Name: Multi-Tracer Studies of Brain Oxygen and Glucose Metabolism Using a Time-of-Flight Positron Emission Tomography-Computed Tomography Scanner (Video) | JoVE Journal
Uploaded: 2024-06-07T12:30:00.000+00:00
Duration: 8 min 36 s
Description: Learn a PET-CT protocol for quantifying brain glucose and oxygen metabolism in vivo. This non-invasive method enables physiologically meaningful measurements across subjects and studies.

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5 minutes

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&#39;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.

PET-CT Scanning for Multi-Tracer Study of Cerebral Oxygen and Glucose Metabolism

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There are no conflicts of interest, financial or otherwise, between the authors and the content of this paper.

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 scanners14,15,16,17,26,27. These data commonly relied on transmission scanning with germanium/gallium sources for attenuation mapping, luminescence-limited bismuth germanate (BGO) scintillator arrays, high-activity dosing, and 2D acquisitions with ringed septa to accommodate limited scintillator luminescence and filtered back-projection reconstructions that are computationally inexpensive. Newer scanners, including that described in this protocol, use high-resolution CT for attenuation correction, highly luminescent lutetium-yttrium oxyorthosilicate (LYSO) scintillator arrays arranged in spatially dense scintillator configurations, 3D acquisitions that multiplex the efficiency of photon detection, TOF detection electronics that improve spatial localization of annihilation events, and computationally advanced reconstruction methods with 3D ordinary-Poisson ordered subsets of expectation maximization (OP-OSEM). New scanners provide superior image quality at a lower radiation dose29,30. Comparable exemplars from three generations of PET scanners are detailed in Figure 6.
This protocol takes advantage of several additional modifications to advance the quality of information from PET scanning from newer scanners: feet-first positioning, meticulously timed dose administrations, and automated arterial input function measurements25. These permit collection of arterial input functions and brain emissions data for four distinct tracers of oxygen and glucose metabolism within a 2-3 h scanning session. These data can then be submitted to traditional and novel kinetic modeling methods, as well as partial volume correction algorithms, to produce high-resolution, high-accuracy quantitative estimates of brain metabolism. Importantly, this protocol not only permits quantitative measurements of brain oxygen and glucose metabolism but also the calculation of brain AG. Notably, superior image quality from state-of-the-art scanners enables more realistic image-derived arterial input functions as well as novel analytical approaches that were previously limited by noise or sensitivity to timing differences between arterial sampling and brain emissions19.
Notably, imaging quality is more challenging to improve with 15O radiotracers than [18F]FDG. The ephemeral 122 s half-life of 15O causes severe loss of information. However, the use of gaseous radiotracers may also be pertinent, as gases may accumulate in the ambient space between the participant&#39;s head and the detection rings of the PET-CT. There, emissions from radiotracer gases can form significant sources of randoms and scattering, thereby confounding vendor-implemented scatter correction methods that use relative scaling of scattering sources compared to regions identified to be air. Even intravenously injected [15O]H2O may pose difficulties if significant amounts are exhaled as [15O]H2O vapor. Methods for scavenging gaseous radiotracers have been reported24 but not implemented in this work. Conventional scatter correction models can be inadequate for imaging 15O radiotracers, and the best performance for these tracers has depended on scattering models that account for the absolute sources of annihilation photons in the field of view, without rescaling, paired with accurate maps of attenuation. Even minor omissions of hardware, such as mirrors attached to head-coils of PET-MR scanners, upon which 15O gases commonly form condensates, can produce substantial artifacts in emissions reconstructions. Related artifacts arising from mismatched maps of attenuation following participant movement have also been reported31. As the interactions of scattering models with point-spread characteristics of gaseous radiotracers are yet poorly characterized, this work has omitted point-spread modeling methods which otherwise are essential for high-resolution PET. Optimizing reconstruction parameters for listmode for each tracer is best practice, but this work provides exemplars using simply console reconstructions that were identically applied to all tracers, as possible, as described in protocol section 9.1. Exemplars necessarily demonstrate frame timing schedules that have been adapted to the variability of tracer-kinetic timescales. The exemplars emphasize simplicity, comparability of counting statistics, and effective spatial resolutions available for each tracer, and minimizing bias that could arise while optimizing reconstruction parameters for each tracer. For comparability with existing studies of 15O, the representative results of this work use 8 iterations of 5 subsets, previously reported to be appropriate for modern PET-CT with time-of-flight acquisitions30,32. Time-of-flight may yield improved imaging resolution with 4 iterations of 5 subsets, and these optimizations are under active investigation for the tracers described in this work.
The longer scanner bore of modern PET-CT scanners encumbers investigators providing radiotracer gases. Confined gantry geometries increase the difficulties of reaching the participant&#39;s mouth when administering gases, communicating instructions to participants, and ensuring that gas administration devices do not leak radiotracers into the ambient space. Thereby, feet-first positioning of participants demonstrates advantages. Most scanner hardware makes feet-first positioning incompatible with the placement of neuroshielding devices, which typically place lead shielding that surrounds the participant&#39;s neck and partitions the participant&#39;s head from the body. Neuroshielding will reduce randoms entering the field-of-view from the body. The relative benefits of neuroshielding compared to avoidance of ambient gas radiotracers are presently poorly understood.
Quantifying brain metabolism 
This paper demonstrates the results of analyses using traditional models for hemodynamics described by Raichle et al. (CBF)16 and Martin et al. (CBV)17, and for metabolism described by Mintun et al. (CMRO2)15 and Huang et al. (CMRGlc)14. These analyses utilize the arterial input functions and emissions data measured using the protocol described in this paper. Alternative means to measure the arterial input function, such as an image-derived method, are being actively pursued and tested against the invasive method. Traditional models also make full use of dynamic imaging to estimate kinetic model parameters. We have preferred the use of polynomial representations of CBF and CMRO226,27. We have favored the methods of Huang et al. for estimating CMRGlc but employing Bayesian parameter estimation28,33. AG was more recently conceived as a measure of glucose that enters glycolytic pathways but contributes to cellular functions other than oxidative phosphorylation4. Calculation of brain AG then simply requires conversion of CMRGlc and CMRO2 to molar equivalents and subtraction of one-sixth of the latter from the former.
Partial volume correction 
We commonly perform regional partial volume correction on SUVR images using the symmetric geometric transfer matrix algorithm (sGTM)34. This relies on the high-resolution data obtained by MRI, which can include anatomic sequences alone, though the current protocol also obtains Human Connectome Project (HCP)-like sequences for more precise regional parcellation. We have used both anatomic (e.g., Desikan-Killiany35) and functional (e.g., Schaeffer36 or Glasser37) atlases. The former atlases often have larger regions of interest that are more appropriate for PET images obtained at a lower resolution and have been more widely used in prior PET research. However, the newer atlases are functionally and cytoarchitecturally more well-defined and may now be more applicable with higher-resolution PET imaging, such as that obtained with the Siemens Vision scanner. SUVR images for 15O scans are calculated as have been previously described and referenced to whole brain values4. Whole-brain CMRGlc and CMRO2 are then calculated using the kinetic modeling as per above to convert the SUVR images to absolute quantitative values. From this, partial volume corrected regional AG can then be calculated. While our exemplars for dynamic emissions imaging do not demonstrate partial volume correction for simplicity of presentation, partial volume correction methods that account for dynamic imaging are now being actively investigated.
Generalizability and adaptability of the protocol 
This protocol describes methodological details pertinent to acquiring the highest achievable accuracy, precision, reproducibility, and interpretability from measurements of oxygen and glucose metabolism by PET in humans. The highest known accuracy and precision of measurements belong to analyses based upon principles and practices of tracer kinetics, which include direct measurements of arterial input functions, determination of regions of interest by co-registration with high-resolution structural MRI, and highly demanding use of computational resources for statistical models. In particular, invasive radial-artery cannulation, and its maintenance over serially repeated emission scans, is costly and bears finite risks of serious injury that demand the involvement of clinically experienced teams. The use of tracers based on 15O is yet another challenge for cyclotrons and their support teams. These provide correspondence with historically reported metabolic measurements in humans and ensure that interpretations of quantitative findings are built upon prior accumulated information. However, these detailed and invasive measures also provide means for validation of less invasive, less demanding methods that may be sufficient for many questions of human metabolism. Following appropriate validation, radial artery cannulation may be suitably replaced with image-derived sources of input functions38 for many specialized studies. Avoiding radial artery cannulation also precludes direct measurements of the primary metabolic product of [15O]O2, namely [15O]H2O, which can be estimated from samples of radial artery that have been centrifuged to estimate [15O]H2O of metabolism from plasma and [15O]O2 from centrifuged red blood cells. However, computationally intensive methods can be used to parametrically solve for the emergence of metabolic [15O]H2O in the arterial circulation, a linear model of which has been proposed by Mintun et al15. Many methodologies using SUVR may also be amenable to validation following comparisons to invasively obtained data. Currently, active research programs seek validation of oxygenation estimates based on the blood oxygenation level-dependent effect, and contemporaneous measurements with 15O can provide further validation39. Additionally, while only mentioned in this protocol without exemplars, detailed optimizations of image reconstructions from listmode are likely to improve the quality of measurements of metabolism. Further, many specialized methods such as motion correction of listmode data and partial volume corrections, may merit effort when study questions demand them, for example, when occasional participants have excessive head movements or studies of cortical atrophy are confounded by partial volume averaging with cerebral spinal fluid.
Cautions for PET scanning 
This protocol exposes participants to ionizing gamma radiation. The current estimates of radiation in participants who have undergone the total PET session described here (including four to six 15O scans and one FDG scan), result in an average total effective dose, inclusive of all radiotracer administrations, of approximately 7 mSv (0.7 rem). This is comparable to the radiation dose of other radiotracers used in research and clinical practice and represents 14% of the total radiation dose allowable to a radiation worker in one year. All participants (and/or their legally acceptable representative) are carefully informed both in writing and verbally of the potential radiation risks prior to obtaining their consent for study enrollment.
Cautions for arterial lines 
Complications of arterial cannulation include bruising (common), pain, swelling, hematoma (uncommon), bleeding at the site of insertion, vasospasm, thrombosis (rare), and reaction to heparinized saline when used (very rare). We routinely employ an interventional radiology service to place arterial lines and manage any complications if they should arise.
Cautions for MRI 
The US Food and Drug Administration requires all medical devices that enter the magnetic field of an MRI scanner to undergo standardized safety testing. If a participant&#39;s device is labeled MRI Safe, then we can proceed using standard FDA-approved scanning conditions without additional risks to the participant. If a participant&#39;s device is MRI Conditional, we review the manufacturer, make, and model of the device, and then adjust the MRI scanning procedures accordingly. Imaging also has the potential risk of revealing incidental findings, which can incur additional risks such as anxiety, financial loss from additional work-up, and, rarely, complications arising from subsequent, clinically indicated invasive procedures.
Summary of limitations 
Unavoidable limitations of measuring oxygen and glucose metabolism are specific to the radiotracer themselves. 15O-tracers have short half-lives that stipulate many of the most demanding requirements of this protocol, including the presence of highly specialized and accessible cyclotron facilities. Gaseous 15O-tracers introduce the complexity of gas management such as scavenging of expired gases24 and specialized methods for scatter corrections. [18F]FDG exchanges the considerable challenges of tracking metabolites in [11C]-glucose tracers for confounding by lumped-constant estimations. This protocol also has limitations arising from the confining geometry of integrated PET-CT scanners. While feet-first positioning of the participant ameliorates confinement problems, it may be incompatible with the use of neuroshielding devices. Finally, the use of invasive radial artery cannulation is itself a significant limitation. The radial artery is a proxy for the primary arterial supply of the brain. However, the radial artery may have discrepant flow characteristics from arterial supplies to the brain. Furthermore, invasive and painful procedures alter the cognitive state of study participants, limiting the scope and generalizability of neuroimaging studies that can be pursued by this protocol.

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&#39;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 orders&#160;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.

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

multi-tracer studies of brain oxygen and glucose metabolism using a time-of-flight positron emission tomography-computed tomography scanner

Multi-Tracer Studies of Brain Oxygen and Glucose Metabolism Using a Time-of-Flight 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.

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 above are easily incorporated into non-quantitative maps of specific activities (Figure 2), including the calculation of ratios of standardized uptake value (SUVR). Whole-brain time activity curves (Figure 3) help identify significant head movements, which would produce discontinuities of the activity curve, and provide characteristic features of tracers, after decay correction, such as the expected plateau of [15O]CO at 120 s and its consequent renal excretion, the plateau of [15O]O2 after bolus passage as it is extracted by brain tissue and metabolized to radiolabeled [15O]H2O, the monotonic decrease of injected [15O]H2O as it increases in volume of distribution throughout the body, and the progressive uptake and phosphorylation of [18F]FDG via hexokinase in the brain over the lifetime of 18F. Detailed model estimates of metabolic [15O]H2O were originally described by Mintun et al15.
A simpler polynomial phenomenology, which omits considerations of intravascular dispersions and emphasizes robust features in emissions data, was advocated by Herscovitch et al26,27. This work's exemplars make use of only this latter phenomenology for oxygen metabolism. Arterial input functions recorded by gamma detection from catheters cannulating the distal radial artery bear substantial dispersion and delay which must be deconvolved. We have favored Bayesian methods for parameter estimation of models of series of gamma distributions and exponentially rising steady terms28. Figure 4 demonstrates results for [15O]CO, [15O]O2, [15O]H2O, and [18F]FDG. Results for [15O]O2 also illustrate the emergence of [15O]H2O of metabolism. Figure 5 demonstrates statistical parameter maps of CBV, CBF, CMRO2, CMRGlc, and AG, which we define to be the molar balance of classical glycolysis: CMRGlc - CMRO2/6.
<img alt="PET/CT scanning process; cyclotron, PET synthesis; diagram and equipment for participant scanning." class="xfigimg" src="/files/ftp_upload/65510/65510fig01.jpg" data-altupdatedat="1788304762000" data-alt="Figure 1"> 
Figure 1: Summary of setup and operational workflows. (A) Schematic illustration of essential instruments and parts needed in the scanner bay. For PET-CT scanners with long scanner bores, feet-first positioning of participants improves the administration of gaseous radiopharmaceuticals by increasing the maneuverability of gas delivery devices and improving verbal and nonverbal communications with the participant. The gas delivery system (cyan and blue) comprises narrow-diameter nylon tubing from the cyclotron, under exhaust for the transport of gaseous radiopharmaceuticals; a shielded gas storage chamber containing expandable bellows and pico-ammeter dose-calibrator; a particulate filter suitable for capturing viral particles; and a terminal large-diameter plastic polymer tubing fitted with clamp and plastic mouthpiece. All parts exposed to respiratory droplets are disposable or compatible with sterilization procedures. Instruments and parts for arterial blood measurements (red and dark gray) provide pressured saline for maintaining radial artery cannulation, compact gamma detection for the coincidence of 511 keV annihilation photons, a peristaltic pump for arterial blood withdrawal, and a container for the collection of withdrawn blood. Radiopharmaceuticals for intravenous injection require synthesis modules for the generation of [15O]H2O from cyclotron-supplied [15O]O2 gas, or pneumatic tube delivery from the cyclotron radiopharmacy (green). Intravenous administration of radiopharmaceuticals requires clinical-grade dosimetry (magenta). Measurements of activity in whole blood and plasma require a well-counter, analytical balance, and microcentrifuge (red). (B) Annotated and detailed views of the gas delivery system. Abbreviation: PET-CT = positron emission tomography-computed tomography. <a href="https://www.jove.com/files/ftp_upload/65510/65510fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="PET brain scans: [15O]CO, [15O]O2, [15O]H2O, [18F]FDG, tracing cerebral blood flow and metabolism." class="xfigimg" src="/files/ftp_upload/65510/65510fig02.jpg" data-altupdatedat="1788304762000" data-alt="Figure 2"> 
Figure 2: Representative static images for [15O]CO, [15O]O2, [15O]H2O, and [18F]FDG, overlaid with ~25% transparency on CT windowed for temporal bone. Scans of 15O radiotracers positioned the participant feet-first with only elastic self-adhesive wrapping securing the head to the gantry table. The scan of [18F]FDG followed a break from scanning, then returning the participant to approximately the original feet-first positioning. Abbreviations: CO = carbon monoxide; FDG = fludeoxyglucose; CT = computed tomography. <a href="https://www.jove.com/files/ftp_upload/65510/65510fig02large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Brain activity graphs for CO2, O2, H2O, FDG; specific activity vs. time; metabolic analysis." class="xfigimg" src="/files/ftp_upload/65510/65510fig03.jpg" data-altupdatedat="1788304762000" data-alt="Figure 3"> 
Figure 3: Representative tracer activity curves of the whole brain. (A) [15O]CO, (B) [15O]O2, (C) [15O]H2O, and (D) [18F]FDG. The whole brain was defined by masking of anatomical MPRAGE. The arrival of a bolus of administered tracer precedes or coincides with the timing of the first PET frames in panels A and B. Abbreviations: CO = carbon monoxide; FDG = fludeoxyglucose; PET = positron emission tomography; MPRAGE = magnetization-prepared rapid acquisition gradient echo. <a href="https://www.jove.com/files/ftp_upload/65510/65510fig03large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Graph illustrating arterial activity (Bq) vs. time (s) for metabolic analysis with simulation data." class="xfigimg" src="/files/ftp_upload/65510/65510fig4v2.jpg" data-altupdatedat="1788304762000" data-alt="Figure 4"> 
Figure 4: Representative tracer activity curves, continuously sampled from the radial artery and deconvolutions of dispersions and delays in line assemblies. Exemplars describe (A) [15O]CO, (B) [15O]O2, (C) [15O]H2O, and (D) [18F]FDG. Blue circles are data measured by a coincidence detection probe surrounding a narrowly looped catheter that passes arterial blood. Coincidence counting from the probe includes baseline scintillation of LYSO crystals responding to ambient photons (wide spectrum randoms that fall within the device timing window of 100 ns). Arterial blood passes from the radial artery through the probe by distal action of a peristaltic pump. The purple dashed line is the empirical estimate of the kernel for dispersion and delay described in protocol section 11.2. The yellow line describes the tracer activity curve corrected for dispersion and delay. Simulated annealing estimates parameters of a generalized gamma distribution for the yellow line consistent with the estimated kernel and data from coincidence detection. The fitted data appear as a red line. Panel (B) also indicates [15O]H2O from the metabolism of [15O]O2 assumed to have linear characteristics described by Mintun et al.15. Abbreviations: CO = carbon monoxide; FDG = fludeoxyglucose; PET = positron emission tomography; LYSO = lutetium-yttrium oxyorthosilicate. <a href="https://www.jove.com/files/ftp_upload/65510/65510fig4v2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Brain PET scan analysis; diagram; CBV, CBF, CMRO₂, CMRGlc, AG maps; metabolic activity levels." class="xfigimg" src="/files/ftp_upload/65510/65510fig05.jpg" data-altupdatedat="1788304762000" data-alt="Figure 5"> 
Figure 5: Maps of CBV, CBF, CMRO2, CMRGlc, and AG. CBV is required for the quantitative estimation of CMRO2, CMRGlc, and AG. However, the activity from venous sinuses is confounding for CMRGlc and AG. Consequently, venous sinuses have been removed from CMRO2 and CMRGlc by masking. The contrast between the cerebellum and neocortex is consistent with prior studies of AG. Abbreviations: CBV = cerebral blood volume; CBF = cerebral blood flow; CMRO2 = cerebral metabolic rate of oxygen; CMRGlc = cerebral metabolic rate of glucose; AG = aerobic glycolysis. <a href="https://www.jove.com/files/ftp_upload/65510/65510fig05large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Brain imaging comparison, PET scan, resolution analysis across three techniques, neuroscience study." class="xfigimg" src="/files/ftp_upload/65510/65510fig06.jpg" data-altupdatedat="1788304762000" data-alt="Figure 6"> 
Figure 6: Exemplars of static emissions of [15O]H2O from healthy control study participants scanned on three generations of PET scanners. All reconstructions used 3D OP-OSEM with delayed randoms, attenuation correction, and all-pass filtering (no filtering). All reconstructions are from scanner consoles with parameters suitable for efficient clinical workflows. No additional numerical processing, corrections, or blurring were used. For purposes of comparability, all scanner results are shown following rigid-body transformation and trilinear interpolation to the MNI152 atlas at 1.0 mm3 resolution. (A) A PET-only scanner with BGO crystal scintillators, OP-OSEM with 4 iterations and 16 subsets, 2.0 x 2.0 x 2.4 mm3 voxels, 6 min of emissions, transmission scan with Ge/Ga for attenuation mapping, and single scatter simulations. (B) A PET-MR scanner with LYSO crystal scintillators, OP-OSEM with 4 iterations and 16 subsets, 2.1 x 2.1 x 2.0 mm3 voxels, 10 min of emissions, externally acquired CT for attenuation mapping, and model-based absolute scatter scaling. (C) A PET-CT scanner with LYSO crystal scintillators, time-of-flight detection, OP-OSEM with 8 iterations and 5 subsets, 1.65 x 1.65 x 1.65 mm3 voxels, 6 min of emissions, integrated CT for attenuation mapping, and model-based absolute scatter scaling. Abbreviations: PET = positron emission tomography; CT = computed tomography; MR = magnetic resonance; OP-OSEM = ordinary-Poisson ordered subsets of expectation maximization; BGO = bismuth germanate; LYSO = lutetium-yttrium oxyorthosilicate. <a href="https://www.jove.com/files/ftp_upload/65510/65510fig06large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

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 ...

multi-tracer-studies-brain-oxygen-glucose-metabolism-using-time

Research

JoVE Journal

Neuroscience

Source: Jamadar, S. et. al. Radiotracer Administration for High Temporal Resolution Positron Emission Tomography of the Human Brain: Application to FDG-fPET. J. Vis. Exp. (2019)This video demonstrates the quantification of brain glucose metabolism using positron emission tomography (PET). The participant is infused with the tracer F-18 fluorodeoxyglucose (FDG) during scanning. FDG accumulates in active neurons and emits positrons upon F-18 decay. These positrons interact with electrons,...

Positron Emission Tomography Imaging of the Human Brain Using a Radiotracer

Small-animal positron emission tomography enables the assessment of the brain's two main energy substrates: glucose and ketones. In the present method, 11C-acetoacetate and 18F-fluorodeoxyglucose are injected sequentially in each animal, and their uptake is measured quantitatively in specific brain regions determined from the magnetic resonance images.

A Dual Tracer PET-MRI Protocol for the Quantitative Measure of Regional Brain Energy Substrates Uptake in the Rat

[18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography is useful for studying glucose metabolism related to brain function. Here, we present a protocol for an [18F]FDG tracer set-up and semiquantitative assessment of the region-of-interest analysis for targeted brain areas associated with clinical manifestations in patients with severe traumatic brain injury.

Semi-quantitative Assessment Using [18F]FDG Tracer in Patients with Severe Brain Injury

This manuscript describes two radiotracer administration protocols for FDG-PET (constant infusion and bolus plus infusion) and compares them to bolus administration. Temporal resolutions of 16 s are achievable using these protocols.

Radiotracer Administration for High Temporal Resolution Positron Emission Tomography of the Human Brain: Application to FDG-fPET

The acquisition of dynamic positron emission tomography (PET) data and reconstruction into time frames allows for metabolic brain connectivity analysis at the single-subject level. We describe a method to acquire [18F]FDG dynamic PET data of the rat brain and obtain a connectivity matrix through the extraction of time-activity curves of volumes of interest.

Studying Metabolic Brain Connectivity Using 2-Deoxy-2-[18F]Fluoro-D-Glucose Dynamic Positron Emission Tomography at the Single-subject Level

We present an experimental procedure for measuring the partial pressure of oxygen (pO2) in cerebral vasculature based on oxygen-dependent quenching of phosphorescence. Animal preparation and imaging procedures were outlined for both large field of view CCD-based imaging of pO2 in rats and 2-photon excitation based imaging of pO2 in mice.

Cerebral Blood Oxygenation Measurement Based on Oxygen-dependent Quenching of Phosphorescence

This method describes the generation of organotypic cerebellar cultures and the effect of certain apoptotic stimuli on the viability of different cerebellar cell types.

Organotypic Cerebellar Cultures: Apoptotic Challenges and Detection

Here, a procedure to selectively activate a neuronal protein with a short pulse of light by genetically encoding a photo-reactive unnatural amino acid into a target neuronal protein expressed in neurons in culture or in vivo is presented.

Optical Control of a Neuronal Protein Using a Genetically Encoded Unnatural Amino Acid in Neurons

Here, we present a protocol to ablate a genetically labeled subpopulation of neurons by a two-photon laser from Zebrafish larvae.

Ablation of a Neuronal Population Using a Two-photon Laser and Its Assessment Using Calcium Imaging and Behavioral Recording in Zebrafish Larvae

This paper describes a novel model of primary blast traumatic brain injury. A compressed-air driven shock tube is used to expose in vitro mouse hippocampal slice cultures to a single shock wave. This is a simple and rapid protocol generating a reproducible brain tissue injury with a high throughput.

A Novel In Vitro Model of Blast Traumatic Brain Injury

Learn a PET-CT protocol for quantifying brain glucose and oxygen metabolism in vivo. This non-invasive method enables physiologically meaningful measurements across subjects and studies.

Multi-Tracer Studies of Brain Oxygen and Glucose Metabolism Using a Time-of-Flight Positron Emission Tomography-Computed Tomography Scanner (Video) | JoVE Journal

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

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