Imaging of Traumatic Brain Injury Metabolism Using Hyperpolarized Carbon-13 Pyruvate (HPTBI)

Study Description

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Brief Summary:

This project is to evaluate sensitivity and specificity of hyperpolarized 13C-pyruvate as imaging agents of altered cerebral glycolysis and mitochondrial dysfunction and assess pyruvate utilization in mitochondria in Traumatic Brain Injury (TBI) patients.

Condition or disease	Intervention/treatment	Phase
Traumatic Brain Injury	Drug: Hyperpolarized [1-13C] Pyruvate; Drug: Hyperpolarized [2-13C] Pyruvate	Early Phase 1

Detailed Description:

Aim 1:

Investigators will quantify changes in [1-13C]lactate and H13CO3- labeling following a bolus injection of hyperpolarized [1-13C]pyruvate during the time window of secondary injury to assess upregulated glycolysis. Due to heterogeneous presence and severity of damage by TBI, defining the injured brain region can be difficult. Therefore, the metabolite ratio maps ([product]/[pyruvate]) of TBI patients (n = 5) will be compared with those of healthy-controls (n = 3).

Hyperpolarized [2-13C]pyruvate will be examined in a separate group of TBI cohorts (n = 5) and healthy controls (n = 3), and [5-13C]glutamate, [1-13C]acetyl-carnitine, [1-13C]acetoacetate, and [1-13C]citrate from [2-13C]pyruvate will be quantified for assessing the altered mitochondrial metabolism. Imaging procedure with [2-13C]pyruvate is the same as the imaging with hyperpolarized [1-13C]pyruvate.

For both [1-13C]pyruvate and [2-13C]pyruvate studies, each subject will be imaged twice with a 45min interval for confirming the reproducibility of the methods and/or averaging to enhance the signal-to-noise ratios of 13C-metabolite maps.

Aim 2:

After the feasibility study (aim1) is completed, an intra-subject comparison study of [1-13C]pyruvate and [2-13C]pyruvate will be performed. Similar to the aim1, patients with post-TBI neurological disorders having normal or near-normal CT results (n = 6 patients) as well as normal brains of age/gender-matching healthy volunteers (n = 3) will be recruited. Each patient will be imaged twice (one with [1-13C]pyruvate and one with [2-13C]pyruvate with a 45min interval). PDH activity and the TCA cycling will be assessed from measured H13CO3- from hyperpolarized [1-13C]pyruvate and [5-13C]glutamate from [2-13C]pyruvate, respectively. The comparison of [1-13C]pyruvate and [2-13C]pyruvate will identify the detailed information of how pyruvate (and converted acetyl-CoA) is utilized in the mitochondria, and assess the utility and necessity of imaging hyperpolarized [2-13C]pyruvate in TBI, providing critical data for future grant applications and larger clinical trials.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	16 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Intervention Model Description:	TBI patients and healthy control subjects
Masking:	None (Open Label)
Primary Purpose:	Basic Science
Official Title:	Imaging of Traumatic Brain Injury Metabolism Using Hyperpolarized Carbon-13 Pyruvate
Estimated Study Start Date :	May 1, 2018
Estimated Primary Completion Date :	October 31, 2019
Estimated Study Completion Date :	October 31, 2020

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Hyperpolarized [1-13C] Pyruvate; Injection with hyperpolarized [1-13C] Pyruvate during MRI.	Drug: Hyperpolarized [1-13C] Pyruvate; Bolus injection of study drug; Other Name: HP Pyruvate Injection
Experimental: Hyperpolarized [2-13C] Pyruvate; Injection with hyperpolarized [2-13C] Pyruvate during MRI.	Drug: Hyperpolarized [2-13C] Pyruvate; Bolus injection of study drug; Other Name: HP Pyruvate Injection

Outcome Measures

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Primary Outcome Measures :

1. [1-13C]lactate-to-H13CO3- ratio from [1-13C]pyruvate or [2-13C]lactate-to-[5-13C]glutamate ratio from [2-13C]pyruvate [ Time Frame: One visit of three hours: 2 bolus injections during MRI with 45 minute rest period between the two ]
   Product ratio maps of lactate from pyruvate in the brain of TBI patients as compared to those of healthy controls.

Eligibility Criteria

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Ages Eligible for Study:	18 Years to 60 Years (Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

TBI Patients

• Injury occurred within 10 days
• Documented and verified TBI by Glascow coma scal 10-15 and/or Loss of Consciousness >10 minutes.
• Head Computed Tomography at admission.

ALL Subjects:

• 18 through 60 years of age.
• Ability to understand the the willingness to sign a writteninformed consent.
• All races and ethnicities will be included; subjects must be able to read and speak either the English or Spanish language.

Exclusion Criteria:

• Non-traumatic structural brain abnormality identified on head CT.
• Metallic foreign bodies on the scalp or cranium which may interfere with MRI acquisitions.
• Penetrating TBI.
• Significant anatomic distortion of the brain identified on CT images, such as large hematomas, herniation, intraventricular hemorrhage, extensive subarachnoid hemorrhage, hydrocephalus.
• Significant polytrauma that would interfere with follow-up and outcome assessment.
• Patients on psychiatric hold.
• Major debilitating mental health disorders including, but not limited to schizophrenia and bipolar disorder that would limit compliance with study requirements.
• Major debilitating neurological disease including, but not limited to, stroke, CVA, dementia and tumor that would limit compliance with study requirements.
• Under influence of illicit drugs which are known to alter brain physiology/metabolism including, but not limited to cocaine, lysergic acid diethylamide (LSD), and marijuana at the time of MRI/MRSI scanning.
• Any contraindication per MRI Screening Form including
• Implants contraindicated at 3T, pacemakers
• Implantable Cardioverter Defibrillator (ICD)
• Claustrophobia
• Prisoners or patients in custody.
• Medically unstable including
• Heart failure
• Severe left ventricular outflow tract (LVOT) obstruction
• Unstable angina
• Pregnancy
• Lactating
• Subjects who are receiving any other investigational agents.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Jeannie D Baxter, RN	214-645-2726	jeannie.baxter@utsouthwestern.edu
Contact: Lucy H Christie, BSN, RN	214-645-2215	lucy.christie@utsouthwestern.edu

Sponsors and Collaborators

University of Texas Southwestern Medical Center

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Jae Mo Park, Principal Investigator, University of Texas Southwestern Medical Center
ClinicalTrials.gov Identifier:	NCT03502967 History of Changes
Other Study ID Numbers:	STU 072017-009
First Posted:	April 19, 2018
Last Update Posted:	April 25, 2018
Last Verified:	April 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Jae Mo Park, University of Texas Southwestern Medical Center:

Traumatic Brain Injury; TBI

Additional relevant MeSH terms:

Wounds and Injuries; Brain Injuries; Brain Injuries, Traumatic; Brain Diseases	Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System