A ketogenic drink improves cognition in mild cognitive impairment: Results of a 6-month RCT

Mélanie Fortier, Christian-Alexandre Castellano, Valérie St-Pierre, Étienne Myette-Côté, Francis Langlois, Maggie Roy, Marie-Christine Morin, Christian Bocti, Tamas Fulop, Jean-Philippe Godin, Carla Delannoy, Bernard Cuenoud, Stephen C Cunnane, Mélanie Fortier, Christian-Alexandre Castellano, Valérie St-Pierre, Étienne Myette-Côté, Francis Langlois, Maggie Roy, Marie-Christine Morin, Christian Bocti, Tamas Fulop, Jean-Philippe Godin, Carla Delannoy, Bernard Cuenoud, Stephen C Cunnane

Abstract

Introduction: Counteracting impaired brain glucose metabolism with ketones may improve cognition in mild cognitive impairment (MCI).

Methods: Cognition, plasma ketone response, and metabolic profile were assessed before and 6 months after supplementation with a ketogenic drink containing medium chain triglyceride (ketogenic medium chain triglyceride [kMCT]; 15 g twice/day; n = 39) or placebo (n = 44).

Results: Free and cued recall (Trial 1; P = .047), verbal fluency (categories; P = .024), Boston Naming Test (total correct answers; P = .033), and the Trail-Making Test (total errors; P = .017) improved significantly in the kMCT group compared to placebo (analysis of covariance; pre-intervention score, sex, age, education, and apolipoprotein E4 as covariates). Some cognitive outcomes also correlated positively with plasma ketones. Plasma metabolic profile and ketone response were unchanged.

Conclusions: This kMCT drink improved cognitive outcomes in MCI, at least in part by increasing blood ketone level. These data support further assessment of MCI progression to Alzheimer's disease.

Keywords: Alzheimer's disease; acetoacetate; beta-hydroxybutyrate; cognition; episodic memory; executive function; ketone; language; medium chain triglyceride; mild cognitive impairment.

Conflict of interest statement

Stephen C. Cunnane has consulted for or received travel honoraria or test products for research from Nestlé Health Science, Bulletproof, Cerecin, and Abitec. Stephen C. Cunnane is the founder and director of the consulting company, Senotec Ltd. JPG is an employee of the Société des Produits Nestlé S.A. There are no other conflicts to report.

© 2020 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.

Figures

FIGURE 1
FIGURE 1
Change in cognitive scores. Change in raw scores from baseline (0) on the first trial of the RL/RI‐16 test (A) verbal fluency (categories) test (B) and Boston Naming Test (C‐ total correct responses), in the ketogenic medium chain triglyceride (kMCT) versus placebo group (P = .054, P = .005, P = .018, respectively)
FIGURE 2
FIGURE 2
Plasma ketones and cognitive outcomes. Correlation between the change in plasma beta‐hydroxybutyrate (BHB) or change in plasma total ketones (BHB + acetoacetate) and three cognitive outcomes on the placebo (○) or ketogenic medium chain triglyceride (kMCT) (●): trial 1 of the RL/RI‐16 test (A; r = +0.232, P = .039), verbal fluency (categories) test (B; r = +0.325, P = .013), and Boston Naming Test (total correct answers) (C; r = +0.229, P = .042)
FIGURE 3
FIGURE 3
Plasma free caprylic acid (C8) and capric acid (C10) (A) and total ketone response (B) throughout the 4‐hour metabolic study day. A dose of 15 g of ketogenic medium chain triglyceride (kMCT) (A, B) or placebo drink (B) was consumed (arrow) before (◇C8 kMCT; ∇C10 kMCT; ○ Placebo; □ kMCT) and 6 months after supplementation (◆ C8 kMCT; ▾ C10 kMCT; ⬤ Placebo; ■ kMCT). For clarity, placebo data are not shown for C8 and C10 (A) but did not exceed the baseline values shown at T0 for C8 (3.9 μM) or C10 (7.9 μM). Data are means ± standard deviation

References

    1. Cunnane SC, Trushina E, Morland C, et al. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of ageing. Nat Rev Drug Discov. 2020;19(9):609‐633.
    1. Morbelli S, Brugnolo A, Bossert I, et al. Visual versus semi‐quantitative analysis of 18F‐FDG‐PET in amnestic MCI: an European Alzheimer's Disease Consortium (EADC) project. J Alzheimers Dis. 2015;44:815‐826.
    1. Ishibashi K, Onishi A, Wagatsuma K, Fujiwara Y, Ishii K. Longitudinal 18F‐FDG images in patients with Alzheimer disease over more than 9 years from a preclinical stage. Clin Nucl Med. 2020;45:e185‐e9.
    1. Castellano CA, Baillargeon JP, Nugent S, et al. Regional brain glucose hypometabolism in young women with polycystic ovary syndrome: possible link to mild insulin resistance. PLoS One. 2015;10:e0144116.
    1. Croteau E, Castellano CA, Richard MA, et al. Ketogenic medium chain triglycerides increase brain energy metabolism in Alzheimer's disease. J Alzheimers Dis. 2018;64:551‐561.
    1. Fortier M, Castellano CA, Croteau E, et al. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Alzheimers Dement. 2019;15:625‐634.
    1. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999;56:303‐308.
    1. Yesavage JA, Brink TL, Rose TL. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res. 1982;17:37‐49.
    1. Hébert R, Guilbault J, Desrosiers J, Dubuc N. The functional autonomy measurement system (SMAF): a clinical‐based instrument for measuring disabilities and handicaps in older people. Can Geriatr J. 2001;4:141‐147.
    1. American Psychiatric Association, & Diagnostic and Statistical Manual of Mental Disorders. 5th ed. (DSM‐5): Washington, D.C., USA: American Psychiatric Association; 2013.
    1. Nasreddine ZS, Phillips NA, Bédirian V, et al. The montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53:695‐699.
    1. Folstein MF, Folstein SE, McHugh PR. ‘Mini mental state’. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189‐198.
    1. Van der Linden M, Coyette F, Poitrenaud J. GREMEM. L’épreuve de rappel libre/rappel indicé à 16 items (RL/RI‐16). In: Van der Linden SAM, & Agniel A, eds. L'evaluation des troubles de la mémoire episodique (avec leur etalonnage). Marseille, France: Solal; 2004:25‐47.
    1. Benedict R. Brief Visuospatial Memory Test‐Revised Professional Manual. Odessa, FL: Psychological Assessment Resources; 1997.
    1. Delis D, Kaplan E, Kramer J. In: Corporation P, ed. Delis‐Kaplan Executive Function System (D‐KEFS). San Antonio, TX (USA); 2001.
    1. Wechsler D. Wechsler Memory Scale‐Third Edition. San Antonio, TX: The Psychological Corporation; 1997.
    1. Kaplan E, Goodglass H, Weintraub S. The Boston Naming Test. Philadelphia: Lea & Febiger; 1983.
    1. Zec RF, Burkett NR, Markwell SJ, Larsen DL. Normative data stratified for age, education, and gender on the Boston Naming Test. Clin Neuropsychol. 2007;21:617‐637.
    1. Dion M, Potvin O, Belleville S, et al. Normative data for the rappel libre/Rappel indice a 16 items (16‐item free and cued recall) in the elderly Quebec‐French population. Clin Neuropsychol. 2015;28(Suppl 1):S1‐S19.
    1. St‐Pierre V, Vandenberghe C, Lowry CM, et al. Plasma ketone and medium chain fatty acid response in humans consuming different medium chain triglycerides during a metabolic study day. Front Nutr. 2019;6:46.
    1. St‐Pierre V, Courchesne‐Loyer A, Vandenberghe C, Hennebelle M, Castellano CA, Cunnane SC. Butyrate is more ketogenic than leucine or octanoate‐monoacylglycerol in healthy adult humans. J Funct Foods. 2017;32:170‐175.
    1. Koch W, Ehrenhaft A, Griesser K, et al. TaqMan systems for genotyping of disease‐related polymorphisms present in the gene encoding apolipoprotein E. Clin Chem Lab Med. 2002;40:1123‐1131.
    1. Simard F, Guay F, Girard CL, Giguère A, Laforest JP, Matte JJ. Effects of concentrations of cyanocobalamin in the gestation diet on some criteria of vitamin B12 metabolism in first‐parity sows. J Anim Sci. 2007;85:3294‐3302.
    1. Wan PJ, Dowd MK, Thomas AE, Butler BH. Trimethylsilyl derivatization/gas chromatography as a method to determine the free fatty acid content of vegetable oils. J Am Oil Chem Soc. 2007;84:701‐708.
    1. Faul F, Erdfelder E, Lang AG, Buchner A. G*Power 3: a flexible statistical power analysis program for the social, behavioral, and biomedical sciences. Behav Res Methods. 2007;39:175‐191.
    1. Dimitrov D, Rumrill P. Pretest‐posttest designs and measurement of change. Work. 2003;20:159‐165.
    1. Quade D. Rank analysis of covariance. J Am Statis Assoc. 1967;62:1187‐1200.
    1. Cohen J. Statistical Power Analysis for the Behavioral Sciences, Rev. ed. Hillsdale, NJ, USA: Lawrence Erlbaum Associates, Inc; 1977.
    1. Grober E, Veroff AE, Lipton RB. Temporal unfolding of declining episodic memory on the free and cued selective reminding test in the predementia phase of Alzheimer's disease: implications for clinical trials. Alzheimers Dement. 2018;10:161‐171.
    1. Auriacombe S, Helmer C, Amieva H, Berr C, Dubois B, Dartigues JF. Validity of the free and cued selective reminding test in predicting dementia: the 3C study. Neurology. 2010;74:1760‐1767.
    1. Neth BJ, Mintz A, Whitlow C, et al. Modified ketogenic diet is associated with improved cerebrospinal fluid biomarker profile, cerebral perfusion, and cerebral ketone body uptake in older adults at‐risk for Alzheimer's disease: a Pilot Study. Neurobiol Aging. 2019;86:54‐63.
    1. Ebert D, Haller RG, Walton ME. Energy contribution of octanoate to intact rat brain metabolism measured by 13C nuclear magnetic resonance spectroscopy. J Neurosci. 2003;23:5928‐5935.
    1. Henderson ST, Vogel JL, Barr LJ, Garvin F, Jones JJ, Costantini LC. Study of the ketogenic agent AC‐1202 in mild to moderate Alzheimer's disease: a randomized, double‐blind, placebo‐controlled, multicenter trial. Nutr Metab. 2009;6:31.
    1. Ota M, Matsuo J, Ishida I, et al. Effects of a medium‐chain triglyceride‐based ketogenic formula on cognitive function in patients with mild‐to‐moderate Alzheimer's disease. Neurosci Lett. 2019;690:232‐236.
    1. Xu Q, Zhang Y, Zhang X, et al. Medium‐chain triglycerides improved cognition and lipid metabolomics in mild to moderate Alzheimer's disease patients with APOE4(−/−): a double‐blind, randomized, placebo‐controlled crossover trial. Clin Nutr. 2019;39(7):2092‐2105.
    1. Krikorian R, Shidler MD, Dangelo K, Couch SC, Benoit SC, Clegg DJ. Dietary ketosis enhances memory in mild cognitive impairment. Neurobiol Aging. 2012;33:425.
    1. Taylor MK, Sullivan DK, Mahnken JD, Burns JM, Swerdlow RH. Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer's disease. Alzheimer's Dement. 2018;4:28‐36.
    1. Brandt J, Buchholz A, Henry‐Barron B, Vizthum D, Avramopoulos D, Cervenka MC. Preliminary report on the feasibility and efficacy of the modified atkins diet for treatment of mild cognitive impairment and early Alzheimer's disease. J Alzheimers Dis. 2019;68:969‐981.
    1. Livingston G, Sommerlad A, Orgeta V, Costafreda SG, Huntley J, Ames D, et al. Dementia prevention, intervention, and care. Lancet. 2017;390:2673‐2734.
    1. Doody RS, Ferris SH, Salloway S, et al. Donepezil treatment of patients with MCI: a 48‐week randomized, placebo‐controlled trial. Neurology. 2009;72:1555‐1561.
    1. Salloway S, Ferris S, Kluger A, et al. Efficacy of donepezil in mild cognitive impairment: a randomized placebo‐controlled trial. Neurology. 2004;63:651‐657.
    1. Liu‐Ambrose T, Nagamatsu LS, Graf P, Beattie BL, Ashe MC, Handy TC. Resistance training and executive functions: a 12‐month randomized controlled trial. Arch Intern Med. 2010;170:170‐178.
    1. Nagamatsu LS, Chan A, Davis JC, et al. Physical activity improves verbal and spatial memory in older adults with probable mild cognitive impairment: a 6‐month randomized controlled trial. J Aging Res. 2013;2013:861893.
    1. Fiatarone Singh MA, Gates N, Saigal N, et al. The Study of Mental and Resistance Training (SMART) study—resistance training and/or cognitive training in mild cognitive impairment: a randomized, double‐blind, double‐sham controlled trial. J Am Med Dir Assoc. 2014;15:873‐880.
    1. Baker LD, Frank LL, Foster‐Schubert K, et al. Effects of aerobic exercise on mild cognitive impairment: a controlled trial. Arch Neurol. 2010;67:71‐79.
    1. Grande G, Vanacore N, Vetrano DL, et al. Free and cued selective reminding test predicts progression to Alzheimer's disease in people with mild cognitive impairment. Neurol Sci. 2018;39:1867‐1875.
    1. Derby CA, Burns LC, Wang C, et al. Screening for predementia AD: time‐dependent operating characteristics of episodic memory tests. Neurology. 2013;80:1307‐1314.
    1. Association As. 2019 Alzheimer's disease facts and figures. Alzheimer's Dement. 2019;15:321‐387.
    1. Zilberter M, Ivanov A, Ziyatdinova S, et al. Dietary energy substrates reverse early neuronal hyperactivity in a mouse model of Alzheimer's disease. J Neurochem. 2013;125:157‐171.
    1. Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL. D‐beta‐hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease. Proc Natl Acad Sci U S A. 2000;97:5440‐5444.
    1. Washburn RA, Smith KW, Jette AM, Janney CA. The Physical Activity Scale for the Elderly (PASE): development and evaluation. J Clin Epidemiol. 1993;46:153‐162.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel