Dynamic Connectivity Under Metabolic Constraints

NCT ID: NCT04106882

Last Updated: 2019-09-27

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-06-19
• Study Completion Date: 2022-09-30

Brief Summary

The investigators are studying the impact of insulin resistance on the acceleration of brain aging and testing 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. Impact of fuel (glucose in one session, ketones in the other) on brain metabolism and associated functioning is measured during each session. For Arms 1-2, the primary experimental measure is functional magnetic resonance imaging (fMRI), which is used 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, simultaneous magnetic resonance spectroscopy/positron-emission tomography (MR/PET) is used 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), the investigators 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, the investigators measure brain response to cognitive load, transitioning from resting-state to spatial reasoning through a spatial navigation video task. To assess effects of increased metabolic supply, the investigators measure brain response to glucose or ketone bolus.

Conditions

Insulin Resistance; Healthy; Diet Modification; Aging

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: SINGLE

Study Groups

Arm 1: Metabolic Manipulation via Diet fMRI

All subjects are tested three times, each in a different diet-induced metabolic state: glycolytic (glucose burning), fasting (8 hours no food), and ketotic (fat burning). While having their brains scanned with MRI, subjects are initially tested at rest, and then perform a task. Midway through the session, subjects are removed from the scanner and drink up to 75g glucose. Data analyses quantify network reorganization in response to changing energy constraints (i.e., cognitive demand, fuel).

Group Type: EXPERIMENTAL

Glucose

Intervention Type: DRUG

Supplement administered mid-scan.

Arm 2: Metabolic Manipulation via Ketone Supplement fMRI

All subjects are tested twice, both times in a fasting condition (8 hours no food, unrestricted water). While having their brains scanned with MRI, subjects are initially tested at rest, and then perform a task. Midway through the session, subjects are removed from the scanner and drink either of two fuel sources. In the ketotic (ketone burning) session they will drink a ketone sports drink dosed at 395mg/kg. During the glycolytic (glucose burning) session the same subjects will drink a bolus of glucose, calorie-matched to the ketones. Data analyses quantify network reorganization in response to changing energy constraints (i.e., cognitive demand, fuel).

Group Type: EXPERIMENTAL

Ketones

Intervention Type: DRUG

Supplement administered mid-scan.

Glucose

Intervention Type: DRUG

Supplement administered mid-scan.

Arm 3: Metabolic Manipulation via Ketone Supplement MR/PET

All subjects are tested twice, both times in a fasting condition (8 hours no food, unrestricted water). For both sessions, the investigators will intravenously administer the FDG radioisotope continuously throughout the scan. Thus, PET will map glucose uptake across the brain, while MRS is simultaneously used to measure production of the neurotransmitters glutamine and GABA. While having their brains scanned with MR/PET, subjects are initially tested at rest, and then perform a task. Subjects will drink a ketone sports drink dosed at 395mg/kg. During the glycolytic (glucose burning) session the same subjects will drink a bolus of glucose, calorie-matched to the ketones.

Group Type: EXPERIMENTAL

Ketones

Intervention Type: DRUG

Supplement administered mid-scan.

Glucose

Intervention Type: DRUG

Supplement administered mid-scan.

Interventions

Ketones

Supplement administered mid-scan.

Intervention Type: DRUG

Glucose

Supplement administered mid-scan.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• BMI < 30
• MRI compatible
• For PET with Optional 150 ml Blood Sampling Only: Must weigh at least 110 lbs to minimize risks per PHRC guidelines.
• 20/20 vision or correctable to 20/20 with contact lenses

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 79 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Martinos Center for Biomedical Imaging

OTHER

Sponsor Role: collaborator

Stony Brook University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Martinos Center for Biomedical Research, Building 149

Charlestown, Massachusetts, United States

Site Status: RECRUITING

Bioengineering Building , Stony Brook University

Stony Brook, New York, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Lilianne Mujica-Parodi, PhD

Role: CONTACT

lilianne.strey@stonybrook.edu

631-371-4413

Liam McMahon, BA

Role: CONTACT

liam.mcmahon@stonybrook.edu

Other Identifiers

2017D001434

Identifier Type: -

Identifier Source: org_study_id