Clinical trial NCT04840095: Dynamic Connectivity Under Metabolic Constraints
Official title: Dynamic Connectivity Under Metabolic Constraints
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Insulin Resistance
Healthy
Diet Modification
Aging
Keywords: exogenous ketone
insulin resistance
glucose
diet
aging
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: Martinos Center for Biomedical Imaging
First posted: 2021-04-09
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 79
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

Brief 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.


Eligibility criteria: 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.

Primary outcomes:
measure: fMRI stability measures: endogenous ketones vs exogenous glucose
timeFrame: Within two weeks of enrollment completion
measure: fMRI stability measures: exogenous ketones vs exogenous glucose
timeFrame: Within two weeks of enrollment completion
measure: PET: glucose uptake and neurotransmitter production with and without ketone supplement
timeFrame: Within two weeks of enrollment completion
Secondary outcomes:
measure: Cognitive performance will be assessed and correlated with brain stability values and insulin resistance levels
timeFrame: Within two weeks of enrollment completion
Other outcomes:
Locations:
city: Charlestown
country: United States
facility: Martinos Center for Biomedical Research, Building 149
state: Massachusetts
city: Stony Brook
country: United States
facility: Bioengineering Building , Stony Brook University
state: New York
Study officials:
affiliation: Stony Brook University
name: Lilianne Mujica-Parodi, PhD
role: PRINCIPAL_INVESTIGATOR
References: