Imaging the Neuroimmune System in PTSD

Phase 1

Completed

• Conditions: Post Traumatic Stress Disorder
• Interventions: Drug: Lipopolysaccharide

• Registration Number: NCT04236986
• Lead Sponsor: Yale University

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2017-03-28
• Study First Submitted: 2020-01-11
• Study First Submitted QC: 2020-01-16
• Study First Posted: 2020-01-22
• Primary Completion: 2023-05-30
• Study Completion: 2023-05-30
• Results First Submitted: 2024-05-02
• Results First Submitted QC: 2024-09-20
• Results First Posted: 2024-09-26
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-20
• Last Update Posted: 2024-12-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 80

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

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Post-LPS [11C]PBR28 PET Scan	Lipopolysaccharide	Subjects will complete a second120-minute \[11C\]PBR28 PET scan 3-hours after LPS administration (1.0ng/kg; IV)

Primary Outcome Measures

Name	Time	Method
Baseline TSPO Availability	Before LPS administration (baseline)	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.
Post-LPS TSPO Availability	3-hours after LPS administration (1.0 ng/kg; IV)	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.

Secondary Outcome Measures

Name	Time	Method
Baseline Visual Attention	Before LPS administration	Visual attention: response latency to identify card color (log10(ms); higher \~ worse attention).
Post-LPS Visual Attention	Approximately ~1-hour after LPS administration	Visual attention: response latency to identify card color (log10(ms); higher \~ worse attention).
Baseline Visual Learning	Before LPS administration	Visual learning: % of correctly identified repeat cards (arcsine(% correct); higher values \~ better learning).
Post-LPS Visual Learning	Approximately ~1-hour after LPS administration	Visual learning: % of correctly identified repeat cards (arcsine(% correct); higher values \~ better learning).
Baseline Verbal Memory	Before LPS administration	Verbal memory: summed number of correctly recalled items from a grocery list (over 3 trials). Each trial is not calculated individually. The reported value is the sum of all three trials.
Post-LPS Verbal Memory	Approximately ~1-hour after LPS administration	Verbal memory: summed # of correctly recalled items from a grocery list (over 3 trials). Each trial is not calculated individually. The reported value is the sum of all three trials.
Baseline Executive Function	Before LPS administration	Executive function: summed number of errors navigating a 'hidden' maze (5 trials; higher \~ worse executive function).
Post-LPS Executive Function	Approximately ~1-hour after LPS administration	Executive function: summed number of errors navigating a 'hidden' maze (5 trials; higher \~ worse executive function).
Baseline Visual-Motor Processing Speed	Before LPS administration	Visual-motor processing speed: response latency to detect a card flipped over (log10(ms); higher \~ worse processing speed).
Post-LPS Visual-Motor Processing Speed	Approximately ~1-hour after LPS administration	Visual-motor processing speed: response latency to detect a card flipped over (log10(ms); higher \~ worse processing speed).
Baseline Social Cognition	Before LPS administration	Social cognition: response latency to identify the mismatched facial expression based on its emotional content (ms; log10; higher \~ worse social cognition).
Post-LPS Social Cognition	Approximately ~1-hour after LPS administration	Social cognition: response latency to identify the mismatched facial expression based on its emotional content (ms; log10; higher \~ worse social cognition).

Trial Locations

Locations (1)

Yale University; 🇺🇸 New Haven, Connecticut, United States