Effects of Acute Ketone Supplementation on the Brain

Official title

Effects of Acute Ketone Supplementation on the Brain [KETO-BRAIN]

Overview

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 supplement Ketone 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 supplement Placebo
  The placebo drink will be calorie and volume matched to the KE and be formulated with standard dietary ingredients.

Primary outcome measures

• Cerebral Blood Flow [Time frame: Acute response following 2-day lead in]
• Brain Glutamate Concentration [Time frame: Acute response following 2-day lead in]
• Brain GABA Concentration [Time frame: Acute response following 2-day lead in]
• Brain Lactate Concentration [Time frame: Acute response following 2-day lead in]
• Brain Choline Concentration [Time frame: Acute response following 2-day lead in]
• Brain N-Acetylaspartate (NAA) Concentration [Time frame: Acute response following 2-day lead in]
• Brain Glucose Concentration [Time frame: Acute response following 2-day lead in]
• Brain Beta-Hydroxybutyrate (BHB) Concentration [Time frame: Acute response following 2-day lead in]
• Functional Brain Connectivity [Time frame: Acute response following 2-day lead in]
• Brain Acetoacetate Concentration [Time frame: Acute response following 2-day lead in]

Secondary outcome measures (3)

• Blood Ketone Concentration [Time frame: Acute response following 2-day lead in]
• Blood Glucose Concentration [Time frame: Acute response following 2-day lead in]
• Cognitive Performance (RBANS Total Scale Score) [Time frame: Acute response following 2-day lead in]

Eligibility criteria

Inclusion criteria

• Age ≥45 years and ≤65 years
• 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.
• BMI between 18.5 and 30 kg/m2

Exclusion criteria

• Non-English Speaking
• Currently taking a ketone ester supplement, ketone salt supplement, or on a ketogenic diet
• Pregnancy, a urine pregnancy test will be given to all women before scanning to confirm nonpregnant status
• Currently breastfeeding
• Allergies to components in the test products, including milk protein, and not lactose intolerant
• History of high blood pressure
• History of alcoholism (previous 2 years)
• History of illicit drug use
• History of head trauma involving loss of consciousness or skull fracture
• Diagnosed neurological disease
• 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)
• Current smoker
• Currently consuming a habitual ketogenic diet, or was consuming a habitual ketogenic diet in the past three months
• Any condition or material in the body that is a contraindication for MRI procedures

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

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Crossover

Masking

Single blind

Primary purpose

Basic science

Study locations

United States · 1 center

• The Ohio State University — Columbus

Identifiers

NCT: NCT07711990 · STUDY20251460

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗