Multi-Tracer Studies of Brain Oxygen and Glucose Metabolism Using a Time-of-Flight Positron Emission Tomography-Computed Tomography Scanner

Summary

Quantitative measurements of oxygen and glucose metabolism by PET are established technologies, but details of practical protocols are sparsely described in the literature. This paper presents a practical protocol successfully implemented on a state-of-the-art positron emission tomography-computed tomography scanner.

Abstract

The authors have developed a paradigm using positron emission tomography (PET) with multiple radiopharmaceutical tracers that combines measurements of cerebral metabolic rate of glucose (CMRGlc), cerebral metabolic rate of oxygen (CMRO₂), cerebral blood flow (CBF), and cerebral blood volume (CBV), culminating in estimates of brain aerobic glycolysis (AG). These in vivo estimates of oxidative and non-oxidative glucose metabolism are pertinent to the study of the human brain in health and disease. The latest positron emission tomography-computed tomography (PET-CT) scanners provide time-of-flight (TOF) imaging and critical improvements in spatial resolution and reduction of artifacts. This has led to significantly improved imaging with lower radiotracer doses.

Optimized methods for the latest PET-CT scanners involve administering a sequence of inhaled ¹⁵O-labeled carbon monoxide (CO) and oxygen (O₂), intravenous ¹⁵O-labeled water (H₂O), and ¹⁸F-deoxyglucose (FDG)-all within 2-h or 3-h scan sessions that yield high-resolution, quantitative measurements of CMRGlc, CMRO₂, CBF, CBV, and AG. This methods paper describes practical aspects of scanning designed for quantifying brain metabolism with tracer kinetic models and arterial blood samples and provides examples of imaging measurements of human brain metabolism.

Introduction

The human brain is a heavy consumer of oxygen and glucose for metabolism. A proportion of glucose metabolism in the healthy human brain occurs outside of oxygen use, known as brain aerobic glycolysis (AG), the purposes of which are under intense investigation^1,2,3,4,5. Prior studies in animal models and humans report an association between AG and development and aging, synaptic and neurite development, memory, amyloid deposition in Alzheimer's disease, and white matter function and disease

Protocol

NOTE: The Institutional Review Board and Radioactive Drug Research Committee of Washington University School of Medicine approved all studies based on the protocol described below. All human participants provided informed written consent prior to participating in research studies based on the protocol below. See the Table of Materials for details related to all equipment, materials, and reagents used in this protocol.

1. Participant Selection

1. Inclusion criteria
   1. Include only adult participants. Ensure participants can follow study procedures, including instructions for the inhalation ....

Results

Some of the most technically challenging aspects of this protocol involve configuring, managing, and successfully collecting data from arterial lines while simultaneously administering short half-life radiotracers and running the scanner. Figure 1 provides a bird's eye viewpoint of the current setup that summarizes the organization and operational workflows required from study coordinators, interventionalist, nursing, technologists, and investigators. The radiopharmaceuticals described a.......

Discussion

PET imaging of oxygen and glucose metabolism using inhaled [¹⁵O]CO and [¹⁵O]O₂ gases, intravenous injection of [¹⁵O]H₂O, and intravenous injection of [¹⁸F]FDG have significant historical priors based on imaging accumulated from older generations of PET scanners^{14,15,16,17,26,}

Materials

Name	Company	Catalog Number	Comments
3/16" outer diameter 1/8" innner diameter nylaflow tubing	Nylaflow Tubing, Zazareth, PA
4 x 4 in. gauze	McKesson MedSurg	16-4242
Analytical balance	Fisher Scientific/OHUAS	Pioneer Exal Model 90 mm platform #PA84
Bacterial/Viral filter	Hudson RCI, Teleflex, Perak, Malaysia	REF 1605 (IPN042652)
BD SmartSite Needle-Free Valve	Becton Dickinson	2000E
Biograph mMR	Siemens, Erlangen, Germany
Biograph Vision 600 Edge	Siemens, Erlangen, Germany
Caprac wipe counter	Mirion Medical (Capintec), Florham Park, NJ	from 1991 or newer	NaI drilled well crystal
Coban self-adhesive wrap	3M		commonly used in intensive care units
dressing, tegaderm, 4 x 4"	3M Health Care	#1626
ECAT EXACT HR+	CTI PET Systems, Knoxville, TN
Edwards TruWave 3 cc/84 in (210 cm)	Edwards Lifescience	PX284R
extension catheter 48 cm length, 0.642 mL priming volume	Braun	V5424
heparin sodium, solution 2 U/mL, 1,000 mL	Hospira Worldwide	#409762059
I.V. armboard flexible 4 x 9 in. adult	DeRoyal	M8125-A
Keithley pico-ammeter	Tekronix
Magnetom Prisma fit	Siemens, Erlangen, Germany		3T
male-male adapter for Luer valves	Argon Medical Co.	040184000A
MiniSpin Personal Microcentrifuge	Eppendorf, Hamburg, Germany	EP-022620151
Mouthpiece 15 mm ID, 22 mm OD	Hudson RCI, Teleflex, Perak, Malaysia	REF 1565 (IPN042595)
MRIdium	Iradmed, Winter Springs, FL	3860+
Nalgene square PET media bottle with closure, 650 mL	Thermo Scientific	#3420400650	for cross-calibration
pressure infusion bag with bulb, accommodating 1,000 mL	Health Care Logi	#10401
pressure monitoring tray polyethylene catheter; 2.5Fr (2.5 cm) angiocath; 0.015" 15 cm wire; 22G (2 cm) needle	Cook Medical	C-P MSY-250, G02854
RDS 11 MeV Cyclotron	Siemens, Erlangen, Germany		proton bombardment of 15N to generate 15O
sodium chloride IV solution 0.9%, 1,000 mL	B. Braun Medical	E8000
steri-strips (closure, skin reinf LF 1/2x4")	McKesson MecSurg	#3010
Twilite II	Swisstrace, Zurich, Switzerland
Uninterruptible Power Supply battery backup and surge protector	APC	BR1500MS2