Abstracts

RATIONALE: The mechanism of anti-epileptic action of the ketogenic diet is not well defined. Furthermore, dietary management is often empiric, evaluated through its efficacy and measurement of plasma ketones. To better understand the diet[ssquote]s mechanism of action and possibly manage the diet, more data are needed on how the brain takes up and uses ketones. This study measures brain [beta] hydroxybutyrate (BHB) in acutely hyperketonemic healthy adults using MR spectroscopy.
METHODS: A 4T Varian Inova whole body MR system and 7cm surface coil was used. The surface coil was placed adjacent to the occipital ridge. After scout imaging, BHB was detected using an adiabatic homonuclear editing sequence from a coronal volume measuring 4x4x1cc. The TR=2sec, TE=148msec (minimum scan time, 4.5min). The spectra were quantified in reference to N-acetyl aspartate at 10mM. Under an IRB approved protocol, all subjects (n=6 adults) were healthy, non-obese and overnight fasted. IV catheters were placed in both antecubital fossa veins, and 200mM sodium-D-BHB was ramp infused at 80uM/kg-minx 10min and then maintained at 20uM/kg-min x80min. MR measurements of brain BHB and lactate were acquired during the 60-90min period into the infusion.
RESULTS: All subjects became acutely ketonemic, with plasma levels rising from a mean of 0.01 to 2.12[plusminus]0.30mM. The figure shows spectra demonstrating lactate and the low levels of baseline brain BHB (overnight fasted; difference spectrum, fig. 1a), and the increased level seen with the acute hyperketonemia (fig. 1b). Comparing this with data obtained in a 2day fasted subject (fig. 1c) shows that although brain BHB is elevated in acute hyperketonemia, the amount of increase is less than that seen after 2days of fasting, when plasma levels are similar. Quantifying the acute hyperketonemia data shows that in these subjects the brain BHB level rose from a base of 195[plusminus]43uM to 275[plusminus]78uM (p[lt]0.05).
CONCLUSIONS: These data are compared to that obtained earlier with fasting induced hyperketonemia. The plasma levels of BHB achieved in the present study are similar to that reached after fasting 40-48hr. Under these fasting conditions, the measured brain BHB concentration was 0.6[plusminus]0.26mM, and correlated to the plasma BHB concentration (r=0.86, p[lt]0.001). These data suggest that ketone body transport is upregulated with fasting. This also gives some basis for the use of fasting to initiate the ketogenic diet, as well as the improved seizure control often observed with fasting.[figure]
Support: Charles A. Dana Foundation (JWP), NIH NS-PO1-39092 (HPH).