Abstract
Glucose metabolism is impaired in brain aging and several neurological conditions. Beneficial effects of ketones have been reported in the context of protecting the aging brain, however, their neurophysiological effect is still largely uncharacterized, hurdling their development as a valid therapeutic option. In this report, we investigate the neurochemical effect of the acute administration of a ketone d-beta-hydroxybutyrate (d-βHB) monoester in fasting healthy participants with ultrahigh-field proton magnetic resonance spectroscopy (MRS). In two within-subject metabolic intervention experiments, 7 T MRS data were obtained in fasting healthy participants (1) in the anterior cingulate cortex pre- and post-administration of d-βHB (N = 16), and (2) in the posterior cingulate cortex pre- and post-administration of d-βHB compared to active control glucose (N = 26). Effect of age and blood levels of d-βHB and glucose were used to further explore the effect of d-βHB and glucose on MRS metabolites. Results show that levels of GABA and Glu were significantly reduced in the anterior and posterior cortices after administration of d-βHB. Importantly, the effect was specific to d-βHB and not observed after administration of glucose. The magnitude of the effect on GABA and Glu was significantly predicted by older age and by elevation of blood levels of d-βHB. Together, our results show that administration of ketones acutely impacts main inhibitory and excitatory transmitters in the whole fasting cortex, compared to normal energy substrate glucose. Critically, such effects have an increased magnitude in older age, suggesting an increased sensitivity to ketones with brain aging.
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References
Attwell D, Laughlin SB. An energy budget for signaling in the grey matter of the brain. J Cereb Blood Flow Metab. 2001;21:1133–45.
Mergenthaler P, Lindauer U, Dienel GA, Meisel A. Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci. 2013;36:587–97.
Mosconi L. Glucose metabolism in normal aging and Alzheimer’s disease: methodological and physiological considerations for PET studies. Clin Transl imaging. 2013;1:217–33.
Mullins R, Reiter D, Kapogiannis D. Magnetic resonance spectroscopy reveals abnormalities of glucose metabolism in the Alzheimer’s brain. Ann Clin Transl Neurol. 2018;5:262–72.
Kapogiannis D, Mattson MP. Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer’s disease. Lancet Neurol. 2011;10:187–98.
Wirth M, Bejanin A, La Joie R, Arenaza-Urquijo EM, Gonneaud J, Landeau B, et al. Regional patterns of gray matter volume, hypometabolism, and beta-amyloid in groups at risk of Alzheimer’s disease. Neurobiol aging. 2018;63:140–51.
Kalpouzos G, Chételat G, Baron JC, Landeau B, Mevel K, Godeau C, et al. Voxel-based mapping of brain gray matter volume and glucose metabolism profiles in normal aging. Neurobiol aging. 2009;30:112–24.
Mosconi L, Pupi A, De Leon MJ. Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci. 2008;1147:180–195.
Krell-Roesch J, Syrjanen JA, Vassilaki M, Lowe VJ, Vemuri P, Mielke MM, et al. Brain regional glucose metabolism, neuropsychiatric symptoms, and the risk of incident mild cognitive impairment: the Mayo Clinic study of aging. The. Am J Geriatr Psychiatry. 2021;29:179–91.
Hammond TC, Xing X, Wang C, Ma D, Nho K, Crane PK, et al. β-amyloid and tau drive early Alzheimer’s disease decline while glucose hypometabolism drives late decline. Commun Biol. 2020;3:1–13.
Higuchi M, Tashiro M, Arai H, Okamura N, Hara S, Higuchi S, et al. Glucose hypometabolism and neuropathological correlates in brains of dementia with Lewy bodies. Exp Neurol. 2000;162:247–56.
Ciarmiello A, Cannella M, Lastoria S, Simonelli M, Frati L, Rubinsztein DC, et al. Brain white-matter volume loss and glucose hypometabolism precede the clinical symptoms of Huntington’s disease. J Nucl Med. 2006;47:215–22.
Firbank MJ, Yarnall AJ, Lawson RA, Duncan GW, Khoo TK, Petrides GS, et al. Cerebral glucose metabolism and cognition in newly diagnosed Parkinson’s disease: ICICLE-PD study. J Neurol, Neurosurg Psychiatry. 2017;88:310–316.
Ruud J, Steculorum SM, Brüning JC. Neuronal control of peripheral insulin sensitivity and glucose metabolism. Nat Commun. 2017;8:1–12.
Steculorum SM, Solas M, Brüning JC. The paradox of neuronal insulin action and resistance in the development of aging‐associated diseases. Alzheimer’s Dement. 2014;10:S3–S11.
Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 2016;24:256–68.
Owen OE, Morgan AP, Kemp HG, Sullivan JM, Herrera MG, Cahill GF Jr. Brain metabolism during fasting. J Clin Investig. 1967;46:1589–95.
Courchesne-Loyer A, Croteau E, Castellano CA, St-Pierre V, Hennebelle M, Cunnane SC. Inverse relationship between brain glucose and ketone metabolism in adults during short-term moderate dietary ketosis: a dual tracer quantitative positron emission tomography study. J Cereb Blood Flow Metab. 2017;37:2485–93.
Flatt J. On the maximal possible rate of ketogenesis. Diabetes. 1972;21:50–53.
Reichard GA Jr., Owen OE, Haff AC, Paul P, Bortz WM. Ketone-body production and oxidation in fasting obese humans. J Clin Investig. 1974;53:508–15.
Cunnane SC, Courchesne-Loyer A, St-Pierre V, Vandenberghe C, Pierotti T, Fortier M, et al. Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer’s disease. Ann N. Y Acad Sci. 2016;1367:12–20.
Mujica-Parodi LR, Amgalan A, Sultan SF, Antal B, Sun X, Skiena S, et al. Diet modulates brain network stability, a biomarker for brain aging, in young adults. Proc Natl Acad Sci. 2020;117:6170–7.
Yomogida Y, Matsuo J, Ishida I, Ota M, Nakamura K, Ashida K, et al. An fMRI investigation into the effects of ketogenic medium-chain triglycerides on cognitive function in elderly adults: a pilot study. Nutrients. 2021;13:2134.
Torosyan N, Sethanandha C, Grill JD, Dilley ML, Lee J, Cummings JL, et al. Changes in regional cerebral blood flow associated with a 45 day course of the ketogenic agent, caprylidene, in patients with mild to moderate Alzheimer’s disease: results of a randomized, double-blinded, pilot study. Exp Gerontol. 2018;111:118–21.
Ota M, Matsuo J, Ishida I, Takano H, Yokoi Y, Hori H, 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;690:232–6.
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 Alzheimer’s Dis. 2019;68:969–81.
Fortier M, Castellano CA, Croteau E, Langlois F, Bocti C, St-Pierre V, et al. A ketogenic drink improves brain energy and some measures of cognition in mild cognitive impairment. Alzheimer’s Dement. 2019;15:625–34.
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–e19-425. e27
Rebello CJ, Keller JN, Liu AG, Johnson WD, Greenway FL. Pilot feasibility and safety study examining the effect of medium chain triglyceride supplementation in subjects with mild cognitive impairment: a randomized controlled trial. BBA Clin. 2015;3:123–5.
Reger MA, Henderson ST, Hale C, Cholerton B, Baker LD, Watson GS, et al. Effects of β-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol aging. 2004;25:311–314.
Cunnane SC, Courchesne-Loyer A, Vandenberghe C, St-Pierre V, Fortier M, Hennebelle M, et al. Can ketones help rescue brain fuel supply in later life? Implications for cognitive health during aging and the treatment of Alzheimer’s disease. Front Mol Neurosci. 2016;9:53.
Castellano C-A, Nugent S, Paquet N, Tremblay S, Bocti C, Lacombe G, et al. Lower brain 18F-fluorodeoxyglucose uptake but normal 11C-acetoacetate metabolism in mild Alzheimer’s disease dementia. J Alzheimer’s Dis. 2015;43:1343–53.
Peterman M. The ketogenic diet in epilepsy. J Am Med Assoc. 1925;84:1979–83.
Freeman JM, Vining EPG, Pillas DJ, Pyzik PL, Casey JC, Kelly MT. The efficacy of the ketogenic diet—1998: a prospective evaluation of intervention in 150 children. Pediatrics. 1998;102:1358–63.
Wilder RM. The effects of ketonemia on the course of epilepsy. Mayo Clin Bull. 1921;2:307–8.
Vining EP, Freeman JM, Ballaban-Gil K, Camfield CS, Camfield PR, Holmes GL, et al. A multicenter study of the efficacy of the ketogenic diet. Arch Neurol. 1998;55:1433–7.
Sourbron J, Klinkenberg S, van Kuijk S, Lagae L, Lambrechts D, Braakman H, et al. Ketogenic diet for the treatment of pediatric epilepsy: review and meta-analysis. Child’s Nerv Syst. 2020;36:1099–109.
Martin K, Jackson CF, Levy RG, Cooper PN. Ketogenic diet and other dietary treatments for epilepsy. Cochrane Database of Syst Rev. 2016;2:CD001903.
Martin-McGill KJ, Bresnahan R, Levy RG, Cooper PN. Ketogenic diets for drug‐resistant epilepsy. Cochrane Database of Syst Rev. 2020;6:CD001903.
Wijnen B, de Kinderen R, Lambrechts D, Postulart D, Aldenkamp AP, Majoie M, et al. Long-term clinical outcomes and economic evaluation of the ketogenic diet versus care as usual in children and adolescents with intractable epilepsy. Epilepsy Res. 2017;132:91–9.
Yamanashi T, Iwata M, Kamiya N, Tsunetomi K, Kajitani N, Wada N, et al. Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses. Sci Rep. 2017;7:1–11.
Yamanashi T, Iwata M, Shibushita M, Tsunetomi K, Nagata M, Kajitani N, et al. Beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, attenuates anxiety-related behavior in a rodent post-traumatic stress disorder model. Sci Rep. 2020;10:1–11.
Youm Y-H, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease. Nat Med. 2015;21:263–9.
Rae CD. A guide to the metabolic pathways and function of metabolites observed in human brain 1 H magnetic resonance spectra. Neurochem Res. 2014;39:1–36.
Befroy DE, Shulman GI. Magnetic resonance spectroscopy studies of human metabolism. Diabetes. 2011;60:1361–9.
Hertz, L and DL Rothman, Glucose, lactate, β-hydroxybutyrate, acetate, GABA, and succinate as substrates for synthesis of glutamate and GABA in the glutamine–glutamate/GABA cycle, in The Glutamate/GABA-Glutamine Cycle. 2016, Springer. p. 9–42.
Cuenoud B, Hartweg M, Godin JP, Croteau E, Maltais M, Castellano CA, et al. Metabolism of exogenous D-beta-hydroxybutyrate, an energy substrate avidly consumed by the heart and kidney. Front in Nutr. 2020;7:1–9.
Clarke K, Tchabanenko K, Pawlosky R, Carter E, Todd King M, Musa-Veloso K, et al. Kinetics, safety and tolerability of (R)−3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regulatory Toxicol Pharmacol. 2012;63:401–8.
Clarke K, Tchabanenko K, Pawlosky R, Carter E, Knight NS, Murray AJ, et al. Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. Regulatory Toxicol Pharmacol. 2012;63:196–208.
Provencher SW. Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med. 1993;30:672–9.
Near J, Harris AD, Juchem C, Kreis R, Marjańska M, Öz G, et al. Preprocessing, analysis and quantification in single‐voxel magnetic resonance spectroscopy: experts’ consensus recommendations. NMR Biomedicine. 2021;34:e4257.
Edden RAE, Puts NAJ, Harris AD, Barker PB, Evans CJ. Gannet: a batch‐processing tool for the quantitative analysis of gamma‐aminobutyric acid–edited MR spectroscopy spectra. J Magn Reson Imaging. 2014;40:1445–52.
Harris AD, Puts NA, Edden RA. Tissue correction for GABA‐edited MRS: considerations of voxel composition, tissue segmentation, and tissue relaxations. J Magn Reson Imaging. 2015;42:1431–40.
Atassi N, Xu M, Triantafyllou C, Keil B, Lawson R, Cernasov P, et al. Ultra high-field (7tesla) magnetic resonance spectroscopy in Amyotrophic Lateral Sclerosis. PLoS One. 2017;12:e0177680.
Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc: Ser B (Methodol). 1995;57:289–300.
Team RC, R Core Team R: a language and environment for statistical computing. Foundation for Statistical Computing, 2020.
Juge N, Gray JA, Omote H, Miyaji T, Inoue T, Hara C, et al. Metabolic control of vesicular glutamate transport and release. Neuron. 2010;68:99–112.
Chmiel-Perzyńska I, Kloc R, Perzyński A, Rudzki S, Urbańska EM. Novel aspect of ketone action: β-hydroxybutyrate increases brain synthesis of kynurenic acid in vitro. Neurotox Res. 2011;20:40–50.
Pflanz NC, Daszkowski AW, James KA, Mihic SJ. Ketone body modulation of ligand-gated ion channels. Neuropharmacology. 2019;148:21–30.
Yudkoff M, Daikhin Y, Horyn O, Nissim I, Nissim I. Ketosis and brain handling of glutamate, glutamine, and GABA. Epilepsia. 2008;49:73–75.
Lund TM, Risa O, Sonnewald U, Schousboe A, Waagepetersen HS. Availability of neurotransmitter glutamate is diminished when β‐hydroxybutyrate replaces glucose in cultured neurons. J neurochemistry. 2009;110:80–91.
McKenna MC. Glutamate pays its own way in astrocytes. Front Endocrinol. 2013;4:191.
McKenna MC. The glutamate‐glutamine cycle is not stoichiometric: fates of glutamate in brain. J Neurosci Res. 2007;85:3347–58.
McKenna MC. Substrate competition studies demonstrate oxidative metabolism of glucose, glutamate, glutamine, lactate and 3-hydroxybutyrate in cortical astrocytes from rat brain. Neurochem Res. 2012;37:2613–26.
Rao R, Ennis K, Long JD, Ugurbil K, Gruetter R, Tkac I. Neurochemical changes in the developing rat hippocampus during prolonged hypoglycemia. J neurochemistry. 2010;114:728–38.
Terpstra M, Moheet A, Kumar A, Eberly LE, Seaquist E, Öz G. Changes in human brain glutamate concentration during hypoglycemia: insights into cerebral adaptations in hypoglycemia-associated autonomic failure in type 1 diabetes. J Cereb Blood Flow Metab. 2014;34:876–82.
Bischof MG, Brehm A, Bernroider E, Krssák M, Mlynárik V, Krebs M, et al. Cerebral glutamate metabolism during hypoglycaemia in healthy and type 1 diabetic humans. Eur J Clin Investig. 2006;36:164–9.
Kapogiannis D, Avgerinos KI. Brain glucose and ketone utilization in brain aging and neurodegenerative diseases. Int Rev Neurobiol. 2020;154:79–110.
Valdebenito R, et al. Targeting of astrocytic glucose metabolism by beta-hydroxybutyrate. J Cereb Blood Flow Metab. 2016;36:1813–22.
Suzuki Y, Takahashi H, Fukuda M, Hino H, Kobayashi K, Tanaka J, et al. β-hydroxybutyrate alters GABA-transaminase activity in cultured astrocytes. Brain Res. 2009;1268:17–23.
Achanta LB, Rowlands BD, Thomas DS, Housley GD, Rae CD. β-Hydroxybutyrate boosts mitochondrial and neuronal metabolism but is not preferred over glucose under activated conditions. Neurochem Res. 2017;42:1710–23.
Achanta LB, Rae CD. β-Hydroxybutyrate in the brain: one molecule, multiple mechanisms. Neurochem Res. 2017;42:35–49.
Nasrallah FA, Griffin JL, Balcar VJ, Rae C. Understanding your inhibitions: modulation of brain cortical metabolism by GABAB receptors. J Cereb Blood Flow Metab. 2007;27:1510–20.
Porges EC, Jensen G, Foster B, Edden RA, Puts NA. The trajectory of cortical GABA across the lifespan, an individual participant data meta-analysis of edited MRS studies. Elife. 2021;10:e62575.
Hone-Blanchet, A, et al., Frontal metabolites and Alzheimer’s disease biomarkers in healthy older women and women diagnosed with mild cognitive impairment. Journal of Alzheimer’s Disease. 2022;87:1131–41.
Hone-Blanchet A, Bohsali A, Krishnamurthy LC, Shahid S, Lin Q, Zhao L, et al. Relationships between frontal metabolites and Alzheimer’s disease biomarkers in cognitively normal older adults. Neurobiol Aging. 2022;109:22–30.
Cleeland C, Pipingas A, Scholey A, White D. Neurochemical changes in the aging brain: a systematic review. Neurosci Biobehav Rev. 2019;98:306–19.
Pan JW, Rothman TL, Behar KL, Stein DT, Hetherington HP. Human brain β-hydroxybutyrate and lactate increase in fasting-induced ketosis. J Cereb Blood Flow Metab. 2000;20:1502–7.
Wang F, Smith NA, Xu Q, Goldman S, Peng W, Huang JH, et al. Photolysis of caged Ca2+ but not receptor-mediated Ca2+ signaling triggers astrocytic glutamate release. J Neurosci. 2013;33:17404–12.
Acknowledgements
The authors wish to thank Dr Dinesh Deelchand from the Center for Magnetic Resonance Research at the University of Minnesota for providing us with the 7T-LCModel basis-set.
Funding
The research described in this paper was funded by the W. M. Keck Foundation (to LRM-P), the White House Brain Research Through Advancing Innovative Technologies (BRAIN) Initiative (NSFNCS-FR 1926781 to LRM-P), the National Institutes of Health Grant K01NS110981 (to NAS), the Department of Defense Army Research Office Award W91NF2020189 (to NAS), and the Edward M. Connor Family Endowment for Innovation in Research (to NAS). Scanning at A.A. Martinos Center for Biomedical Imaging enabled by grant P41EB015896. The authors also wish to thank the Baszucki Brain Research Foundation. None of the funding sources played any role in the design of the experiments, data collection, analysis, interpretation of the results, the decision to publish, or any aspect relevant to the study. None of the authors received funding or in-kind support from pharmaceutical and/or other companies to write this manuscript.
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AH-B: acquisition, analysis, interpretation of data, drafting the work, final approval of the version to be published. BA: substantial contribution to acquisition of data presented in this work. LMcM: substantial contribution to acquisition data presented in this work. AL: substantial contribution to acquisition of data presented in this work. NAS: substantial contribution to revising the work and interpretation of data. SS: substantial contribution to conception and design and acquisition of data. Y-FY: substantial contribution to revising the work. APL: substantial contribution to revising the work. BGJ: substantial contribution to revising the work. LRM-P: substantial contribution to conception and design, interpretation of data and final approval of the version to be published. E-MR: substantial contribution to conception and design, interpretation of data and final approval of the version to be published.
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AH-B, BA, LMcM, APL, SS, NAS, Y-FY, BGJ and LRM-P declare no conflict of interest. APL is a consultant for Agios Pharmaceuticals, Biomarin Pharmaceuticals, and Moncton MRI; is co-founder of BrainSpec Inc.; and receives research funding from NINDS, NIA, the Department of Defense, and the Alzheimer’s Association. E‐MR is a member on the advisory board for BrainSpec, Inc.
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Hone-Blanchet, A., Antal, B., McMahon, L. et al. Acute administration of ketone beta-hydroxybutyrate downregulates 7T proton magnetic resonance spectroscopy-derived levels of anterior and posterior cingulate GABA and glutamate in healthy adults. Neuropsychopharmacol. 48, 797–805 (2023). https://doi.org/10.1038/s41386-022-01364-8
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DOI: https://doi.org/10.1038/s41386-022-01364-8
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