Cerebrovascular Reactivity Assessed With fNIRS as a Biomarker of TCVI After Acute Traumatic Brain Injury in Military

Summary

The study includes people who have recently had a traumatic brain injury (TBI) and healthy controls who have not had a TBI and is designed to measure brain blood flow serially after a TBI. Studies have shown that small blood vessels in the brain may be injured during a TBI. The goal is to learn about brain blood vessel function from as early as the first week to 6 months after a TBI . The study uses Near Infrared Spectroscopy (NIRS) which uses small lights that detect oxygen levels in the blood, measuring blood flow in the brain. This is compared with magnetic resonance imaging (MRI). When blood flow increases in the brain in response to a stimulus, this is called cerebral vascular reactivity (CVR).

The study aims to learn about CVR using a few minutes of special breathing similar to breath holding while in an MRI (magnetic resonance imaging), and CVR measures after one dose of a common drug called sildenafil (generic Viagra) 50 mg taken once during CVR measurements at each of up to 4 visits. The investigators will measure CVR at different times during a 6-month period in participants who have had a TBI to see how CVR measures and blood vessels function during the first 6 months after a brain injury.

Conditions

• Traumatic Brain Injury

Interventions

DRUG

Sildenafil Citrate 50Mg Tab

sildenafil citrate (Viagra®, Pfizer. Inc., NY, NY). Sildenafil citrate is designated chemically as 1-\[\[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1Hpyrazolo\[4,3-d\]pyrimidin-5-yl)-4- ethoxyphenyl\]sulfonyl\]-4-methylpiperazine citrate. Sildenafil citrate is a white to off-white crystalline powder with a solubility of 3.5 mg/mL in water and a molecular weight of 666.7. For this study, we will use 50 mg tablets for the single dose studies.

DEVICE

functional Near-infrared Spectroscopy (fNIRS)

Functional Near-Infrared Spectroscopy (fNIRS): Functional near-infrared spectroscopy (fNIRS) a noninvasive technique that can measure cerebrovascular reactivity (CVR) will be used to measure regional cerebral blood flow and cerebrovascular reactivity in the brain. The device (fNRIS100, fNIR Device LLC), uses laser emission diodes (730nm and 850nm)which in a headband that is worn on the front of the scalp and forehead. Surrounding detectors a few centimeters away detect the light as it scatters through the underlying tissues. The technique is able to detect changes in the absorption spectrum of the tissue corresponding to the concentrations of oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR), and indicate local perfusion changes. fNIRS will be performed twice at each study visit, once before and once about 45 minutes after single dose administration of sildenafil 50 mg.

OTHER

Carbon Dioxide (CO2) 5%

Carbon Dioxide (CO2) 5% mixed with room air. Both the fNIRS procedure and one Magnetic Resonance Imaging (MRI) session at visits that include imaging will be done with a hypercapnia challenge for comparison. CO2 (hypercapnia) challenge is similar to holding one's breath. Participant will wear a nose clip and a mouth breathing apparatus while in the MRI scanner or sitting in a chair during the fNIRS procedure. During the 7-minute hypercapnia procedure, participants will breathe room air and then switch to room air mixed with 5% CO2, from one to the other for one minute each.

OTHER

Neuropsychological Assessments

TBI Neuropsychological Assessments: Study participants will be administered a set of Neuropsychological Tests designed by the NINDS Common Data Elements (CDEs) initiative for TBI, in order to provide a comprehensive and broad assessment of deficits commonly found after TBI. We anticipate that the neuropsychological battery will require approximately 1 hour to complete. The measures (pencil and paper exercises, questionnaires, and interview by the examiner) to be administered are: Glasgow Outcome Scale-Extended (GOS-E). Learning trials portion of the California Verbal Learning Test (CVLT-II): The Trail Making Tests A and B (TMT): Subsets of the Wechsler Adult Intelligence Scale (WAIS-IV) (Digit Symbol and Symbol Search): Behavioral Symptoms Inventory-18: Satisfaction with Life Scale (SWLS): Word Reading subtest of Wide Range Achievement Test (WRAT)-4: Rivermead Post-Concussion Symptom Questionnaire.

DRUG

Gadolinium contrast infusion

Gadolinium contrast infusion: Brain MRI with gadolinium contrast: Dynamic contrast-enhanced (DCE) MRI with intravenous gadolinium-based contrast agents (GBCAs) to measure their transfer rate between intravascular and extravascular compartments as a marker of blood-brain barrier (BBB) permeability. For the DCE sequence, the participant is injected with the contrast agent through a heplock/iv in the scanner and the sequence takes about 15 min. Half-life of gadolinium is about 1 ½ hours and 90-98% clearance from the body in 24 hours in people with normal kidney function.

PROCEDURE

Blood sample collection for research purposes

Serum and plasma (5 ml each) will be collected at at each study visit 10 m or 2 tsp. per visit or up to 40 ml or 8 tsp. over the 180 day course of the study). Samples will be collected by study personnel.

OTHER

Structural brain Magnetic Resonance Imaging (MRI

Structural brain Magnetic Resonance Imaging (MRI): The scanner used is a 3.0 Tesla MR (Model 750, General Electric Healthcare), which is equipped with a high-performance gradient subsystem and a 32-channel head coil (General Electric Healthcare). These scans involve lying still in a scanner for several minutes at a time which is tube shaped, using magnetism to take images of the brain. There is no radiation in MRI. The participants will have up to 3 research brain MRIs. Healthy controls will have 1 MRI session. Common TBI MRI techniques will be performed. Block-design BOLD fMRI during which there will be a 7 minute hypercapnia challenge will be done to assess brain blood flow and measure cerebral vascular reactivity (CVR).

Sponsors & Collaborators

• Walter Reed National Military Medical Center

  collaborator FED

• Uniformed Services University of the Health Sciences

  lead FED

Principal Investigators

• Kimbra Kenney, MD · Uniformed Services University of the Health Sciences

Study Design

Allocation

NON_RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

NONE

Model

PARALLEL

Eligibility

Min Age

18 Years

Max Age

55 Years

Sex

ALL

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2019-08-09

Primary Completion

2020-03-01

Completion

2020-03-01

FDA Drug

Yes

Countries

• United States

Study Locations