is represented by black lines, an increase in HOC by blue lines. Among all participants who completed the study with 2 valid MRI brain scans, 148 (66%) exhibited a decrease in HOC after 18 mo. (B) Unbiased standard MRI template brain volume for the normal population, the distance of 4 slices or 4 mm between coronal cross-sections. The color represents the relative change (%) in volume of all available brain structures across the entire cohort and in participants ≥ 50 y of age. The analysis was corrected for multiple comparisons using the false discovery rate (0.05) method. (C) Changes in lateral ventricle volume (red) and hippocampal volume (blue) after 18 mo. Hippocampal atrophy and lateral ventricle expansion were significantly more prominent in older participants than in younger participants (P < 0.001 for both). The slice location is y = 96 in ab unbiased standard MRI template. (D) The relative decrease in HOC was significantly more prominent in older participants than in younger participants (cutoff = age 50 y, P < 0.001, independent-sample t tests). HOC, hippocampal occupancy score.
FIGURE 4
FIGURE 4
The effect of 18-mo dietary interventions on MRI-derived brain volume structures. (A) No significant difference in change in HOC (from baseline) between groups of the entire study population. The HDG and the MED group participants had a significant decrease in HOC. In contrast, participants in the Green-MED group did not have a significant change in HOC after 18 mo of intervention. (B) Compared with the HDG group, the Green-MED group had attenuated LVV expansion across the entire study population. (C, D) Among participants ≥ 50 y of age, both the MED and Green-MED diet groups demonstrated less HOC decline and LVV expansion than the HDG group. The analysis was performed with general linear modeling. Comparisons of changes in HOC and LVV between intervention groups were analyzed using Bonferroni correction for 3 comparisons. The age-by-group interaction was significant for change in HOC (P-interaction = 0.017) and marginal for change in LVV (P-interaction = 0.07). The time-by-group interaction in change in HOC was significant among participants ≥ 50 y old (P-interaction = 0.032). *Significant change from baseline within groups. **Significant difference between groups. Green-MED diet, Mediterranean diet higher in polyphenols and lower in red/processed meat; HOC, hippocampal occupancy score; LVV, lateral ventricle volume; MED, Mediterranean diet.
FIGURE 5
FIGURE 5
Relative change in HOC according to specific “green” dietary components (age ≥ 50 y). (A) Weekly walnut consumption: low was defined as ≤2/wk (n = 28), medium as 3–4/wk (n = 33), and high as ≥5/wk (n = 47). (B) Daily green tea consumption: low was defined as ≤1/d (n = 4), medium as 2/d (n = 6), and high as ≥3/d (n = 22). (C) Mankai consumption: low was defined as <3/wk (n = 12), medium as 4–6/wk (n = 13), and high as daily (n = 7). All analyses were performed for data from older participants of the study population (age ≥ 50 y). Mankai and green tea consumption were measured and analyzed only for the Green-MED diet (Mediterranean diet higher in polyphenols and lower in red/processed meat) group. All analyses were nonparametric. HOC, hippocampal occupancy score.

References

    1. Heister D, Brewer JB, Magda S, Blennow K, McEvoy LK. Predicting MCI outcome with clinically available MRI and CSF biomarkers. Neurology. 2011;77(17):1619–28.
    1. Jak AJ, Panizzon MS, Spoon KM, Franz CE, Thompson K, Jacobson C, Xian H, Eyler LT, Vuoksimaa E, Toomey Ret al. . Hippocampal atrophy varies by neuropsychologically-defined MCI among men in their 50s. Am J Geriatr Psychiatry. 2015;23(5):456–65.
    1. Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kåreholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol. 2005;62(10):1556–60.
    1. Taki Y, Kinomura S, Sato K, Inoue K, Goto R, Okada K, Uchida S, Kawashima R, Fukuda H. Relationship between body mass index and gray matter volume in 1,428 healthy individuals. Obesity. 2008;16(1):119–24.
    1. Gu Y, Brickman AM, Stern Y, Habeck CG, Razlighi QR, Luchsinger JA, Manly JJ, Schupf N, Mayeux R, Scarmeas N. Mediterranean diet and brain structure in a multiethnic elderly cohort. Neurology. 2015;85(20):1744–51.
    1. Livingston G, Huntley J, Sommerlad A, Ames D, Ballard C, Banerjee S, Brayne C, Burns A, Cohen-Mansfield J, Cooper Cet al. . Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413–46.
    1. Radd-Vagenas S, Duffy SL, Naismith SL, Brew BJ, Flood VM, Fiatarone Singh MA. Effect of the Mediterranean diet on cognition and brain morphology and function: a systematic review of randomized controlled trials. Am J Clin Nutr. 2018;107(3):389–404.
    1. Billingsley HE, Carbone S. The antioxidant potential of the Mediterranean diet in patients at high cardiovascular risk: an in-depth review of the PREDIMED. Nutr Diabetes. 2018;8(1):13.
    1. Figueira I, Tavares L, Jardim C, Costa I, Terrasso AP, Almeida AF, Govers C, Mes JJ, Gardner R, Becker JDet al. . Blood–brain barrier transport and neuroprotective potential of blackberry-digested polyphenols: an in vitro study. Eur J Nutr. 2019;58(1):113–30.
    1. Abraham J, Johnson RW. Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice. Rejuvenation Res. 2009;12(6):445–53.
    1. Dias GP, Cavegn N, Nix A, Do Nascimento Bevilaqua MC, Stangl D, Zainuddin MSA, Nardi AE, Gardino PF, Thuret S. The role of dietary polyphenols on adult hippocampal neurogenesis: molecular mechanisms and behavioural effects on depression and anxiety. Oxid Med Cell Longev. 2012:541971.
    1. Valls-Pedret C, Sala-Vila A, Serra-Mir M, Corella D, de la Torre R, Martínez-González MÁ, Martínez-Lapiscina EH, Fitó M, Pérez-Heras A, Salas-Salvadó Jet al. . Mediterranean diet and age-related cognitive decline: a randomized clinical trial. JAMA Intern Med. 2015;175(7):1094–103.
    1. Ammar A, Trabelsi K, Müller P, Bouaziz B, Boukhris O, Glenn JM, Bott N, Driss T, Chtourou H, Müller Net al. . The effect of (poly)phenol-rich interventions on cognitive functions and neuroprotective measures in healthy aging adults: a systematic review and meta-analysis. J Clin Med. 2020;9(3):835.
    1. Espeland MA, Erickson K, Neiberg RH, Jakicic JM, Wadden TA, Wing RR, Desiderio L, Erus G, Hsieh MK, Davatzikos Cet al. . Brain and white matter hyperintensity volumes after 10 years of random assignment to lifestyle intervention. Diabetes Care. 2016;39(5):764–71.
    1. Spencer JPE, Vafeiadou K, Williams RJ, Vauzour D. Neuroinflammation: modulation by flavonoids and mechanisms of action. Mol Aspects Med. 2012;33(1):83–97.
    1. Yaskolka Meir A, Tuohy K, von Bergen M, Krajmalnik-Brown R, Heinig U, Zelicha H, Tsaban G, Rinott E, Kaplan A, Aharoni Aet al. . The metabolomic-gut-clinical axis of Mankai plant-derived dietary polyphenols. Nutrients. 2021;13(6):1866.
    1. Gepner Y, Shelef I, Schwarzfuchs D, Zelicha H, Tene L, Meir AY, Tsaban G, Cohen N, Bril N, Rein Met al. . Effect of distinct lifestyle interventions on mobilization of fat storage pools: CENTRAL magnetic resonance imaging randomized controlled trial. Circulation. 2018;137(11):1143–57.
    1. Rothwell JA, Perez-Jimenez J, Neveu V, Medina-Remón A, M'Hiri N, García-Lobato P, Manach C, Knox C, Eisner R, Wishart DSet al. . Phenol-Explorer 3.0: a major update of the Phenol-Explorer database to incorporate data on the effects of food processing on polyphenol content. Database. 2013:bat070.
    1. Bhanthumnavin K, Mcgarry MG. Wolffia arrhiza as a possible source of inexpensive protein. Nature. 1971;232(5311):495.
    1. Daduang J, Vichitphan S, Daduang S, Hongsprabhas P, Boonsiri P. High phenolics and antioxidants of some tropical vegetables related to antibacterial and anticancer activities. Afr J Pharm Pharmacol. 2011;5(5):608–15.
    1. Kaplan A, Zelicha H, Tsaban G, Yaskolka Meir A, Rinott E, Kovsan J, Novack L, Thiery J, Ceglarek U, Burkhardt Ret al. . Protein bioavailability of Wolffia globosa duckweed, a novel aquatic plant – a randomized controlled trial. Clin Nutr. 2019;38(6):2576–82.
    1. Yaskolka Meir A, Tsaban G, Zelicha H, Rinott E, Kaplan A, Youngster I, Rudich A, Shelef I, Tirosh A, Brikner Det al. . A green-Mediterranean diet, supplemented with Mankai duckweed, preserves iron-homeostasis in humans and is efficient in reversal of anemia in rats. J Nutr. 2019;149(6):1004–11.
    1. Shai I, Shahar DR, Vardi H, Fraser D. Selection of food items for inclusion in a newly developed food-frequency questionnaire. Public Health Nutr. 2004;7(6):745–9.
    1. Shai I, Rosner BA, Shahar DR, Vardi H, Azrad AB, Kanfi A, Schwarzfuchs D, Fraser D. Dietary evaluation and attenuation of relative risk: multiple comparisons between blood and urinary biomarkers, food frequency, and 24-hour recall questionnaires: the DEARR study. J Nutr. 2005;135(3):573–9.
    1. Chasan-Taber S, Rimm EB, Stampfer MJ, Spiegelman D, Colditz GA, Giovannucci E, Ascherio A, Willett WC. Reproducibility and validity of a self-administered physical activity questionnaire for male health professionals. Epidemiology. 1996;7(1):81–6.
    1. Ainsworth BE, Haskell WL, Whitt MC, Irwin ML, Swartz AM, Strath SJ, O'Brien WL, Bassett DR, Schmitz KH, Emplaincourt POet al. . Compendium of Physical Activities: an update of activity codes and MET intensities. Med Sci Sports Exerc. 2000;32(Supplement):S498–516.
    1. Emesh TB, Garbi D, Kaplan A, Zelicha H, Yaskolka Meir A, Tsaban G, Rinott E, Meiran N. Retest reliability of integrated speed–accuracy measures. Assessment. 2021; Feb 1 (Epub ahead of print; doi: 10.1177/1073191120985609).
    1. Liesefeld HR, Janczyk M. Combining speed and accuracy to control for speed-accuracy trade-offs(?). Behav Res Methods. 2019;51(1):40–60.
    1. Yaskolka Meir A, Rinott E, Tsaban G, Zelicha H, Kaplan A, Rosen P, Shelef I, Youngster I, Shalev A, Blüher Met al. . Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial. Gut. 2021;70(11):2085–95.
    1. Deng W, Aimone JB, Gage FH. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?. Nat Rev Neurosci. 2010;11(5):339–50.
    1. Wei M, Shi J, Ni J, Zhang X, Li T, Chen Z, Zhou M, Zhang L, Tan Z, Wang Yet al. . A new age-related cutoff of medial temporal atrophy scale on MRI improving the diagnostic accuracy of neurodegeneration due to Alzheimer's disease in a Chinese population. BMC Geriatr. 2019;19(1):59.
    1. Schuff N, Tosun D, Insel PS, Chiang GC, Truran D, Aisen PS, Jack CR Jr, Weiner MW, Alzheimer's Disease Neuroimaging Initiative . Nonlinear time course of brain volume loss in cognitively normal and impaired elders. Neurobiol Aging. 2012;33(5):845–55.
    1. Schmidt MF, Storrs JM, Freeman KB, Jack CR Jr, Turner ST, Griswold ME, Mosley TH. A comparison of manual tracing and FreeSurfer for estimating hippocampal volume over the adult lifespan. Hum Brain Mapp. 2018;39(6):2500–13.
    1. Oschwald J, Guye S, Liem F, Rast P, Willis S, Röcke C, Jäncke L, Martin M, Mérillat S. Brain structure and cognitive ability in healthy aging: a review on longitudinal correlated change. Rev Neurosci. 2019;31(1):1–57.
    1. Cacciaglia R, Molinuevo JL, Falcón C, Brugulat-Serrat A, Sánchez-Benavides G, Gramunt N, Esteller M, Morán S, Minguillón C, Fauria Ket al. . Effects of APOE-ε4 allele load on brain morphology in a cohort of middle-aged healthy individuals with enriched genetic risk for Alzheimer's disease. Alzheimers Dement. 2018;14(7):902–12.
    1. Song R, Xu H, Dintica CS, Pan K-Y, Qi X, Buchman AS, Bennett DA, Xu W. Associations between cardiovascular risk, structural brain changes, and cognitive decline. J Am Coll Cardiol. 2020;75(20):2525–34.
    1. Erickson KI, Voss MW, Shaurya R, Basak C, Szabo A. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci U S A. 2011;108(7):3017–22.
    1. Luciano M, Corley J, Cox SR, Hernández MCV, Craig LCA, Dickie DA, Karama S, McNeill GM, Bastin ME, Wardlaw JMet al. . Mediterranean-type diet and brain structural change from 73 to 76 years in a Scottish cohort. Neurology. 2017;88(5):449–55.
    1. Rodrigues B, Coelho A, Portugal-Nunes C, Magalhães R, Moreira PS, Castanho TC, Amorim L, Marques P, Soares JM, Sousa Net al. . Higher adherence to the Mediterranean diet is associated with preserved white matter integrity and altered structural connectivity. Front Neurosci. 2020;14:786.
    1. Gu Y, Vorburger RS, Gazes Y, Habeck CG, Stern Y, Luchsinger JA, Manly JJ, Schupf N, Mayeux R, Brickman AM. White matter integrity as a mediator in the relationship between dietary nutrients and cognition in the elderly. Ann Neurol. 2016;79(6):1014–25.
    1. Giorgio A, Santelli L, Tomassini V, Bosnell R, Smith S, de Stefano N, Johansen-Berg H. Age-related changes in grey and white matter structure throughout adulthood. Neuroimage. 2010;51(3):943–51.
    1. Chauhan A, Chauhan V. Beneficial effects of walnuts on cognition and brain health. Nutrients. 2020;12(2):550.
    1. Sala-Vila A, Valls-Pedret C, Rajaram S, Coll-Padrós N, Cofán M, Serra-Mir M, Pérez-Heras AM, Roth I, Freitas-Simoes TM, Doménech Met al. . Effect of a 2-year diet intervention with walnuts on cognitive decline. The Walnuts And Healthy Aging (WAHA) study: a randomized controlled trial. Am J Clin Nutr. 2020;111(3):590–600.
    1. Letenneur L, Proust-Lima C, Le Gouge A, Dartigues JF, Barberger-Gateau P. Flavonoid intake and cognitive decline over a 10-year period. Am J Epidemiol. 2007;165(12):1364–71.
    1. Zelicha H, Kaplan A, Meir AY, Tsaban G, Rinott E, Shelef I, Tirosh A, Brikner D, Pupkin E, Qi Let al. . The effect of Wolffia globosa Mankai, a green aquatic plant, on postprandial glycemic response: a randomized crossover controlled trial. Diabetes Care. 2019;42(7):1162–9.
    1. Oppedisano F, Maiuolo J, Gliozzi M, Musolino V, Carresi C, Nucera S, Scicchitano M, Scarano F, Bosco F, Macrì Ret al. . The potential for natural antioxidant supplementation in the early stages of neurodegenerative disorders. Int J Mol Sci. 2020;21(7):2618.
    1. Sorond FA, Hurwitz S, Salat DH, Greve DN, Fisher NDL. Neurovascular coupling, cerebral white matter integrity, and response to cocoa in older people. Neurology. 2013;81(10):904–9.
    1. Janssen CIF, Zerbi V, Mutsaers MPC, Jochems M, Vos CA, Vos JO, Berg BM, van Tol EAF, Gross G, Jouni ZEet al. . Effect of perinatally supplemented flavonoids on brain structure, circulation, cognition, and metabolism in C57BL/6J mice. Neurochem Int. 2015;89:157–69.
    1. Gong Z, Huang J, Xu B, Ou Z, Zhang L, Lin X, Ye X, Kong X, Long D, Sun Xet al. . Urolithin A attenuates memory impairment and neuroinflammation in APP/PS1 mice. J Neuroinflammation. 2019;16(1):62.
    1. DaSilva NA, Nahar PP, Ma H, Eid A, Wei Z, Meschwitz S, Zawia NH, Slitt AL, Seeram NP. Pomegranate ellagitannin-gut microbial-derived metabolites, urolithins, inhibit neuroinflammation in vitro. Nutr Neurosci. 2019;22(3):185–95.
    1. Khodanovich MY, Kisel’ AA, Chernysheva GA, Smol'yakova VI, Kudabaeva MS, Krutenkova EP, Tyumentseva YA, Plotnikov MB. p-Tyrosol enhances the production of new neurons in the hippocampal CA1 field after transient global cerebral ischemia in rats. Bull Exp Biol Med. 2019;168(2):224–8.
    1. Pérez-Jiménez J, Hubert J, Hooper L, Cassidy A, Manach C, Williamson G, Scalbert A. Urinary metabolites as biomarkers of polyphenol intake in humans: a systematic review. Am J Clin Nutr. 2010;92(4):801–9.
    1. Xu J, Kobayashi S, Yamaguchi S, Iijima K, Okada K, Yamashita K. Gender effects on age-related changes in brain structure. AJNR Am J Neuroradiol. 2000;21(1):112–18.
    1. Nobis L, Manohar SG, Smith SM, Alfaro-Almagro F, Jenkinson M, Mackay CE, Husain M. Hippocampal volume across age: nomograms derived from over 19,700 people in UK Biobank. Neuroimage Clin. 2019;23:101904.
    1. Ross DE, Ochs AL, Desmit ME, Seabaugh JM, Havranek MED. Man versus machine part 2: comparison of radiologists’ interpretations and NeuroQuant measures of brain asymmetry and progressive atrophy in patients with traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2015;27(2):147–52.

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