Proof of Mechanism of a New Ketogenic Supplement Using Dual Tracer PET (Positron Emission Tomography)

Study Overview
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Brief Summary
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A six month, placebo-controlled, parallel group project in which MCI participants will receive 30 g/day of a custom-made MCT-based ketogenic supplement or a matching placebo. Uptake of both the brain's fuels - ketones (as 11C-AcAc) and glucose (as FDG) - both before and after the intervention will be assessed by PET (position emission tomography) ; imaging and ketone pharmacokinetic as primary objective as well as fMRI, diffusion MRI and cognition.

Official Title
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Effect of a Ketogenic Supplement on Brain Energy Metabolism Measured by Neuroimaging in Mild Cognitive Impairment

Conditions
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Mild Cognitive Impairment

Intervention / Treatment
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* Dietary Supplement: ketogenic drink
* Dietary Supplement: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: subjective memory complaint Montreal Cognitive Assessment (MoCA) score of 18-26/30 or a Mini-mental state exam (MMSE) score of 24-27/30 autonomy for activity of daily living absence of depression Exclusion Criteria: diagnosis of a major cognitive disorder diseases or psychiatric disorders that could interfere with participation uncontrolled diabetes (fasting plasma glucose >7 mM or glycated hemoglobin >6.5%) major depression or history of alcohol or substance abuse within the past 2 years, already supplementing with coconut oil or MCT vitamin B12 deficiency uncontrolled hypertension, dyslipidemia, or thyroid disease, visual or hearing impairment impeding comprehension participation in another intervention trial inability to lie down without moving for 60 min (for the brain imaging) presence of implanted metal objects or devices contraindicated for MRI (phase 1)

Ages Eligible for Study
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Minimum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ketogenic drink<br>MCT ketogenic drink: ketogenic drink providing 30 g/d of MCT oil in 250 ml of lactose-free skim milk for 6 months supplementation | Dietary Supplement: ketogenic drink<br>* 6 months' supplementation with the ketogenic drink . Product will be taken daily - 125 ml will be consumed at the morning meal, and 125 ml at the evening meal.<br>|
| Placebo Comparator: Placebo<br>Lactose-free skim milk-based placebo drink containing high-oleic sunflower oil of equivalent energy value to the active arm for a 6 months supplementation | Dietary Supplement: placebo<br>* 6 months' supplementation with the placebo drink . Product will be taken daily - 125 ml will be consumed at the morning meal, and 125 ml at the<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in global ketone (11C-AcAc) uptake in grey matter | The change in brain ketone uptake will be quantified by PET and expressed as cerebral metabolic rate of AcAc (CMR-A) | Baseline and 6 months of intervention | 
| Change in plasma ketone | The change in plasma ketone will be measure to obtain a ketone chronic response | Baseline and 6 months of intervention | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in global brain FDG uptake in grey matter (CMR-G) | The change in brain glucose uptake will be quantified by PET and expressed as cerebral metabolic rate of glucose (CMR-G) | Baseline and 6 months of intervention | 
| Change in regional CMR-A | The change in brain ketone uptake will be quantified by PET in different regions of the brain | Baseline and 6 months of intervention | 
| regional brain volumes by vMRI | Change in brain volume measure by MRI | Baseline and 6 months of intervention | 
| Change in cognitive status - episodic memory | Change in episodic memory assessed by the 16-item free/cued word learning (Buschke and Grober test- Z score of trial 1, 2, 3 and delay) and the Brief Visuospatial Memory Test-revised (Z score of trial 1) | Baseline and 6 months of intervention | 
| Change in cognitive status- language domain | Change in language assessed by Boston Naming Test (Z score) | Baseline and 6 months of intervention | 
| Change in cognitive status - executive function | Change in executive function assessed by condition 4 of the trail making test, condition 3 and 4 of the Stroop test and the 4 conditions of verbal fluency test (all Z score) | Baseline and 6 months of intervention | 
| Change in cognitive status - processing speed | Change in processing speed assessed by global score of Digit Span (WAIS III), Digit Symbol (WAIS III), condition 1 and 2 of Stroop test and condition 1,2,3,5 of the trail making test (all Z score) | Baseline and 6 months of intervention | 
| Blood metabolite profile triglycerides | Changes in Triglycerides (mM) | Baseline and 6 months of intervention | 
| Blood metabolite profile Glucose | Changes in Glucose (mM) | Baseline and 6 months of intervention | 
| Blood metabolite profile cholesterol | Changes in Total cholesterol (mM) | Baseline and 6 months of intervention | 
| Derived cerebral metabolic rate of total ketones | Cerebral metabolic rate of total ketone derived from ketone PET (dCMRket, μmol/100 g/min) | Baseline and 6 months of intervention | 
| Pharmacokinetic ketone response (phase 2) | Area under the curve of pharmacokinetic of blood ketone | Baseline and 6 months of intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mild cognitive impairment, ketones, medium chain triglycerides, Positron emission tomography, magnetic resonance imaging, cognition, brain, neuroimaging