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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.
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.
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 investigation1,2,3,4,5. 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 disease1,6,7,8,9,10,11,12,13. Thus, there is ongoing interest in studying AG and other aspects of brain metabolism to better understand the human brain as it ages and incurs injury and disease.
At present, methods for evaluating human brain AG in vivo require PET imaging with multiple oxygen and glucose radiotracers to measure each of cerebral metabolic rate of glucose (CMRGlc)14, cerebral metabolic rate of oxygen (CMRO2)15, cerebral blood flow (CBF)16, and cerebral blood volume (CBV)17. Beyond imaging, quantitatively measuring brain metabolism with PET requires other complexities, including evaluating the arterial input function, typically via invasive arterial cannulation and sampling; ensuring that participants precisely follow instructions for radiotracer inhalation while restricting head motion; handling of radiotracers with very short half-lives (2 min) safely and effectively; managing large datasets; and performing advanced analytical methods to calculate metabolic parameters accurately. Also notable are the limitations of using [18F]FDG for the estimation of CMRGlc5,14.
This protocol addresses practical matters most relevant for the successful measurements of quantitative brain metabolism in our experience. This protocol includes a description of essential procedures and cautionary notes for avoiding common errors. It defers careful discussion of more general principles of metabolism, neuroscience, imaging, tracer kinetics, and methods of inference from radiotracer PET imaging. The intended audience includes novices to metabolic measurements using PET, as well as more experienced PET researchers and clinicians interested in employing 15O radiotracers. This protocol assumes familiarity with human imaging studies, invasive medical procedures, radiotracers, and quantitative methods of inference. Numerous, excellent references exist on brain PET imaging in general18, and for 15O-oxygen PET more specifically19. For [18F]FDG, as well as other practical matters of performing PET, Turku PET Centre provides valuable reference materials as well as links to the extensive primary research literature20.
The protocol sections commence with relevant considerations with regard to participant selection that are essential for compliance and successful scanning. Next, the protocol outlines aspects pertaining to supportive scanning with MRI for neuroanatomy. Next, the protocol describes clinical laboratory ordersΒ that include measures important for the quantification of oxygen and glucose metabolism. Next, the protocol lists matters involving the cyclotron and delivery of radiopharmaceuticals. Descriptions merely take the perspective of investigators working at the point of care in the imaging facility, omitting considerations required of cyclotron facilities and staff. Next, the protocol details the preparing and managing of arterial lines. Establishing and maintaining arterial lines require meeting compliance criteria specific to institutions, and the protocol outlines successful workflows. Next, the protocol provides the essential operational procedures for scanning with PET, including details of participant positioning, CT for attenuation correction, administration of radiopharmaceuticals, and performing arterial measurements. Venous sampling discusses potential alternatives to arterial sampling in measurements of CMRGlc with [18F]FDG. A section on PET image reconstruction and data storage details software parameters and practical matters of information technology. The section on discharge and participant follow-up notes essential communications for participant safety. Important calibration activities are also discussed. Many suitable analysis methods and kinetic models are well described in published scientific reports and their numerous antecedents; thus, this protocol largely directs the reader to references of published approaches. Representative results illustrate the successful implementation of protocols. The discussion section elaborates advantageous aspects and limitations of the protocol, its potential in human neuroscience, and matters pertaining to safety.
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
2. MRI for neuroanatomy
3. Laboratory orders
4. Delivery of radiopharmaceuticals
NOTE: Measuring brain oxygen metabolism and AG with PET requires a cyclotron facility capable of producing and delivering 15O radiopharmaceuticals, which have 122 s half-lives. Transport of radiopharmaceuticals between the cyclotron facility and PET scanner must be sufficiently and reliably rapid to provide adequate dosing at the time of radiotracer administration.
5. Arterial lines
6. Scanning
7. Arterial measurements
8. Venous sampling
9. PET image reconstruction and data storage
10. Discharge and participant follow-up
11. Calibrations
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...
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 scanners14,15,16,17,26,
There are no conflicts of interest, financial or otherwise, between the authors and the content of this paper.
We are particularly grateful to our research participants for their altruism. We acknowledge the directors and staff of the Neuroimaging Labs Research Center, Knight Alzheimer's Disease Research Center, Center for Clinical Imaging Research (CCIR), and the Washington University cyclotron facility for making this research possible. We gratefully acknowledge research funding from NIH R01AG053503, R01AG057536, RF1AG073210, RF1AG074992, and 1S10OD025214, the Mallinckrodt Institute of Radiology, and the McDonnell Foundation for Systems Neuroscience at Washington University.
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, NJΒ | from 1991 or newer | NaI drilled well crystal |
Coban self-adhesive wrap | 3M | commonly used in intensive care units | |
dressing, tegaderm, 4 x 4"Β | 3M Health Care | #1626 | |
ECAT EXACT HR+ | CTI PET Systems, Knoxville, TN | ||
Edwards TruWave 3 cc/84 in (210 cm)Β | 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 mLΒ | 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 |
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