Short‐term ketone monoester supplementation improves cerebral blood flow and cognitive function in adults with obesity: A randomized‐crossover trial

Abstract

Background/Objectives Adults with obesity are at increased risk of neurocognitive impairments, due in part to reductions in cerebral blood flow (CBF) and brain-derived neurotrophic factor (BDNF). Ketone supplements containing β-hydroxybutyrate (β-OHB) are a purported therapeutic strategy for improving brain health in at-risk populations. We tested the hypothesis that short-term β-OHB supplementation will elevate CBF and BDNF, and in turn improve cognitive function in individuals with obesity. Subjects/Methods In a placebo-controlled double-blind crossover design 14 adults with obesity (10F; age=56±12 yrs; BMI=33.8±6.9 kg/m2) consumed 30 mL of either placebo or ketone supplement (12 g β-OHB) thrice-daily for 14 days. Participants were provided with all meals and snacks, which were matched between each 14-day period. CBF, cerebrovascular conductance (CVC), and shear rate were measured in the common carotid (CCA), internal carotid (ICA), and vertebral (VA) arteries by duplex ultrasound. Plasma and serum BDNF were measured by ELISA. Cognitive function was assessed by the digit-symbol substitution task (DSST), Stroop test, and task-switching test. All measures were taken in the fasting, non-supplemented state. Results CCA blood flow (25 mL×min-1 [12, 38], P=0.001), ICA shear rate (42 s-1 [15, 69], P=0.004), VA blood flow (18 mL×min-1 [10, 26], P<0.001), VACVC (0.08 mL×min-1×mmHg-1 [0.01, 0.15], P=0.027), and VA shear rate (34 s-1 [10, 59], P=0.008) significantly increased following 14-days of ketone supplementation. DSST performance (correct responses; CR) increased following ketone supplementation (+2.7 CR [1.3, 4.1], P<0.001) and this was positively associated with CCA blood flow (0.001 mL×min-1×CR-1 [0.001, 0.02], P=0.033) and CCACVC (1.24 ml×min-1×mmHg-1 CR-1 [0.24, 2.24], P=0.024), VA blood flow (0.034 mL×min-1×CR-1 [0.002, 0.066], P=0.039) and VACVC (3.32 1.24 ml×min-1×mmHg-1 CR-1 [0.20, 6.43], P=0.04). There were no differences in serum (301.8 pg/mL [-1033.4, 1637.2], P=0.65) and plasma BDNF (-380.4 pg/mL [-1023.9, 263.2], P=0.24) following ketone supplementation. Conclusions Short-duration ketone supplementation improved aspects of cognitive function, which may have been facilitated by enhanced CBF in adults with obesity. Ketone supplementation was well-tolerated and appears safe for cerebrovascular health, suggesting potential therapeutic benefits of β-OHB for brain health in adults with obesity.