Research support was provided by NIH P50AR060752 and GE Healthcare. We would like to acknowledge the support by Vahid Ravanfar.

This prospective feasibility study recruited patients after obtaining Human Study IRB approval and complying with HIPAA regulations.
1. Phantom
<ol>
	<li>Fill a hollow cylindrical phantom with an insert that has hollow cylinders with a range of diameters (5 -&#160;38 mm) with 185 MBq of [18F]-NaF.</li>
	<li>Generate an attenuation map of the phantom using CT or a template that was generated previously for this phantom.</li>
	<li>Place the phantom into the center of PET/MR and acqu...

<ol>
	<li>Brinjikji, W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Systematic+literature+review+of+imaging+features+of+spinal+degeneration+in+asymptomatic+populations.">Systematic literature review of imaging features of spinal degeneration in asymptomatic populations.</a> AJNR American Journal of Neuroradiology. 36 (4), 811-816 (2015).</li><li>Binder, D. S., Nampiaparampil, D. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+provocative+lumbar+facet+joint.">The provocative lumbar facet joint.</a> Current Reviews in Musculoskeletal Medicine. 2 (1), 15-24 (2009).</li><li>Spick, C., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Detection+of+Bone+Metastases+Using+11C-Acetate+PET+in+Patients+with+Prostate+Cancer+with+Biochemical+Recurrence.">Detection of Bone Metastases Using 11C-Acetate PET in Patients with Prostate Cancer with Biochemical Recurrence.</a> Anticancer Research. 35 (12), 6787-6791 (2015).</li><li>Brans, B., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Assessment+of+bone+graft+incorporation+by+18+F-fluoride+positron-emission+tomography/computed+tomography+in+patients+with+persisting+symptoms+after+posterior+lumbar+interbody+fusion.">Assessment of bone graft incorporation by 18 F-fluoride positron-emission tomography/computed tomography in patients with persisting symptoms after posterior lumbar interbody fusion.</a> EJNMMI Research. 2 (1), 42 (2012).</li><li>Jadvar, H., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Prospective+evaluation+of+18F-NaF+and+18F-FDG+PET/CT+in+detection+of+occult+metastatic+disease+in+biochemical+recurrence+of+prostate+cancer.">Prospective evaluation of 18F-NaF and 18F-FDG PET/CT in detection of occult metastatic disease in biochemical recurrence of prostate cancer.</a> Clinical Nuclear Medicine. 37 (7), 637-643 (2012).</li><li>Kinahan, P. E., Fletcher, J. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Positron+emission+tomography-computed+tomography+standardized+uptake+values+in+clinical+practice+and+assessing+response+to+therapy.">Positron emission tomography-computed tomography standardized uptake values in clinical practice and assessing response to therapy.</a> Seminars in Ultrasound, CT, and MR. 31 (6), 496-505 (2010).</li><li>Hawkins, R. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Evaluation+of+the+skeletal+kinetics+of+fluorine-18-fluoride+ion+with+PET.">Evaluation of the skeletal kinetics of fluorine-18-fluoride ion with PET.</a> Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine. 33 (5), 633-642 (1992).</li><li>Hancock, M. J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Systematic+review+of+tests+to+identify+the+disc,+SIJ+or+facet+joint+as+the+source+of+low+back+pain.">Systematic review of tests to identify the disc, SIJ or facet joint as the source of low back pain.</a> European Spine Journal: Official Publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society. 16 (10), 1539-1550 (2007).</li><li>Jenkins, N. W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=[18)F]-Sodium+Fluoride+PET+MR-Based+Localization+and+Quantification+of+Bone+Turnover+as+a+Biomarker+for+Facet+Joint-Induced+Disability.">[18)F]-Sodium Fluoride PET MR-Based Localization and Quantification of Bone Turnover as a Biomarker for Facet Joint-Induced Disability.</a> AJNR American Journal of Neuroradiology. 38 (10), 2028-2031 (2017).</li><li>Czervionke, L. F., Fenton, D. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fat-saturated+MR+imaging+in+the+detection+of+inflammatory+facet+arthropathy+(facet+synovitis)+in+the+lumbar+spine.">Fat-saturated MR imaging in the detection of inflammatory facet arthropathy (facet synovitis) in the lumbar spine.</a> Pain Medicine. 9 (4), 400-406 (2008).</li><li>Phelps, M. E., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Tomographic+measurement+of+local+cerebral+glucose+metabolic+rate+in+humans+with+(F-18)2-fluoro-2-deoxy-D-glucose:+validation+of+method.">Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method.</a> Annals of Neurology. 6 (5), 371-388 (1979).</li><li>Brenner, W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Comparison+of+different+quantitative+approaches+to+18F-fluoride+PET+scans.">Comparison of different quantitative approaches to 18F-fluoride PET scans.</a> Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine. 45 (9), 1493-1500 (2004).</li><li>Schellinger, D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Facet+joint+disorders+and+their+role+in+the+production+of+back+pain+and+sciatica.">Facet joint disorders and their role in the production of back pain and sciatica.</a> Radiographics: A Review Publication of the Radiological Society of North America, Inc. 7 (5), 923-944 (1987).</li><li>Schett, G. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Joint+remodelling+in+inflammatory+disease.">Joint remodelling in inflammatory disease.</a> Annals of the Rheumatic Diseases. 66, 42-44 (2007).</li><li>Baum, R., Gravallese, E. 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The authors have nothing to disclose

In this methodological manuscript, we have provided background on the potential utility of dynamic [18F]-NaF-PET-MRI for evaluating a wide range of bone pathologies and have outlined the techniques for dynamic [18F]-NaF-PET-MRI image acquisition and analysis using the human lumbar facet joints as prototypical regions of interest. Dual modality PET-MRI allows for acquisition of dynamic PET data over a time period similar to that required for MR data acquisition alone, thus maximizing the overlap of s...

Standard clinical imaging techniques of bone pathology are primarily limited to characterizing structural changes, which can be nonspecific. For example, asymptomatic morphologic abnormalities related to the normal aging may be indistinguishable from degenerative alterations which are responsible for severe pain and disability1. Bone is a dynamic tissue undergoing continuous remodeling with the competing activity of osteoblasts, which produce the new bone matrix, and osteoclasts, whose function is to eliminate mineralized bone2. [18F]-NaF is a positron emission tomography (PET) radiotracer that enables visualization of bone tissue metabolism. [18F]-NaF is chemically absorbed into hydroxyapatite in the bone matrix by osteoblasts and can thus noninvasively detect osteoblastic activity, thereby detecting a metabolic process which is occult to conventional imaging techniques. As a result, [18F]-NaF has been used for characterizing bone pathology in an increasing number of bone disorders including neoplasms, inflammatory, and degenerative disease of the bone and joints3,4,5.
PET data is most commonly analyzed in a semi-quantitative fashion, which can be readily performed in routine clinical practice with standardized uptake values (SUVs). As a metric, SUVs are useful to clinicians as they represent tissue uptake relative to the rest of the body6. Values from subsequent scans may be used to observe changes in uptake as a result of treatment or disease progression. The numerical nature of SUVs also aids in comparison between patients and between successive scans in the same patient. The algorithm used to calculate SUVs, Equation 1, makes the assumption that the tracer is equally distributed throughout the body and that the lean body mass accurately represents whole body volume. As such, SUVs are a semi-quantitative measurement. For a given region of interest (ROI), SUVmax (the maximum SUV value within a ROI), and SUVmean (the mean of all sampled SUVs within an ROI) are commonly used SUV metrics in clinical practice6.
Kinetic modeling of dynamic PET data can also be performed for more detailed quantitative analysis. While SUV data acquisition is static, kinetic modeling utilizes dynamic image data where tracer levels are continuously acquired providing a temporal dimension.&#160; From the more complex kinetic modeling of dynamic data, quantitative values and informative metrics of tracer dynamics can be extracted with respect to the measured activity in the image data. A sample two-tissue compartment model employed for dynamic kinetic modeling is shown in Figure 17. &#160;Cp is the concentration of tracer in the blood plasma while Ce and Ct represent the concentration in the unbound interstitial space and bound tracer in the target bone matrix respectively. K1, k2, k3, k4, are 4 rate parameters that describe the kinetic model for tracer wash in/out and binding. K1 describes the tracer taken up from arterial plasma into interstitial space (Ct), k2 describes the fraction of tracer that diffuses back from the interstitial space to plasma, k3 describes the tracer that moves from interstitial (Ce) space to bone (Ct), and k4 describes the tracer that moves from bone (Ct) back to the interstitial space (Ce).
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/58491/58491fig1.jpg" /> 
Figure 1. A sample two-tissue compartment model for dynamic kinetic modeling. Cp is the tracer concentration in the blood plasma compartment, Ce free and non-specifically bound tracer concentration in tissue, and Ct specifically bound tracer concentration in the tissue. <a href="https://www.jove.com/files/ftp_upload/58491/58491fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
The Patlak kinetic model produces Ki_Patlak as a measure of radiotracer influx rate (mL/ccm/min, cubic cm = ccm) from the blood pool into the bone matrix. The tracer influx rate from the blood pool to the bone matrix can then be calculated using Equation 2 and Equation 3 for Ki_Patlak and Ki_NonLinear respectively. Ki_Patlak and Ki_NonLinear are the rates at which [18F]-NaF leaves the arterial blood pool and irreversibly binds to a subsite bone matrix, using the two models respectively. A difference between the Patlak and non-linear kinetic model is in their utilization of the dynamic data. The Patlak model requires equilibrium to be met and then calculates the influx rate from the established linear slope. The Patlak kinetic model produces Ki_Patlak influx rates, by using a 24-minute time to equilibration of the plasma pool, Cp, to the unbound pool, Cu.&#160; The 24-minute time can change depending on the time found for all subsites to reach equilibration with the plasma pool in the sample. The more computationally rigorous non-linear model uses the entirety of the temporal data to fit a curve.
The goal of this methodological manuscript is to outline detailed techniques for performing dynamic [18F]-NaF-PET-MRI.&#160; The lumbar facet joint is a common site of degenerative arthritis disease and a common cause for axial low back pain8.&#160; Recent studies suggest [18F]-NaF-PET-MRI may serve as a useful biomarker of painful facetogenic disease9.&#160; The human lumbar facet joints from a single patient with facetogenic low back pain will thus be analyzed as a prototypical ROI for dynamic [18F]-NaF-PET-MRI analysis.

<table border="0" cellpadding="0" cellspacing="0" style="width:1045px;" width="1046">
	<colgroup>
		<col />
		<col />
		<col />
		<col />
	</colgroup>
	<tbody>
		<tr height="21">
			<td height="21" style="height:21px;width:307px;">Gadolinium Contrast agent (Gadovist)</td>
			<td style="width:211px;">Bayer</td>
			<td style="width:271px;">na</td>
			<td style="width:257px;">1.0mmol/ml solution for IV injection.</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:307px;">[18F]-NaF Radiotracer</td>
			<td style="width:211px;">na</td>
			<td style="width:271px;">na</td>
			<td>2.96 MBq/kg</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:307px;">GE Signa PET-MRI Scanner</td>
			<td style="width:211px;">General Electric</td>
			<td style="width:271px;">na</td>
			<td>3.0Tesla 60cm Bore PET-MRI scanner</td>
		</tr>
		<tr height="21">
			<td height="21" style="height:21px;width:307px;">PMOD Kinetic Modeling Software</td>
			<td style="width:211px;">PMOD Technologies, LLC</td>
			<td style="width:271px;">na</td>
			<td>Version 3.8</td>
		</tr>
	</tbody>
</table>

quantitative [18f]-naf-pet-mri analysis for the evaluation of dynamic bone turnover in a patient with facetogenic low back pain

Imaging techniques that reflect dynamic bone turnover may aid in characterizing a wide range of bone pathologies. Bone is a dynamic tissue undergoing continuous remodeling with the competing activity of osteoblasts, which produce the new bone matrix, and osteoclasts, whose function is to eliminate mineralized bone. [18F]-NaF is a positron emission tomography (PET) radiotracer that enables visualization of bone metabolism. [18F]-NaF is chemically absorbed into hydroxyapatite in the bone matrix by osteoblasts and can thus noninvasively detect osteoblastic activity, which is occult to conventional imaging techniques. Kinetic modeling of dynamic [18F]-NaF-PET data provides detailed quantitative measures of bone metabolism. Conventional semi-quantitative PET data, which utilizes standardized uptake values (SUVs) as a measure of radiotracer activity, is referred to as a static technique due to its snapshot of tracer uptake in time.&#160; Kinetic modeling, however, utilizes dynamic image data where tracer levels are continuously acquired providing tracer uptake temporal resolution. From the kinetic modeling of dynamic data, quantitative values like blood flow and metabolic rate (i.e., potentially informative metrics of tracer dynamics) can be extracted, all with respect to the measured activity in the image data. When combined with dual modality PET-MRI, region-specific kinetic data can be correlated with anatomically registered high-resolution structural and pathologic information afforded by MRI. The goal of this methodological manuscript is to outline detailed techniques for performing and analyzing dynamic [18F]-NaF-PET-MRI data. The lumbar facet joint is a common site of degenerative arthritis disease and a common cause for axial low back pain.&#160; Recent studies suggest [18F]-NaF-PET may serve as a useful biomarker of painful facetogenic disease.&#160; The human lumbar facet joint will, therefore, be used as a prototypical region of interest for dynamic [18F]-NaF-PET-MRI analysis in this manuscript.

18NaF-PET uptake values are measured in the bilateral facet joints at the L1-L2 through L5-S1 vertebral levels for a total of 10 ROIs in a single representative patient with axial low back pain. Representative [18F]-NaF-PET, axial T2 fat suppressed, and axial T1 post-contrast fat-suppressed MR images through the level of the L3-L4 facet joints are shown in Figure 2.&#160; The Ki_Patlak, SUVmean, SUVmax, and MRI facet arthropathy grade fo...

Watch this Scientific Journal Video about Quantitative [18F]-Naf-PET-MRI Analysis for the Evaluation of Dynamic Bone Turnover in a Patient with Facetogenic Low Back Pain at JoVE.com

Quantitative [18F]-Naf-PET-MRI Analysis for the Evaluation of Dynamic Bone Turnover in a Patient with Facetogenic Low Back Pain

Imaging techniques that reflect dynamic bone turnover may aid in characterizing a wide range of bone pathologies. We present detailed methodologies for performing and analyzing dynamic [18F]-NaF-PET-MRI data in a patient with facetogenic low back pain using the lumbar facet joints as a prototypical region of interest.

Quantitative [18F]-Naf-PET-MRI Analysis for the Evaluation of Dynamic Bone Turnover in a Patient with Facetogenic Low Back Pain

Imaging techniques that reflect dynamic bone turnover may aid in characterizing a wide range of bone pathologies. Bone is a dynamic tissue undergoing ...

With this technique, we use PET-MRI to identify physiologic biomarkers of bone turnover. We believe these physiologic biomarkers may more accurately reflect facet joint pathology than CT and MRI static images. We believe this technique may help us identify painful and symptomatic joints in the lumbar spine.We also hope that this technique can be applied to other regions of the spine, such as the cervical and thoracic spine for identification of symptomatic facet joints, and even degenerative disc disease. For simultaneous PET and magnetic resonance image or MRI acquisition, using a posterior array central molecular imaging array coil and a 3.0 PET and MR imager, center the field of view in both imaging modalities to cover the lower spine region from T-12 to S-3. Set the appropriate parameters for a PET acquisition and for a clinical MRI sequence for a lumbar spine protocol.Immediately before acquiring the MRI sequences, intravenously inject a 0.1 millimeters per kilogram of gadobutrol contrast into the patient's antecubital fossa and a 2.96 megabecquerel per kilogram radioactive dose of sodium fluoride F-18. Next, using three separate temporal phases centered over the lower spine, perform a 60-minute dynamic PET scan acquiring the first phase of the scan with 12 frames of 10 seconds each, the second phase of four frames of 30 seconds each, and the last phase of 14 frames of four minutes each. Then set a 60 centimeter field of view with a three millimeter filter cutoff, a standard Z-axis filter, no cardiac 3D filter, 28 subsets, and a Time-of-Flight ordered subsets expectation maximization with four iterations to reconstruct the PET data on the console.For analysis of the acquired PET and MR images, transfer the images to a dedicated work station equipped to analyze dynamic PET data. Locate the bilateral facet joints of the lumbar spine from L-1 to L-2 and L-5 to S-1. Visually triangulate with the sagittal and axial plane T-2 MR images and record the the slice number of the approximate center to identify the center point of each lumbar facet joint.With the patient data open in the view tab, click the volume of interest button and select sphere object. Within the predefined popup window, enter 7.5 millimeters as the radius and click create new volume of interest. Left click to place a 7.5 millimeter spherical volume of interest in the center of each facet joint, adjusting the sphere by left clicking and dragging until the volume is visually centered on the facet.When a volume of interest has been placed onto each facet, place a five millimeter spherical volume of interest in the right iliac crest in the central marrow cavity to exclude the cortex involvement as a reference region. Then position the volume of interest so the edges are within the marrow entirely. Right click on the axial image and select data inspection to measure the diameter of the abdominal aorta proximal to its bifurcation.To calculate the partial volume correction coefficient, left click on the right side of the aortic wall and move the cursor to the left side of the aortic wall to record the distance of the aortic wall diameter in the data inspector window. Next, left click the volume of interest button and select circle region of interest to create a circular region of interest with a radius of half of the aortic diameter. Click create new volume of interest and left click in the center of the aorta, repositioning the volume as necessary to ensure the circle approximates the aortic wall position.Then descend one slice in the axial plane and create a second circular region of interest to make a cylindrical region of interest from the two overlapping circular regions of interest. To create a partial volume corrected arterial input, use the recovery coefficients derived from the PET computed tomography phantom to apply the recovery coefficients to the image-based measurement over the descending aorta. Then substitute this partial volume-corrected arterial input into the image analysis software for use in kinetic modeling and the accurate quantification of tracer kinetics.Here, represented of sodium fluoride F-18 PET, axial T-2 fat suppressed, and axial T-1 post-contrast fat suppressed MR images through the level of the L-3 to L-4 facet joints can be seen. In this table, the Patlak kinetic model, standardized uptake value mean and maximum, and MRI facet arthropathy grade for each of the 10 sampled facet joints in a representative patient have been summarized. When the patient Patlak kinetic model influx rates were plotted against the standardized uptake value mean and the MRI-based facet arthropathy grades, the facet joint with the highest MRI grade of degenerative facet arthropathy had the highest Patlak kinetic model and standardized uptake value mean values.We are in the midst of a clinical trial to validate our technique in patients with lumbar facet joint pain. We look forward to publishing this data soon. There's a steep learning curve for understanding how to do the analysis with the PET MR software.Additionally, it can be difficult to locate the facet joints for those people unfamiliar with spinal anatomy. As a result, we believe that a visual depiction of the image processing steps will greatly enhance understanding of our process.

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7.1K Views.  University of California San Francisco. With this technique, we use PET-MRI to identify physiologic biomarkers of bone turnover. We believe these physiologic biomarkers may more accurately reflect facet joint pathology than CT and MRI static images. We believe this technique may help us identify painful and symptomatic joints in the lumbar spine.We also hope that this technique can be applied to other regions of the spine, such as the cervical and thoracic spine for identification of symptomatic facet joints, and even degene...