Dynamic Connectivity Under Metabolic Constraints

Healthy Clinical Trial

Official title:

Dynamic Connectivity Under Metabolic Constraints

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04840095
• Other study ID #: 2015P000652
• Status: Recruiting
• Phase: Phase 4
• Start date: June 19, 2015
• Est. completion date: September 2023

Study information

• Verified date: January 2023
• Source: Massachusetts General Hospital
• Contact: Lilianne Mujica-Parodi, PhD
• Phone: 631-371-4413
• Email: lilianne.strey[@]stonybrook.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

In this study, we investigate the impact of insulin resistance on the acceleration of brain aging, and test whether increased neuron insulin resistance can be counteracted by utilization of alternate metabolic pathways (e.g., ketones rather than glucose). This study has three Arms, which together provide synergistic data. For all three Arms, subjects are tested in a within-subjects design that consists of 2-3 testing sessions, 1-14 days apart, and counter-balanced for order. During each session we measure the impact of fuel (glucose in one session, ketones in the other) on brain metabolism and associated functioning. For Arms 1-2, our primary experimental measure is functional magnetic resonance imaging (fMRI), which we will use to trace the self-organization of functional networks following changes in energy supply and demand. Arm 1 tests the impact of endogenous ketones produced by switching to a low carbohydrate diet, while Arm 2 tests the impact of exogenous ketones consumed as a nutritional supplement. For Arm 3, we use simultaneous magnetic resonance spectroscopy/positron-emission tomography (MR/PET) to quantify the impact of exogenous ketones on production of glutamate and GABA, key neurotransmitters.

Subjects will be given the option to participate in more than one of the Arms, but doing so is not expected nor required.

Prior to scans, subjects will receive a clinician-administered History and Physical (H&P), which includes vital signs, an oral glucose tolerance test (OGTT), and the comprehensive metabolic blood panel. These will be used to assess diabetes, kidney disease, and electrolytes. If subjects pass screening, they will be provided the option to participate in one or more Arms, which include neuroimaging. To provide a quantitative measure of time-varying metabolic activity throughout the scan, based upon quantitative models of glucose and ketone regulation, as well as to be able to implement safety stopping rules (see below), we will obtain pin-prick blood samples three times: prior to the scan, following consumption of the glucose or ketone drink, and following completion of the scan. To assess effects of increased metabolic demand, we measure brain response to cognitive load, transitioning from resting-state to spatial reasoning through a Tetris task. To assess effects of increased metabolic supply, we measure brain response to glucose or ketone bolus.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 80
• Est. completion date: September 2023
• Est. primary completion date: September 2023
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 79 Years

Eligibility

Exclusion Criteria:

• claustrophobia

• history of neurological disease, heart attack, stroke, kidney disease, or myxedema

• chronic usage of alcohol

• current usage of psychotropic medication

• Type 1 diabetes mellitus

• Regular consumption of insulin, Metformin® or other medications (statins, NSAIDs, beta-blockers, glucocorticoids) that affect glucose and/or insulin utilization.

• difficulty swallowing

• pregnancy

• breastfeeding

• For PET: research imaging-related radiation exposure that exceeds current MGH Radiology Radiation Safety Commitee guidelines.

Inclusion Criteria:

• BMI < 30

• 20/20 vision or correctable to 20/20 with contact lenses

• MRI compatible

• For PET with Optional 150 ml Blood Sampling Only: Must weigh at least 110 lbs to minimize risks per PHRC guidelines.

Related Conditions & MeSH terms

• Aging
• Diet Modification
• Healthy
• Insulin Resistance

Intervention

Drug:
• Ketones
Sports supplement that is administered mid-scan.
• Glucose
Supplement is administered mid-scan.

Locations

Country	Name	City	State
United States	Martinos Center for Biomedical Research, Building 149	Charlestown	Massachusetts
United States	Bioengineering Building , Stony Brook University	Stony Brook	New York

Sponsors (2)

Lead Sponsor	Collaborator
Massachusetts General Hospital	Martinos Center for Biomedical Imaging

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	fMRI stability measures: endogenous ketones vs exogenous glucose	BOLD signal measurements will be obtained at baseline and during either a glycolytic, fasting, or ketotic state. We hypothesize that ketones provide the brain with greater baseline access to energy, particularly as individuals age and become insulin resistant, and that subsequent ingestion of glucose disrupts this access. We also expect that these effects will become more pronounced when metabolic demands are higher (i.e., task vs resting-state).	Within two weeks of enrollment completion
Primary	fMRI stability measures: exogenous ketones vs exogenous glucose	BOLD signal measurements will be obtained at baseline and following either a glucose or ketone supplement. We hypothesize that ketones provide the brain with greater baseline access to energy, particularly as individuals age and become insulin resistant, and that subsequent ingestion of glucose disrupts this access. We also expect that these effects will become more pronounced when metabolic demands are higher (i.e., task vs resting-state).	Within two weeks of enrollment completion
Primary	PET: glucose uptake and neurotransmitter production with and without ketone supplement	During MR/PET scans, continuous FDG infusion will be used to measure glucose uptake both during rest and task. Magnetic resonance spectroscopy will be used to measure production of neurotransmitters. In individuals who are insulin resistant, we expect to find diminished neurotransmitter levels that will then be replenished through exogenous ketones. We also hypothesize that these effects will become more pronounced when metabolic demands are higher (i.e., task vs resting-state).	Within two weeks of enrollment completion
Secondary	Cognitive performance will be assessed and correlated with brain stability values and insulin resistance levels		Within two weeks of enrollment completion