Β-OHB Supplementation and Brain Health in Older Adults

February 24, 2025 updated by: Jeremy Walsh, McMaster University

The Effect of Exogenous Β-OHB Supplementation on Cerebral Blood Flow and Functional Brain Characteristics in Adults with Subjective Cognitive Decline

The goal of this randomized placebo controlled crossover trial is investigate the effects of short-term ketone monoester (KME) supplementation to brain function in older adults with subjective cognitive decline. We will test the hypothesis that KME supplementation will increase cerebral blood flow and improve resting-state functional connectivity in the brain compared to placebo supplementation in older adults with subjective cognitive decline.

Participants will be randomly assigned to either placebo of KME supplementation for 14 days. Following a washout period, participants will complete the alternate condition for 14 days. Outcome measures will be assessed before and after each intervention period.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

In this randomized placebo-controlled crossover double-blind designed clinical trial, 48 adults with SCD (50% female; aged 55 to 75 years old) will be allocated to a ketone monoester (KME) or placebo condition in random order (e.g., A-B or B-A), stratified by sex. Participants will be recruited from the local community through McMaster University, the local Alzheimer Society, and community outreach.

In total, participants will be asked to complete 5 visits. Data will be collected at a single site in Hamilton, Ontario associated with McMaster University. All interested individuals will complete an eligibility screening study visit (Visit 1) to establish inclusion/exclusion. Written, informed consent will be obtained before data collection. Demographic information and medical history will be collected at the beginning of Visit 1 to obtain information regarding medication use, medical history, age, years of education, and sex and gender-based variables. This information will be collected using a participant history questionnaire and the GENESIS-PRAXY questionnaire. Participants will also be introduced to the lab and the different tests that we will run during the experimental visits. Data will be collected at two time points for each condition: 1) Pre-intervention (Visits 2 & 4: baseline); and post-intervention (Visits 3 & 5: following 14-day intervention). In a randomized crossover design, participants will be randomly allocated to a condition (placebo or KME) for a 14-day intervention. Participants will then undergo a washout period, afterwhich participants will be complete the alternate condition including baseline data collection (Visit 4) and post-intervention visit (Visit 5) after the second 14-day intervention period.

Study Type

Interventional

Enrollment (Estimated)

48

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Canada
    • Ontario
      • Hamilton, Ontario, Canada, L8S 4K1
        • McMaster University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Being objectively cognitively normal as determined by a Montreal Cognitive Assessment (MoCA) score ≥26 with independent living and ambulating
  • SCD will be determined using the Prospective-Retrospective Memory Questionnaire (PRMQ) following the SCD Initiative Working Group framework

Exclusion Criteria:

  • A diagnosis of mild cognitive impairment, dementia, or psychiatric and/or mood disorders (e.g., major depression)
  • MoCA score <26
  • Diagnosis of cardiometabolic disease (e.g., hypertension, type 2 diabetes)
  • Obesity (BMI >30 kg/m2)
  • History of heart attack or stroke
  • History of smoking
  • Currently following a ketogenic diet or taking ketogenic supplements
  • Having MRI contraindications
  • Participants with literacy, visual, hearing, and/or speech issues, as well as individuals who are not proficient in English will not be eligible for this trial

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Ketone monoester (KME) supplement
Participants will be instructed to consume a ketone monoester (KME) supplement prior to each meal (3x/day) for 14 days.
Dietary supplement: Ketone monoester (KME) supplement
15g of a KME supplement orally consumed 3x daily for 14 days. This dosing protocol raises plasma β-OHB consistently during the waking hours. Oral KME will be provided in opaque bottles labelled A or B to maintain condition blinding. Each bottle will contain a drink providing 15g of a KME supplement: [R]-3-hydroxybutyl [R]-3-hydroxybutyrate (ΔG®, TDeltaS, Oxford, UK).
Other Names:
  • [R]-3-hydroxybutyl [R]-3-hydroxybutyrate (ΔG®, TDeltaS, Oxford, UK)
Placebo Comparator: Placebo supplement
Participants will be instructed to consume a bottle of placebo supplement prior to each meal (3x/day) for 14 days.
Dietary supplement: Placebo supplement
50mL taste-match inert calorie-free placebo drink orally consumed 3x daily for 14 days. Oral placebo will be provided in opaque bottles labelled A or B to maintain condition blinding.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Global cerebral blood flow (gCBF)
Time Frame: Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions
Measured by magnetic resonance imaging (MRI) under resting, normocapnic conditions. Arterial flow measurement will be performed using a phase contrast flow sensitizing MRI pulse sequence. Cross-sectional areas and mean blood flow of the carotid and vertebral arteries will be measured, with total blood flow in all four vessels equaling global CBF.
Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions
Resting-state functional connectivity
Time Frame: Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions
A resting state functional magnetic resonance imaging (rsfMRI) scan will be performed eyes closed using a gradient echo EPI sequence. The temporal and regional co-activation of brain regions in the resting state provide a measure of functional connectivity in the brain. rsfMRI data will be analyzed to measure global whole-brain functional connectivity and within localized brain regions of interest.
Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Cognitive testing
Time Frame: Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions
A battery of computerized validated psychometric tests will be used, including: the Mnemonic similarities task (MST) to assess hippocampal-dependent learning and memory, the Stroop colour-word task to assess processing speed, working memory, attention, and inhibitory control, and a shortened version of the Odd-One-Out test to measure working memory and executive function. A non-computerized dual-task test will be performed to assess the multitasking ability of walking while performing another cognitive task.
Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions
Microstructural white matter health
Time Frame: Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions
Dual spin echo, echo-planar imaging (EPI) diffusion tensor imaging (DTI) sequence collected by magnetic resonance imaging (MRI) to assess brain white matter microstructural integrity.
Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions
Cerebrovascular reactivity
Time Frame: Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions
The phase contrast flow sensitizing MRI pulse and resting state functional MRI sequences will both be repeated while participants undergo an elevated CO2 breathing task. Cerebrovascular function will be calculated from the stimulus-response relationship between PaCO2 and (1) phase contrast: cross sectional areas of the internal carotid and vertebral arteries, and (2) rsfMRI: % change BOLD/mmHg.
Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions
Blood-borne biomarkers
Time Frame: Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions
A venous blood sample will be collected to assess circulating concentrations of various hormones and metabolites (e.g., brain-derived neurotrophic factor [BDNF]) that relate to brain health, metabolism, and inflammation.
Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

McMaster University

Collaborators

Heart and Stroke Foundation of Canada

Investigators

  • Principal Investigator: Jeremy Walsh, PhD, McMaster University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

March 1, 2025

Primary Completion (Estimated)

August 1, 2027

Study Completion (Estimated)

August 1, 2027

Study Registration Dates

First Submitted

September 5, 2024

First Submitted That Met QC Criteria

September 5, 2024

First Posted (Actual)

September 19, 2024

Study Record Updates

Last Update Posted (Actual)

March 25, 2025

Last Update Submitted That Met QC Criteria

February 24, 2025

Last Verified

February 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 05992572

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The investigators will share individual patient data (de-identified) with researchers upon request.

IPD Sharing Time Frame

Beginning 9 months and ending 36 months following article publication.

IPD Sharing Access Criteria

Researchers from a reputable institution who wish to access the data may submit a request to the Principal Investigator.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ANALYTIC_CODE

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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