Imaging the Neuroimmune System in PTSD

Imaging the Neuroimmune System in PTSD With PET

In this study, individuals with and without post-traumatic stress disorder (PTSD) will undergo one positron emission tomography (PET) scan using the radiotracer [11C]PBR28, which binds to the 18kDa translocator protein (TSPO). A subset of individuals who complete the first PET [11C]PBR28 scan will be invited to complete an inflammatory challenge and second PET [11C]PBR28 scan. Approximately 3 hours prior to the second [11C]PBR28 PET scan, lipopolysaccharide (LPS; endotoxin) will be administered to evoke a robust neuroimmune response. Subjects will also undergo behavioral and cognitive testing. Vital signs, subjective response, and peripheral biomarker levels will be assayed periodically throughout the experimental session.

Specific aims: 1) Determine if individuals with PTSD exhibit neuroimmune system disruption relative to well-matched comparators at baseline. 2) Determine if individuals with PTSD exhibit a disrupted neuroimmune response after a classical immune stimulus relative to well-matched comparators. 3) Determine if LPS differentially alters cognitive function, subjective response, or physiological markers in individuals with PTSD compared to well-matched comparators.

Hypothesis: Individuals with PTSD will exhibit a suppressed neuroimmune system at baseline and an attenuated neuroimmune response following LPS challenge, relative to matched trauma controls.

Study Overview

• Status: Active, not recruiting
• Conditions: Post Traumatic Stress Disorder
• Intervention / Treatment: Drug: Lipopolysaccharide

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jon Anderson; Phone Number: 2037377074; Email: jonmikael.anderson@yale.edu

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Men and women, aged 18-55 years
2. Subjects with PTSD will have a primary, current diagnosis of PTSD according to DSM-V criteria (i.e., CAPS-5 ascertained diagnosis)
3. Able to read and write English and to provide voluntary, written informed consent

Exclusion Criteria:

1. Current medical condition such as neurological, cardiovascular, endocrine, renal, liver, or thyroid pathology including COPD, anemia, uncontrolled daily asthma or asthma requiring the use of an inhaler more than 1x/week with an ACT score below 20. [We will not exclude individuals taking SSRIs and TRIs due to high prevalence of use within the PTSD population and due to evidence suggesting no effect of these drug classes on endotoxin response].
2. Past or current neurological disorder or disorders affecting the brain including but not limited to multiple sclerosis, history of stroke, brain tumors, traumatic brain injury with loss of consciousness, seizure disorder
3. Current or regular use of over-the-counter medication that may affect the immune system
4. Women who are pregnant or nursing, or fail to use one of the following methods of birth control unless she or partner is surgically sterile or she is postmenopausal (hormone contraceptives [oral, implant, injection, patch, or ring], contraceptive sponge, double barrier [diaphragm or condom plus spermicide], or IUD
5. Contraindications to MRI such as claustrophobia or metal in their body
6. Individuals who are classified as "low binders" for the rs6971 polymorphism (<10% of the population)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Baseline [11C]PBR28 PET Scan; Subjects will complete a 120-minute baseline [11C]PBR28 PET scan.
Experimental: Post-LPS [11C]PBR28 PET Scan; Subjects will complete a second120-minute [11C]PBR28 PET scan 3-hours after LPS administration (1.0ng/kg; IV)	Drug: Lipopolysaccharide; LPS will be administered intravenously (1.0ng/kg; IV); Other Names: LPS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline TSPO Availability	Time-activity curves will be extracted from brain regions of interest and analyzed using multilinear analysis-1 (t*=30) incorporating the metabolite-corrected arterial input function to yield [11C]PBR28 total volumes of distribution (VT) across brain regions.	Before LPS administration (baseline)
Post-LPS TSPO Availability	Time-activity curves will be extracted from brain regions of interest and analyzed using multilinear analysis-1 (t*=30) incorporating the metabolite-corrected arterial input function to yield [11C]PBR28 total volumes of distribution (VT) across brain regions.	3-hours after LPS administration (1.0 ng/kg; IV)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Baseline Visual Attention	Visual attention: response latency to identify card color (log10(ms); higher ~ worse attention).	Before LPS administration
Post-LPS Visual Attention	Visual attention: response latency to identify card color (log10(ms); higher ~ worse attention).	Approximately ~1-hour after LPS administration
Baseline Visual Learning	Visual learning: % of correctly identified repeat cards (arcsine(% correct); higher values ~ better learning).	Before LPS administration
Post-LPS Visual Learning	Visual learning: % of correctly identified repeat cards (arcsine(% correct); higher values ~ better learning).	Approximately ~1-hour after LPS administration
Baseline Verbal Memory	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).	Before LPS administration
Post-LPS Verbal Memory	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).	Approximately ~1-hour after LPS administration
Baseline Executive Function	Executive function: number of errors navigating a 'hidden' maze (5 trials; higher ~ worse executive function).	Before LPS administration
Post-LPS Executive Function	Executive function: number of errors navigating a 'hidden' maze (5 trials; higher ~ worse executive function).	Approximately ~1-hour after LPS administration
Baseline Visual-Motor Processing Speed	Visual-motor processing speed: response latency to detect a card flipped over (log10(ms); higher ~ worse processing speed).	Before LPS administration
Post-LPS Visual-Motor Processing Speed	Visual-motor processing speed: response latency to detect a card flipped over (log10(ms); higher ~ worse processing speed).	Approximately ~1-hour after LPS administration
Baseline Working Memory	Working memory: % of correctly identified cards that matched the card presented either one- or two-cards previously (arcsine(% correct); higher ~ better working memory).	Before LPS administration
Post-LPS Working Memory	Working memory: % of correctly identified cards that matched the card presented either one- or two-cards previously (arcsine(% correct); higher ~ better working memory).	Approximately ~1-hour after LPS administration
Baseline Social Cognition	Social cognition: response latency to identify the mismatched facial expression based on its emotional content (ms; log10; higher ~ worse social cognition).	Before LPS administration
Post-LPS Social Cognition	Social cognition: response latency to identify the mismatched facial expression based on its emotional content (ms; log10; higher ~ worse social cognition).	Approximately ~1-hour after LPS administration
Baseline Reward Responsiveness	Reward responsiveness will be quantified via computerized Probabilistic Reward Task	Before LPS administration
Post-LPS Reward Responsiveness	Reward responsiveness will be quantified via computerized Probabilistic Reward Task	Approximately ~2-hour after LPS administration

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Kelly Cosgrove, PhD, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): March 28, 2017
• Primary Completion (Actual): May 30, 2023
• Study Completion (Estimated): September 30, 2024

Study Registration Dates

• First Submitted: January 11, 2020
• First Submitted That Met QC Criteria: January 16, 2020
• First Posted (Actual): January 22, 2020

Study Record Updates

• Last Update Posted (Actual): October 24, 2023
• Last Update Submitted That Met QC Criteria: October 23, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Lipopolysaccharide; Neuroimmune System
• Additional Relevant MeSH Terms: Mental Disorders; Trauma and Stressor Related Disorders; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
• Other Study ID Numbers: 2000020347; 1R01MH110674-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No