Imaging the Neuroimmune System in PTSD

Imaging the Neuroimmune System in PTSD With PET

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT04236986

Enrollment

Registered

2020-01-22

Start date

2017-03-28

Completion date

2023-05-30

Last updated

2024-12-09

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Post Traumatic Stress Disorder

Keywords

Neuroimmune System, Lipopolysaccharide

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.

Interventions

DRUGLipopolysaccharide

LPS will be administered intravenously (1.0ng/kg; IV)

Study design

Allocation

NON_RANDOMIZED

Intervention model

PARALLEL

Primary purpose

BASIC_SCIENCE

Masking

NONE

Intervention 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).

Eligibility

Sex/Gender

ALL

Age

18 Years to 55 Years

Healthy volunteers

Yes

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)

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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).
Baseline Visual Attention	Before LPS administration	Visual attention: response latency to identify card color (log10(ms); higher \ worse attention).
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).
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).
Post-LPS Visual Attention	Approximately ~1-hour after LPS administration	Visual attention: response latency to identify card color (log10(ms); higher \ worse attention).

Countries

United States

Participant flow

Participants by arm

Arm	Count
Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347 We will recruit men and women aged 18-55 who have been exposed to trauma without PTSD into the study. Men and women, aged 18-55 years, any race, with a history of trauma exposure. Trauma-exposed controls will have a CAPS-5 score of 0-22 (no/minimal to mild/subthreshold symptoms) Able to read and write English and to provide voluntary, written informed consent	18
PTSD Controls for HIC 2000020347 We will recruit men and women aged 18-55 who have been exposed to trauma with PTSD into the study. Men and women, aged 18-55 years, any race, with a history of PTSD, Subjects with posttraumatic stress disorder (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	16
Total	34

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Withdrawal by Subject	3	1

Baseline characteristics

Characteristic	Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347	PTSD Controls for HIC 2000020347	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	18 Participants	16 Participants	34 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	1 Participants	1 Participants
Race (NIH/OMB) Black or African American	3 Participants	5 Participants	8 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants	2 Participants	7 Participants
Race (NIH/OMB) White	7 Participants	7 Participants	14 Participants
Region of Enrollment United States	18 participants	16 participants	34 participants
Sex: Female, Male Female	4 Participants	6 Participants	10 Participants
Sex: Female, Male Male	11 Participants	9 Participants	20 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 18	0 / 16
other Total, other adverse events	1 / 18	0 / 16
serious Total, serious adverse events	0 / 18	0 / 16

Outcome results

Primary

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.

Time frame: Before LPS administration (baseline)

Arm	Measure	Group	Value (MEAN)	Dispersion
Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347	Baseline TSPO Availability	Amygdala	5.11 mL/cm3	Standard Deviation 0.85
Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347	Baseline TSPO Availability	insula	5.07 mL/cm3	Standard Deviation 0.85
Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347	Baseline TSPO Availability	vmPFC	5.33 mL/cm3	Standard Deviation 0.9
Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347	Baseline TSPO Availability	hippocampus	4.89 mL/cm3	Standard Deviation 0.78
PTSD Controls for HIC 2000020347	Baseline TSPO Availability	hippocampus	4.38 mL/cm3	Standard Deviation 1.1
PTSD Controls for HIC 2000020347	Baseline TSPO Availability	Amygdala	4.75 mL/cm3	Standard Deviation 1.35
PTSD Controls for HIC 2000020347	Baseline TSPO Availability	vmPFC	5.33 mL/cm3	Standard Deviation 1.16
PTSD Controls for HIC 2000020347	Baseline TSPO Availability	insula	4.38 mL/cm3	Standard Deviation 1.1

Primary

Post-LPS TSPO Availability

Time frame: 3-hours after LPS administration (1.0 ng/kg; IV)

Arm	Measure	Group	Value (MEAN)	Dispersion
Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347	Post-LPS TSPO Availability	Amygdala	7.2 mL/cm3	Standard Deviation 1.37
Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347	Post-LPS TSPO Availability	Hippocampus	6.82 mL/cm3	Standard Deviation 0.87
Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347	Post-LPS TSPO Availability	Insula	7.14 mL/cm3	Standard Deviation 1.3
Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347	Post-LPS TSPO Availability	vmPFC	7.73 mL/cm3	Standard Deviation 1.6
PTSD Controls for HIC 2000020347	Post-LPS TSPO Availability	vmPFC	7.73 mL/cm3	Standard Deviation 1.8
PTSD Controls for HIC 2000020347	Post-LPS TSPO Availability	Amygdala	6.07 mL/cm3	Standard Deviation 2.12
PTSD Controls for HIC 2000020347	Post-LPS TSPO Availability	Insula	7.14 mL/cm3	Standard Deviation 2.1
PTSD Controls for HIC 2000020347	Post-LPS TSPO Availability	Hippocampus	5.66 mL/cm3	Standard Deviation 1.8

Secondary

Baseline Executive Function

Executive function: summed number of errors navigating a 'hidden' maze (5 trials; higher \ worse executive function).

Time frame: Before LPS administration

Arm	Measure	Value (MEAN)
Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347	Baseline Executive Function	51.11111111 Number of errors
PTSD Controls for HIC 2000020347	Baseline Executive Function	45.36363636 Number of errors

Secondary

Baseline Social Cognition

Social cognition: response latency to identify the mismatched facial expression based on its emotional content (ms; log10; higher \ worse social cognition).

Time frame: Before LPS administration

Population: Data were not collected.

Secondary

Baseline Verbal Memory

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.

Time frame: Before LPS administration

Arm	Measure	Value (MEAN)
Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347	Baseline Verbal Memory	29.11111111 Number of correct responses
PTSD Controls for HIC 2000020347	Baseline Verbal Memory	27.45454545 Number of correct responses

Secondary

Baseline Visual Attention

Visual attention: response latency to identify card color (log10(ms); higher \ worse attention).

Time frame: Before LPS administration

Arm	Measure	Value (MEAN)
Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347	Baseline Visual Attention	2.624842444 log10(ms)
PTSD Controls for HIC 2000020347	Baseline Visual Attention	6.877150091 log10(ms)

Secondary

Baseline Visual Learning

Visual learning: % of correctly identified repeat cards (arcsine(% correct); higher values \ better learning).

Time frame: Before LPS administration

Arm	Measure	Value (MEAN)
Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347	Baseline Visual Learning	0.926197556 percentage of correct responses
PTSD Controls for HIC 2000020347	Baseline Visual Learning	1.005693 percentage of correct responses

Secondary

Baseline Visual-Motor Processing Speed

Visual-motor processing speed: response latency to detect a card flipped over (log10(ms); higher \ worse processing speed).

Time frame: Before LPS administration

Arm	Measure	Value (MEAN)
Healthy Controls AKA Trauma Exposed Individuals Without PTSD For HIC 2000020347	Baseline Visual-Motor Processing Speed	2.415812111 log10(ms)
PTSD Controls for HIC 2000020347	Baseline Visual-Motor Processing Speed	5.285026273 log10(ms)

Secondary

Post-LPS Executive Function

Executive function: summed number of errors navigating a 'hidden' maze (5 trials; higher \ worse executive function).