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 acquire PET data for 5-10 min recording the resultant image using the imaging console.</li>
	<li>Reconstruct using the imaging console with the CT-based attenuation map using an algorithm that matches with the same reconstruction algorithm to be used for imaging human subjects.</li>
	<li>Calculate the mean activity in each cylinder (left and right) of equal size for all sizes using freeware AMIDE.</li>
	<li>Tabulate the mean activity versus cylinder size.</li>
	<li>Calculate the partial volume errors (PVE) by dividing the mean activity of each cylinder by the reference cylinder mean activity.</li>
	<li>Plot the PVE by the size of the cylinder.</li>
	<li>Use the linear equation between two-cylinder sizes when correcting for PVE in the patient data.</li>
</ol>
2. Patient Preparation
<ol>
	<li>Before recruiting patients, obtain any necessary Human Study IRB approval and comply with HIPPA regulations.</li>
	<li>Establish appropriate inclusion and exclusion criteria for the study of interest.
	<ol>
		<li>Inclusion criteria were as follows: adults, at least 18 years old with the capacity for informed consent; a reported history of axial non-radicular low back pain; recommended by the spine interventional radiologists.</li>
		<li>Exclusion criteria were as follows: the history of fracture or tumor of the spine; women who are pregnant or breast-feeding; contraindications to having MRI or administration of tracer or contrast; prior lumbar surgery or instrumentation.</li>
	</ol>
	</li>
	<li>Gather patient&#8217;s written informed consent, approved by the Committee on Human Research.</li>
	<li>Obtain any relevant clinical exam and/or patient survey data pertinent to your study of interest.</li>
	<li>Have subject change into the gown, establish IV access, administer pregnancy test if the patient is female and of child-bearing age, check creatinine/GFR for the safe use of contrast, and retrieve [18F]-NaF dose. Coach the patient on the importance of remaining still throughout the duration of the exam.</li>
	<li>Position patient supine and feet first in the PET/MRI.</li>
</ol>
3. Imaging Protocol
<ol>
	<li>Use a 3.0 T PET/MRI scanner for simultaneous PET and MR image acquisition.</li>
	<li>Use the posterior array central molecular imaging array coil for the MR imaging.</li>
	<li>Ensure the FOV of both MR and PET imaging modalities is centered to cover the lower spine region from T12 to S3.</li>
	<li>The Clinical MRI sequences for the lumbar spine protocol includes: Sagittal T1 (repetition time/echo time (TR/TE) = 510/8.6 ms, in-plane resolution = 0.75mm, through-plane resolution = 4mm), Sagittal T2 fat saturated (FS) (TR/TE = 4208/86.2 ms, in-plane resolution = 0.75mm, through-plane resolution = 4mm) Axial T2 fast relaxation fast spin echo (FRFSE) with and without fat saturation (TR/TE&#160; = 750/9.2 ms, in-plane resolution = 0.7mm, through-plane resolution = 4mm), Axial T1 fast spin echo (FSE) Pre Gadolinium (TR/TE = 575/8.9 ms, in-plane resolution = 0.65mm, through-plane resolution = 4mm), Axial T1 FSE Post Gadolinium (TR/TE = 562/8.6 ms, in-plane resolution = 0.65mm, through-plane resolution = 4mm).</li>
	<li>Inject 0.1 mm/kg of gadobutrol (1M Gadavist) contrast into the patient&#8217;s antecubital fossa IV directly before acquiring the MRI sequences requiring it.</li>
	<li>Prior to the dynamic PET scan inject the radioactive dose of [18F]-NaF into the patient at a concentration of 2.96 MBq/kg of [18F]-NaF.</li>
	<li>Perform a 60 min of dynamic PET scan using 3 separate temporal phases centered over the lower spine, T12 to S3.</li>
	<li>Acquire the first phase of the dynamic scan with 12 frames of 10 s each.</li>
	<li>Acquire the second phase of 4 frames of 30 s each.</li>
	<li>Acquire the last phase of 14 frames of 4 min each.</li>
	<li>Calculate MR attenuation correction (MRAC) for the lumbar spine region using the standard two-point Dixon method. The Dixon method segments the MR signals of fat and water into air, soft tissue, lung and fat (though not bone).</li>
	<li>Ensure PET data is co-registered to axial T2 fat saturated FRFSE images.</li>
	<li>Reconstruct the PET data on the console using the following parameters: 60 cm field of view (FOV), 3 mm post-filter, Standard Z-axis filter, 256 x 256 matrix, 28 subsets, and VPFX (Time of Flight - Ordered Subsets Expectation Maximization, TOF-OSEM) with 4 iterations.</li>
	<li>Ensure reconstruction includes post processing to correct for decay, attenuation, scatter, and dead time.</li>
</ol>
4. Image analysis
<ol>
	<li>Have blinded radiologist interpret the clinical MRI sequences.</li>
	<li>Evaluate fat-suppressed T2- weighted and fat suppressed T1-weighted post-contrast sequences for grading facet synovitis as previously described by Czervionke and Fenton10.
	<ol>
		<li>Use the following facet grading is: MRI grade 0 = no abnormality of the facet joint, 1 = abnormal enhancement or T2 hyperintensity limited to joint capsule, 2 = abnormal extracapsular enhancement or T2 hyperintensity involving &#60; 50% of FJ perimeter, 3 = abnormal extracapsular enhancement or T2 hyperintensity involving &#62;50% of FJ perimeter, and 4 = grade 3 with extension of edema into the neuroforamen, ligementum flavum, pedicle, transverse process, or vertebral body. As explained in the ref: Czervionke LF, Fenton DS. Fat-saturated MR imaging in the detection of inflammatory facet arthropathy (facet synovitis) in the lumbar spine.10</li>
	</ol>
	</li>
</ol>
5. Data analysis
<ol>
	<li>Transfer PET and MRI images to a dedicated workstation equipped to analyze dynamic PET data such as the software PMOD. Analyze the facet joints of the lumbar spine from L1-L2 to L5-S1.</li>
	<li>Locate regions that will be evaluated for [18F]-NaF uptake measurements: bilateral facet joints at each level. Select volumes of interest (VOI) using anatomic T2 MR images and then transfer to the PET images.</li>
	<li>Identify the center point of each lumbar facet joint by visually triangulating with sagittal and axial plane T2 MR images and recording the slice number of the approximate center.</li>
	<li>With the patient data open in the View tab, click the VOI button from the sidebar and select SPHERE (Object).</li>
	<li>Within the Predefined window that pops up, type in 7.5 mm as the radius and click Create New VOI.</li>
	<li>Place a spherical VOI (7.5 mm diameter) in the center of each facet joint by left clicking on the facet. Adjust the sphere by left clicking and dragging until visually centered on the facet.</li>
	<li>Repeat as necessary for all facets of interest by clicking Create New VOI and performing step 5.5</li>
	<li>Place a spherical VOI (5 mm diameter) in the right iliac crest in the central marrow cavity (to exclude cortex involvement) as a reference region. Click Create New VOI and left click in the marrow of right iliac.</li>
	<li>Position VOI so edges are within marrow entirely.</li>
	<li>Ensure VOI&#8217;s are placed similarly to the image showing vertebral body facet joint (FJ) VOIs in Figure 2 in that they encapsulate the center of the facet joint.</li>
</ol>
6. SUV Calculations and Kinetic Data
<ol>
	<li>To calculate the arterial input function place a cylindrical VOI covering two axial slices of the abdominal aorta. Ensure the diameter is equal to the aorta&#8217;s diameter.</li>
	<li>Right click on the Axial image, select data inspection.</li>
	<li>Measure the diameter of the abdominal aorta proximal to its bifurcation.</li>
	<li>Left click on the right side of the aortic wall and move the cursor to the left side of the aortic wall.</li>
	<li>Record the distance of the aortic wall diameter in the Data Inspector window. This will be used to calculate the partial volume correction (PVC) coefficient.</li>
	<li>Left click the VOI button from the sidebar, select CIRCLE (ROI).</li>
	<li>Create a Circle ROI with a specified radius of half of the previously measured diameter in Step 6.5</li>
	<li>Click Create New VOI and left click in the center of the aorta, reposition if necessary, to ensure circle approximates aortic wall position.</li>
	<li>Descend one slice in the axial plane and repeat steps 6.7-6.9, thereby, making a cylinder from the two circular ROI&#8217;s.</li>
</ol>
7. PET Partial Volume Correction
NOTE: Due to PVE the tracer activity is underestimated in relation to the size of the target. Therefore, steps are taken to correct for the PVE.
<ol>
	<li>Use the recovery coefficients that were derived earlier using the PET/CT phantom by plotting the size of the cylinder diameter versus the ratio of recovered activity to true activity.</li>
	<li>Apply the recovery coefficients to the image-based measurement over the descending aorta to create a partial-volume corrected arterial input.</li>
	<li>Substitute this partial-volume corrected arterial input into PMOD for use in kinetic modeling and accurate quantification of tracer kinetics.</li>
</ol>
8. SUV Calculations and Kinetic Data
Note: The algorithm used to calculate Standard Uptake Value (SUV), 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. Therefore, SUVs are referred to as a semi-quantitative measurement. 
Equation 1: Standard Uptake Value 
<img alt="Equation 1" src="/files/ftp_upload/58491/58491eq1.jpg" />
<ol>
	<li>Calculate the SUVmax, and SUVmean values for each subsite using the 60-minute time point. 
	Note: The two-tissue compartment model used for kinetic modeling is shown in Fig 1. 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 parameters that describe the kinetic model for tracer wash in/out and binding.</li>
	<li>Use the two-tissue compartment irreversible for Patlak Linear model and Non-Linear regression models during kinetic analysis 
	Note: A two-tissue irreversible compartment model is used to calculate region-specific influx rate constants (in min-1) for [18F]-NaF11.</li>
	<li>Ensure the time to equilibrium is set to 24 minutes when using the Patlak kinetic model</li>
	<li>Input k4 = 0 when using the nonlinear regression model to produce Ki_NonLinear influx rates.</li>
	<li>Calculate the tracer influx rate from the blood pool to the bone matrix 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.
	<ol>
		<li>Equation 2: Patlak Graphical Kinetic Model 
		<img alt="Equation 2" src="/files/ftp_upload/58491/58491eq2.jpg" /> + Intercept</li>
		<li>Equation 3: Nonlinear Regression Kinetic Model 
		<img alt="Equation 3" src="/files/ftp_upload/58491/58491eq3.jpg" /></li>
	</ol>
	</li>
</ol>
9. Statistical Analysis
<ol>
	<li>Use a linear regression analysis to evaluate if [18F]-NaF Ki_Patlak influx rate was correlated to: SUVmean, SUVmax, Ki_NonLinear, and any clinical scoring grades specific to the study.</li>
	<li>Use two-tailed t-test and Pearson correlation to test for statistical significance in previous correlations.</li>
</ol>

<ol><li>Brinjikji, W., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Systematic+literature+review+of+imaging+features+of+spinal+degeneration+in+asymptomatic+populations%5BTitle%5D)+AND+%22AJNR+American+Journal+of+Neuroradiology%22%5BJournal%5D)">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/pubmed?term=((The+provocative+lumbar+facet+joint%5BTitle%5D)+AND+%22Current+Reviews+in+Musculoskeletal+Medicine%22%5BJournal%5D)">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/pubmed?term=((Detection+of+Bone+Metastases+Using+11C-Acetate+PET+in+Patients+with+Prostate+Cancer+with+Biochemical+Recurrence%5BTitle%5D)+AND+%22Anticancer+Research%22%5BJournal%5D)">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/pubmed?term=((Assessment+of+bone+graft+incorporation+by+18+F-fluoride+positron-emission+tomography%2Fcomputed+tomography+in+patients+with+persisting+symptoms+after+posterior+lumbar+interbody+fusion%5BTitle%5D)+AND+%22EJNMMI+Research%22%5BJournal%5D)">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/pubmed?term=((Prospective+evaluation+of+18F-NaF+and+18F-FDG+PET%2FCT+in+detection+of+occult+metastatic+disease+in+biochemical+recurrence+of+prostate+cancer%5BTitle%5D)+AND+%22Clinical+Nuclear+Medicine%22%5BJournal%5D)">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/pubmed?term=((Positron+emission+tomography-computed+tomography+standardized+uptake+values+in+clinical+practice+and+assessing+response+to+therapy%5BTitle%5D)+AND+%22Seminars+in+Ultrasound%2C+CT%2C+and+MR%22%5BJournal%5D)">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/pubmed?term=((Evaluation+of+the+skeletal+kinetics+of+fluorine-18-fluoride+ion+with+PET%5BTitle%5D)+AND+%22Journal+of+Nuclear+Medicine%3A+Official+Publication%2C+Society+of+Nuclear+Medicine%22%5BJournal%5D)">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/pubmed?term=((Systematic+review+of+tests+to+identify+the+disc%2C+SIJ+or+facet+joint+as+the+source+of+low+back+pain%5BTitle%5D)+AND+%22European+Spine+Journal%3A+Official+Publication+of+the+European+Spine+Society%2C+the+European+Spinal+Deformity+Society%2C+and+the+European+Section+of+the+Cervical+Spine+Research+Society%22%5BJournal%5D)">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/pubmed?term=((%5B18%29F%5D-Sodium+Fluoride+PET+MR-Based+Localization+and+Quantification+of+Bone+Turnover+as+a+Biomarker+for+Facet+Joint-Induced+Disability%5BTitle%5D)+AND+%22AJNR+American+Journal+of+Neuroradiology%22%5BJournal%5D)">[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/pubmed?term=((Fat-saturated+MR+imaging+in+the+detection+of+inflammatory+facet+arthropathy+%28facet+synovitis%29+in+the+lumbar+spine%5BTitle%5D)+AND+%22Pain+Medicine%22%5BJournal%5D)">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/pubmed?term=((Tomographic+measurement+of+local+cerebral+glucose+metabolic+rate+in+humans+with+%28F-18%292-fluoro-2-deoxy-D-glucose%3A+validation+of+method%5BTitle%5D)+AND+%22Annals+of+Neurology%22%5BJournal%5D)">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/pubmed?term=((Comparison+of+different+quantitative+approaches+to+18F-fluoride+PET+scans%5BTitle%5D)+AND+%22Journal+of+Nuclear+Medicine%3A+Official+Publication%2C+Society+of+Nuclear+Medicine%22%5BJournal%5D)">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/pubmed?term=((Facet+joint+disorders+and+their+role+in+the+production+of+back+pain+and+sciatica%5BTitle%5D)+AND+%22Radiographics%3A+A+Review+Publication+of+the+Radiological+Society+of+North+America%2C+Inc%22%5BJournal%5D)">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/pubmed?term=((Joint+remodelling+in+inflammatory+disease%5BTitle%5D)+AND+%22Annals+of+the+Rheumatic+Diseases%22%5BJournal%5D)">Joint remodelling in inflammatory disease.</a> Annals of the Rheumatic Diseases. 66, Suppl 3 42-44 (2007).</li>
<li>Baum, R., Gravallese, E. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/pubmed?term=((Impact+of+inflammation+on+the+osteoblast+in+rheumatic+diseases%5BTitle%5D)+AND+%22Current+Osteoporosis+Reports%22%5BJournal%5D)">Impact of inflammation on the osteoblast in rheumatic diseases.</a> Current Osteoporosis Reports. 12 (1), 9-16 (2014).</li>
</ol>

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><tbody><tr><td>Gadolinium Contrast agent (Gadovist)</td><td>Bayer</td><td>na</td><td>1.0mmol/ml solution for IV injection.</td></tr><tr><td>[18F]-NaF Radiotracer</td><td>na</td><td>na</td><td>2.96 MBq/kg</td></tr><tr><td>GE Signa PET-MRI Scanner</td><td>General Electric</td><td>na</td><td>3.0Tesla 60cm Bore PET-MRI scanner</td></tr><tr><td>PMOD Kinetic Modeling Software</td><td>PMOD Technologies, LLC</td><td>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 ...

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Medicine

7.3K Views.  University of California San Francisco. Met deze techniek gebruiken we PET-MRI om fysiologische biomarkers van botomzet te identificeren. Wij geloven dat deze fysiologische biomarkers de pathologie van facetgewrichts nauwkeuriger kunnen weergeven dan CT- en MRI-statische beelden. Wij geloven dat deze techniek ons kan helpen pijnlijke en symptomatische gewrichten in de lumbale wervelkolom te identificeren.We hopen ook dat deze techniek kan worden toegepast op andere gebieden van de wervelkolom, zoals de cervicale en thoracale...

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

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 ...

Hybrid &#181;CT-FMT imaging and image analysis

Fluorescence-mediated tomography (FMT) enables longitudinal and quantitative determination of the fluorescence distribution in vivo and can be used to assess the biodistribution of novel probes and to assess disease progression using established molecular probes or reporter genes. The combination with an anatomical modality, e.g., micro computed tomography (&#181;CT), is beneficial for image analysis and for fluorescence reconstruction. We describe a protocol for multimodal &#181;CT-FMT imaging including the image processing steps necessary to extract quantitative measurements. After preparing the mice and performing the imaging, the multimodal data sets are registered. Subsequently, an improved fluorescence reconstruction is performed, which takes into account the shape of the mouse. For quantitative analysis, organ segmentations are generated based on the anatomical data using our interactive segmentation tool. Finally, the biodistribution curves are generated using a batch-processing feature. We show the applicability of the method by assessing the biodistribution of a well-known probe that binds to bones and joints.

Hybrid  &#181;CT-FMT imaging and image analysis

We describe a protocol for hybrid imaging, combining fluorescence-mediated tomography (FMT) with micro computed tomography (&#181;CT). After fusion and reconstruction, we perform interactive organ segmentation to extract quantitative measurements of the fluorescence distribution.

Fluorescence-mediated tomography (FMT) enables longitudinal and quantitative determination of the fluorescence distribution in vivo and can be used to ...

Bioengineering

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

Quantitative Magnetic Resonance Imaging of Skeletal Muscle Disease

Quantitative magnetic resonance imaging (qMRI) describes the development and use of MRI to quantify physical, chemical, and/or biological properties of living systems. Neuromuscular diseases often exhibit a temporally varying, spatially heterogeneous, and multi-faceted pathology. The goal of this protocol is to characterize this pathology using qMRI methods. The MRI acquisition protocol begins with localizer images (used to locate the position of the body and tissue of interest within the MRI system), quality control measurements of relevant magnetic field distributions, and structural imaging for general anatomical characterization. The qMRI portion of the protocol includes measurements of the longitudinal and transverse relaxation time constants (T1 and T2, respectively). Also acquired are diffusion-tensor MRI data, in which water diffusivity is measured and used to infer pathological processes such as edema. Quantitative magnetization transfer imaging is used to characterize the relative tissue content of macromolecular and free water protons. Lastly, fat-water MRI methods are used to characterize fibro-adipose tissue replacement of muscle. In addition to describing the data acquisition and analysis procedures, this paper also discusses the potential problems associated with these methods, the analysis and interpretation of the data, MRI safety, and strategies for artifact reduction and protocol optimization.

Neuromuscular diseases often exhibit a temporally varying, spatially heterogeneous, and multi-faceted pathology. The goal of this protocol is to characterize this pathology using non-invasive magnetic resonance imaging methods.

Quantitative magnetic resonance imaging (qMRI) describes the development and use of MRI to quantify physical, chemical, and/or biological properties of ...

Semiautomated Longitudinal Microcomputed Tomography-based Quantitative Structural Analysis of a Nude Rat Osteoporosis-related Vertebral Fracture Model

Osteoporosis-related vertebral compression fractures (OVCFs) are a common and clinically unmet need with increasing prevalence as the world population ages. Animal OVCF models are essential to the preclinical development of translational tissue engineering strategies. While a number of models currently exist, this protocol describes an optimized method for inducing multiple highly reproducible vertebral defects in a single nude rat. A novel longitudinal semiautomated microcomputed tomography (&#181;CT)-based quantitative structural analysis of the vertebral defects is also detailed. Briefly, rats were imaged at multiple time points post-op. The day 1 scan was reoriented to a standard position, and a standard volume of interest was defined. Subsequent &#181;CT scans of each rat were automatically registered to the day 1 scan so the same volume of interest was then analyzed to assess for new bone formation. This versatile approach can be adapted to a variety of other models where longitudinal imaging-based analysis could benefit from precise 3D semiautomated alignment. Taken together, this protocol describes a readily quantifiable and easily reproducible system for osteoporosis and bone research. The suggested protocol takes 4 months to induce osteoporosis in nude ovariectomized rats and between 2.7 and 4 h to generate, image, and analyze two vertebral defects, depending on tissue size and equipment.

The goal of this protocol is to generate a nude rat osteoporosis-related vertebral compression fracture model that can be longitudinally evaluated in vivo using a semiautomated microcomputed tomography-based quantitative structural analysis.

Osteoporosis-related vertebral compression fractures (OVCFs) are a common and clinically unmet need with increasing prevalence as the world population ...

Analysis of 18FDG PET/CT Imaging as a Tool for Studying Mycobacterium tuberculosis Infection and Treatment in Non-human Primates

Mycobacterium tuberculosis remains the number one infectious agent in the world today. With the emergence of antibiotic resistant strains, new clinically relevant methods are needed that evaluate the disease process and screen for potential antibiotic and vaccine treatments. Positron Emission Tomography/Computed Tomography (PET/CT) has been established as a valuable tool for studying a number of afflictions such as cancer, Alzheimer&#39;s disease, and inflammation/infection. Outlined here are a number of strategies that have been employed to evaluate PET/CT images in cynomolgus macaques that are infected intrabronchially with low doses of M. tuberculosis. Through evaluation of lesion size on CT and uptake of 18F-fluorodeoxyglucose (FDG) in lesions and lymph nodes in PET images, these described methods show that PET/CT imaging can predict future development of active versus latent disease and the propensity for reactivation from a latent state of infection. Additionally, by analyzing the overall level of lung inflammation, these methods determine antibiotic efficacy of drugs against M. tuberculosis in the most clinically relevant existing animal model. These image analysis methods are some of the most powerful tools in the arsenal against this disease as not only can they evaluate a number of characteristics of infection and drug treatment, but they are also directly translatable to a clinical setting for use in human studies.

Analysis of 18FDG PET/CT Imaging as a Tool for Studying Mycobacterium tuberculosis Infection and Treatment in Non-human Primates

Here, we present a protocol to describe the analysis of 18F-FDG PET/CT imaging in non-human primates that have been infected with M. tuberculosis to study disease process, drug treatment, and disease reactivation.

Mycobacterium tuberculosis remains the number one infectious agent in the world today. With the emergence of antibiotic resistant strains, new clinically ...

Immunology and Infection

Cortical Bone Assessment Using the Ultrasonic BDAT Device

Cortical Bone Assessment Using Ultrasonic Guided Waves: A Reproducibility Study in a Healthy Population

Fragility fractures are still a worldwide health burden in the context of population aging. In particular, the global number of hip fractures is expected to double between 2020 and 2050. Therefore, it is essential to detect patients at risk of fragility fracture at the population scale. The current golden standard is dual X-ray absorptiometry (DXA), providing the areal bone mineral density (aBMD). Ultrasonic devices, usually more portable and cheaper than X-ray devices, represent interesting DXA alternatives as screening tools. However, operator dependency is usually recognized as their main drawback. In this study, the measurement protocol of the bi-directional axial transmission (BDAT) ultrasonic device is presented in detail. The dedicated ultrasonic probe is placed at the one-third distal radius of the non-dominant forearm using conventional coupling gel. The guided interface provides in quasi-real time (about 2 Hz) four parameters of interest: velocities of the first arriving signal (vFAS) and the A0 mode (vA0),&#160;cortical thickness (Ct.Th) and porosity (Ct.Po), as well as four quality parameters. The operator moves the probe slowly at the measurement site, carefully observing the feedback provided by the interface until finding a stable position and starting a series of 10 acquisitions. When at least four consistent series are obtained, the measurement ends, and an automatic report is generated. The measurement usually takes about 5 min to complete. To determine the robustness of this protocol, a reproducibility study was conducted among 3 operators (one expert and two novices) and 14 healthy participants (6 women, 8 men, 21-53 years old). The intraclass correlation coefficients (ICC) were found good for vA0 (0.76), Ct.Po (0.80) or excellent for Ct.Th (0.87) and vFAS (0.91). The standard deviations were found to be less than 10% of the total ranges in clinical practice.

Here, we present the measurement protocol of the bi-directional axial transmission (BDAT) ultrasonic device in detail and test it in a reproducibility study, considering 14 healthy participants and 3 operators. Reliability, measured with the intraclass correlation coefficients (ICC), was good to excellent for four parameters of interest.

Fragility fractures are still a worldwide health burden in the context of population aging. In particular, the global number of hip fractures is expected ...

Longitudinal Quantification of Cardiovascular Calcification Using PET/CT Imaging

Novel Quantification Protocol for Cardiovascular Calcification Progression Using Longitudinal MicroPET/MicroCT Images

Micro positron emission tomography (PET) and micro computed tomography (CT) imaging are powerful, ideal research tools for following the progression of cardiovascular calcification. Due to their non-invasive nature, small research animals can be imaged at multiple time points. The challenge lies in the accurate quantification of cardiovascular calcification. Here, we provide a protocol, using images from the later disease stages as a template, to accurately quantify the progression of cardiovascular calcification in longitudinal studies. The protocol involves 1) the alignment of the chest area in multiple images from the same animal during a longitudinal study as the first step, 2) the definition of a region of interest (ROI) situated within the heart and the aorta at the site of larger calcium deposits that become apparent in later images, and 3) simultaneous segmentation and quantification of calcium deposits across all images acquired during the longitudinal study. This streamlined method enhances the accuracy of image analysis in following the progression of cardiovascular calcification by improving the precision of ROI definition and reducing the variability associated with earlier techniques that analyze individual scans independently.

Author Spotlight: Enhanced Quantification of Cardiovascular Calcification Progression for Longitudinal Micro PET/CT Studies in Small Research Animals

This novel protocol entails the quantification of cardiovascular calcification progression from serial micro positron emission tomography (PET)/micro computed tomography (CT) images in small research animals.

Micro positron emission tomography (PET) and micro computed tomography (CT) imaging are powerful, ideal research tools for following the progression of ...

Innovative Video-Based Tool for Precision Assessment and Rehabilitation of LBP

Biomechanical Changes Related to Low Back Pain: An Innovative Tool for Movement Pattern Assessment and Treatment Evaluation in Rehabilitation

Low back pain (LBP) is a highly prevalent disorder frequently related to biomechanical alterations. Movement pattern assessments have a role in the rehabilitation management of patients with LBP; however, a precise assessment is challenging in routine clinical settings. Thus, this study aims to assess the biomechanical alterations related to LBP through the development and application of an innovative assessment tool named CameraLab. Patients with LBP were assessed through a video analysis system. The movement pattern assessment tool includes a touchscreen interface and four high-velocity cameras, enabling real-time data acquisition during movement assessments. The cameras capture dynamic movements, facilitating a thorough examination of motor function. A video analysis software application is employed for precise angle assessments and joint tracking. Three patients with LBP were assessed, demonstrating positive results in pain intensity, functional independence, and overall well-being. The integration of advanced technology highlighted the movement pattern alterations and contributed to tailored rehabilitation strategies. The study offers a paradigm shift toward precision rehabilitation. This innovative approach provides valuable insights into the biomechanical changes related to LBP, fostering a deeper understanding for clinicians and paving the way for effective personalized interventions in the management of LBP.

This study shows the role of an innovative tool for assessing and treating biomechanical alterations in low back pain (LBP) patients. Three LBP patients demonstrated improved pain intensity and functional independence post-assessment. The technology aids in tailored rehabilitation strategies, offering insights into LBP biomechanics for personalized interventions.

Low back pain (LBP) is a highly prevalent disorder frequently related to biomechanical alterations. Movement pattern assessments have a role in the ...

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

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