Neuroimmune Mechanisms in Obesity
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
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Phase 1 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| No Intervention: Baseline [11C]PBR28 PET Scan Subjects will complete a 120-minute baseline [11C]PBR28 PET scan. |
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| Experimental: Post-Intralipid Infusion [11C]PBR28 PET Scan Subjects will complete a second 120-minute [11C]PBR28 PET scan 4 hours after Intralipid Infusion |
Drug: Intralipid Infusion
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.
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Outcome Measures
Primary Outcome Measures
- Baseline [11C]PBR28 VT values [At baseline]
[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.
- Post-Intralipid [11C]PBR28 VT values [Approximately 3 Hours After Intralipid Infusion]
[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.
- Baseline Functional Connectivity [At baseline]
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.
- Post-Intralipid Functional Connectivity [Approximately 3 Hours After Intralipid Infusion]
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.
- Baseline Microglial Activation [At baseline]
Regional [11C]PBR28 VT values from pre-lipid infusion PET Scan
- Post-Intralipid Microglial Activation [Approximately 3 Hours After Intralipid Infusion]
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
Secondary Outcome Measures
- Baseline Visual Attention [At baseline]
Visual attention: response latency to identify card color (log10(ms); higher ~ worse attention).
- Post-Intralipid Infusion Visual Attention [Approximately 1 Hour After Intralipid Infusion]
Visual attention: response latency to identify card color (log10(ms); higher ~ worse attention).
- Baseline Visual Learning [At baseline]
Visual learning: % of correctly identified repeat cards (arcsine(% correct); higher values ~ better learning).
- Post-Intralipid Infusion Visual Learning [Approximately 1 Hour After Intralipid Infusion]
Visual learning: % of correctly identified repeat cards (arcsine(% correct); higher values ~ better learning).
- Baseline Verbal Memory [At baseline]
Verbal memory: # of correctly recalled items from a grocery list (3 trials). Verbal recall: # of correctly recalled items from a grocery list after a delay (1 trial; higher ~ better memory/recall).
- Post-Intralipid Verbal Memory [Approximately 1 Hour After Intralipid Infusion]
Verbal memory: # of correctly recalled items from a grocery list (3 trials). Verbal recall: # of correctly recalled items from a grocery list after a delay (1 trial; higher ~ better memory/recall).
- Baseline Executive Function [At baseline]
Executive function: number of errors navigating a 'hidden' maze (5 trials; higher ~ worse executive function).
- Post-Intralipid Executive Function [Approximately 1 Hour After Intralipid Infusion]
Executive function: number of errors navigating a 'hidden' maze (5 trials; higher ~ worse executive function).
- Baseline Visual-Motor Processing Speed [At baseline]
Visual-motor processing speed: response latency to detect a card flipped over (log10(ms); higher ~ worse processing speed).
- Post-Intralipid Visual-Motor Processing Speed [Approximately 1 Hour After Intralipid Infusion]
Visual-motor processing speed: response latency to detect a card flipped over (log10(ms); higher ~ worse processing speed).
- Baseline Working Memory [At baseline]
Working memory: % of correctly identified cards that matched the card presented either one- or two-cards previously (arcsine(% correct); higher ~ better working memory).
- Post-Intralipid Working Memory [Approximately 1 Hour After Intralipid Infusion]
Working memory: % of correctly identified cards that matched the card presented either one- or two-cards previously (arcsine(% correct); higher ~ better working memory).
- Baseline Social Cognition [At baseline]
Social cognition: response latency to identify the mismatched facial expression based on its emotional content (ms; log10; higher ~ worse social cognition).
- Post-Intralipid Social Cognition [Approximately 1 Hour After Intralipid Infusion]
Social cognition: response latency to identify the mismatched facial expression based on its emotional content (ms; log10; higher ~ worse social cognition).
- Baseline Reward Responsiveness [At baseline]
Reward responsiveness will be quantified via computerized Probabilistic Reward Task
- Post-Intralipid Reward Responsiveness [Approximately 1 Hour After Intralipid Infusion]
Reward responsiveness will be quantified via computerized Probabilistic Reward Task
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age 18-55 years
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Able to read and write English and provide voluntary informed consent
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Physically and psychiatrically healthy by medical history, physical, psychiatric, neurological, EKG and laboratory examinations
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For Aims 1-3: HbA1C < 5.7%
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For Aim 4: HbA1C >6.5% and known diagnosis of T1DM or T2DM
Exclusion Criteria:
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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
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Known significant thyroid, hepatic, neurologic, psychiatric, cerebrovascular, or cardiovascular disease
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5% body weight change in last 6 months
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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
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Current regular use of psychotropic and/or potentially psychoactive prescription medications
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Regular use of any vitamins/supplements that could affect lipids
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Current regular use of non-steroidal anti-inflammatory medications, statins, or lipid lowering agents
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Vaccination in the last month
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Individuals who are classified as "low binders" for the rs6971 polymorphism (<10% of the population)
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Yale University | New Haven | Connecticut | United States | 06519 |
Sponsors and Collaborators
- Yale University
Investigators
- Principal Investigator: Kelly Cosgrove, PhD, Yale University
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 2000031993