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Dynamic Connectivity Under Metabolic Constraints

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ClinicalTrials.gov Identifier: NCT04106882
Recruitment Status : Recruiting
First Posted : September 27, 2019
Last Update Posted : September 27, 2019
Sponsor:
Collaborator:
Martinos Center for Biomedical Imaging
Information provided by (Responsible Party):
Stony Brook University

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.


Condition or disease Intervention/treatment Phase
Insulin Resistance Healthy Diet Modification Aging Drug: Ketones Drug: Glucose Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
Official Title: Dynamic Connectivity Under Metabolic Constraints
Actual Study Start Date : June 19, 2015
Estimated Primary Completion Date : September 2022
Estimated Study Completion Date : September 2022

Arm Intervention/treatment
Experimental: 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).
Drug: Glucose
Supplement administered mid-scan.

Experimental: 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).
Drug: Ketones
Supplement administered mid-scan.

Drug: Glucose
Supplement administered mid-scan.

Experimental: 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.
Drug: Ketones
Supplement administered mid-scan.

Drug: Glucose
Supplement administered mid-scan.




Primary Outcome Measures :
  1. Diet related changes in brain network stability will be assessed by fMRI BOLD measurements. [ Time Frame: Within two weeks of enrollment completion ]
    Changes in BOLD signal measurements will be observed between baseline and during a glycolytic, fasting, or ketotic state.

  2. Glucose uptake will be measured by PET, with and without ketone supplement [ Time Frame: Within two weeks of enrollment completion ]
    Continuous FDG PET infusion is used as a measure of glucose uptake during rest and task, with and without the ketone supplement.

  3. Neurotransmitter production with and without ketone supplement will be measured by magnetic resonance spectroscopy [ Time Frame: Within two weeks of enrollment completion ]
    Changes in neurotransmitter concentration under metabolic demands (i.e., task vs resting-state) with and without ketone supplement will be assessed by magnetic resonance spectroscopy.


Secondary Outcome Measures :
  1. Cognitive performance will be assessed by Mini Mental State Exam (MMSE). [ Time Frame: Within two weeks of enrollment completion ]
    All subjects will undergo cognitive testing prior to MRI scanning using the MMSE exam.

  2. Cognitive performance will be assessed by CNS Vital Signs. [ Time Frame: Within two weeks of enrollment completion ]
    All subjects will undergo cognitive testing prior to MRI scanning using the CNS Vital Signs exam.

  3. Insulin resistance will be assessed by HbA1C. [ Time Frame: Within two weeks of enrollment completion ]
    All subjects will be tested for insulin resistance prior to MRI scanning using veinous blood collected and tested for HbA1C.

  4. Insulin resistance will be assessed by blood insulin level. [ Time Frame: Within two weeks of enrollment completion ]
    All subjects will be tested for insulin resistance prior to MRI scanning using veinous blood collected and tested for insulin during a 2-hour Oral Glucose Tolerance Test (OGTT).

  5. Insulin resistance will be assessed by blood glucose level. [ Time Frame: Within two weeks of enrollment completion ]
    All subjects will be tested for insulin resistance prior to MRI scanning using veinous blood collected and tested for glucose during a 2-hour Oral Glucose Tolerance Test (OGTT).



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Ages Eligible for Study:   18 Years to 79 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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
  • 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04106882


Contacts
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Contact: Lilianne Mujica-Parodi, PhD 631-371-4413 lilianne.strey@stonybrook.edu
Contact: Liam McMahon, BA liam.mcmahon@stonybrook.edu

Locations
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United States, Massachusetts
Martinos Center for Biomedical Research, Building 149 Recruiting
Charlestown, Massachusetts, United States, 02129
United States, New York
Bioengineering Building , Stony Brook University Recruiting
Stony Brook, New York, United States, 11794
Principal Investigator: Lilianne Mujica-Parodi, PhD         
Sponsors and Collaborators
Stony Brook University
Martinos Center for Biomedical Imaging

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Responsible Party: Stony Brook University
ClinicalTrials.gov Identifier: NCT04106882    
Other Study ID Numbers: 2017D001434
First Posted: September 27, 2019    Key Record Dates
Last Update Posted: September 27, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Stony Brook University:
insulin resistance
exogenous ketone
glucose
diet
aging
Additional relevant MeSH terms:
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Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases