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Dynamic Connectivity Under Metabolic Constraints

25. september 2019 oppdatert av: Stony Brook University

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.

Studieoversikt

Status

Ukjent

Forhold

Intervensjon / Behandling

Studietype

Intervensjonell

Registrering (Forventet)

80

Fase

  • Fase 4

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiesteder

  • Forente stater
    • Massachusetts
      • Charlestown, Massachusetts, Forente stater, 02129
        • Rekruttering
        • Martinos Center for Biomedical Research, Building 149
    • New York
      • Stony Brook, New York, Forente stater, 11794
        • Rekruttering
        • Bioengineering Building , Stony Brook University
        • Hovedetterforsker:
          • Lilianne Mujica-Parodi, PhD

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

18 år til 79 år (Voksen, Eldre voksen)

Tar imot friske frivillige

Nei

Kjønn som er kvalifisert for studier

Alle

Beskrivelse

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

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Grunnvitenskap
  • Tildeling: Randomisert
  • Intervensjonsmodell: Crossover-oppdrag
  • Masking: Enkelt

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Eksperimentell: 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).
Legemiddel: Glucose
Supplement administered mid-scan.
Eksperimentell: 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).
Legemiddel: Glucose
Supplement administered mid-scan.
Legemiddel: Ketones
Supplement administered mid-scan.
Eksperimentell: 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.
Legemiddel: Glucose
Supplement administered mid-scan.
Legemiddel: Ketones
Supplement administered mid-scan.

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Diet related changes in brain network stability will be assessed by fMRI BOLD measurements.
Tidsramme: Within two weeks of enrollment completion
Changes in BOLD signal measurements will be observed between baseline and during a glycolytic, fasting, or ketotic state.
Within two weeks of enrollment completion
Glucose uptake will be measured by PET, with and without ketone supplement
Tidsramme: 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.
Within two weeks of enrollment completion
Neurotransmitter production with and without ketone supplement will be measured by magnetic resonance spectroscopy
Tidsramme: 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.
Within two weeks of enrollment completion

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Cognitive performance will be assessed by Mini Mental State Exam (MMSE).
Tidsramme: Within two weeks of enrollment completion
All subjects will undergo cognitive testing prior to MRI scanning using the MMSE exam.
Within two weeks of enrollment completion
Cognitive performance will be assessed by CNS Vital Signs.
Tidsramme: Within two weeks of enrollment completion
All subjects will undergo cognitive testing prior to MRI scanning using the CNS Vital Signs exam.
Within two weeks of enrollment completion
Insulin resistance will be assessed by HbA1C.
Tidsramme: 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.
Within two weeks of enrollment completion
Insulin resistance will be assessed by blood insulin level.
Tidsramme: 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).
Within two weeks of enrollment completion
Insulin resistance will be assessed by blood glucose level.
Tidsramme: 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).
Within two weeks of enrollment completion

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

Stony Brook University

Samarbeidspartnere

Martinos Center for Biomedical Imaging

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart (Faktiske)

19. juni 2015

Primær fullføring (Forventet)

1. september 2022

Studiet fullført (Forventet)

1. september 2022

Datoer for studieregistrering

Først innsendt

17. september 2019

Først innsendt som oppfylte QC-kriteriene

25. september 2019

Først lagt ut (Faktiske)

27. september 2019

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

27. september 2019

Siste oppdatering sendt inn som oppfylte QC-kriteriene

25. september 2019

Sist bekreftet

1. september 2019

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • 2017D001434

Legemiddel- og utstyrsinformasjon, studiedokumenter

Studerer et amerikansk FDA-regulert medikamentprodukt

Ja

Studerer et amerikansk FDA-regulert enhetsprodukt

Nei

produkt produsert i og eksportert fra USA

Nei

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