* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project
Volume 04 / Issue 03 / September 2016 Page 60 boa.ac.uk JTO Peer-Reviewed Articles Advances in osteoarthritis imaging: What will make it into clinical practice? Stephen McDonnell Tom Turmezei, Martin Graves, Andrew McCaskie & Joshua Kaggie Osteoarthritis is one of the fastest increasing global health problems, causing pain and disability. End stage disease is treated effectively with joint replacement, but the number of replacements is increasing year-on-year, with increased costs for already stretched healthcare systems. population, less than 1% by mass. Therefore, compositional techniques rely on the ability to quantitatively measure changes in this macromolecular environment. A critical question is whether these techniques will have relevance to global joint health and treatment decisions in future clinical practice? Structural imaging Surgical interventions for early stage disease, such as regenerative treatments1, are currently limited, in part due to the lack of diagnostic imaging methods to accurately quantify disease severity and select patients for treatment. Looking ahead, cutting-edge imaging technologies may provide detailed assessments of the arthritic joint at an early stage, allowing the development and improvement of treatment strategies in early disease. Stephen McDonnell Improvements in regular clinical imaging techniques, such as x-ray, computed tomography (CT) and magnetic resonance imaging (MRI) will give more detailed anatomical resolution and be combined with assessment of biological function. In this review article we explore imaging techniques likely to impact on clinical practice, focusing on plain radiography, CT and MRI. Other techniques such as ultrasound and nuclear medicine may also play an important role. The difference between structural and compositional imaging One important distinction in imaging osteoarthritis is whether the technique provides structural or compositional information. Structural imaging is the basis of current clinical imaging and depicts joint morphology from a limited range of tissue characteristics such as mineralisation, fat and water content. This can be used to assess the early features that might predispose to later disease, or for monitoring progression towards end-stage joint failure. Compositional imaging techniques assess joint tissue characteristics beyond the macroscopic structural level, identifying early changes, prior to cartilage loss, that would otherwise be considered irreversible (OARSI grade IV2). Cartilage is an avascular, aneural and alymphatic extracellular matrix formed predominantly from collagen and glycosaminoglycans (GAG) networks, with a small chondrocyte X-ray Radiography Planar X-rays have been the mainstay of clinical and research osteoarthritis imaging. It is low cost, accessible, quick and relatively easy to interpret. Thus it will continue to inform clinical assessment and decision-making, particularly in monitoring progression and following up therapies, such as joint replacement. However, compared to other modalities its two-dimensional nature makes it insensitive to structural change and unlikely to have an extended role. Computed Tomography (CT) CT is excellent at imaging bone. As such, it has mainly been used as a tool for the pre-operative planning of surgery, for example alignment, dysplasia, patientspecific implants. Similar to radiography, CT is low cost, accessible and can be acquired rapidly. Although the relatively higher exposure to ionising radiation compared to radiography, is a concern, particularly if planning multiple exposures for follow-up Volume 04 / Issue 03 / September 2016 Page 61 boa.ac.uk © 2016 British Orthopaedic Association Journal of Trauma and Orthopaedics: Volume 04, Issue 03, pages 60-63 Title: Advances in osteoarthritis imaging: What will make it into clinical practice? Authors: Stephen McDonnell, Tom Turmezei, Martin Graves, Andrew McCaskie & Joshua Kaggie Division of Trauma and Orthopaedics, University of Cambridge Arthritis Research UK Tissue Engineering Centre Figure 1: Quantitative measurement of cortical thickness at the hip in 3D from clinical CT imaging data using Stradwin software (http://mi.eng.cam.ac.uk/~rwp/stradwin) displayed as a colour map on a 3D mesh framework. Note increased thickness compared to other articular regions at the femoral superior subchondral bone plate, a key load-bearing site imaging or if used in a younger population. Increasingly low-dose protocols are being developed that will make this less of an issue3. CT can also be used to quantitatively map structural features of disease such as subchondral bone thickness, density, and joint space width (JSW) in three-dimensions (Figure 1)4. Given their association with recognised tissue changes in the development of osteoarthritis5, changes in these parameters are likely to be meaningful in disease progression or response to therapy. Magnetic resonance imaging (MRI) MRI has traditionally been used to supplement radiography in the clinical evaluation of osteoarthritis, mainly in the characterisation of structural joint damage and cartilage health. One of the main strengths of structural MRI is its ability to evaluate early soft tissue features, such as synovitis6 and bone marrow edema7 whilst also detecting ligament, fibrocartilage and hyaline cartilage damage. Semi-quantitative systems exist for scoring these features, but these scores are mainly used as research tools. The MOCART system has been used to assess cartilage repair technique viability and is likely to be become more familiar as these surgical techniques become more established. We refer readers with an interest in semi-quantitative MRI scoring on to an in-depth review by Guermazi et al.8. In addition to observergenerated scoring, there are a variety of 3D MRI methods that can create contrast between cartilage and bone, allowing 3D visualisation and structural quantification9,10. These can be used for measurement of cartilage thickness and volume (Figure 2). Such measures are likely to become increasingly important with the advent of whole joint therapies, which look to reverse deterioration in cartilage health. Compositional/Physiological Imaging MRI is the forerunner in compositional imaging. Although many compositional techniques are not used clinically as a result of the lack of early osteoarthritis management options, this is likely to change as new therapies become available. There is a range of techniques that have been validated in small, specific cohorts of early osteoarthritis which are beginning to be used in clinical practice: here we look at the most relevant#. dGEMRIC Delayed Gadonlinium Enhanced MRI with Contrast (dGEMRIC) measures the T1 relaxation time in cartilage before and 90 minutes after the intravascular injection of a gadolinium-based contrast agent12-14. Damage to articular cartilage is associated with Glycosaminoglycans (GAG) loss, so decreased GAG levels allow greater penetration of gadolinium from synovial fluid into the cartilage matrix, leading to reduced T1 relaxation times. dGEMRIC has proven ability to identify cartilage damage relevant to disease outcome before structural changes13-17. However, the long times required for joint perfusion has so far kept it from widespread clinical application. dGEMRIC’s use of gadolinium is also a concern due to recently discovered retention in the brain and established toxicity in patients with renal impairment18. As a result, non-gadolinium-based measures of cartilage integrity may well play a wider role (Figure 319). Proton Relaxation MRI: T2, T1rho and T2* mapping Other types of quantitative MRI acquisition are sensitive to compositional changes that can be probed through relaxation time measurements. Four main relaxation times can be measured: T1 (as in dGEMRIC), T2, T1rho, and T2*. Each of these creates different image contrasts between tissues types, with additional post-processing to give quantitative results that can be mapped in 2D or 3D. T2 mapping using spin echo based MRI sequences has been the most common method for identifying changes relevant to osteoarthritis (Figure 4)20,21, with >> T2 values shown to correlate Figure 2: Quantitative cartilage thickness at the femoral articular surface in 3D as measured from segmentation in a 3D T1-weighted MRI series using Stradwin software. The tibial articular surfaces are shown in grey # For in depth reading into the full range of compositional MRI techniques currently available, we refer readers on to a recent review by Guermazi et al.11 Volume 04 / Issue 03 / September 2016 Page 62 boa.ac.uk JTO Peer-Reviewed Articles MRI systems, and while T1rho is becoming increasingly available it does require additional specialised software. Figure 3: dGEMRIC of articular cartilage at the knee joint (sagittal). Note the increased T1 values at the weight-bearing surfaces of the femur and tibia (dashed lines) compared to the rest of the cartilage19 with water levels in cartilage, synovial fluid, and muscle22. The underlying principle is that since damaged cartilage has increased water content, T2 values will be higher in unhealthy regions. However, changes in these values are not correlated with acute injury. T1rho images appear similar to T2, but use a special technique that measures relaxation dominated by macromolecular correlation times. It has the advantage over T2 of being more sensitive to early microscopic change23, and more repeatable in one study involving anterior cruciate ligament injuries24. Both T2 and T1rho correlate with age, which is a strong indication of their sensitivity to related proteoglycan changes25,26. T2 maps can be acquired on many Figure 4: Sagittal T1rho image (a) and map (b, T2 image (c) and map (d), and T2* image (e) and map (f) in a healthy knee. All three techniques can be used to quantitatively assess the state of cartilage health. Maps can be masked to provide values exclusive to cartilage regions The principle of T2* mapping is similar to T2 mapping, except that it is based on gradient-echo based MRI sequences that demonstrate susceptibility to local magnetic field inhomogeneities. Using a similar effect as harnessed in T2 mapping, T2* maps similar properties of cartilage as T2 but using much faster acquisitions. T2* mapping is available on many clinical imaging systems, and as with T2 and T1rho mapping, we are likely to see this in clinical practice once the clinical relevance of these quantitative cartilage measures is established. Ultrashort Echo Time (UTE) MRI MRI signals decay rapidly (T2 < 10 ms) in bone or near the bonecartilage interface27-29 so they are unseen on conventional MR images. Ultra-short echo time (UTE) MRI captures this fast-decaying signal by using novel acquisition methods30,31. UTE MRI can therefore image the deep cartilage layers31. Subtracted UTE images can also be used to highlight differences at the osteochondral junction (Figure 5)31. UTE techniques are becoming more clinically available, although commercial implementation has been slow partially due to increased computational requirements30,32. The relevance of UTE imaging is yet to be established in disease progression. Sodium MRI Instead of using hydrogen atoms as the basis for tissue signal, it is possible to use other atoms. Sodium MRI can create image contrast not available with other standard protonbased methods33,34 (Figure 6). Positively-charged sodium is attracted to negatively charged proteoglycans, such that healthy cartilage contains more sodium than osteoarthritic cartilage35-37. Sodium MRI requires specialised software and hardware that is not widely available on clinical MRI systems, but these can be found at various research institutions38,39 and is likely that it will ultimately be used in disease assessment40. Conclusion Orthopaedics is continually evolving and is our diagnostic resource. Even the very familiar MRI examination will, as 3T field strength imaging becomes routinely available, provide quantitative structural and compositional imaging techniques described here, which will in turn provide realistic diagnostic and prognostic options. In the coming decade it is likely that patients with early osteoarthritis will have access to quantitative imaging methods. This will be an unprecedented opportunity for the clinician to refine and develop new treatments for cartilage repair and early osteoarthritis. Figure 5: Sagittal UTE image of a healthy knee. The short TE of the first image (32 µs) allows UTE structures to be visualised; these signals have decayed by the late echo image (4.5 ms). The subtraction image shows the delineation of deep cartilage (arrow), which is usually an undefined low-signal structure in standard MRI Volume 04 / Issue 03 / September 2016 Page 63 boa.ac.uk © 2016 British Orthopaedic Association Journal of Trauma and Orthopaedics: Volume 04, Issue 03, pages 60-63 Title: Advances in osteoarthritis imaging: What will make it into clinical practice? Authors: Stephen McDonnell, Tom Turmezei, Martin Graves, Andrew McCaskie & Joshua Kaggie Division of Trauma and Orthopaedics, University of Cambridge Arthritis Research UK Tissue Engineering Centre Figure 6: Standard sagittal proton T2 image (a), sodium MRI image (b), in a healthy knee. The sodium image gives an indirect measurement of proteoglycan content, which has been shown to be an indicator of cartilage health Acknowledgements Correspondence The UTE images are courtesy of Dr. James MacKay. Dr. Joshua Kaggie is funded by GlaxoSmithKline. The work was supported by the Addenbrooke’s Charitable Trust and the NIHR comprehensive Biomedical Research Centre award to Cambridge University Hospitals NHS Foundation Trust in partnership with the University of Cambridge. n Email: [email protected] Stephen McDonnell is a University Lecturer and Honorary Consultant Orthopaedic Surgeon in Cambridge. He has an interest in early arthritis phenotypes, novel radiology techniques, patient stratification and treatments. References References can be found online at www.boa.ac.uk/publications/JTO or by scanning the QR Code. References 1. Pers YM, Rackwitz L, Ferreira R, et al. Adipose Mesenchymal Stromal Cell-Based Therapy for Severe Osteoarthritis of the Knee: A Phase I Dose-Escalation Trial. Stem cells translational medicine. 2016. 2. Pritzker KP, Gay S, Jimenez SA, et al. Osteoarthritis cartilage histopathology: grading and staging. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2006;14:13-29. 3. Henckel J, Richards R, Lozhkin K, et al. Very low-dose computed tomography for planning and outcome measurement in knee replacement. The imperial knee protocol. The Journal of bone and joint surgery British volume. 2006;88:1513-1518. 4. Turmezei TD, Treece GM, Gee AH, et al. Quantitative 3D analysis of bone in hip osteoarthritis using clinical computed tomography. Eur Radiol. 2015. 5. Bousson V, Lowitz T, Laouisset L, et al. CT imaging for the investigation of subchondral bone in knee osteoarthritis. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 2012;23 Suppl 8:S861-865. 6. Hill CL, Hunter DJ, Niu J, et al. Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis. Annals of the rheumatic diseases. 2007;66:1599-1603. 7. Graif M, Schweitzer M, Deely D, et al. The septic versus nonseptic inflamed joint: MRI characteristics. Skeletal radiology. 1999;28:616-620. 8. Guermazi A, Roemer FW, Haugen IK, et al. MRI-based semiquantitative scoring of joint pathology in osteoarthritis. Nature Reviews Rheumatology. 2013;9:236-251. 9. Hardy PA, Recht MP, Piraino D, et al. Optimization of a dual echo in the steady state (DESS) free‐precession sequence for imaging cartilage. Journal of Magnetic Resonance Imaging. 1996;6:329-335. 10. Eckstein F, Hudelmaier M, Wirth W, et al. Double echo steady state magnetic resonance imaging of knee articular cartilage at 3 Tesla: a pilot study for the Osteoarthritis Initiative. Annals of the rheumatic diseases. 2006;65:433-441. 11. Guermazi A, Alizai H, Crema MD, et al. Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis. Osteoarthritis Cartilage. 2015;23:1639-1653. 12. Tiderius CJ, Svensson J, Leander P, et al. dGEMRIC (delayed gadolinium‐enhanced MRI of cartilage) indicates adaptive capacity of human knee cartilage. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2004;51:286-290. 13. Trattnig S, Mlyńarik Vr, Breitenseher M, et al. MRI visualization of proteoglycan depletion in articular cartilage via intravenous administration of Gd-DTPA. Magnetic resonance imaging. 1999;17:577-583. 14. Bashir A, Gray ML, Boutin RD, et al. Glycosaminoglycan in articular cartilage: in vivo assessment with delayed Gd (DTPA)(2-)-enhanced MR imaging. Radiology. 1997;205:551-558. 15. Bittersohl B. Delayed gadolinium-enhanced magnetic resonance imaging of hip joint cartilage (dGEMRIC): pearls and pitfalls. Orthopedic reviews. 2011;3:11. 16. Burstein D, Velyvis J, Scott KT, et al. Protocol issues for delayed Gd (DTPA) 2–‐enhanced MRI (dGEMRIC) for clinical evaluation of articular cartilage. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2001;45:36-41. 17. Cunningham T, Jessel R, Zurakowski D, et al. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage to predict early failure of Bernese periacetabular osteotomy for hip dysplasia. J Bone Joint Surg Am. 2006;88:1540-1548. 18. Kanda T, Ishii K, Kawaguchi H, et al. High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1-weighted MR images: relationship with increasing cumulative dose of a gadolinium-based contrast material. Radiology. 2013;270:834-841. 19. Williams, A., Sharma, L., McKenzie, C. A., Prasad, P. V. and Burstein, D. (2005), Delayed gadolinium-enhanced magnetic resonance imaging of cartilage in knee osteoarthritis: Findings at different radiographic stages of disease and relationship to malalignment. Arthritis & Rheumatism, 52: 3528–3535. doi: 10.1002/art.21388 20. Kijowski R, Blankenbaker DG, Munoz del Rio A, et al. Evaluation of the articular cartilage of the knee joint: value of adding a T2 mapping sequence to a routine MR imaging protocol. Radiology. 2013;267:503-513. 21. Dunn TC, Lu Y, Jin H, et al. T2 Relaxation Time of Cartilage at MR Imaging: Comparison with Severity of Knee Osteoarthritis 1. Radiology. 2004;232:592-598. 22. Liess C, Lüsse S, Karger N, et al. Detection of changes in cartilage water content using MRI T 2-mapping in vivo. Osteoarthritis and Cartilage. 2002;10:907-913. 23. Akella SV, Reddy Regatte R, Gougoutas AJ, et al. Proteoglycan‐induced changes in T1ρ‐relaxation of articular cartilage at 4T. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2001;46:419-423. 24. Nishioka H, Hirose J, Nakamura E, et al. Detecting ICRS grade 1 cartilage lesions in anterior cruciate ligament injury using T1ρ and T2 mapping. European journal of radiology. 2013;82:1499-1505. 25. Wang Y-XJ, Griffith JF, Leung JC, et al. Age related reduction of T1rho and T2 magnetic resonance relaxation times of lumbar intervertebral disc. Quantitative imaging in medicine and surgery. 2014;4:259. 26. Mosher TJ, Liu Y, Yang QX, et al. Age dependency of cartilage magnetic resonance imaging T2 relaxation times in asymptomatic women. Arthritis & Rheumatism. 2004;50:2820-2828. 27. Freeman DM, Bergman G, Glover G. Short TE MR microscopy: accurate measurement and zonal differentiation of normal hyaline cartilage. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 1997;38:72-81. 28. Xia Y, Farquhar T, Burton‐Wurster N, et al. Diffusion and relaxation mapping of cartilage‐bone plugs and excised disks using microscopic magnetic resonance imaging. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 1994;31:273-282. 29. Williams A, Qian Y, Bear D, et al. Assessing degeneration of human articular cartilage with ultra-short echo time (UTE) T 2* mapping. Osteoarthritis and Cartilage. 2010;18:539-546. 30. Gold GE, Thedens DR, Pauly JM, et al. MR imaging of articular cartilage of the knee: new methods using ultrashort TEs. AJR American journal of roentgenology. 1998;170:1223-1226. 31. Bae WC, Dwek JR, Znamirowski R, et al. Ultrashort Echo Time MR Imaging of Osteochondral Junction of the Knee at 3 T: Identification of Anatomic Structures Contributing to Signal Intensity 1. Radiology. 2010;254:837-845. 32. Samsonov A, Block WF, Field AS. Reconstruction of MRI data using sparse matrix inverses. Signals, Systems and Computers, 2007 ACSSC 2007 Conference Record of the Forty-First Asilomar Conference on: IEEE; 2007:1884-1887. 33. Madelin G, Regatte RR. Biomedical applications of sodium MRI in vivo. Journal of Magnetic Resonance Imaging. 2013;38:511-529. 34. Zbýň Š, Mlynárik V, Juras V, et al. Evaluation of cartilage repair and osteoarthritis with sodium MRI. NMR in Biomedicine. 2016;29:206-215. 35. Shapiro EM, Borthakur A, Gougoutas A, et al. 23Na MRI accurately measures fixed charge density in articular cartilage. Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine. 2002;47:284-291. 36. Reddy R, Insko EK, Noyszewski EA, et al. Sodium MRI of human articular cartilage in vivo. Magn Reson Med. 1998;39:697-701. 37. Madelin G, Babb J, Xia D, et al. Articular cartilage: evaluation with fluid-suppressed 7.0-T sodium MR imaging in subjects with and subjects without osteoarthritis. Radiology. 2013;268:481-491. 38. Wiggins GC, Brown R, Lakshmanan K. High-performance radiofrequency coils for 23Na MRI: brain and musculoskeletal applications. NMR in Biomedicine. 2016;29:96-106. 39. Bangerter NK, Kaggie JD, Taylor MD, et al. Sodium MRI radiofrequency coils for body imaging. NMR in Biomedicine. 2016;29:107-118. 40. de Bruin PW, Versluis MJ, Koken P, et al. Time-efficient interleaved 23Na and 1H acquisition at 7T. Milan, Italy: Proc. Intl. Soc. Mag. Reson. Med.; 2014:0034.