Use of R-beta-[1-11C]hydroxybutyrate in PET studies of regional cerebral uptake of ketone bodies in humans

Abstract

A method for determining regional cerebral utilization of ketone bodies in humans is described. After a bolus injection of R-beta-[1-11C]hydroxybutyrate, the time course of the tracer in the brain was measured with positron emission tomography in five healthy volunteers. The regional cerebral blood flow was measured separately. The tracer uptake in the brain could be well described by a single rate constant, indicating that the concentration of unmetabolized ketone bodies in the brain is very low and that transport across the blood-brain barrier is the rate-limiting step. At an average plasma concentration of beta-hydroxybutyrate of 0.043 mumol/ml, the utilization rate was estimated to be 0.48 nmol.ml-1.min-1. In accordance with previous animal studies, the utilization rate was found to increase almost linearly with increasing plasma concentration of beta-hydroxybutyrate. Furthermore, the utilization was higher in gray than in white matter. Finally, the ratio between the utilization in the basal ganglia and the brain as a whole was lower for ketone bodies than for glucose.

Effect of acute hyperketonemia on the cerebral uptake of ketone bodies in nondiabetic subjects and IDDM patients

“…4. Plot of the accumulation rate constant (Kket) against [␤-HB]plas for each subject in groups of nondiabetic subjects (s) and IDDM patients (OE) at hyperglycemia and in the group of nondiabetic subjects at normoketonemia (F) studied previously (1). The linear regression line (slope Ϫ0.0025 Ϯ 0.0006, intercept 0.0114 Ϯ 0.0006, and R value 0.76) is also displayed.…”

“…3. Plot of the cerebral metabolic rate of ketone body utilization (CMRket, obtained with the 2-tissue compartment model) against ␤-HB concentration in plasma ([␤-HB]plas) for each subject in the groups of nondiabetic subjects (s) and IDDM patients (OE) at hyperglycemia and in the group of nondiabetic subjects at normoketonemia (F) studied previously (1). The displayed regression line is calculated with all data in the previous and present studies; it has the slope 7.9 Ϯ 0.5, the intercept 0.39 Ϯ 0.54, and the R value of 0.97.…”

“…For the 1k model and the Gjedde-Patlak analysis, the parameters were obtained by linear regression, whereas for the 3k model the parameters were estimated by using a nonlinear, iterative, least squares method (12). These models were also applied in the previous study at normoketonemia by use of the same tracer (1).…”

“…A method has previously been developed for measuring regional cerebral utilization of ketone bodies in humans with positron emission tomography (PET) using R-␤- [1-11 C]hydroxybutyrate (␤-[ 11 C]HB) as tracer (1). The method was applied in studies of healthy male subjects at normoketonemia.…”

[2,4-13C2]-β-Hydroxybutyrate Metabolism in Human Brain

“…In studies of lightly anesthetized rodents, brain ketone consumption has been reported to be small, at approximately 3% of total (Hawkins et al, 1986). This contrasts to measurements made in humans, performed through [ 11 C]-β-hydroxybutyrate (BHB) positron emission tomography (PET) (Blomqvist et al, 1995) and AV difference measurements (Owen et al, 1965;Hasselbalch et al, 1994Hasselbalch et al, , 1996. In fasted and nonfasted human studies, ketones have been reported to provide a substantially larger fraction of brain oxidative metabolism, up to 50% of energy production in 3-week fasted obese subjects.…”