Abstracts

RATIONALE: The 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, more data are needed on how the brain uses ketones. This study uses ^13C-labeled ketones and in vivo MR spectroscopy to evaluate how [beta]hydroxybutyrate (BHB) is used in the brain of healthy adults.
METHODS: Under an IRB approved protocol, four healthy overnight fasted adults were studied. IV catheters were placed in both antecubital fossa veins, and 200mM sodium [2,4-¹³C[sub]2[/sub]]-D-BHB was bolus infused at 16.7ml/minx 20min and then maintained at 22uM/kg-min x100min. A Bruker Biospec 2.1T human MR system and a ¹³C (22.55MHz) surface coil with quadrature ¹H (89.64MHz) decoupling coils were used for all studies. As previously described, a localized adiabatic ¹³C-[¹H] polarization transfer sequence was used for detection of ¹³C, resulting in a sample volume of 6x4x6cc selected from the occipital-parietal lobes (Shen et al 1999).
RESULTS: The rise in plasma BHB is rapid, and is accompanied by a near simultaneous rise in brain BHB. From the four subjects, the achieved plasma concentration of BHB was 2.25[plusminus]0.24mM with an apparent brain concentration of 0.18[plusminus]0.06mM measured at the end of the infusion. Fig. 1 demonstrates the 13C labeling of the amino acid pools acquired during the 60-120min period of a two hour infusion study from a volunteer. The positions of glutamate, glutamine and aspartate are well resolved. The anticipated point of ¹³C entry in the amino acid pools is glutamate-4 (from oxidative degradation of [2,4]-¹³C[sub]2[/sub]-BHB) with subsequent labeling into glutamine-4 and glutamate-3 (neurotransmission and metabolism). The relative labeling of glutamate-4, glutamine-4 and glutamate-3 were 6.78[plusminus]1.71%, 5.68[plusminus]1.84% and 5.91[plusminus]1.70%.
CONCLUSIONS: The steady state BHB measurement of 0.18[plusminus]0.04mM is consistent with that determined in earlier studies using non-labeled D-BHB infusions (Pan et al 2001), at approximately 0.2mM. Because of contributions from brain and non-brain components (vascular, CSF), this value is an upper bound to the brain BHB concentration. The distribution of ¹³C label seen in glutamate and glutamine resembles that for glucose. Analysis of the glutamate-4 and glutamine-4 labeling using a metabolic model based on interacting neuronal and astrocytic pools suggests that under these conditions, BHB consumption is preferred by the neuronal compartment by at least a factor of 1.85. This suggests that with regards to ketogenic diet therapy, that ketones may provide a fuel that is preferentially earmarked for neuronal consumption, thereby bypassing the astrocytic metabolism hypothesized with glucose consumption (Magistretti et al 1996).
References:
Pan JW, Telang FW, Lee JH et al (2001). J Neurochem. 79:539-544.
Shen J, Petersen KF, Behar KL et al (1999). Proc Natl Acad Sci USA 96:8235-8240.
Magistretti PJ and Pellerin L. (1996) Cerebral Cortex 6(1):50-61.[figure1]
[Supported by: NIH R01 NS40550-1, P01 NS39092, R01 NS37527 and the Charles A. Dana Foundation .]