Neuroimmune Mechanisms in Obesity

NCT05553405 | Withdrawn Phase 1 FDA Drug

• 1 other identifier: 2000031993
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Aim 1: To measure levels of microglia using the radiotracer \[11C\]PBR28 and PET brain imaging in obese (n=50) vs. lean individuals (n=50). The investigators will recruit 100 subjects who will participate in a single \[11C\]PBR28 scan to measure levels of TSPO, a marker of microglia. Aim 2: To determine differences in brain functional connectivity at rest and in response to a decision- making task in obese (n=50) vs. lean individuals (n=50) using fMRI imaging. The same subjects from Aim 1 will participate in a resting state functional magnetic resonance imaging (fMRI) followed by a decision making task during fMRI acquisition. Aim 3: To assess whether acute elevation of lipid levels through intralipid infusion in lean, healthy individuals (n=20) will induce microglial activation. 20 lean individuals will be recruited to participate in a paradigm that includes a baseline \[11C\]PBR28 scan, an infusion of intralipid, and a second \[11C\]PBR28 scan approximately 4 hours post intralipid infusion. The investigators will attempt to utilize subjects from aim 1 in order to use their baseline scans for this paradigm. Aim 4: To determine whether there are differences in levels of microglia between individuals with and without type 1 diabetes (n=20). 20 patients with diabetes (type 1 diabetes or type 2 diabetes)will be recruited to participate in a single \[11C\]PBR28 scan to compare to Aim 1 participants.

Conditions

Obesity

Outcome Measures

Primary Outcomes (6)

• Baseline [11C]PBR28 VT values

  \[11C\]PBR28 VT values in our primary regions of interest (PFC and hippocampus) from PET Scan. Linear mixed-effect models will be conducted to evaluate differences in \[11C\]PBR28 VT values between lean, healthy controls (n=40) and individuals with obesity (n=40), controlling for rs6971 genotype, age, and sex.

  At baseline

• Post-Intralipid [11C]PBR28 VT values

  \[11C\]PBR28 VT values in our primary regions of interest (PFC and hippocampus) from PET Scan. Linear mixed-effect models will be conducted to evaluate differences in \[11C\]PBR28 VT values between lean, healthy controls (n=40) and individuals with obesity (n=40), controlling for rs6971 genotype, age, and sex.

  Approximately 3 Hours After Intralipid Infusion

• Baseline Functional Connectivity

  ICD values will be obtained from primary a priori regions of interest (vmPFC and hippocampus) with PET Scan. Independent t-tests will be used to compare the ICD data between the study groups.

  At baseline

• Post-Intralipid Functional Connectivity

  ICD values will be obtained from primary a priori regions of interest (vmPFC and hippocampus) with PET Scan. Independent t-tests will be used to compare the ICD data between the study groups.

  Approximately 3 Hours After Intralipid Infusion

• Baseline Microglial Activation

  Regional \[11C\]PBR28 VT values from pre-lipid infusion PET Scan

  At baseline

• Post-Intralipid Microglial Activation

  Percent change in regional \[11C\]PBR28 VT values from pre-lipid infusion PET Scan to post-lipid infusion PET Scan will be calculated across brain regions. Increased microglial activation will be measured as a 20% or more increase in TSPO levels from scan 1 to scan 2

  Approximately 3 Hours After Intralipid Infusion

Secondary Outcomes (16)

• Baseline Visual Attention

  At baseline

• Post-Intralipid Infusion Visual Attention

  Approximately 1 Hour After Intralipid Infusion

• Baseline Visual Learning

  At baseline

• Post-Intralipid Infusion Visual Learning

  Approximately 1 Hour After Intralipid Infusion

• Baseline Verbal Memory

  At baseline

Study Arms (2)

Baseline [11C]PBR28 PET Scan

NO INTERVENTION

Subjects will complete a 120-minute baseline \[11C\]PBR28 PET scan.

Post-Intralipid Infusion [11C]PBR28 PET Scan

EXPERIMENTAL

Subjects will complete a second 120-minute \[11C\]PBR28 PET scan 4 hours after Intralipid Infusion

Drug: Intralipid Infusion

Interventions

Intralipid Infusion DRUG

Intralipid 20% (a 20% IV fat emulsion) is a sterile, non-pyrogenic fat emulsion prepared for IV administration as a source of calories and essential fatty acids. It is made up of 20% soybean oil, 1.2% egg yolk phospholipids, 2.25% glycerin and water for injection. In addition, sodium hydroxide has been added to adjust the pH so that the final product pH is 8.

Post-Intralipid Infusion [11C]PBR28 PET Scan

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Age 18-55 years
• Able to read and write English and provide voluntary informed consent
• Physically and psychiatrically healthy by medical history, physical, psychiatric, neurological, EKG and laboratory examinations
• For Aims 1-3: HbA1C \< 5.7%
• For Aim 4: HbA1C \>6.5% and known diagnosis of T1DM or T2DM

You may not qualify if:

• Abnormal labs including Creatinine\>1.5mg/dL, Hematocrit \< 35% for females and \< 39% for males, ALT/AST \>2.5X upper limit of normal, abnormal TSH
• Known significant thyroid, hepatic, neurologic, psychiatric, cerebrovascular, or cardiovascular disease
• \>5% body weight change in last 6 months
• Current or recent regular steroid use in last 6 months, illicit drug use that is deemed to interfere with results including problematic alcohol use as defined by NIAAA
• Current regular use of psychotropic and/or potentially psychoactive prescription medications
• Regular use of any vitamins/supplements that could affect lipids
• Current regular use of non-steroidal anti-inflammatory medications, statins, or lipid lowering agents
• Vaccination in the last month
• Individuals who are classified as "low binders" for the rs6971 polymorphism (\<10% of the population)
• For females, physical or laboratory (-HCG) evidence of pregnancy, seeking pregnancy, or lactating. A urine drug screen and pregnancy test will be performed at screening and prior to the imaging session. Subjects who screen positive will be excluded.
• Note: If a subject tests positive for an illicit substance, the PI will determine if the substance would interfere with the results and may terminate participation if applicable. Results of the test would only be noted in the subjects de-identified chart to document the occurrence.

Sponsors & Collaborators

• Yale University: lead

Study Sites (1)

Yale University

New Haven, Connecticut, 06519, United States

Location

MeSH Terms

Conditions

Obesity

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Officials

• Kelly Cosgrove, PhD

  Yale University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Psychiatry and of Neuroscience and of Radiology and Biomedical Imaging

Study Record Dates

• First Submitted: September 20, 2022
• First Posted: September 23, 2022
• Study Start: January 1, 2024
• Primary Completion (Estimated): January 1, 2033
• Study Completion (Estimated): January 1, 2033
• Last Updated: June 18, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)