Β-OHB Supplementation and Brain Health in Older Adults

Official title

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

Overview

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.

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.

Interventions

• 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).
• 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.

Primary outcome measures

• Global cerebral blood flow (gCBF) [Time frame: 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]

Secondary outcome measures (4)

• Cognitive testing [Time frame: 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]
• Cerebrovascular reactivity [Time frame: 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]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Double blind

Primary purpose

Basic science

Study locations

Canada · 1 center

• McMaster University — Hamilton

Publications

• 2023 Alzheimer's disease facts and figures. Alzheimers Dement. 2023 Apr;19(4):1598-1695. doi: 10.1002/alz.13016. Epub 2023 Mar 14. PMID 36918389
• 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. PMID 34139129
• Alzheimer's Society of Canada. Rising Tide: The Impact of Dementia on Canadian Society. 2010; ISBN 978-0-9733522-2-1
• Cunnane SC, Courchesne-Loyer A, Vandenberghe C, St-Pierre V, Fortier M, Hennebelle M, Croteau E, Bocti C, Fulop T, Castellano CA. Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer's Disease. Front Mol Neurosci. 2016 Jul 8;9:53. doi: 10.3389/fnmol.2016.00053. eCollection 2016. PMID 27458340
• Cunnane SC, Trushina E, Morland C, Prigione A, Casadesus G, Andrews ZB, Beal MF, Bergersen LH, Brinton RD, de la Monte S, Eckert A, Harvey J, Jeggo R, Jhamandas JH, Kann O, la Cour CM, Martin WF, Mithieux G, Moreira PI, Murphy MP, Nave KA, Nuriel T, Oliet SHR, Saudou F, Mattson MP, Swerdlow RH, Millan MJ. Brain energy rescue: an emerging therapeutic concept for neurodegenerative disorders of agein PMID 32709961
• Frei M, Berres M, Kivisaari SL, Henzen NA, Monsch AU, Reinhardt J, Blatow M, Kressig RW, Krumm S. Can you find it? Novel oddity detection task for the early detection of Alzheimer's disease. Neuropsychology. 2023 Oct;37(7):717-740. doi: 10.1037/neu0000859. Epub 2022 Oct 6. PMID 36201797
• GBD 2019 Dementia Forecasting Collaborators. Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: an analysis for the Global Burden of Disease Study 2019. Lancet Public Health. 2022 Feb;7(2):e105-e125. doi: 10.1016/S2468-2667(21)00249-8. Epub 2022 Jan 6. PMID 34998485
• Han YM, Bedarida T, Ding Y, Somba BK, Lu Q, Wang Q, Song P, Zou MH. beta-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4. Mol Cell. 2018 Sep 20;71(6):1064-1078.e5. doi: 10.1016/j.molcel.2018.07.036. Epub 2018 Sep 6. PMID 30197300

Identifiers

NCT: NCT06588946 · 05992572

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗