Ketone Dose and Cerebral Blood Flow Study

Study Overview
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Brief Summary
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Ketone bodies are produced by the liver during periods of food scarcity or severe carbohydrate restriction. Blood ketones are an alternative fuel source used by the brain, heart, and skeletal muscle during periods of fasting. Further, ketones bodies act as a signalling molecule that have pleiotropic effects that upregulate cellular stress-resistance pathways throughout the body. Oral supplements containing exogenous ketones have recently become available and represent a novel tool for increasing plasma ketone bodies without the need for dietary restriction. Early evidence suggests that oral ketone supplements may enhance cerebral blood flow and improve cognition. However, the dose-dependent effects of a single ketone supplement on cerebral blood flow and cognition in young adults is currently unknown. The purpose of this study is to characterize the effects of ingesting a high versus low dose of an oral ketone monoester on cerebral blood flow, circulating blood markers, and cognition in young adults. As an exploratory aim, this study will investigate how oxygen uptake kinetics during submaximal exercise are impacted 2 hours after ingestion of a ketone supplement. Recent findings indicate that ketone supplementation may impair exercise performance due to the physiological stress (i.e., pH disturbances) imposed by an acute ketone dose. Delaying exercise onset by 2 hours after ingestion of a ketone supplement may enhance oxygen kinetics in a dose-dependent manner.

Official Title
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The Acute Effects of a High Versus Low Dose of a Ketone Monoester Supplement on Cerebral Blood Flow and Cognition

Conditions
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Cerebrovascular Function, Cognition

Intervention / Treatment
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* Dietary Supplement: Low Dose β-OHB
* Dietary Supplement: High Dose β-OHB
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Between the ages of 18 and 35 Exclusion Criteria: Presence of obesity (body mass index > 30 kg/m^2) Presence of known cardiovascular disease Presence of type 2 diabetes History of cardiovascular events requiring hospitalization (i.e., heart attack) History of concussion(s) with persistent symptoms Currently following a ketogenic diet and/or taking ketone body supplements

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: A randomized double-blind placebo-controlled crossover design will be used to test 3 conditions. Participants will consume 60 mL of a supplement containing: 1) a low β-OHB dose (0.3g/kg) body weight of the ketone monoester; [R]-3-hydroxybutyl [R]-3-hydroxybutyrate); 2) a high β-OHB dose (0.6g/kg body weight); or 3) a taste-matched calorie-free inert placebo drink.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Single dose of a taste-matched calorie-free placebo | Other: Placebo<br>* Ingestion of a taste-matched calorie-free placebo drink followed by 2-hours of rest. Submaximal exercise to be performed following 2-hour resting measures.<br>|
| Experimental: High Dose β-OHB<br>Single dose of a ketone monoester ([R]-3-hydroxybutyl [R]-3-hydroxybutyrate; 0.6 g β-OHB/kg body weight) | Dietary Supplement: High Dose β-OHB<br>* Ingestion of a high dose [R]-3-hydroxybutyl [R]-3-hydroxybutyrate (0.6 g β-OHB/kg body weight) followed by 2-hours of rest. Submaximal exercise to be performed following 2-hour resting measures.<br>|
| Experimental: Low Dose β-OHB<br>Single dose of a ketone monoester ([R]-3-hydroxybutyl [R]-3-hydroxybutyrate; 0.3 g β-OHB/kg body weight) | Dietary Supplement: Low Dose β-OHB<br>* Ingestion of a low dose [R]-3-hydroxybutyl [R]-3-hydroxybutyrate (0.3 g β-OHB/kg body weight) followed by 2-hours of rest. Submaximal exercise to be performed following 2-hour resting measures.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Resting cerebral blood flow (CBF) | Measured via duplex ultrasound of the extra-cranial arteries (internal carotid and vertebral arteries). | 2-hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive Function | The MST (Mnemonic Similarity Task) will be used to assess hippocampal-dependent memory and pattern separation. | 2-hour | 
| Plasma beta-hydroxybutyrate area under the curve | Venous blood samples will be obtained via intravenous catheter | 2-hour | 
| Brain-derived neurotrophic factor (BDNF) | Serum and plasma BDNF measured in venous blood samples will be obtained via intravenous catheter | 2-hour, then following completion of submaximal exercise bout | 
| Oxygen uptake (VO2) | Breath-by-breath analysis performed via metabolic cart | 2-hour, then during submaximal exercise (performed after 2-hour rest period) | 
| End-tidal CO2 | Breath-by-breath analysis performed via PowerLab Gas Analyzer (AD Instruments) | 2-hour, then during submaximal exercise (performed after 2-hour rest period) | 
| Mean arterial pressure (MAP) | Automated blood pressure cuff measurement of brachial artery pressure in mmHg. | 2-hour | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cerebral Blood Flow, Cognition, Beta-hydroxybutyrate (β-OHB)