It is well known that the brain can switch from its primary fuel of glucose to ketone bodies under states of fasting, vigorous exercise, specific diets as well as a number of clinical disorders. However, specifically how the human brain uses ketones is not well defined. This question is of major interest particularly since the ketogenic diet (KD) is known to be of significant therapeutic value in the treatment of intractable epilepsies. In order to understand how the metabolic state of ketosis is affecting brain function inepileptic patients, an understanding of how ketosis affects the non-epileptic brain is critical. Human brain ketone metabolism is thought to be limited by plasma levels and blood brain barrier transport reflecting the belief that brain ketone oxidation is rapid, thus preventing accumulation of ketones. However, recent human brain data have shown that significant accumulation of b-hydroxybutyrate (BHB) can occur. Since the brain pool of ketones is not negligible, especially during ketotic states such as fasting, this implies that oxidation of ketones is limited relative to its net influx. In this proposal we will investigate the brain accumulation of ketones to define its transport in healthy fasted and non-fasted adults, to determine whether induction of transport occurs with fasting. We will investigate how much ketones fractionally contribute towards oxidative flow, and determine how much this contribution changes with chronic (fasting induced) ketosis. These data will define the baseline effects of ketosis. In the last part of this application we will apply this work in adult and pediatric epilepsy patients being treated with the ketogenic diet. We will determine whether accumulation of cerebral ketonesin these two patient groups is comparable to healthy controls. In doing so, we will establish a means by which the cerebral metabolic evaluation of the patients on the ketogenic diet can be made. We anticipate that these data will contribute towards better understanding of themechanism of seizure control by theketogenic diet.
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