The ketogenic diet increases brain glucose and ketone uptake in aged rats: A dual tracer PET and volumetric MRI study

Despite decades of study, it is still unclear whether regional brain glucose uptake is lower in the cognitively healthy elderly. Whether regional brain uptake of ketones (β-hydroxybutyrate and acetoacetate [AcAc]), the main alternative brain fuel to glucose, changes with age is unknown. We used a sequential, dual tracer positron emission tomography (PET) protocol to quantify brain 18F-fluorodeoxyglucose (18F-FDG) and 11C-AcAc uptake in two studies with healthy, male Sprague-Dawley rats: (i) Aged (21 months; 21M) versus young (4 months; 4M) rats, and (ii) The effect of a 14 day high-fat ketogenic diet (KD) on brain 18F-FDG and 11C-AcAc uptake in 24 month old rats (24M). Similar whole brain volumes assessed by magnetic resonance imaging, were observed in aged 21M versus 4M rats, but the lateral ventricles were 30% larger in the 21M rats (p=0.001). Whole brain cerebral metabolic rates of AcAc (CMRAcAc) and glucose (CMRglc) did not differ between 21M and 4M rats, but were 28% and 44% higher, respectively, in 24M-KD compared to 24M rats. The region-to-whole brain ratio of CMRglc was 37–41% lower in the cortex and 40–45% lower in the cerebellum compared to CMRAcAc in 4M and 21M rats. We conclude that a quantitative measure of uptake of the brain’s two principal exogenous fuels was generally similar in healthy aged and young rats, that the % of distribution across brain regions differed between ketones and glucose, and that brain uptake of both fuels was stimulated by mild, experimental ketonemia.

► Cerebral metabolic rates of acetoacetate (CMRAcAc) and glucose (CMRglc) were similar in 21 compared to 4 month old rats.
► The high-fat ketogenic diet increases both CMRAcAc and CMRglc in 24 month old rats.
► The region-to-whole brain ratios differ significantly between CMRAcAc and CMRglc.