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| Name | Class |
|---|---|
| Heart and Stroke Foundation of Canada | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ketone monoester (KME) supplement | Experimental | Participants will be instructed to consume a ketone monoester (KME) supplement prior to each meal (3x/day) for 14 days. |
|
| Placebo supplement | Placebo Comparator | Participants will be instructed to consume a bottle of placebo supplement prior to each meal (3x/day) for 14 days. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ketone monoester (KME) supplement | Dietary 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). |
| Measure | Description | Time Frame |
|---|---|---|
| Global cerebral blood flow (gCBF) | 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 | 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 |
| Measure | Description | Time Frame |
|---|---|---|
| Cognitive testing | 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. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Walsh | Contact | (905) 525-9140 | walshj18@mcmaster.ca |
| Name | Affiliation | Role |
|---|---|---|
| Jeremy Walsh, PhD | McMaster University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| McMaster University | Hamilton | Ontario | L8S 4K1 | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 36918389 | Background | 2023 Alzheimer's disease facts and figures. Alzheimers Dement. 2023 Apr;19(4):1598-1695. doi: 10.1002/alz.13016. Epub 2023 Mar 14. | |
| 34139129 | Background | Al-Khazraji BK, Buch S, Kadem M, Matushewski BJ, Norozi K, Menon RS, Shoemaker JK. Protocol-dependence of middle cerebral artery dilation to modest hypercapnia. Appl Physiol Nutr Metab. 2021 Sep;46(9):1038-1046. doi: 10.1139/apnm-2021-0220. Epub 2021 Jun 17. |
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The investigators will share individual patient data (de-identified) with researchers upon request.
Beginning 9 months and ending 36 months following article publication.
Researchers from a reputable institution who wish to access the data may submit a request to the Principal Investigator.
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| ID | Term |
|---|---|
| D003704 | Dementia |
| ID | Term |
|---|---|
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D019965 | Neurocognitive Disorders |
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placebo-controlled
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| Placebo supplement | Dietary 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. |
|
| Baseline and post-intervention (i.e., 14-days later) for both KME and placebo conditions |
| Microstructural white matter health | 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 | 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 | 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 |
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| D001523 | Mental Disorders |