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

Antoine Hone-Blanchet, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA.
Botond Antal, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA.
Liam McMahon, Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, 11794, USA.
Andrew Lithen, Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY, 11794, USA.
Nathan A. Smith, Center for Neuroscience Research, Children's National Research Institute, Children's National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC, 20012, USA.
Steven Stufflebeam, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA.
Yi-Fen Yen, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA.
Alexander Lin, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA.
Bruce G. Jenkins, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA.
Lilianne R. Mujica-Parodi, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA.
Eva-Maria Ratai, Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA. ERATAI@mgh.harvard.edu.

Document Type

Journal Article

Publication Date

8-22-2022

Journal

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

DOI

10.1038/s41386-022-01364-8

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.

Department

Pediatrics

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