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Case Reports
. 2015 Jan;11(1):99-103.
doi: 10.1016/j.jalz.2014.01.006. Epub 2014 Oct 7.

A New Way to Produce Hyperketonemia: Use of Ketone Ester in a Case of Alzheimer's Disease

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Case Reports

A New Way to Produce Hyperketonemia: Use of Ketone Ester in a Case of Alzheimer's Disease

Mary T Newport et al. Alzheimers Dement. .
Free PMC article

Abstract

Background: Providing ketone bodies to the brain can bypass metabolic blocks to glucose utilization and improve function in energy-starved neurons. For this, plasma ketones must be elevated well above the ≤ 0.2 mM default concentrations normally prevalent. Limitations of dietary methods currently used to produce therapeutic hyperketonemia have stimulated the search for better approaches.

Method: Described herein is a new way to produce therapeutic hyperketonemia, entailing prolonged oral administration of a potent ketogenic agent--ketone monoester (KME)--to a patient with Alzheimer's disease dementia and a pretreatment Mini-Mental State Examination score of 12.

Results: The patient improved markedly in mood, affect, self-care, and cognitive and daily activity performance. The KME was well tolerated throughout the 20-month treatment period. Cognitive performance tracked plasma β-hydroxybutyrate concentrations, with noticeable improvements in conversation and interaction at the higher levels, compared with predose levels.

Conclusion: KME-induced hyperketonemia is robust, convenient, and safe, and the ester can be taken as an oral supplement without changing the habitual diet.

Keywords: Brain insulin resistance; Fasting; Ketogenic diet; Ketone bodies; Ketone monoester; Medium-chain triglyceride; Pyruvate dehydrogenase; β-Hydroxybutyrate.

Conflict of interest statement

Conflict-of-interest statements:

Dr. Newport, Dr. VanItallie, and MT King have no financial interest in ketone monoester. Dr. VanItallie is a minority shareholder in a company that produces a food product containing medium-chain fatty acids. Dr. Veech has patent right from invention determined by NIH and DHHS standards.

Figures

Figure 1
Figure 1
Glucose and the ketone bodies, β-hydroxybutyrate (βHB) and acetoacetate (AcAc), enter neurons via different plasma membrane transporters; namely, glucose transporter 3 (GLUT3) and (ordinarily) monocarboxylate transporter 2 (MCT2), respectively. Following cytosolic glycolysis, glucose-derived pyruvate enters mitochondria, undergoing oxidative decarboxylation by pyruvate dehydrogenase (PDH). The resulting acetyl-CoA is then metabolized via the Krebs cycle. Inhibition of PDH activity (i.e., as caused by local insulin resistance) can reduce availability to mitochondria of energy-generating substrate, which may compromise neuronal function. In contrast, AcAc (derived in part from circulating βHB) is converted to acetyl-CoA distal to the pyruvate→acetyl-CoA step, thereby circumventing possible blocks to glucose metabolism at, or proximal to, that step.
Figure 2
Figure 2
β-hydroxybutyrate (βHB) concentrations rose to 3–7mM one hour after ingestion of ketone monoester (KME) in three different doses, 25g, 35g, and 50g, taken on separate days. The peak levels measured are in the range of those obtained during adherence to the classical ketogenic diet, and are about tenfold the concentrations achievable by medium-chain triglyceride (MCTG) administration. Because no more than two βHB measurements were made during the first 2 hours after KME ingestion, higher levels might have been reached that were not detected. The findings suggest that substantially elevated blood ketone concentrations can be maintained throughout the day if KME is taken every 3–4 hours. Precision Xtra Glucose and Ketone Monitoring System® (Abbott) was used to measure βHB levels in capillary blood samples. Acetoacetate (AcAc), ordinarily a minor fraction of total blood ketones, was not measured.

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