Name: determining glucose metabolism kinetics using 18f-fdg micro-pet/ct
Uploaded: 2017-05-02T14:30:00.000+00:00
Duration: 7 min 7 s
Description: Watch this Scientific Journal Video about Determining Glucose Metabolism Kinetics Using 18F-FDG Micro-PET/CT at JoVE.com

This work was supported by a National Imaging Facility Subsidised Access Grant to BJC, a National Health and Medical Research Council of Australia program grant (482800) to KAR and PJB. The authors would like to thank Andrew Arthur, Hasar Hazme and Marie-Claude Gregoire for support in developing this method.

All procedures described in this study were approved by the Sydney Local Health District and University of Sydney Animal Ethics Committees and followed the NIH Guide for the care and use of laboratory animals, Eighth edition (2011).
1. Animal Preparation
NOTE: In this protocol male db/db mice (BKS.Cg-Dock7m +/+ Leprdb/J) were maintained in group housing with ad libitum access to chow and water until 6 weeks of age. At the time of imaging, mice weighed ~ 30 g. All mice used in this protocol had fasting blood glucose levels between 10 and 14 mmol/L.
<ol>
	<li>If required, fast the mice. In the present example, fast the mice for 5 h prior to the experimental procedure.</li>
	<li>Treat mice with the desired agent (e.g. drug, protein, peptide) before the commencement of imaging. In this example, administer a subcutaneous injection of insulin (3 U/kg human insulin) or equivalent volume PBS 30 min prior to the start of imaging.</li>
</ol>
2. Set up Workflow
NOTE: This protocol was implemented on a PET/CT scanner. Acquire PET data first, followed by acquisition of CT data.
<ol>
	<li>PET settings:
	<ol>
		<li>Select isotope as 18F, set scan duration to 3,600 s, and upper and lower level energy discrimination to 350 keV - 650 keV (default) with a coincidence timing window of 3.432 ns (default). Histogram list-mode data into 16 frames (6 &#215; 10 s, 4 &#215; 60 s, 1 &#215; 300 s, 5 &#215; 600 s) for the period 0 - 60 min after tracer injection. Reconstruct emission sinograms using 2D-FBP with a zoom 1.5. 
		NOTE: The reconstructed images consisted of 16 dynamic frames, each with 128 &#215; 128 &#215; 159 voxels and a voxel size of 0.52 &#215; 0.52 &#215; 0.796 mm3.</li>
	</ol>
	</li>
	<li>CT settings:
	<ol>
		<li>For a whole body CT scan, set the current at 500 A, voltage at 50 kV, exposure time 500 ms and 200 projections over a 360 rotation. Set the detector field of view (FoV) to 30722048, number of bed positions to 3 (to cover full PET FoV range), overlap between bed positions = 30.234713% and detector binning to 4. 
		NOTE: CT reconstruction was performed using cone beam tomography image reconstruction software with HU calibration, bilinear interpolation and Shepp-Logan filter.</li>
	</ol>
	</li>
	<li>18 F-FDG:
	<ol>
		<li>Order sufficient 18F-FDG (for example 450 MBq in 0.5 mL) from a local provider to arrive ~ 30 min before the first injection. Aliquot and dilute the 18F-FDG so that animals receive ~ 10 MBq of 18F-FDG in a final volume of 0.1 mL.</li>
	</ol>
	</li>
</ol>
3. Imaging Protocol
<ol>
	<li>Wipe down induction chamber and imaging bed with 80% (v/v) ethanol to maintain aseptic conditions. Place the mouse in an induction chamber and anesthetize with 5% isoflurane in oxygen.</li>
	<li>Place the mouse onto an imaging bed fitted with an electric heating pad to maintain body temperature and a precision vaporizer nose cone to deliver isoflurane (maintenance, 1.5 - 2%) at a flow rate of 1 L/min. Apply ophthalmic ointment onto eyes to prevent dryness whilst under anesthesia.</li>
	<li>Position the mouse in a prone position on a sensor pad to monitor breathing and ensure an adequate plane of anesthesia is maintained.</li>
	<li>Warm the tail using a heat pack for 1 - 2 min to dilate the lateral tail vein. Catheterize the lateral tail vein by inserting a 30-gauge needle into the lateral tail vein. Secure the needle in place with surgical glue and secure the catheter.</li>
	<li>Load imaging bed into the scanner and move the bed through the machine so that the catheter can be accessed from the rear of the machine.</li>
	<li>Attach the catheter to the 18F-FDG syringe in a syringe driver. Calculate the exact 18F-FDG dose (10 MBq) based on activity in syringe before injection and the volume to be administered (&#60; 100 &#956;L, injected over 10 s).</li>
	<li>To minimize the impact of anesthesia on variability of glucose uptake, ensure a constant time between induction of anesthesia and injection of 18F-FDG (for example, 30 min).</li>
	<li>Commence the PET scan immediately before injection of 18F-FDG. After finishing the PET scan (3,600 s), perform a CT scan (~ 10 min) to allow for co-registration of radiotracer uptake with tissues.</li>
	<li>Move the imaging bed to the starting position, remove the animal from the bed.</li>
	<li>At this point euthanize the animal or allow it to recover:
	<ol>
		<li>For euthanasia, perform cervical dislocation whilst still under anesthesia and collect organs of interest for subsequent analysis.</li>
		<li>If allowing the mouse to recover, place the mouse in single housing on a heating pad or in front of a heating lamp. Monitor the mouse until it has regained sufficient consciousness to maintain sternal recumbency. Allow the mouse to recover for 1 h before returning to group housing.</li>
	</ol>
	</li>
</ol>
4. PET Image Processing
NOTE: Image reconstruction was performed using acquisition workplace software v1.5.0.28 and analysis in research workplace software v4.2.
<ol>
	<li>Co-register CT and PET images and ensure that the alignment is correct in all 3 dimensions.
	<ol>
		<li>In the &#39;File&#39; menu, select &#39;Folder Search/Import&#39; and select the folder containing the data. Select the desired PET and CT data and click on the &#39;General Analysis&#39; tab.</li>
		<li>Sort the data so that the CR is designated &#39;Source&#39; and PET is designated &#39;Target&#39;. In the &#39;Workflow&#39; menu, select &#39;Registration&#39;. If the images require adjustment to be correctly co-registered, use the tools in the &#39;Registration&#39; menu.</li>
	</ol>
	</li>
	<li>In the &#39;Workflow&#39; menu, select &#39;ROI Quantification&#39;.
	<ol>
		<li>Use the &#39;Pan&#39; and &#39;Zoom&#39; functions in the &#39;Image&#39; tab to locate the desired region. In the &#39;Tools&#39; menu, select the &#39;Create&#39; tab and click the paintbrush icon. Draw the ROI on the image</li>
	</ol>
	</li>
	<li>Extract time-activity curves by selecting &#39;Save ROI Quantification&#39; from the &#39;Save&#39; menu. Save the data as a CSV file.</li>
	<li>Quantify radioactivity uptake as Bq per cm3 of tissue. Convert values into percentage of injected dose per cm3 (% ID/ cm3) by loading the CSV file into a spreadsheet.</li>
</ol>
5. Input Function
<ol>
	<li>To correct for the system point spread function, deconvolve the estimated system PSF for 5 iterations using the reblurred Van Cittert deconvolution method as previously described9. 
	NOTE: This is required due to the small size of the vena cava in a mouse.</li>
	<li>Use post deconvolution images to generate a blood input function time-activity curve as described above.</li>
</ol>
6. Kinetic Modeling
NOTE: The FDG two-tissue compartment model (Figure 1) requires the plasma input function.
<ol>
	<li>Convert the blood input function in the CSV file to the plasma input function using the following equation10: Input_plasma = Input_blood &#215; (0.386e&#8722;0.191t + 1.165).</li>
	<li>In the kinetic modelling tool click the &#39;Kinetic&#39; button. Import the tissue and plasma total activity count CSV files into the kinetic modelling tool by selecting &#39;Load Time Activity Curve&#39; from the &#39;Menu&#39;.</li>
	<li>In the &#39;Model&#39; menu select 2 tissue compartments. Ensure that the box next to k4 is unselected and enter a value of 0. For initial fitting, uncheck the box for vB (blood volume fraction) and enter a value of 2%.</li>
	<li>Click the &#39;Fit current region&#39;. Correct the extracted region of interest for dispersion11,12. Achieve this by minimizing the Chi-square value for the FDG model for different dispersion times.</li>
	<li>Perform a second fit using floating vB value (check the box next to the box for vB) and the optimized dispersion value to calculate the regional rate constants (k1-k3). Calculate the regional influx constant as Ki = (k1 &#215; k3) / (k2 + k3).</li>
</ol>

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The authors have nothing to disclose.

The protocol described here represents a robust, non-invasive methodology to determine the kinetics of glucose uptake from the blood stream into tissue and subsequent metabolism in mice.
The db/db mouse is a is a well-established animal model of type 2 diabetes14 that has been used extensively to examine insulin resistance and relevant interventions. However, previous studies have only quantified endpoint uptake in the heart15 and cardiac and skeletal muscle16.
The use of kinetic analysis to determine physiological rate constants and model the uptake of 18F-FDG from plasma into tissue allows for insights into the impact of antidiabetic treatments on glucose uptake and metabolism. In addition, these experiments can be performed longitudinally to assess, for example, the impact of age or diet on glucose metabolism. This is advantageous over traditional methods that require euthanasia and collection of organs of interest and thus provide information only at a single time point.
Whilst input functions have previously been determined using the whole heart17 as well as heart, liver and a blood samples18 in mice, the protocol described here permits calculation of the input function using a region of interest over the vena cava19. It is also possible to calculate input functions using arterial blood samples during a PET study. However, this is impractical due to the small blood volume of mice.
The use of a plasma input function rather than the 18F-FDGsignal in whole blood is due to the uptake of 18F-FDG into mouse red blood cells20. Furthermore, the red blood cell associated activity represents 18F-FDG inside red cells, and hence is not readily available for transport into other tissue compartments.
In this protocol, it is critical to ensure correct placement of the catheter placed into the tail vein for delivery of the 18F-FDG bolus to the vena cava and throughout the body of the mouse. Warming of the tail to dilate the tail vein significantly improves the ease of inserting this catheter. It is also important to ensure that the PET and CT images are properly coregistered so that the ROIs drawn on the CT image correctly correspond to the PET signal.
There is some debate over the choice of anesthetic agent in studies examining glucose uptake. Whilst isoflurane is a commonly used veterinary anesthetic, the use of sevoflurane may be advantageous in 18F-FDG PET experiments21. In this protocol, it is important to ensure that any potential bias associated with isoflurane anesthesia is minimized by keeping the time between induction of anesthesia and the commencement of imaging constant.

The purpose of this study was to develop a positron emission tomography/computed tomography (PET/CT) based methodology to quantify the in vivo, real-time uptake of glucose from the blood stream into specific tissues in mice. This was achieved using 18F-labelled fluorodeoxyglucose (FDG) to measure glucose uptake and kinetic modelling to estimate the rates of 18F-FDG uptake from the plasma to the intracellular space, the rate of transport from intracellular space to plasma and the rate of 18F-FDG phosphorylation.
In rodents, 18F-FDG has been used in the pre-clinical assessment of numerous cancer treatments1, studies of tumor progression2 and tumor metabolism3 as well as imaging of brown fat depots4, neuroinflamation5 and brain metabolism6.
Traditional methods used to examine the tissue specific uptake of glucose in mice (and rats) generally involve treatment with 2-deoxyglucose radiolabeled with either 3H or 14C followed by euthanasia, tissue collection and measurement of radioactivity in each tissue7. The use of PET/CT allows for noninvasive determination of glucose uptake and metabolism in multiple organs and regions simultaneously in live animals. Additionally, as euthanasia is not a requirement, this technique is suitable for use in longitudinal studies.
Type 2 diabetes mellitus (T2DM) is characterized by disrupted glucose metabolism and hyperglycemia secondary to reduced tissue responsiveness to insulin (insulin resistance) and the inability of pancreatic -cells to produce adequate amounts of insulin8. Kinetic analysis of glucose uptake and metabolism can provide important insights into the mechanism of action and efficacy of therapeutic interventions as well as allow for advanced monitoring of disease progression.

<table><tbody><tr><td>PET/CT Scanner</td><td>Siemens</td><td>Inveon&amp;nbsp;</td><td></td></tr><tr><td>&lt;sup&gt;18&lt;/sup&gt;F-FDG</td><td>PETNET Solutions</td><td></td><td></td></tr><tr><td>Isoflurane</td><td>Pharmachem</td><td></td><td></td></tr><tr><td>30 guage needle</td><td>BD</td><td>305106</td><td></td></tr><tr><td>PMOD modelling software</td><td>PMOD Technologies</td><td></td><td></td></tr><tr><td>BKS.Cg-&lt;em&gt;Dock7m&lt;/em&gt;&amp;nbsp;+/+&amp;nbsp;&lt;em&gt;Leprdb/J&lt;/em&gt; mice</td><td>Jackson Laboratory</td><td>000642</td><td></td></tr><tr><td>Human insulin</td><td>Sigma-Aldrich</td><td></td><td></td></tr></tbody></table>

determining glucose metabolism kinetics using 18f-fdg micro-pet/ct

This paper describes the use of 18F-FDG and micro-PET/CT imaging to determine in vivo glucose metabolism kinetics in mice (and is transferable to rats). Impaired uptake and metabolism of glucose in multiple organ systems due to insulin resistance is a hallmark of type 2 diabetes. The ability of this technique to extract an image-derived input function from the vena cava using an iterative deconvolution method eliminates the requirement of the collection of arterial blood samples. Fitting of tissue and vena cava time activity curves to a two-tissue, three compartment model permits the estimation of kinetic micro-parameters related to the 18F-FDG uptake from the plasma to the intracellular space, the rate of transport from intracellular space to plasma and the rate of 18F-FDG phosphorylation. This methodology allows for multiple measures of glucose uptake and metabolism kinetics in the context of longitudinal studies and also provides insights into the efficacy of therapeutic interventions.

We have previously used the db/db mouse model to investigate the impact of increasing plasma apoA-I levels on the kinetics of glucose uptake and metabolism13. In this study we used db/db mice treated with insulin to demonstrate the utility of PET/CT imaging to monitor the uptake of 18F-FDG from the plasma into the gastrocnemius muscle in real time.
Six week old db/db mice were anesthetized and treated with 3 U human insulin/kg, or equivalent volume PBS via subcutaneous injection 30 min before the start of the PET scan. Mice received 10 MBq of 18F-FDG via intravenous injection and uptake measured by PET for 60 min. A CT scan was performed for anatomical reference.
Regions of interest were drawn on the vena cava and gastrocnemius muscle using the CT images (Figure 2). Treatment of db/db mice with insulin increased the 18F-FDG activity in the gastrocnemius ROI over the acquisition time period (Figure 3A). The values obtained for the vena cava ROI were converted from blood to plasma values and were not altered by insulin treatment in insulin treated mice relative to control (Figure 3B).
Time activity curves were loaded into the kinetic modelling tool for calculation of kinetic parameters. Data was initially fitted to a two-tissue compartment method with k4=0 with a Vb (blood volume fraction) value of 2% to calculate dispersion values (80 s and 70 s for PBS and insulin treated mice, respectively). Fitting was then performed using the above dispersion values and a floating Vb value.
No significant difference in the rate of 18F-FDG transport from the arterial plasma to the intracellular space (k1) or from the intracellular space to plasma (k2) was observed in insulin treated mice compared to control (Table 1). The rate of 18F-FDG phosphorylation (k3) was significantly increased in insulin treated mice (7.06 &#177; 6.60 &#215; 10-3 vs 2.26 &#177; 0.72 &#215; 10-2 min-1 for PBS and insulin treated groups, respectively; p &#60; 0.05). Insulin treatment also significantly increased the influx constant (Ki) compared to the PBS-treated animals (5.51 &#177; 4.25 &#215; 10-4 vs 2.01 &#177; 0.28 &#215; 10-3 mL min-1 g-1, respectively; p &#60; 0.05).
<img alt="Figure 1" src="/files/ftp_upload/55184/55184fig1.jpg" /> 
Figure 1: Regional time-activity curves were fitted to a two-tissue, three compartment model, with C1 being the concentration of FDG in plasma and C2 and C3 the concentration of FDG and phosphorylated FDG in tissue, respectively. k1 represents the FDG uptake rate in tissue, k2 the clearance rate from the tissue back to the plasma compartment and k3 the phosphorylation rate of FDG. The dephosphorylation of FDG was assumed to be negligible (k4=0).
<img alt="Figure 2" src="/files/ftp_upload/55184/55184fig2.jpg" /> 
Figure 2: Example of drawing of regions of interest in gastrocnemius muscle (A) and vena cava (B) on a co-registered PET-CT image. <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55184/55184fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" src="/files/ftp_upload/55184/55184fig3.jpg" /> 
Figure 3: Time-activity curves for regions of interest in gastrocnemius muscle (A) and vena cava (B). Male db/db mice were fasted for 4.5 h prior to receiving 3 U/kg insulin (red) or equivalent volume PBS (black). 18F-FDG (10 MBq) was delivered via intravenous injection and 18F-FDG levels in the gastrocnemius muscle and vena cava determined by PET/CT for 60 min. Values are mean &#177; SD and expressed as percentage of injected dose, calculated from a full field of view (n=4/group). Modified from Cochran et al. 13 <a href="https://cloudflare-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/55184/55184fig3large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td rowspan="2">Treatment</td>
			<td>k1</td>
			<td>k2</td>
			<td>k3</td>
			<td>Ki</td>
		</tr>
		<tr>
			<td>(mL min-1 g-1)</td>
			<td>(min-1)</td>
			<td>(min-1)</td>
			<td>(mL min-1 g-1)</td>
		</tr>
		<tr>
			<td>PBS</td>
			<td>1.31&#177;0.42&#215;10-2</td>
			<td>0.12&#177;0.11</td>
			<td>7.06&#177;6.60&#215;10-3</td>
			<td>5.51&#177;4.25&#215;10-4</td>
		</tr>
		<tr>
			<td>Insulin</td>
			<td>1.45&#177;0.59&#215;10-2</td>
			<td>0.09&#177;0.05</td>
			<td>2.26&#177;0.72&#215;10-2 *</td>
			<td>2.01&#177;0.28&#215;10-3 *</td>
		</tr>
	</tbody>
</table>
Table 1: Kinetic analysis of increased 18F-FDG from plasma to gastrocnemius muscle in insulin treated db/db mice. Values are mean &#177; SD. *p&#60;0.05 vs PBS according to a Mann-Whitney test (n=4/group).

Watch this Scientific Journal Video about Determining Glucose Metabolism Kinetics Using 18F-FDG Micro-PET/CT at JoVE.com

Determining Glucose Metabolism Kinetics Using 18F-FDG Micro-PET/CT

This study describes a protocol that uses 18F-FDG and positron emission tomography/computed tomography (PET/CT) imaging, together with kinetic modelling, to quantify the in vivo, real-time uptake of 18F-FDG into tissues.

Determining Glucose Metabolism Kinetics Using 18F-FDG Micro-PET/CT

This paper describes the use of 18F-FDG and micro-PET/CT imaging to determine in vivo glucose metabolism kinetics in mice (and is transferable to rats). ...

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Nanyang Technological University

Research

JoVE Journal

Medicine

13.8K Views.  UNSW Australia. This study describes a protocol that uses 18F-FDG and positron emission tomography/computed tomography (PET/CT) imaging, together with kinetic modelling, to quantify the in vivo, real-time uptake of 18F-FDG into tissues.

Video: Determining Glucose Metabolism Kinetics Using 18F-FDG Micro-PET/CT

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

A hallmark of advanced tumors is a switch to aerobic glycolysis that is readily measured by [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) imaging. Co-mutations in the KRAS proto-oncogene and the LKB1 tumor suppressor gene are frequent events in lung cancer that drive hypermetabolic, glycolytic tumor growth. A critical pathway regulating the growth and metabolism of these tumors is the mechanistic target of the rapamycin (mTOR) pathway, which can be effectively targeted using selective catalytic mTOR kinase inhibitors. The mTOR inhibitor MLN0128 suppresses glycolysis in mice bearing tumors with Kras and Lkb1 co-mutations, referred to as KL mice. The therapy response in KL mice is first measured by 18F-FDG PET and computed tomography (CT) imaging before and after the delivery of MLN0128. By utilizing 18F-FDG PET/CT, researchers are able to measure dynamic changes in the glucose metabolism in genetically engineered mouse models (GEMMs) of lung cancer following a therapeutic intervention with targeted therapies. This is followed by ex vivo autoradiography and a quantitative immunohistochemical (qIHC) analysis using morphometric software. The use of qIHC enables the detection and quantification of distinct changes in the biomarker profiles following treatment as well as the characterization of distinct tumor pathologies. The coupling of PET imaging to quantitative histology is an effective strategy to identify metabolic and therapeutic responses in vivo in mouse models of disease.

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

In this protocol, we describe how to utilize [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (18F-FDG PET/CT) imaging to measure the tumor metabolic response to the targeted therapy MLN0128 in a Kras/Lkb1 mutant mouse model of lung cancer and coupled imaging with high resolution ex vivo autoradiography and quantitative histology.

A hallmark of advanced tumors is a switch to aerobic glycolysis that is readily measured by [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography ...

Cancer Research

Quantification of Atherosclerotic Plaque Activity and Vascular Inflammation using [18-F] Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET/CT)

Conventional non-invasive imaging modalities of atherosclerosis such as coronary artery calcium (CAC)1 and carotid intimal medial thickness (C-IMT)2 provide information about the burden of disease. However, despite multiple validation studies of CAC3-5, and C-IMT2,6, these modalities do not accurately assess plaque characteristics7,8, and the composition and inflammatory state of the plaque determine its stability and, therefore, the risk of clinical events9-13.
[18F]-2-fluoro-2-deoxy-D-glucose (FDG) imaging using positron-emission tomography (PET)/computed tomography (CT) has been extensively studied in oncologic metabolism14,15. Studies using animal models and immunohistochemistry in humans show that FDG-PET/CT is exquisitely sensitive for detecting macrophage activity16, an important source of cellular inflammation in vessel walls. More recently, we17,18 and others have shown that FDG-PET/CT enables highly precise, novel measurements of inflammatory activity of activity of atherosclerotic plaques in large and medium-sized arteries9,16,19,20. FDG-PET/CT studies have many advantages over other imaging modalities: 1) high contrast resolution; 2) quantification of plaque volume and metabolic activity allowing for multi-modal atherosclerotic plaque quantification; 3) dynamic, real-time, in vivo imaging; 4) minimal operator dependence. Finally, vascular inflammation detected by FDG-PET/CT has been shown to predict cardiovascular (CV) events independent of traditional risk factors21,22 and is also highly associated with overall burden of atherosclerosis23. Plaque activity by FDG-PET/CT is modulated by known beneficial CV interventions such as short term (12 week) statin therapy24 as well as longer term therapeutic lifestyle changes (16 months)25.
The current methodology for quantification of FDG uptake in atherosclerotic plaque involves measurement of the standardized uptake value (SUV) of an artery of interest and of the venous blood pool in order to calculate a target to background ratio (TBR), which is calculated by dividing the arterial SUV by the venous blood pool SUV. This method has shown to represent a stable, reproducible phenotype over time, has a high sensitivity for detection of vascular inflammation, and also has high inter-and intra-reader reliability26. Here we present our methodology for patient preparation, image acquisition, and quantification of atherosclerotic plaque activity and vascular inflammation using SUV, TBR, and a global parameter called the metabolic volumetric product (MVP). These approaches may be applied to assess vascular inflammation in various study samples of interest in a consistent fashion as we have shown in several prior publications.9,20,27,28

Quantification of Atherosclerotic Plaque Activity and Vascular Inflammation using [18-F] Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography FDG-PET/CT

There is great need to identify atherosclerosis non-invasively, and here we demonstrate how FDG-PET/CT can be used to detect and quantify atherosclerotic plaque activity and vascular inflammation.

Conventional non-invasive imaging modalities of atherosclerosis such as coronary artery calcium (CAC)1 and carotid intimal medial thickness (C-IMT)2 ...

Management of Respiratory Motion Artefacts in 18F-fluorodeoxyglucose Positron Emission Tomography using an Amplitude-Based Optimal Respiratory Gating Algorithm

Positron emission tomography (PET) combined with X-ray computed tomography (CT) is an important molecular imaging platform that is required for accurate diagnosis and clinical staging of a variety of diseases. The advantage of PET imaging is the ability to visualize and quantify a myriad of biological processes in vivo with high sensitivity and accuracy. However, there are multiple factors that determine image quality and quantitative accuracy of PET images. One of the foremost factors influencing image quality in PET imaging of the thorax and upper abdomen is respiratory motion, resulting in respiration-induced motion blurring of anatomical structures. Correction of these artefacts is required for providing optimal image quality and quantitative accuracy of PET images.
Several respiratory gating techniques have been developed, typically relying on acquisition of a respiratory signal simultaneously with PET data. Based on the respiratory signal acquired, PET data is selected for reconstruction of a motion-free image. Although these methods have been shown to effectively remove respiratory motion artefacts from PET images, the performance is dependent on the quality of the respiratory signal being acquired. In this study, the use of an amplitude-based optimal respiratory gating (ORG) algorithm is discussed. In contrast to many other respiratory gating algorithms, ORG permits the user to have control over image quality versus the amount of rejected motion in the reconstructed PET images. This is achieved by calculating an optimal amplitude range based on the acquired surrogate signal and a user-specified duty cycle (the percentage of PET data used for image reconstruction). The optimal amplitude range is defined as the smallest amplitude range still containing the amount of PET data required for image reconstruction. It was shown that ORG results in effective removal of respiration-induced image blurring in PET imaging of the thorax and upper abdomen, resulting in improved image quality and quantitative accuracy.

Management of Respiratory Motion Artefacts in 18F-fluorodeoxyglucose Positron Emission Tomography using an Amplitude-Based Optimal Respiratory Gating Algorithm

Amplitude-based optimal respiratory gating (ORG) effectively removes respiratory-induced motion blurring from clinical 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) images. Correction of FDG-PET images for these respiratory motion artefacts improves image quality, diagnostic and quantitative accuracy. Removal of respiratory motion artefacts is important for adequate clinical management of patients using PET.

Positron emission tomography (PET) combined with X-ray computed tomography (CT) is an important molecular imaging platform that is required for accurate ...

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

Functional positron emission tomography (fPET) provides a method to track molecular targets in the human brain. With a radioactively-labelled glucose analogue, 18F-fluordeoxyglucose (FDG-fPET), it is now possible to measure the dynamics of glucose metabolism with temporal resolutions approaching those of functional magnetic resonance imaging (fMRI). This direct measure of glucose uptake has enormous potential for understanding normal and abnormal brain function and probing the effects of metabolic and neurodegenerative diseases. Further, new advances in hybrid MR-PET hardware make it possible to capture fluctuations in glucose and blood oxygenation simultaneously using fMRI and FDG-fPET.
The temporal resolution and signal-to-noise of the FDG-fPET images is critically dependent upon the administration of the radiotracer. This work presents two alternative continuous infusion protocols and compares them to a traditional bolus approach. It presents a method for acquiring blood samples, time-locking PET, MRI, experimental stimulus, and administering the non-traditional tracer delivery. Using a visual stimulus, the protocol results show cortical maps of the glucose-response to external stimuli on an individual level with a temporal resolution of 16 s.

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.

Functional positron emission tomography (fPET) provides a method to track molecular targets in the human brain. With a radioactively-labelled glucose ...

Behavior

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

We present a method for comparing the uptake of the brain&#39;s two key energy substrates: glucose and ketones (acetoacetate [AcAc] in this case) in the rat. The developed method is a small-animal positron emission tomography (PET) protocol, in which&#160;11C-AcAc and 18F-fluorodeoxyglucose (18F-FDG) are injected sequentially in each animal. This dual tracer PET acquisition is possible because of the short half-life of 11C (20.4 min). The rats also undergo a magnetic resonance imaging (MRI) acquisition seven days before the PET protocol. Prior to image analysis, PET and MRI images are coregistered to allow the measurement of regional cerebral uptake (cortex, hippocampus, striatum, and cerebellum). A quantitative measure of 11C-AcAc and 18F-FDG brain uptake (cerebral metabolic rate; &#956;mol/100 g/min) is determined by kinetic modeling using the image-derived input function (IDIF) method. Our new dual tracer PET protocol is robust and flexible; the two tracers used can be replaced by different radiotracers to evaluate other processes in the brain. Moreover, our protocol is applicable to the study of brain fuel supply in multiple conditions such as normal aging and neurodegenerative pathologies such as Alzheimer&#39;s and Parkinson&#39;s diseases.

Small-animal positron emission tomography enables the assessment of the brain&#39;s two main energy substrates:&#160;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.

We present a method for comparing the uptake of the brain&#39;s two key energy substrates: glucose and ketones (acetoacetate [AcAc] in this case) in the ...

Neuroscience

Functional Imaging of Brown Fat in Mice with 18F-FDG micro-PET/CT

Brown adipose tissue (BAT) differs from white adipose tissue (WAT) by its discrete location and a brown-red color due to rich vascularization and high density of mitochondria. BAT plays a major role in energy expenditure and non-shivering thermogenesis in newborn mammals as well as the adults 1. BAT-mediated thermogenesis is highly regulated by the sympathetic nervous system, predominantly via &beta; adrenergic receptor 2, 3. Recent studies have shown that BAT activities in human adults are negatively correlated with body mass index (BMI) and other diabetic parameters 4-6. BAT has thus been proposed as a potential target for anti-obesity/anti-diabetes therapy focusing on modulation of energy balance 6-8. While several cold challenge-based positron emission tomography (PET) methods are established for detecting human BAT 9-13, there is essentially no standardized protocol for imaging and quantification of BAT in small animal models such as mice. Here we describe a robust PET/CT imaging method for functional assessment of BAT in mice. Briefly, adult C57BL/6J mice were cold treated under fasting conditions for a duration of 4 hours before they received one dose of 18F-Fluorodeoxyglucose (FDG). The mice were remained in the cold for one additional hour post FDG injection, and then scanned with a small animal-dedicated micro-PET/CT system. The acquired PET images were co-registered with the CT images for anatomical references and analyzed for FDG uptake in the interscapular BAT area to present BAT activity. This standardized cold-treatment and imaging protocol has been validated through testing BAT activities during pharmacological interventions, for example, the suppressed BAT activation by the treatment of &beta;-adrenoceptor antagonist propranolol 14, 15, or the enhanced BAT activation by &beta;3 agonist BRL37344 16. The method described here can be applied to screen for drugs/compounds that modulate BAT activity, or to identify genes/pathways that are involved in BAT development and regulation in various preclinical and basic studies.

Functional Imaging of Brown Fat in Mice with 18F-FDG micro-PET/CT

A method of functional imaging of mouse brown adipose tissue (BAT) is described in which cold-stimulated uptake of 18F-Fluorodeoxyglucose (FDG) in BAT is non-invasively assessed with a standardized micro-PET/CT protocol. This method is robust and sensitive to detect differences in BAT activities in mouse models.

Brown adipose tissue (BAT) differs from white adipose  tissue (WAT) by its discrete location and a brown-red color due to rich  vascularization and high ...

Biology

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

Patients with severe traumatic brain injury (sTBI) have difficulty knowing whether they are accurately expressing their thoughts and emotions because of disorders of consciousness, disrupted higher brain function, and verbal disturbances. As a consequence of an insufficient ability to communicate, objective evaluations are needed from family members, medical staff, and caregivers. One such evaluation is the assessment of functioning brain areas. Recently, multimodal brain imaging has been used to explore the function of damaged brain areas. [18F]-fluorodeoxyglucose positron emission tomography-computed tomography ([18F]FDG-PET/CT) is a successful tool for examining brain function. However, the assessment of brain glucose metabolism based on [18F]FDG-PET/CT is not standardized and depends on several varying parameters, as well as the patient&#39;s condition. Here, we describe a series of semiquantitative assessment protocols for a region-of-interest (ROI) image analysis using self-produced [18F]FDG tracers in patients with sTBI. The protocol focuses on screening the participants, preparing the [18F]FDG tracer in the hot lab, scheduling the acquisition of [18F]FDG-PET/CT brain images, and measuring glucose metabolism using the ROI analysis from a targeted brain area.

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

[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.

Patients with severe traumatic brain injury (sTBI) have difficulty knowing whether they are accurately expressing their thoughts and emotions because of ...

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

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.

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 ...

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

To this day, metabolic brain connectivity is mostly studied on a group level through the acquisition of static positron emission tomography (PET) data of multiple subjects. Our research groups are currently studying changes in metabolic connectivity across multiple time points following an intracerebral hemorrhage on an intrasubject level in rats. To investigate intrasubject metabolic brain connectivity, temporal information of the tracer uptake in different brain regions is required, which can be achieved through dynamic PET. In this publication, we give a detailed description of our data acquisition and analysis protocol.
Dynamic PET data of the rat brain are acquired on a dedicated preclinical PET system using 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) as tracer. The tracer is injected intravenously as a bolus at the start of the PET scan. During the 60 min acquisition, animals are sedated with medetomidine.
After acquisition, the PET data are reconstructed into thirty 2 min time frames using an iterative reconstruction algorithm (Maximum-Likelihood Expectation-Maximization). A parcellated atlas consisting of multiple volumes of interest (VOIs) is used to extract time-activity curves of each VOI, which are then used to calculate the Pearson correlation coefficient between each pair of VOIs.
This dynamic PET protocol enables the assessment of metabolic connectivity differences between two single scans, rather than between groups of scans. This approach allows for the study of changes in metabolic connectivity within a single subject across different time points, or for the comparison of an individual&#39;s metabolic connectivity to a normal database. Such comparisons could be useful for tracking disease progression or aiding in the diagnosis of neurological disorders characterized by disrupted communication between brain regions, such as epilepsy or dementia.

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.

To this day, metabolic brain connectivity is mostly studied on a group level through the acquisition of static positron emission tomography (PET) data of ...

Visualization and Quantification of Brown and Beige Adipose Tissues in Mice using [18F]FDG Micro-PET/MR Imaging

Brown and beige adipocytes are now recognized as potential therapeutic targets for obesity and metabolic syndromes. Non-invasive molecular imaging methods are essential to provide critical insights into these thermogenic adipose depots. Here, the protocol presents a PET/MR imaging-based method to evaluate the activity of brown and beige adipocytes in mouse interscapular brown adipose tissue (iBAT) and inguinal subcutaneous white adipose tissue (iWAT). Visualization and quantification of the thermogenic adipose depots were achieved using [18F]FDG, the non-metabolizable glucose analog, as the radiotracer, when combined with the precise anatomical information provided by MR imaging. The PET/MR imaging was conducted 7 days after cold acclimation and quantitation of [18F]FDG signal in different adipose depots was conducted to assess the relative mobilization of thermogenic adipose tissues. Removal of iBAT substantially increased cold-evoked [18F]FDG uptake in iWAT of the mice.

Visualization and Quantification of Brown and Beige Adipose Tissues in Mice using [18F]FDG Micro-PET/MR Imaging

Functional imaging and quantitation of thermogenic adipose depots in mice using a micro-PET/MR imaging-based approach.

Brown and beige adipocytes are now recognized as potential therapeutic targets for obesity and metabolic syndromes. Non-invasive molecular imaging methods ...

Determining Glucose Metabolism Kinetics Using ¹⁸F-FDG Micro-PET/CT

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