Eric D Vidoni1,2, In-Young Choi1,3,2,4, Phil Lee1,3,4,5, Gregory Reed6, Na Zhang6, Joseph Pleen1,2, Jonathan D Mahnken1,7, Jonathan Clutton1, Annette Becker1, Erica Sherry1, Rebecca Bothwell1, Heidi Anderson1, Robert A Harris8, William Brooks1,3,2,4, Heather M Wilkins1,2, Lisa Mosconi9, Jeffrey M Burns1,2,4, Russell H Swerdlow1,2,4,8. 1. University of Kansas Alzheimer's Center, Fairway, Kansas, USA. 2. Department of Neurology, Kansas University Medical Center, Kansas City, Kansas, USA. 3. Hoglund Biomedical Imaging Center, Kansas City, Kansas, USA. 4. Department of Molecular and Integrative Physiology, Kansas University Medical Center, Kansas City, Kansas, USA. 5. Department of Radiology, Kansas University Medical Center, Kansas City, Kansas, USA. 6. Department of Pharmacology and Toxicology, Kansas University Medical Center, Kansas City, Kansas, USA. 7. Department of Biostatistics, Kansas University Medical Center, Kansas City, Kansas, USA. 8. Biochemistry and Molecular Biology, Kansas University Medical Center, Kansas City, Kansas, USA. 9. Department of Neurology, Weill Cornell Medical College, New York, New York, USA.
Abstract
INTRODUCTION: Brain bioenergetics are defective in Alzheimer's disease (AD). Preclinical studies find oxaloacetate (OAA) enhances bioenergetics, but human safety and target engagement data are lacking. METHODS: We orally administered 500 or 1000 mg OAA, twice daily for 1 month, to AD participants (n = 15 each group) and monitored safety and tolerability. To assess brain metabolism engagement, we performed fluorodeoxyglucose positron emission tomography (FDG PET) and magnetic resonance spectroscopy before and after the intervention. We also assessed pharmacokinetics and cognitive performance. RESULTS: Both doses were safe and tolerated. Compared to the lower dose, the higher dose benefited FDG PET glucose uptake across multiple brain regions (P < .05), and the higher dose increased parietal and frontoparietal glutathione (P < .05). We did not demonstrate consistent blood level changes and cognitive scores did not improve. CONCLUSIONS: 1000 mg OAA, taken twice daily for 1 month, is safe in AD patients and engages brain energy metabolism.
INTRODUCTION: Brain bioenergetics are defective in Alzheimer's disease (AD). Preclinical studies find oxaloacetate (OAA) enhances bioenergetics, but human safety and target engagement data are lacking. METHODS: We orally administered 500 or 1000 mg OAA, twice daily for 1 month, to AD participants (n = 15 each group) and monitored safety and tolerability. To assess brain metabolism engagement, we performed fluorodeoxyglucose positron emission tomography (FDG PET) and magnetic resonance spectroscopy before and after the intervention. We also assessed pharmacokinetics and cognitive performance. RESULTS: Both doses were safe and tolerated. Compared to the lower dose, the higher dose benefited FDG PET glucose uptake across multiple brain regions (P < .05), and the higher dose increased parietal and frontoparietal glutathione (P < .05). We did not demonstrate consistent blood level changes and cognitive scores did not improve. CONCLUSIONS: 1000 mg OAA, taken twice daily for 1 month, is safe in AD patients and engages brain energy metabolism.
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