TY - JOUR

T1 - Short-term ketone monoester supplementation improves cerebral blood flow and cognition in obesity: A randomized cross-over trial

AU - Walsh, Jeremy J

AU - Caldwell, Hannah Grace

AU - Neudorf, Helena

AU - Ainslie, Philip N

AU - Little, Jonathan P

N1 - Publisher Copyright: © 2021 The Authors. The Journal of Physiology © 2021 The Physiological Society

PY - 2021

Y1 - 2021

N2 - Adults with obesity are at increased risk of neurocognitive impairments, partly as a result of reduced cerebral blood flow 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 cerebral blood flow and BDNF, as well as improve cognition in adults with obesity. In a placebo-controlled double-blind, cross-over design, 14 adults with obesity (10 females; aged 56 ± 12 years; body mass index = 33.8 ± 6.9 kg m–2) consumed 30 mL (12 g) of β-OHB or placebo thrice-daily for 14 days. Blood flow (Q) and cerebrovascular conductance (CVC) were measured in the common carotid (CCA), internal carotid (ICA) and vertebral (VA) arteries by duplex ultrasound. BDNF was measured by an enzyme-linked immunosorbent assay. Cognition was assessed by the digit-symbol substitution (DSST), Stroop and task-switching tests. Following 14 days of ketone supplementation, we observed significant improvements in cerebrovascular outcomes including QCCA (+12%), QVA (+11%), VACVC (+12%) and VA shear rate (+10%). DSST performance significantly improved following ketone supplementation (+2.7 correct responses) and improved DSST performance was positively associated improvements in cerebrovascular outcomes including QCCA, CCACVC, QVA and VACVC. By contrast to one hypothesis, β-OHB did not impact fasting serum and plasma BDNF. β-OHB supplementation improved cognition in adults with obesity, which may be partly facilitated by improvements in cerebral blood flow. β-OHB supplementation was well-tolerated and appears to be safe for cerebrovascular health, suggesting potential therapeutic benefits of β-OHB in a population at risk of neurocognitive impairment. (Figure presented.). Key points: People with obesity are at increased risk of neurocognitive dysfunction, partly as a result of -induced reductions in cerebral blood flow (CBF) and brain-derived neurotrophic factor (BDNF). Ketone supplements containing β-hydroxybutyrate (β-OHB) reduce postprandial hyperglycaemia, which may increase CBF and BDNF, thereby protecting against obesity-related cognitive dysfunction. We show for the first time that 14 days of thrice-daily β-OHB supplementation improves aspects of cognition and increases cerebrovascular flow, conductance and shear rate in the extracranial arteries of adults with obesity. Our preliminary data indicate a significant positive relationship between elevated CBF and improved cognition following β-OHB supplementation. This trial provides a foundation for the potential non-pharmacological therapeutic application of β-OHB supplementation in patient groups at risk of hyperglycaemic cerebrovascular disease and cognitive dysfunction.

AB - Adults with obesity are at increased risk of neurocognitive impairments, partly as a result of reduced cerebral blood flow 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 cerebral blood flow and BDNF, as well as improve cognition in adults with obesity. In a placebo-controlled double-blind, cross-over design, 14 adults with obesity (10 females; aged 56 ± 12 years; body mass index = 33.8 ± 6.9 kg m–2) consumed 30 mL (12 g) of β-OHB or placebo thrice-daily for 14 days. Blood flow (Q) and cerebrovascular conductance (CVC) were measured in the common carotid (CCA), internal carotid (ICA) and vertebral (VA) arteries by duplex ultrasound. BDNF was measured by an enzyme-linked immunosorbent assay. Cognition was assessed by the digit-symbol substitution (DSST), Stroop and task-switching tests. Following 14 days of ketone supplementation, we observed significant improvements in cerebrovascular outcomes including QCCA (+12%), QVA (+11%), VACVC (+12%) and VA shear rate (+10%). DSST performance significantly improved following ketone supplementation (+2.7 correct responses) and improved DSST performance was positively associated improvements in cerebrovascular outcomes including QCCA, CCACVC, QVA and VACVC. By contrast to one hypothesis, β-OHB did not impact fasting serum and plasma BDNF. β-OHB supplementation improved cognition in adults with obesity, which may be partly facilitated by improvements in cerebral blood flow. β-OHB supplementation was well-tolerated and appears to be safe for cerebrovascular health, suggesting potential therapeutic benefits of β-OHB in a population at risk of neurocognitive impairment. (Figure presented.). Key points: People with obesity are at increased risk of neurocognitive dysfunction, partly as a result of -induced reductions in cerebral blood flow (CBF) and brain-derived neurotrophic factor (BDNF). Ketone supplements containing β-hydroxybutyrate (β-OHB) reduce postprandial hyperglycaemia, which may increase CBF and BDNF, thereby protecting against obesity-related cognitive dysfunction. We show for the first time that 14 days of thrice-daily β-OHB supplementation improves aspects of cognition and increases cerebrovascular flow, conductance and shear rate in the extracranial arteries of adults with obesity. Our preliminary data indicate a significant positive relationship between elevated CBF and improved cognition following β-OHB supplementation. This trial provides a foundation for the potential non-pharmacological therapeutic application of β-OHB supplementation in patient groups at risk of hyperglycaemic cerebrovascular disease and cognitive dysfunction.

KW - BDNF

KW - Cerebrovascular

KW - Double-blind

KW - Executive functions

KW - Intervention

KW - Placebo-controlled

KW - β-hydroxybutyrate

U2 - 10.1113/JP281988

DO - 10.1113/JP281988

M3 - Journal article

C2 - 34605026

AN - SCOPUS:85116112554

VL - 599

SP - 4763

EP - 4778

JO - The Journal of Physiology

JF - The Journal of Physiology

SN - 0022-3751

IS - 21

ER -