Imaging the Neuroimmune System in PTSD

Study Overview
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Brief Summary
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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.

Official Title
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Imaging the Neuroimmune System in PTSD With PET

Conditions
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Post Traumatic Stress Disorder

Intervention / Treatment
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* Drug: Lipopolysaccharide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, aged 18-55 years Subjects with PTSD will have a primary, current diagnosis of PTSD according to DSM-V criteria (i.e., CAPS-5 ascertained diagnosis) Able to read and write English and to provide voluntary, written informed consent Exclusion Criteria: 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]. 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 Current or regular use of over-the-counter medication that may affect the immune system 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 Contraindications to MRI such as claustrophobia or metal in their body Individuals who are classified as low binders for the rs6971 polymorphism (<10% of the population)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: All subjects will complete a baseline PET [11C]PBR28 scan. A subset of subjects will complete a second PET [11C]PBR28 scan 3-hours after systemic LPS challenge (1.0 ng/kg; IV).
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuroimmune System, Lipopolysaccharide