Brain Health
Conditions
Keywords
ketone supplement, brain MRI, brain MRS
Brief summary
The purpose of this study is to determine how a ketone ester supplement affects brain function, brain blood flow, and brain metabolism in healthy middle-aged and older adults. Ketones are naturally produced by the body during periods of fasting or carbohydrate restriction and serve as an alternative fuel source for the brain. Researchers are interested in whether increasing blood ketone levels through supplementation can alter brain activity and blood flow in ways that may support healthy brain function. Participants will consume a ketone ester supplement and a placebo in separate study visits. Brain imaging, blood measurements, and cognitive testing will be used to evaluate the effects of each intervention. Findings from this study will help researchers better understand how ketones influence the healthy aging brain and may provide preliminary data for future studies in populations at risk for cognitive decline.
Detailed description
Alzheimer's disease and other age-related neurodegenerative conditions are associated with changes in brain energy metabolism that can occur years before symptoms develop. One of the earliest findings in these conditions is reduced utilization of glucose by certain brain regions. Ketones, including beta-hydroxybutyrate, can serve as an alternative fuel source for the brain and may help support brain metabolism when glucose utilization is impaired. Experimental evidence also suggests ketones may influence cerebral blood flow, neurotransmitter balance, and functional brain connectivity. Despite growing interest in ketone supplementation, the acute effects of ketone esters on multiple aspects of human brain function have not been comprehensively evaluated. This study will investigate whether acute ketone ester ingestion alters cerebral blood flow, brain neurochemistry, resting-state brain connectivity, and cognitive performance in healthy adults. This is a randomized, double-blind, placebo-controlled crossover study. Participants will complete two intervention periods, receiving a ketone ester supplement during one period and a calorie-matched placebo during the other. The order of interventions will be randomized and separated by a washout period of 3 to 7 days. Participants will consume study beverages for two days prior to each testing session and will undergo detailed testing following an overnight fast. At each testing visit, participants will provide fingerstick blood samples to measure ketone and glucose concentrations, complete standardized cognitive testing, and undergo advanced magnetic resonance imaging (MRI). Brain imaging will include arterial spin labeling (ASL) to evaluate cerebral blood flow, proton magnetic resonance spectroscopy (1H-MRS) to assess brain metabolite and neurotransmitter concentrations, and functional MRI (fMRI) to assess resting-state brain network connectivity. Cardiac MRI measures will also be collected to explore relationships between cardiovascular and cerebrovascular responses. The primary goal is to determine whether acute ketone supplementation changes cerebral blood flow, brain metabolite concentrations, and functional brain connectivity compared with placebo. Secondary analyses will evaluate relationships between blood ketone concentrations, imaging measures, and cognitive performance. Results from this pilot study will provide important mechanistic information regarding how ketones affect the healthy aging brain and will support the development of future clinical trials in populations at risk for cognitive impairment. The study lasts about two weeks. There are two main test days with 3-7 days in between. Each testing session will last up to 3.5 hours at most.
Interventions
DIETARY_SUPPLEMENTKetone Ester Drink
The ketone ester beverage contains 25 g of C8 Diester emulsified in a matrix of water, whey protein concentrate, modified gum acacia, natural and artificial flavors and cocoa powder. It contains 210 kcal, 0.5 g fat, 2 g carbohydrates, and 2 g protein. Dose consumed is 50 g, 2 times per day for 2 days. The placebo (PL) will be calorie and volume matched to the KE and be formulated with standard dietary ingredients.
DIETARY_SUPPLEMENTPlacebo
The placebo drink will be calorie and volume matched to the KE and be formulated with standard dietary ingredients.
Sponsors
Christopher Crabtree
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Intervention model description
This study uses a randomized, double-blind, placebo-controlled crossover design. Participants will complete two intervention periods in random order, receiving a ketone ester supplement during one period and a placebo during the other. Each intervention period includes a two-day supplementation lead-in followed by a testing visit. The two intervention periods are separated by a 3- to 7-day washout period. Investigators and participants will remain blinded to treatment assignment until study completion.
Eligibility
Sex/Gender
ALL
Age
45 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Age ≥45 years and ≤65 years 2. Able to comply with study requirements including presenting for each test session following an overnight fast and not following a ketogenic diet during the duration of the study. 3. BMI between 18.5 and 30 kg/m2
Exclusion criteria
1. Non-English Speaking 2. Currently taking a ketone ester supplement, ketone salt supplement, or on a ketogenic diet 3. Pregnancy, a urine pregnancy test will be given to all women before scanning to confirm nonpregnant status 4. Currently breastfeeding 5. Allergies to components in the test products, including milk protein, and not lactose intolerant 6. History of high blood pressure 7. History of alcoholism (previous 2 years) 8. History of illicit drug use 9. History of head trauma involving loss of consciousness or skull fracture 10. Diagnosed neurological disease 11. Taking psychiatric prescriptive medications (antipsychotics, antidepressants, or barbiturates) or over-the-counter (OTC) medications (other than those taken as nutritional supplements for non-therapeutic indications) 12. Current smoker 13. Currently consuming a habitual ketogenic diet, or was consuming a habitual ketogenic diet in the past three months 14. Any condition or material in the body that is a contraindication for MRI procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cerebral Blood Flow | Acute response following 2-day lead in | To detect a clinically meaningful difference in cerebral blood flow (CBF) between ketone ester and placebo conditions in healthy adults |
| Brain Glutamate Concentration | Acute response following 2-day lead in | To detect a difference in brain glutamate concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS). |
| Brain GABA Concentration | Acute response following 2-day lead in | To detect a difference in brain gamma-aminobutyric acid (GABA) concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS). |
| Brain Lactate Concentration | Acute response following 2-day lead in | To detect a difference in brain lactate concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS). |
| Brain Choline Concentration | Acute response following 2-day lead in | To detect a difference in brain choline concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS). |
| Brain N-Acetylaspartate (NAA) Concentration | Acute response following 2-day lead in | To detect a difference in brain N-acetylaspartate (NAA) concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS). |
| Brain Glucose Concentration | Acute response following 2-day lead in | To detect a difference in brain glucose concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS). |
| Brain Beta-Hydroxybutyrate (BHB) Concentration | Acute response following 2-day lead in | To detect a difference in brain beta-hydroxybutyrate (BHB) concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS). |
| Functional Brain Connectivity | Acute response following 2-day lead in | Change in resting-state brain network connectivity measured using blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI). |
| Brain Acetoacetate Concentration | Acute response following 2-day lead in | To detect a difference in brain acetoacetate concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS). |
| Brain Glutamine Concentration | Acute response following 2-day lead in | To detect a difference in brain glutamine concentration (mM) between ketone ester and placebo conditions in healthy adults, measured using proton magnetic resonance spectroscopy (1H-MRS). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Blood Ketone Concentration | Acute response following 2-day lead in | Blood beta-hydroxybutyrate concentrations measured by fingerstick testing. |
| Blood Glucose Concentration | Acute response following 2-day lead in | Blood glucose concentrations measured by fingerstick testing. |
| Cognitive Performance (RBANS Total Scale Score) | Acute response following 2-day lead in | Total Scale Score on the RBANS, comparing ketone ester and placebo conditions in healthy adults. |
Countries
United States
Contacts
CONTACTChristopher Crabtree, Ph.D.
Outcome results
None listed