Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis

Osteoarthritis and Cartilage xxx (2015) 1e15

Review

Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis A. Guermazi y z *, H. Alizai x k, M.D. Crema y z ¶, S. Trattnig #, R.R. Regatte k, F.W. Roemer y z yy y Department of Radiology, Boston University School of Medicine, Boston, MA, USA z Department of Research, Aspetar Orthopaedic and Sports Medicine Hospital, Doha, Qatar x Department of Radiology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA k Department of Radiology, New York University Langone Medical Center, New York, NY, USA ~o and Teleimagem, Sa ~o Paulo, Brazil ¶ Department of Radiology, Hospital do Coraça # Department of Biomedical Imaging and Image Guided Therapy, Medical University of Vienna, Vienna, Austria yy Department of Radiology, University of Erlangen, Erlangen, Germany

a r t i c l e i n f o

s u m m a r y

Article history: Received 11 November 2014 Accepted 25 May 2015

Osteoarthritis (OA), a leading cause of disability, affects 27 million people in the United States and its prevalence is rising along with the rise in obesity. So far, biomechanical or behavioral interventions as well as attempts to develop disease-modifying OA drugs have been unsuccessful. This may be partly due to antiquated imaging outcome measures such as radiography, which are still endorsed by regulatory agencies such as the United States Food and Drug Administration (FDA) for use in clinical trials. Morphological magnetic resonance imaging (MRI) allows unparalleled multi-feature assessment of the OA joint. Furthermore, advanced MRI techniques also enable evaluation of the biochemical or ultrastructural composition of articular cartilage relevant to OA research. These compositional MRI techniques have the potential to supplement clinical MRI sequences in identifying cartilage degeneration at an earlier stage than is possible today using morphologic sequences only. The purpose of this narrative review is to describe compositional MRI techniques for cartilage evaluation, which include T2 mapping, T2* Mapping, T1 rho, dGEMRIC, gagCEST, sodium imaging and diffusion weighted imaging (DWI). We also reviewed relevant clinical studies that have utilized these techniques for the study of OA. The different techniques are complementary. Some focus on isotropy or the collagen network (e.g., T2 mapping) and others are more specific in regard to tissue composition, e.g., gagCEST or dGEMRIC that convey information on the GAG concentration. The application and feasibility of these techniques is also discussed, as they will play an important role in implementation in larger clinical trials and eventually clinical practice. © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Keywords: Cartilage Compositional imaging MRI Osteoarthritis

Introduction Osteoarthritis (OA) is one of the most prevalent musculoskeletal conditions, affecting up to 27 million people in the United States with a further increase in prevalence to be expected in the future

* Address correspondence and reprint requests to: A. Guermazi, Quantitative Imaging Center (QIC), Boston University School of Medicine, Section Chief, Musculoskeletal Imaging, Boston Medical Center, 820 Harrison Avenue, FGH Building, 3rd Floor, Boston, MA 02118, USA. Tel: 1-617-414-3893; Fax: 1-617-6386616. E-mail address: [email protected] (A. Guermazi).

due to an aging population and the obesity pandemic1,2. One of the hallmark features of OA from a structural perspective is cartilage degradation, which has a progressive, irreversible course and is closely interrelated with pathology of other joint tissues, including the subchondral bone, meniscus, synovium and others3. The structural diagnosis of OA is based on the presence of a definite osteophyte on an anterior-posterior radiograph. Joint space narrowing (JSN) is considered to be a surrogate for cartilage loss although it is well established that meniscal damage and particularly extrusion contribute to JSN4,5. Although radiography is not sensitive to progression of cartilage loss, JSN on radiographs is recommended by regulatory agencies including the United States

http://dx.doi.org/10.1016/j.joca.2015.05.026 1063-4584/© 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026

2

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15

Food and Drug Administration (FDA) as the primary imaging endpoint to establish the effectiveness of disease-modifying OA drugs3,6e8. Magnetic resonance imaging (MRI) allows direct visualization of all tissues involved in the OA disease process including articular cartilage. In addition to qualitative or quantitative morphologic assessment, MRI-based techniques have been developed that allow characterization and quantification of the biochemical composition of cartilage. These include relaxometry measurements (T2, T2*, T1rho mapping and T1), sodium imaging, delayed gadoliniumenhanced MRI of cartilage (dGEMRIC), glycosaminoglycan specific chemical exchange saturation transfer (gagCEST), diffusion weighted imaging (DWI), and diffusion tensor imaging (DTI). These compositional MRI techniques may have the potential to serve as quantitative, reproducible, non-invasive and objective endpoints for OA research, particularly in early and pre-radiographic stages of the disease. The purpose of this review article is to describe the currently available MRI-based compositional cartilage imaging techniques, and to provide an update on the application of these techniques in OA research. This study is a non-systematic, narrative review based on a comprehensive literature search in PubMed and Medline, completed in May 2014, using the search terms “osteoarthritis” and “magnetic resonance imaging” (or MRI). This search strategy yielded 3027 results. Additional keywords including “compositional MRI”, “T2”, “T2*”, “T1rho”, “T1”, “sodium imaging”, “gagCEST”, “dGEMRIC”, “DWI” and “DTI”, were used to narrow the search. The authors screened the resulting abstracts and finally 91 articles published in English were included for this review.

Basic principles of compositional MRI techniques and application of compositional MRI techniques in OA research Articular cartilage is responsible for resistance to compressive forces, distribution of load, and together with synovial fluid, frictionless movement of the articular joint components9. It consists of approximately 70e80% fluid and 20e30% solid extracellular matrix (ECM) with a sparse distribution (about 2%) of chondrocytes10. Chondrocytes are presumed to be responsible for any homeostatic and repair processes that modulate the composition of the fluid-like macromolecular network of cartilage11. The ECM is made up of a network of collagen fibrils and proteoglycan molecules. Collagen, a fibrillar macromolecule, is by far the most abundant macromolecule, accounting for about 20% of cartilage volume by weight11. Physiologically, the collagen network is highly organized and serves as the tissue's structural framework and its principal source of tensile and shear strength11. Although the collagen network becomes disrupted in OA and there is a net loss in total collagen content, its concentration is not appreciably affected in disease states12e14. A proteoglycan unit includes a protein core and covalently attached glycosaminoglycans (GAGs)9. The negatively charged GAGs contribute to the majority of the fixed charge density in the ECM and are neutralized by mobile cations, usually sodium (23Na) being the most abundant physiologically9. Initial histological and biochemical changes of cartilage degeneration involve disruption of the collagen network, decrease in proteoglycan content and increase in permeability to water15. Compositional MRI techniques enable detection of these biochemical changes in the cartilage ECM before morphological change occurs16. Because of well-documented importance of collagen and GAG to the functional and structural integrity of cartilage, efforts toward developing MRI techniques to interrogate cartilage macromolecules have focused on collagen and GAG11.

Spinespin relaxation (T2) mapping T2 relaxation time is the rate constant of proton dephasing in the transverse plane after a radio frequency (RF) pulse. Articular cartilage T2 reflects the water content, collagen content and collagen fiber orientation in the ECM, with longer T2 values thought to represent cartilage degeneration17e22. Multi-echo, spinecho, and fast spin echo -based sequences are most often used for T2 relaxation time measurements. Calculation of T2 relaxation values from cartilage regions of interest is usually performed by mono exponential curve fitting of the signal intensity of each echotime (TE) for each voxel23. Laminar (multilayer) analysis of normal articular cartilage T2 maps has shown that T2 values are higher in the superficial zone than in the deep cartilage zone (Fig. 1). This is because the deep zone collagen fibers are so densely packed that the mobility of the protons is reduced24. Researchers have to be aware that since the superficial cartilage is progressively lost in OA, laminar analysis may not be particularly useful once advanced degeneration has occurred25,26. Furthermore, T2 measurements are not very reliable for the deep and calcified cartilage layers, which have short inherent spinespin relaxation times27,28. In addition to variation in signal intensity with respect to depth from the articular surface, there are differences with respect to location in the joint29. Goodwin and colleagues have correlated this regional variation in signal intensity with obliquity of the collagen matrix cleavage planes on freeze fracture specimens30. Xia and colleagues have performed high-resolution correlations of cartilage T2 and fibril anisotropy measured with polarized light microscopy in canine humeral head samples31. These studies showed the high degree of structural variation of the cartilage tissue with respect to location of the joint, and the sensitivity of cartilage T2 relaxation to the tissue architecture11. T2 relaxation also is prone to magic angle effects, an artifact encountered with respect to the relative orientation of cartilage to applied magnetic field (B0)21. When collagen fibers are oriented 55 relative to the applied static magnetic field (B0), this relaxation mechanism is minimized resulting in a longer T2. This has been termed the “magic angle effect,” derived from the technique of magic angle spinning used to reduce the residual dipolar interaction of crystalline solids in nuclear MR spectroscopy32. In clinical MR imaging, the magic angle effect has been invoked to explain the etiology of the focally increased signal observed on short TE images

Fig. 1. Sagittal T2 map obtained from a healthy volunteer subject (32 years old male volunteer with Kellgren and Lawrence grade 0 knee) shows lower relaxation times compared to OA patients. The global T2 relaxation times from multiple slices in the healthy subject are 41 ± 5.6 ms.

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15

of cartilage with curved articular surfaces, such as the femoral condyle33 and talar dome34. Because increased T2 is associated with cartilage damage, artifact from the magic angle effect is a potential source of diagnostic error21. The T2 mapping pulse sequence is available on most of the vendor platforms, which means it could be widely applicable. Reproducibility35 and validity of T2 quantification17,18 have been well documented. Numerous clinical studies have used T2 mapping of cartilage demonstrating its ability to show evidence of cartilage degeneration even in morphologically normal knees on conventional MRI as well as in OA-affected cartilage (i.e., with radiographic JSN)18, but studies to evaluate the association of cartilage T2 measurements with symptoms are sparse. One study assessed cartilage T2 values in a matched cohort with and without knee pain; it found elevated T2 values in subjects with knee pain36. Another study involving persons with and without radiographic knee OA showed positive correlation with higher T2 values in the medial compartment cartilage and higher degree of knee pain18. On the other hand the association of T2 values with risk factors for OA including age, gender, obesity, and malalignment has been extensively studied. Mosher et al. demonstrated an association of elevated T2 values in superficial cartilage layers with age, suggesting that initial degenerative changes may occur at the articular surface with aging37. A study comparing differences in T2 values between healthy men and women found no differences between genders38. A study of 267 subjects from the Osteoarthritis Initiative found higher knee cartilage T2 values in obese subjects compared to those with normal weight39. Serebrakian and colleagues found a decrease in body mass index of 10% or more to be associated with slower progression of cartilage T2 values over 4 years in the knees of subjects with risk factors for OA40. While commonly increased T2 values are associated with cartilage degeneration, a study reporting no significant change in T2 values with cartilage degeneration relative to normal cartilage does exist in the literature41. Longitudinal studies of the effect of knee malalignment on cartilage T2 values are lacking. One cross-sectional study, however, compared the knees of 12 subjects with varus and 12 with valgus malalignment, and found an association of increased cartilage T2 with varus malalignment in the medial compartment42. The association of physical activity with cartilage degeneration remains controversial and only a few studies have assessed the relationship using T2 mapping. Acute loading of the knee after physical exercise results in decreased T2 values in the weight bearing femur and tibia, likely secondary to water mobility43,44. Studies examining long-term effects of physical activity have found higher levels of exercise to be associated with higher cartilage T2 values45,46. In a longitudinal study that assessed activity based on a physical activity scale for the elderly (PASE), increased cartilage T2 value progression was seen in those with high levels of physical activity as well as those with very low physical activity levels. This suggests that sedentary lifestyle and high-loading both effect cartilage integrity47. Using arthroscopy as the reference, one recent study suggested that the addition of a T2 mapping sequence to a routine MRI protocol at 3.0 T improved sensitivity in the detection of cartilage lesions within the knee joint with only a small reduction in specificity48. A long-term follow-up study, up to maximum of 11 years, by Potter and colleagues showed patients with acute traumatic anterior cruciate ligament disruption sustained a chondral injury at the time of initial impact with subsequent longitudinal chondral degradation in compartments unaffected by the initial “bone bruise”, a process that is accelerated at 5e7 years' follow-up49.

3

T2* mapping Compared with other biochemically sensitive MRI techniques, T2* mapping has unique features including speed of imaging, high image resolution, and the ability to carry out isotropic threedimensional (3D) cartilage evaluation. It is also easy to implement on clinical MRI systems, as pulse sequences and inline processing software for generating quantitative T2* maps are available commercially. In addition, there is no need for contrast media administration or special hardware50. Reproducibility studies for T2* have demonstrated good inter- and intra-observer reproducibility51e53. T2* relaxation is unique for gradient echo (GRE) imaging because it requires a de-phasing effect that is eliminated in spinecho MRI. GRE sequences are more time-efficient than spin-echo sequences, but are also more prone to local field inhomogeneities and susceptibility54. In common with T2 mapping, T2* mapping enables assessment of water content, collagen fiber network, and zonal variation reflecting biochemical composition of cartilage. As for T2 measurements, a decrease in T2* is noted toward the deep cartilage zones in normal cartilage and the T2* values are higher in diseased cartilage55e58. Despite these similarities, there are significant differences between the two imaging modalities that have led to diverging T2 and T2* values in various grades of cartilage degeneration52,56,59. T2 mapping spin-echo sequences utilize echo times of ~ 10e100 ms. Therefore, T2 mapping techniques capture T2 relaxation, which to a large extent is related to bulk water, while they are rather insensitive to T2 signals that decay more rapidly (T2 relaxation < 10 ms)60,61. T2* mapping, in contrast, includes shorter echo times and as such reflects a wider range of T2 relaxation occurring in cartilage tissue. Notably, because of the absent 180 refocusing pulse, T2* relaxation is less sensitive to stimulated echoes and magnetization transfer62,63. Ultrashort echo-time enhanced T2* (UTE-T2*) mapping of cartilage is a new technique with the potential to visualize deep cartilage characteristics better than standard T2 mapping64. Previous spectroscopic approaches to measuring cartilage UTE-T2* have determined that UTE-T2* values in deep tissue are short, perhaps as short as 1 ms in calcified cartilage, and increase toward the articular surface65,66. UTE-T2* mapping of human articular cartilage explants has been shown to be more robust in deep cartilage than the standard T2 mapping, and UTE-T2* values have been shown to increase with increasing collagen matrix degeneration64. Williams et al. demonstrated clinical feasibility of in vivo 3D UTE-T2* mapping at 3 T using a standard clinical MRI scanner and knee coil. In asymptomatic subjects, UTE T2* values were shown to be higher in superficial cartilage compared to deep cartilage in central weight-bearing medial femoral condyle and tibial plateau59. Other recent studies demonstrated reduction in T2* values with degeneration of articular cartilage in the knee and hip joints67e69. This decrease in T2* values has also been shown to correlate with morphological cartilage damage56. However, one study showed the opposite result, i.e., higher T2* values with patients who have symptomatic arthrosis of the ankle secondary to cavovarus feet compared to asymptomatic patients or those without the pathology70. More scientific evidence is needed to definitively determine the meaning and clinical significance of T2* values and their correlation with cartilage degeneration. T1rho imaging T1rho is spin-lattice relaxation in the rotating frame and is similar to T2 relaxation except that there is an additional RF pulse applied after the magnetization is tipped into transverse plane. The

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026

4

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15

magnetization becomes aligned or “spin-locked” with the applied RF field. The signal decay is exponential with a time constant, T1rho, and is typically calculated from multiple images by changing the duration of the spin-locking pulse. In liquids, T1, T2, and T1rho relaxation times may be similar, but in tissue these values are typically different (T2 < T1rho < T1). The measurements of T1rho probe molecular fluctuations in the kHz range because of the dependence on the RF-generated magnetic field (B1), whereas T2 probes fluctuations in the MHz range because of the dependence on the static magnetic field (B0)11,71. T1rho values may reflect nonspecific changes in the cartilage ECM and proteoglycan content72,73. In vitro studies have demonstrated that depletion of proteoglycan results in increased T1rho values, suggesting that T1rho estimates proteoglycan content74. Specifically T1rho probes the slow motion interactions between motion-restricted water molecules and their local macromolecular environment. As with T2 and T2*, there is a depth-wise distribution of T1rho values, with the highest values seen at the articular surface74. This technique requires neither contrast agent injection nor special RF hardware but does need an MR scanner that is capable of a customized pulse sequence specific to this application. Regatte et al. have suggested that T1rho relaxation mapping is a sensitive imaging marker for quantitative monitoring of macromolecules in early OA75. Normal articular cartilage from a healthy volunteer shows shorter T1rho values compared to cartilage affected by OA (Fig. 2). Also, T1rho relaxation time has been shown to be longer in cartilage with advanced degeneration than in cartilage with intermediate degeneration76. Although T1rho value changes are correlated with proteoglycan loss in vitro77, other studies have suggested that T1rho values may not be specific to any one inherent tissue parameter78. There is evidence that other factors, including collagen fiber orientation and the concentration of other macromolecules, also contribute to changes in T1rho values79. T1rho imaging has been suggested to be more sensitive than T2 mapping for differentiating between normal cartilage and early-stage OA80 (Fig. 3). A recent study by Wang et al. compared parallel changes of quantitative T2 and T1rho, mapping of human cartilage and suggested that T1rho mapping seem to be more sensitive in detecting early stages of cartilage degeneration than quantitative T281. A study by Thuillier et al. showed that the T1rho technique was able to differentiate subjects with patellofemoral pain from controls, but T2 values were not82. However, studies by Li

Fig. 2. Sagittal T1r map obtained from a healthy volunteer subject (32 years old male volunteer with Kellgren and Lawrence grade 0 knee) shows lower relaxation times compared to OA patients. The T1r relaxation times in the healthy subject are 52 ± 3.5 ms.

et al. have shown that T2 and T1rho values show different spatial distributions and may provide complementary information83. A few studies have examined the associations between T1rho values and OA risk factors. A study by Wang et al. suggested some degree of association between knee alignment and subregional T1rho values of femorotibial cartilage in patients with clinical OA84. They found significantly higher T1rho values in the medial femoral cartilage subregion in the varus group than in any other cartilage subregions in the valgus group. A study by Stahl et al. found that physically active subjects with focal cartilage morphological abnormalities have elevated T1rho values of cartilage compared to those without such abnormalities80. Souza et al. observed significant elevations in T1rho values of the adjacent compartment (medial tibia) and medial meniscus in subjects with medial femoral cartilage lesions85. A study by Zarins et al. correlated meniscal damage with cartilage degeneration, using both T2 and T1rho measurements86. Bolbos et al. demonstrated injury related changes in cartilage and meniscal biochemical composition using T1rho mapping in patients with acute ACL injuries87. The T1rho mapping technique has been shown to noninvasively detect cartilage pathology in knees with injured ACL88. Li et al. have shown that T1rho can detect the changes in the cartilage matrix in ACL-reconstructed knees as early as 1 year after reconstruction89. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) dGEMRIC is a T1 relaxation-time measurement technique, that uses the negative ionic charge of gadopentetate dimeglumine (Gd-DTPA2) to map the fixed charge density of cartilage GAGs90,91. Gd-DTPA2 is repelled by the negatively charged GAGs and therefore distributed in inverse proportion to the local proteoglycan concentration. Gd-DTPA2 accumulates in areas of low GAG content and cartilage will consequently have a shorter T1 relaxation time in these regions. The ability to measure spatial variations in cartilage GAG concentration in vitro with dGEMRIC has been validated biochemically and histologically using both bovine and human cartilage92e95. The feasibility of using dGEMRIC in vivo was demonstrated, and the interpretation of the MR images as representing GAG distribution was supported by literature evidence. Excellent correlation between in vivo images of patients scheduled for total knee replacement surgery and ex vivo images of the same joint after surgery95. Similarly, when Gd(DTPA)2 was injected intravenously into patients 2 h before total joint replacement surgery, with subsequent post-excision MRI and histology, the distribution of Gd(DTPA)2 in the cartilage after excision compared well with histologic results79,96. Thus it was demonstrated that in vivo spatial variations in cartilage T1 values in the presence of Gd(DTPA)2, under suitable conditions, can be interpreted as variations in tissue GAG concentration91. However, whether one should use ionic or non-ionic contrast for dGEMRIC remains to be a matter of discussion. In one study, spatial variations in in vivo T1 values were observed following penetration of an ionic contrast agent but not of a nonionic contrast agent, indicating that T1 variations depend on the tissue charge93. However, a more recent study97 showed the differences between ionic and non-ionic contrast agents for dGEMRIC were not as clear as the aforementioned study93 and even concluded that the use of non-ionic contrast enables better discrimination of the health status of cartilage97. dGEMRIC images are typically obtained after 90-min delay following injection of gadolinium contrast agent to allow diffusion and contrast equilibration within the cartilage. However, the different time delays may be required from joint to joint and even between compartments within the same joint due to different

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15

5

Fig. 3. 62-year-old woman with KellgreneLawrence grade 1 OA and no abnormalities on conventional morphological MRI. Two representative sagittal T2 (a, b; spatial resolution 0.59  0.59  1.5 mm) and T1rho (c, d; spatial resolution 0.59  0.59  3.0 mm) MRI with overlaid maps, show that the relaxation times for the T2 and T1rho mapping fall into distinctly different ranges of values with the obviously higher dynamic range in T1rho for the osteoarthritic subject. Generally, T2 reflects the collagen structural integrity and T1rho probes the slow motion interactions between motion-restricted water molecules and their local macromolecular environment. The profile plots of the T2 and T1rho (e) relaxation times measured in the same subject as in Fig. 2(A) and (C). The vertical rectangular white ROIs were used for profile plotting (solid line for T2 and dashed line for T1rho respectively). Each point on the profile is an average of 5  5 pixels, i.e., a small ROI in the weight bearing region, and error bars show the respective standard deviation. The profile plots show the difference across the cartilage thickness. (Image reproduced with written permission: original publication e Wang L, Regatte RR. Acad Radiol. 2014; 21:463e71.)

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026

6

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15

Fig. 4. dGEMRIC assessment of the medial tibiofemoral compartment of an asymptomatic female volunteer (Kellgren and Lawrence grade 0 knee) using a sagittal 3D inversion recovery-prepared SPGR sequence with selective water excitation acquired 90 min after Gd-DTPA(2) intravenous administration (in-plane resolution of 0.31 mm  0.31 mm and a slice thickness of 1.0 mm; TE ¼ 7.2e8.5 ms, TR ¼ 16e17 ms, flip angle ¼ 12 , bandwidth ¼ 130 Hz/pixel, matrix size ¼ 512  512). Using the color coded map as the reference, high dGEMRIC indices are depicted in the medial compartment (values varied from 760 ms to 932 ms in this slice).

cartilage thicknesses. Challenges in applying dGEMRIC in clinical studies include the lack of standardization of patient physical activity required before MR examination and potential side effects of gadolinium, which is usually applied in a double dose91. On the other hand there is long-standing experience with dGEMRIC and it is probably one of the best-understood compositional methodologies98e103. dGEMRIC is sensitive to cartilage proteoglycan content and may predict the development of OA100. Generally, normal healthy cartilage demonstrates high dGEMRIC values (Fig. 4) which decreases with increasing degree of cartilage degeneration. It was recently demonstrated that T1Gd values in medial tibiofemoral compartments decrease as the radiographic KellgreneLawrence grade increases103 (Figs. 5e7). Prescribed immobilization after injury, of only 6 weeks, has been shown to result in biochemical changes in the cartilage measureable by dGEMRIC with a mean decrease seen in T1 relaxation time (T1Gd) seen at 4 months, which persisted for up to a year99. In a longitudinal study, Owman et al. found that low baseline T1Gd using dGEMRIC in medial and lateral femoral cartilage was associated with a higher grade of JSN after 11 years, and also with development of osteophytes98. A study by

Crema et al. found high-grade medial meniscal damage to be associated with low T1Gd times in the medial tibiofemoral compartment102. Lattanzi et al. recently demonstrated that dGEMRIC was accurate in detecting, at the hip, cartilage damage due to femoroacetabular impingement104. In an earlier study, Kim et al. also showed that dGEMRIC index was significantly different in subgroups with mild, moderate, and severe grades of hip dysplasia105, which suggests the ability of dGEMRIC to detect varying cartilage degeneration among these groups. In a study of 111 obese adults, dGEMRIC showed that weight loss over the course of a year resulted in increased cartilage proteoglycan content106. A recently published study evaluated articular cartilage using dGEMRIC after viscosupplementation with hyaluronic acid in patients with early knee OA107. The study found no change in the structural composition of cartilage after 14 weeks, even though symptomatic improvement was reported. However, another recent study showed that a decrease in T1Gd values over time predicted an increase in cartilage thickness in the same tibiofemoral compartment after 2 years, mainly in middle-aged women with no radiographic OA or early radiographic OA101. The authors suggested that such an association might occur in the early stages of degeneration when swelling of cartilage (with increased thickness) is seen. Sodium (23Na) imaging The nucleus of the sodium ion 23Na possesses a quadrupolar moment that interacts with the electric field gradients of the surroundings, leading to complex relaxation processes in biological tissues that can result in biexponential T1 and T2 relaxation times108. Sodium concentration is known to be correlated directly with the proteoglycan concentration in cartilage109,110. In healthy cartilage, the average sodium concentration is generally in the range 200e300 mmol/L, which is around 260e400 times lower than the in vivo water proton concentration108. The combination of all these factors results in a sodium MRI signal that is approximately 3000e4500 times lower than the proton signal in cartilage. The low sodium concentration in cartilage combined with the low MR receptivity of sodium nuclear spins and their very short transverse relaxation time makes the detection of sodium signal very challenging and results in images with low signal to noise ratio, low resolution (2e4 mm isotropic) and long acquisition times (15e30 min)108. Due to the aforementioned low resolution of sodium images, partial volume effects from surrounding tissues, such as subchondral edema or synovial fluid (sodium concentration of 140e150 mmol/L compared to cartilage sodium concentration ~250e300 mmol/L) can influence the accuracy of quantitative sodium MRI results. To minimize the contamination of cartilage signal

Fig. 5. 23-year-old man with a moderate osteochondral defect on the patellar cartilage seen on axial proton density-weighted MRI (a). T1 before (b) and after intravenous contrast administration (c) show a significant decrease of T1 relaxation times in the cartilage lesion area of the medial facet of the patella. There is a focal small but deep lesion and a larger superficial lesion medially which correspond to regions of lower glycosaminoglycan (GAG) content. Precontrast T1 map (a) does not show significant changes, underscoring the importance of postcontrast T1 mapping (c) for GAG evaluation.

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15

7

Fig. 6. 62-year-old woman with advanced OA in the medial femorotibial compartment. Sagittal proton density-weighted MRI (a) shows marked thinning of cartilage at the weightbearing central medial femur adjacent to the medial meniscus (large white arrows). Note the large intrachondral osteophyte of the anterior part of the weight-bearing medial femur (small white arrows). Diffuse cartilage damage is also shown at the anterior medial femur (arrowhead). The tibial cartilage appears morphologically normal. The corresponding dGEMRIC image (b) shows a decrease in the dGEMRIC index particularly in the weight bearing areas at the central and posterior tibia (large white arrows) as well as in the superficial zones of the central medial femoral cartilage (small white arrows) representing low GAG concentration.

from synovial fluid or joint effusion, various techniques can be employed such as inversion recovery preparation based fluid suppression (based on T1 differences), double-echo subcontracting methods (based on T2* differences) compared to the reference standard triple-quantum filtering (based on T2 differences). In order to correct the within-voxel contamination, we need to measure the voxel-wise water content mapping. From the hardware point of view, sodium MRI requires the use of high magnetic field (e.g., 3 T and 7 T) with high magnetic field gradients and special RF coils and broadband hardware108,111,112. Sodium imaging correlates with the fixed charge density and GAG content in cartilage113 and therefore may also be used in early detection of OA. Clinical studies using sodium MRI, however, are limited. A feasibility study by Wheaton et al.109 used sodium imaging to compare the cartilage of healthy subjects with subjects with symptoms of early OA. They found a higher mean fixed-charge density in the healthy individuals. The symptomatic subjects had focal regions of decreased fixed charge density, with mean values ranging from 108 to 144 mmol/L, indicative of proteoglycan loss109 (Fig. 8). Madelin et al. reported the reproducibility and repeatability of sodium quantification in cartilage in vivo using intraday and interday acquisitions at 3 T and 7 T, with a radial 3D sequence, with and without fluid suppression112. No significant intermagnet, intersequence, intraday, or interday differences were observed in the coefficients of variation. A recently described sodium quantification technique using inversion recovery wide-band uniform rate and smooth truncation (IR-WURST) gave values that were closer to those reported in the literature for healthy cartilage (220e310 mM) than the values from radial 3D112. A recent study111 also reported that the sodium concentration in both healthy and OA knees at 7 T imaging with fluid suppressed sodium MRI can be used for detection of OA (Kellgren and Lawrence grade 1e4 knees in symptomatic patients fulfilling the criteria by the American College of Rheumatology) with 82% sensitivity, 74% specificity and 78% accuracy (Fig. 9). Findings of these studies suggest quantitative sodium MR imaging of articular cartilage in vivo may be a useful biomarker for detecting clinical and radiographic OA. DWI and DTI Intra- and extracellular barriers determine the molecular motion of water. Diffusion MRI techniques are sensitive to the

restriction of motion of water molecules bound within a macromolecular environment. These methods use paired magnetic field gradient pulses to probe the motion of nuclei in the direction of the applied magnetic field gradient114. The two pulses are of equal duration and amplitude and are separated by a time delay (D). The net effect of the paired gradient pulses is to dephase magnetisation from nuclei which have undergone diffusion during the time delay, resulting in measurable signal attenuation16. Typically, a diffusion-sensitive MRI sequence comprises a number of diffusion gradient pulses applied along multiple axes as well as imaging gradients for spatial localization of the signal. It then becomes convenient to summarize the combined influence of the gradients through calculation of the b-factor115. The sb-factor determines the overall diffusion weighting of a sequence in the same way that the echo time characterizes the degree of T2 weighting. Acquisition of images with multiple b-factors thus allows the diffusion coefficient to be mapped on a pixel-by-pixel basis16. When measuring the diffusion coefficient of water molecules in physiological systems, there is significant interaction between the water molecules and their surrounding environment during the timescale of the experiment, and the parameter measured is the apparent diffusion coefficient (ADC)16. Consequently, measuring the ADC of water molecules within the cartilage ECM can be used to infer cartilage tissue structure and architecture, with increased diffusivity linked to structural degradation of the ECM116,117. The two most popular DWI techniques are the diffusionweighted turbo spin echo (DW-TSE) and the diffusion-weighted echo planar imaging (DW-EPI) sequences. The most useful sequence for DWI of the musculoskeletal system is the reversed fast imaging with steady precession with diffusion weighting (DWFISP), which allows the acquisition of high resolution images in as little as a few seconds per slice, due to the short repetition times used118. Quantitative in vivo diffusion imaging of cartilage using diffusion-weighted double echo steady state free precession (SSFP) has also been described119. This technique provides diffusion quantification independent of the relaxation time. Studies have shown Diffusion-weighted imaging (DWI) can be potentially used for evaluating cartilage degeneration in vivo120 and monitoring its repair following surgery121,122. A recent longitudinal study demonstrated the ability of DWI to differentiate between healthy and repaired cartilage at different time points after surgery

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026

8

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15

Fig. 7. 68-year-old man with KellgreneLawrence grade 1 OA. Two representative dGEMRIC-T1 maps from T1 values (spatial resolution 0.7  0.7  1.5 mm) obtained before (a, b) and after contrast agent injection (c, d). The color bar scale at the right indicates the T1 values in ms. The profile plots (e) show the variations in T1 relaxation times of cartilage regions along the vertical lines in Fig. 5(A) and (C) with T1 mapping before and after contrast agent injection. The T1 relaxation times varied in a different range OR in different ranges before and after contrast agent injection with the range obviously much higher before contrast agent injection. The error bars show the standard deviations of values of 5  5 pixels centered on each point along the vertical line within the cartilage regions. The average dGEMRIC-T1 value was sharply decreased after intravenous administration of Gd contrast agent (1244.134 ms vs. 643.227 ms, P < 0.05), depending upon the degree of cartilage degeneration. (Image reproduced with written permission: original publication e Wang L, Regatte RR. Acad Radiol. 2014;21:463e71.)

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15

9

Fig. 8. 37-year-old man with a large area of low sodium signal to noise ratio on the patellar cartilage layer on the axial sodium image of the apex patella, corresponding to a low GAG content (a) while on the morphological axial proton density-weighted only image early signs of degeneration can be detected as a superficial cartilage irregularity (b). The image resolution is 1.5  1.4  3.0 mm.

Fig. 9. Sodium maps from a 30-year-old male KellgreneLawrence grade 0 control subject (Control) and a 64-year-old woman with KellgreneLawrence grade 2 OA. Maps (spatial resolution 2.0  2.0  2.0 mm) were reconstructed from data acquired with fluid suppression (inversion recovery wide-band uniform rate and smooth truncation (IR-WURST [IRW]) sequence) and without fluid suppression (radial 3D sequence [R3D]). Sodium concentrations in the radial 3D sequence are similar for both subjects. Note the higher difference in sodium concentration with IR WURST between femorotibial medial and femorotibial lateral regions of control subject and patient with OA compared with radial 3D. (Image reproduced with written permission: original publication e Madelin G, Babb J, Xia D, et al. Radiology. 2013;268:481e91.)

of patients following matrix-assisted autologous chondrocyte transplantation123. The authors, however, highlighted the difficulty in obtaining precise measures of the diffusion values, and compared only the relative changes in diffusivity in this study. DTI is a DWI based technique that evaluates the direction of water mobility with the ECM. The microarchitecture of normal cartilage causes anisotropic water diffusion. A change in anisotropy can indicate changes in collagen architecture124. One limitation of DTI is that it is time consuming. Additionally, the high-resolution

DTI protocols required to measure the articular cartilage are difficult to implement in vivo. Diffusion imaging may supplement other quantitative techniques for evaluating cartilage, but clinical studies that use the technique are scarce. Recent studies by Raya and colleagues to determine the feasibility of in vivo DTI have shown promising results124e126. In a study that included histological analysis, DTI of cartilage-on-bone samples drilled from human patellae at 17.6 T showed samples with OARSI grade greater than 0 had significantly increased

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026

10

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15

longitudinal, transverse and mean diffusivity in the superficial cartilage growing deeper into cartilage with increasing OARSI grade124. Moreover, samples with an OARSI grade greater than 0 showed significantly decreased fractional anisotropy in the deep cartilage, suggesting that changes in the collagen architecture may occur early in cartilage degradation124. In vivo DTI of articular cartilage of the knee at 7 T could differentiate knees with and without radiographic knee OA and showed excellent reproducibility125. Magnetization Transfer Contrast (MTC)-based techniques including gagCEST Water in the ECM is found in two physical states, either associated with macromolecules or in a free state. Water associated with macromolecules has short T2 relaxation times, and, thus, a broad resonance peak. Off-resonance RF pulses can therefore be applied prior to imaging to saturate the water associated with macromolecules. This saturation is exchanged to the free water causing a loss of image signal intensity. The magnetization exchange can occur by either dipolar coupling or chemical exchange. MTC can therefore estimate cartilage macromolecular concentration (predominantly collagen) by measurement of this effect by acquiring images with and without the off-resonance pulse. Moreover, ex-vivo studies of animal cartilage tissues showed MT ratio is dependent on the amount of free water content/volume and collagen concentration and that MT ratio is depth-dependent and is relatively higher in radial zone compared to the superficial zone127. Yao and colleagues reported the insensitivity of MT ratio measurements to early cartilage degeneration, suggesting that the dependence of the MT ratio on multiple factors makes variation in MT ratios difficult to interpret128. GAG chemical exchange saturation transfer imaging (gagCEST) is an MTC-based technique in which off-resonance RF saturation pulses are applied at frequencies specific to chemically exchangeable protons residing on the hydroxyl groups of cartilage GAGs129. With gagCEST MRI, transfer of magnetization is studied in mobile macromolecules instead of semisolids, in contrast to MTC. Thus, the measurements are GAG-molecule specific and avoid the practical limitations of dGEMRIC and 23Na imaging. Limitations of gagCEST include that an ultra-high field MR system is required, the increased energy deposition due to long saturation RF pulses, and complex post-processing. A recent study with gagCEST using 3 T MRI, found the technique to be comparable to dGEMRIC and T2 mapping for detecting normal and damaged cartilage130. Clinical studies examining the potential role of gagCEST in assessment of OA related cartilage degeneration are lacking. Feasibility studies using in vivo gagCEST have shown gagCEST MRI to be sensitive to GAG levels in the cartilage (Fig. 10)129. In addition, the method allows one to clearly demarcate glycosaminoglycan measurements from cartilage and synovial fluid regions131. A recent study by Rehnitz et al. prospectively compared gagCEST with dGEMRIC and T2130. The authors of this study reported that gagCEST was non-inferior in distinguishing healthy from damaged cartilage when compared to dGEMRIC and T2 mapping. Further studies are needed to establish the potential value of this technique in assessment of OA related cartilage degeneration. Summary and outlook Advanced MRI techniques enable evaluation of the biochemical or ultrastructural composition of articular cartilage relevant to OA research. Compositional MRI techniques have the potential to supplement clinical MRI sequences in identifying cartilage degeneration at an earlier stage than is possible today using morphologic sequences only. To date, however, the relevance of these techniques

Fig. 10. 45-year-old woman with a normal femoral cartilage layer on standard MRI (not shown). The sagittal gagCEST MRI shows lower gagCEST asymmetries (by means of MTRasym values) in the weight-bearing zone (blue, arrow) compared to other nonweight-bearing cartilage regions of the femoral condyle, correlating with a lower GAG content as an early sign of focal cartilage degeneration. Blue area represents gagCEST MTR asymmetry value of 6, which correspond to the low GAG region. Red area corresponds to the MTRasym values of þ13, which is high in GAG content. Light green area shows intermediate MTRasym values, which correspond to the intermediate GAG content. The gagCEST does not provide absolute GAG quantification. The scale goes from negative to positive since this is a technical property of gagCEST.

to clinical or structural outcomes is unclear and there is a lack of studies focusing on responsiveness. Although the different techniques are complementary with some focusing on isotropy or the collagen network (e.g., T2 mapping) others are more specific in regard to tissue composition, e.g., gagCEST or dGEMRIC that convey information on the GAG concentration. In addition to the different tissue components that are targeted by the different techniques, applicability and feasibility will play an important role in the implementation of the different techniques. Some techniques such as T2 mapping and dGEMRIC are easily applied at standard clinical platforms, while others such as T1rho, gagCEST or sodium imaging require either ultra high field systems or other dedicated hardware or software. Compositional MRI techniques are likely to enhance our understanding of early disease, thanks to their capability to detect ultrastructural tissue alterations that are not conceivable by visual assessment. These techniques may potentially be applied to monitor response to conservative, pharmacologic or surgical treatment approaches in order to show either delayed onset or slowing of progression of disease, or improvement of already established tissue damage. Once joint damage has progressed to stages beyond focal or ultrastructural pathology, compositional MRI will likely only play a secondary role in joint assessment. At present it seems paramount to engage in study endeavors that focus on early disease and disease onset to develop and evaluate interventional approaches in stages of potential reversibility132. In addition, the role of compositional MRI in pre-treatment stratification needs to be elucidated further to characterize patients or joints that are likely to benefit most from a given established intervention105. Although the particular strengths and weaknesses of the different compositional MRI techniques still need to be determined, they seem to offer much in terms of predicting structural and clinical outcomes, taking into account feasibility of application, reliability and responsiveness of the different techniques available today.

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15

Author contributions (a) Conception and design, acquisition of data, analysis and interpretation of data: All authors (b) Drafting the article or revising it critically for important intellectual content: All authors (c) Final approval of the version to be published: All authors (d) Literature search: All authors (e) Statistical expertise: N/A (f) Guarantor of the integrity of the study: AG (guermazi@bu. edu)

11.

12.

13. 14.

Conflict of interest statement A Guermazi is a shareholder of BICL, LLC and consultant to MerckSerono, TissueGene, Genzyme and OrthoTrophix. H Alizai has no conflict of interest. MD Crema is a shareholder of BICL, LLC. S Trattnig has no conflict of interest. RR Regatte has no conflict of interest. FW Roemer is a shareholder of BICL, LLC.

15.

16.

Acknowledgment We thank S Pavol, MD, and D Hayashi, MD PhD, for their technical assistance with preparation of the revised manuscript and figures.

17.

References 18. 1. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, Deyo RA, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008;58:26e35. 2. Bliddal H, Leeds AR, Christensen R. Osteoarthritis, obesity and weight loss: evidence, hypotheses and horizons e a scoping review. Obes Rev 2014;15:578e86. 3. Tonge DP, Pearson MJ, Jones SW. The hallmarks of osteoarthritis and the potential to develop personalised diseasemodifying pharmacological therapeutics. Osteoarthritis Cartilage 2014;22:609e21. 4. Crema MD, Nevitt MC, Guermazi A, Felson DT, Wang K, Lynch JA, et al. Progression of cartilage damage and meniscal pathology over 30 months is associated with an increase in radiographic tibiofemoral joint space narrowing in persons with knee OA e the MOST study. Osteoarthritis Cartilage 2014;22:1743e7. 5. Hunter DJ, Zhang YQ, Tu X, Lavalley M, Niu JB, Amin S, et al. Change in joint space width: hyaline articular cartilage loss or alteration in meniscus? Arthritis Rheum 2006;54:2488e95. 6. Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: an update with relevance for clinical practice. Lancet 2011;377: 2115e26. 7. Boegard TL, Rudling O, Petersson IF, Jonsson K. Joint space width of the tibiofemoral and of the patellofemoral joint in chronic knee pain with or without radiographic osteoarthritis: a 2-year follow-up. Osteoarthritis Cartilage 2003;11: 370e6. 8. Guermazi A, Roemer FW, Felson DT, Brandt KD. Motion for debate: osteoarthritis clinical trials have not identified efficacious therapies because traditional imaging outcome measures are inadequate. Arthritis Rheum 2013;65:2748e58. 9. Huber M, Trattnig S, Lintner F. Anatomy, biochemistry, and physiology of articular cartilage. Invest Radiol 2000;35: 573e80. 10. Buckwalter JA, Hunziker E, Rosenberg L, Coutts RD, Adams M, Eyre D. Articular cartilage: composition and structure. In:

19.

20.

21.

22.

23.

24.

25.

26.

11

Woo SLY, Buckwalter JA, Eds. Injury and Repair of the Musculoskeletal Soft Tissues. Park Ridge, Ill: American Academy of Orthopaedic Surgeons; 1988:405e25. Burstein D, Gray M, Mosher T, Dardzinski B. Composition and structure in osteoarthritis. Radiol Clin North Am 2009;47: 675e86. Billinghurst RC, Dahlberg L, Ionescu M, Reiner A, Bourne R, Rorabeck C, et al. Enhanced cleavage of type II collagen by collagenases in osteoarthritic articular cartilage. J Clin Invest 1997;99:1534e45. Buckwalter JA, Martin J. Degenerative joint disease. Clin Symp 1995;47:1e32. Maroudas AI. Balance between swelling pressure and collagen tension in normal and degenerate cartilage. Nature 1976;260:808e9. Buckwalter JA, Mankin HJ. Articular cartilage: degeneration and osteoarthritis, repair, regeneration, and transplantation. Instr Course Lect 1998;47:487e504. Binks DA, Hodgson RJ, Ries ME, Foster RJ, Smye SW, McGonagle D, et al. Quantitative parametric MRI of articular cartilage: a review of progress and open challenges. Br J Radiol 2013;86:20120163. Nissi MJ, Rieppo J, Toyras J, Laasanen MS, Kiviranta I, Jurvelin JS, et al. T(2) relaxation time mapping reveals ageand species-related diversity of collagen network architecture in articular cartilage. Osteoarthritis Cartilage 2006;14: 1265e71. Dunn TC, Lu Y, Jin H, Ries MD, Majumdar S. T2 relaxation time of cartilage at MR imaging: comparison with severity of knee osteoarthritis. Radiology 2004;232:592e8. Joseph GB, Baum T, Alizai H, Carballido-Gamio J, Nardo L, Virayavanich W, et al. Baseline mean and heterogeneity of MR cartilage T2 are associated with morphologic degeneration of cartilage, meniscus, and bone marrow over 3 yearsedata from the Osteoarthritis Initiative. Osteoarthritis Cartilage 2012;20:727e35. Prasad AP, Nardo L, Schooler J, Joseph GB, Link TM. T(1)rho and T(2) relaxation times predict progression of knee osteoarthritis. Osteoarthritis Cartilage 2013;21:69e76. Mosher TJ, Smith H, Dardzinski BJ, Schmithorst VJ, Smith MB. MR imaging and T2 mapping of femoral cartilage: in vivo determination of the magic angle effect. AJR Am J Roentgenol 2001;177:665e9. Liess C, Lusse S, Karger N, Heller M, Gluer CC. Detection of changes in cartilage water content using MRI T2-mapping in vivo. Osteoarthritis Cartilage 2002;10:907e13. Baum T, Joseph GB, Karampinos DC, Jungmann PM, Link TM, Bauer JS. Cartilage and meniscal T2 relaxation time as noninvasive biomarker for knee osteoarthritis and cartilage repair procedures. Osteoarthritis Cartilage 2013;21:1474e84. Carballido-Gamio J, Blumenkrantz G, Lynch JA, Link TM, Majumdar S. Longitudinal analysis of MRI T(2) knee cartilage laminar organization in a subset of patients from the osteoarthritis initiative. Magn Reson Med 2010;63:465e72. Jungmann PM, Kraus MS, Nardo L, Liebl H, Alizai H, Joseph GB, et al. T2 relaxation time measurements are limited in monitoring progression, once advanced cartilage defects at the knee occur: longitudinal data from the osteoarthritis initiative. J Magn Reson Imaging 2013;38:1415e24. Hovis KK, Alizai H, Tham SC, Souza RB, Nevitt MC, McCulloch CE, et al. Non-traumatic anterior cruciate ligament abnormalities and their relationship to osteoarthritis using morphological grading and cartilage T2 relaxation times: data from the Osteoarthritis Initiative (OAI). Skeletal Radiol 2012;41:1435e43.

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026

12

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15

27. Bae WC, Du J, Bydder GM, Chung CB. Conventional and ultrashort time-to-echo magnetic resonance imaging of articular cartilage, meniscus, and intervertebral disk. Top Magn Reson Imaging 2010;21:275e89. 28. Bae WC, Dwek JR, Znamirowski R, Statum SM, Hermida JC, D'Lima DD, et al. Ultrashort echo time MR imaging of osteochondral junction of the knee at 3 T: identification of anatomic structures contributing to signal intensity. Radiology 2010;254:837e45. 29. Goodwin DW. Visualization of the macroscopic structure of hyaline cartilage with MR imaging. Semin Musculoskelet Radiol 2001;5:305e12. 30. Goodwin DW, Wadghiri YZ, Zhu H, Vinton CJ, Smith ED, Dunn JF. Macroscopic structure of articular cartilage of the tibial plateau: influence of a characteristic matrix architecture on MRI appearance. AJR Am J Roentgenol 2004;182: 311e8. 31. Xia Y, Moody JB, Alhadlaq H, Burton-Wurster N, Lust G. Characteristics of topographical heterogeneity of articular cartilage over the joint structure of a humeral head. Osteoarthritis Cartilage 2002;10:370e80. 32. Xia Y. Magic-angle effect in magnetic resonance imaging of articular cartilage: a review. Invest Radiol 2000;35:602e21. 33. Wacker FK, Bolze X, Felsenberg D, Wolf KJ. Orientationdependent changes in MR signal intensity of articular cartilage: a manifestation of the “magic angle” effect. Skeletal Radiol 1998;27:306e10. 34. Erickson SJ, Prost RW, Timins ME. The “magic angle” effect: background physics and clinical relevance [editorial]. Radiology 1993;188:23e5. 35. Mosher TJ, Zhang Z, Reddy R, Boudhar S, Milestone BN, Morrison WB, et al. Knee articular cartilage damage in osteoarthritis: analysis of MR image biomarker reproducibility in ACRIN-PA 4001 multicenter trial. Radiology 2011;258: 832e42. 36. Baum T, Joseph GB, Arulanandan A, Nardo L, Virayavanich W, Carballido-Gamio J, et al. Association of magnetic resonance imaging-based knee cartilage T2 measurements and focal knee lesions with knee pain: data from the Osteoarthritis Initiative. Arthritis Care Res (Hoboken) 2012;64:248e55. 37. Mosher TJ, Liu Y, Yang QX, Yao J, Smith R, Dardzinski BJ, et al. Age dependency of cartilage magnetic resonance imaging T2 relaxation times in asymptomatic women. Arthritis Rheum 2004;50:2820e8. 38. Mosher TJ, Collins CM, Smith HE, Moser LE, Sivarajah RT, Dardzinski BJ, et al. Effect of gender on in vivo cartilage magnetic resonance imaging T2 mapping. J Magn Reson Imaging 2004;19:323e8. 39. Baum T, Joseph GB, Nardo L, Virayavanich W, Arulanandan A, Alizai H, et al. Correlation of magnetic resonance imagingbased knee cartilage T2 measurements and focal knee lesions with body mass index: thirty-six-month followup data from a longitudinal, observational multicenter study. Arthritis Care Res (Hoboken) 2013;65:23e33. 40. Serebrakian AT, Poulos T, Liebl H, Joseph GB, Lai A, Nevitt MC, et al. Weight loss over 48 months is associated with reduced progression of cartilage T2 relaxation time values: data from the osteoarthritis initiative. J Magn Reson Imaging 2015;41: 1272e80. 41. Hirose J, Nishioka H, Nakamura E, Oniki Y, Yamashita Y, Mizuta H. T1rho and T2 mapping of the proximal tibiofibular joint in relation to aging and cartilage degeneration. Eur J Radiol 2012;81:2776e82.

42. Friedrich KM, Shepard T, Chang G, Wang L, Babb JS, Schweitzer M, et al. Does joint alignment affect the T2 values of cartilage in patients with knee osteoarthritis? Eur Radiol 2010;20:1532e8. 43. Mosher TJ, Smith HE, Collins C, Liu Y, Hancy J, Dardzinski BJ, et al. Change in knee cartilage T2 at MR imaging after running: a feasibility study. Radiology 2005;234:245e9. 44. Mosher TJ, Liu Y, Torok CM. Functional cartilage MRI T2 mapping: evaluating the effect of age and training on knee cartilage response to running. Osteoarthritis Cartilage 2010;18:358e64. 45. Hovis KK, Stehling C, Souza RB, Haughom BD, Baum T, Nevitt M, et al. Physical activity is associated with magnetic resonance imaging-based knee cartilage T2 measurements in asymptomatic subjects with and those without osteoarthritis risk factors. Arthritis Rheum 2011;63:2248e56. 46. Stehling C, Liebl H, Krug R, Lane NE, Nevitt MC, Lynch J, et al. Patellar cartilage: T2 values and morphologic abnormalities at 3.0-T MR imaging in relation to physical activity in asymptomatic subjects from the osteoarthritis initiative. Radiology 2010;254:509e20. 47. Lin W, Alizai H, Joseph GB, Srikhum W, Nevitt MC, Lynch JA, et al. Physical activity in relation to knee cartilage T2 progression measured with 3 T MRI over a period of 4 years: data from the Osteoarthritis Initiative. Osteoarthritis Cartilage 2013;21:1558e66. 48. Kijowski R, Blankenbaker DG, Munoz Del Rio A, Baer GS, Graf BK. Evaluation of the articular cartilage of the knee joint: value of adding a T2 mapping sequence to a routine MR imaging protocol. Radiology 2013;267:503e13. 49. Potter HG, Jain SK, Ma Y, Black BR, Fung S, Lyman S. Cartilage injury after acute, isolated anterior cruciate ligament tear: immediate and longitudinal effect with clinical/MRI followup. Am J Sports Med 2012;40:276e85. 50. Hesper T, Hosalkar HS, Bittersohl D, Welsch GH, Krauspe R, Zilkens C, et al. T2* mapping for articular cartilage assessment: principles, current applications and future prospects. Skeletal Radiol 2014;43:1429e45. 51. Andreisek G, Weiger M. T2* mapping of articular cartilage: current status of research and first clinical applications. Invest Radiol 2014;49:57e62. 52. Newbould RD, Miller SR, Toms LD, Swann P, Tielbeek JA, Gold GE, et al. T2* measurement of the knee articular cartilage in osteoarthritis at 3T. J Magn Reson Imaging 2012;35:1422e9. 53. Welsch GH, Apprich S, Zbyn S, Mamisch TC, Mlynarik V, Scheffler K, et al. Biochemical (T2, T2* and magnetisation transfer ratio) MRI of knee cartilage: feasibility at ultra-high field (7T) compared with high field (3T) strength. Eur Radiol 2011;21:1136e43. 54. Crema MD, Roemer FW, Marra MD, Burstein D, Gold GE, Eckstein F, et al. Articular cartilage in the knee: current MR imaging techniques and applications in clinical practice and research. Radiographics 2011;31:37e61. 55. Qian Y, Williams AA, Chu CR, Boada FE. Multicomponent T2* mapping of knee cartilage: technical feasibility ex vivo. Magn Reson Med 2010;64:1426e31. 56. Bittersohl B, Miese FR, Hosalkar HS, Mamisch TC, Antoch G, Krauspe R, et al. T2* mapping of acetabular and femoral hip joint cartilage at 3 T: a prospective controlled study. Invest Radiol 2012;47:392e7. 57. Bittersohl B, Miese FR, Hosalkar HS, Herten M, Antoch G, Krauspe R, et al. T2* mapping of hip joint cartilage in various histological grades of degeneration. Osteoarthritis Cartilage 2012;20:653e60.

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15

58. Marik W, Apprich S, Welsch GH, Mamisch TC, Trattnig S. Biochemical evaluation of articular cartilage in patients with osteochondrosis dissecans by means of quantitative T2- and T2-mapping at 3T MRI: a feasibility study. Eur J Radiol 2012;81:923e7. 59. Williams A, Qian Y, Chu CR. UTE-T2* mapping of human articular cartilage in vivo: a repeatability assessment. Osteoarthritis Cartilage 2011;19:84e8. 60. Gatehouse PD, Bydder GM. Magnetic resonance imaging of short T2 components in tissue. Clin Radiol 2003;58: 1e19. 61. Lattanzio PJ, Marshall KW, Damyanovich AZ, Peemoeller H. Macromolecule and water magnetization exchange modeling in articular cartilage. Magn Reson Med 2000;44:840e51. 62. Maier CF, Tan SG, Hariharan H, Potter HG. T2 quantitation of articular cartilage at 1.5 T. J Magn Reson Imaging 2003;17: 358e64. 63. Mamisch TC, Hughes T, Mosher TJ, Mueller C, Trattnig S, Boesch C, et al. T2 star relaxation times for assessment of articular cartilage at 3 T: a feasibility study. Skeletal Radiol 2012;41:287e92. 64. Williams A, Qian Y, Bear D, Chu CR. Assessing degeneration of human articular cartilage with ultra-short echo time (UTE) T2* mapping. Osteoarthritis Cartilage 2010;18:539e46. 65. Du J, Takahashi AM, Chung CB. Ultrashort TE spectroscopic imaging (UTESI): application to the imaging of short T2 relaxation tissues in the musculoskeletal system. J Magn Reson Imaging 2009;29:412e21. 66. Gold GE, Thedens DR, Pauly JM, Fechner KP, Bergman G, Beaulieu CF, et al. MR imaging of articular cartilage of the knee: new methods using ultrashort TEs. AJR Am J Roentgenol 1998;170:1223e6. 67. Pauli C, Bae WC, Lee M, Lotz M, Bydder GM, D'Lima DL, et al. Ultrashort-echo time MR imaging of the patella with bicomponent analysis: correlation with histopathologic and polarized light microscopic findings. Radiology 2012;264: 484e93. 68. Bittersohl B, Hosalkar HS, Hughes T, Kim YJ, Werlen S, Siebenrock KA, et al. Feasibility of T2* mapping for the evaluation of hip joint cartilage at 1.5T using a three-dimensional (3D), gradient-echo (GRE) sequence: a prospective study. Magn Reson Med 2009;62:896e901. 69. Miese FR, Zilkens C, Holstein A, Bittersohl B, Kropil P, Mamisch TC, et al. Assessment of early cartilage degeneration after slipped capital femoral epiphysis using T2 and T2* mapping. Acta Radiol 2011;52:106e10. 70. Krause FG, Klammer G, Benneker LM, Werlen S, Mamisch TC, Weber M. Biochemical T2* MR quantification of ankle arthrosis in pes cavovarus. J Orthop Res 2010;28:1562e8. 71. Wang L, Regatte RR. J Magn Reson Imaging 2014 Jun 17, http://dx.doi.org/10.1002/jmri.24677 [Epub ahead of print]. 72. Duvvuri U, Charagundla SR, Kudchodkar SB, Kaufman JH, Kneeland JB, Rizi R, et al. Human knee: in vivo T1(rho)weighted MR imaging at 1.5 Tepreliminary experience. Radiology 2001;220:822e6. 73. Keenan KE, Besier TF, Pauly JM, Han E, Rosenberg J, Smith RL, et al. Prediction of glycosaminoglycan content in human cartilage by age, T1rho and T2 MRI. Osteoarthritis Cartilage 2011;19:171e9. 74. Akella SV, Regatte RR, Gougoutas AJ, Borthakur A, Shapiro EM, Kneeland JB, et al. Proteoglycan-induced changes in T1rho-relaxation of articular cartilage at 4T. Magn Reson Med 2001;46:419e23. 75. Regatte RR, Akella SV, Lonner JH, Kneeland JB, Reddy R. T1rho relaxation mapping in human osteoarthritis (OA) cartilage:

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90. 91.

92.

13

comparison of T1rho with T2. J Magn Reson Imaging 2006;23:547e53. Koskinen SK, Yla-Outinen H, Aho HJ, Komu ME. Magnetization transfer and spin lock MR imaging of patellar cartilage degeneration at 0.1 T. Acta Radiol 1997;38:1071e5. Duvvuri U, Kudchodkar S, Reddy R, Leigh JS. T(1rho) relaxation can assess longitudinal proteoglycan loss from articular cartilage in vitro. Osteoarthritis Cartilage 2002;10:838e44. Menezes NM, Gray ML, Hartke JR, Burstein D. T2 and T1rho MRI in articular cartilage systems. Magn Reson Med 2004;51: 503e9. Mlynarik V, Trattnig S, Huber M, Zembsch A, Imhof H. The role of relaxation times in monitoring proteoglycan depletion in articular cartilage. J Magn Reson Imaging 1999;10: 497e502. Stahl R, Luke A, Li X, Carballido-Gamio J, Ma CB, Majumdar S, et al. T1rho, T2 and focal knee cartilage abnormalities in physically active and sedentary healthy subjects versus early OA patientsea 3.0-Tesla MRI study. Eur Radiol 2009;19: 132e43. Wang L, Regatte RR. Quantitative mapping of human cartilage at 3.0T: parallel changes in T(2), T(1)rho, and dGEMRIC. Acad Radiol 2014;21:463e71. Thuillier DU, Souza RB, Wu S, Luke A, Li X, Feeley BT. T1rho imaging demonstrates early changes in the lateral patella in patients with patellofemoral pain and maltracking. Am J Sports Med 2013;41:1813e8. Li X, Pai A, Blumenkrantz G, Carballido-Gamio J, Link T, Ma B, et al. Spatial distribution and relationship of T1rho and T2 relaxation times in knee cartilage with osteoarthritis. Magn Reson Med 2009;61:1310e8. Wang L, Vieira RL, Rybak LD, Babb JS, Chang G, Krasnokutsky S, et al. Relationship between knee alignment and T1rho values of articular cartilage and menisci in patients with knee osteoarthritis. Eur J Radiol 2013;82:1946e52. Souza RB, Feeley BT, Zarins ZA, Link TM, Li X, Majumdar S. T1rho MRI relaxation in knee OA subjects with varying sizes of cartilage lesions. Knee 2013;20:113e9. Zarins ZA, Bolbos RI, Pialat JB, Link TM, Li X, Souza RB, et al. Cartilage and meniscus assessment using T1rho and T2 measurements in healthy subjects and patients with osteoarthritis. Osteoarthritis Cartilage 2010;18:1408e16. Bolbos RI, Link TM, Ma CB, Majumdar S, Li X. T1rho relaxation time of the meniscus and its relationship with T1rho of adjacent cartilage in knees with acute ACL injuries at 3 T. Osteoarthritis Cartilage 2009;17:12e8. Nishioka H, Hirose J, Nakamura E, Okamoto N, Karasugi T, Taniwaki T, et al. Detecting ICRS grade 1 cartilage lesions in anterior cruciate ligament injury using T1r and T2 mapping. Eur J Radiol 2013;82:1499e505. Li X, Kuo D, Theologis A, Carballido-Gamio J, Stehling C, Link TM, et al. Cartilage in anterior cruciate LigamenteReconstructed Knees: MR imaging T1r and T2dInitial experience with 1-year follow-up. Radiology 2011;258: 505e14. Bashir A, Gray ML, Burstein D. Gd-DTPA2- as a measure of cartilage degradation. Magn Reson Med 1996;36:665e73. Burstein D, Velyvis J, Scott KT, Stock KW, Kim YJ, Jaramillo D, et al. Protocol issues for delayed Gd(DTPA)(2-)-enhanced MRI (dGEMRIC) for clinical evaluation of articular cartilage. Magn Reson Med 2001;45:36e41. Bashir A, Gray ML, Burstein D. Gd-DTPA2e as a measure of cartilage degradation [published erratum appears in Magn Reson Med 1996;36:964]. Magn Reson Med 1996;36: 665e73.

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026

14

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15

93. Bashir A, Gray ML, Boutin RD, Burstein D. Glycosaminoglycan in articular cartilage: in vivo assessment with delayed Gd(DTPA)(2e)denhanced MR imaging. Radiology 1997;205: 551e8. 94. Allen RG, Burstein D, Gray ML. Monitoring glycosaminoglycan replenishment in cartilage explants with gadoliniumenhanced magnetic resonance imaging. J Orthop Res 1999;17:430e6. 95. Bashir A, Gray ML, Hartke J, Burstein D. Nondestructive imaging of human cartilage glycosaminoglycan concentration by MRI. Magn Reson Med 1999;41:857e65. 96. Trattnig S, Mlynarik V, Breitenseher M, Huber M, Zembsch A, Rand T, et al. MRI visualization of proteoglycan depletion in articular cartilage via intravenous administration of GdDTPA. Magn Reson Imaging 1999;17:577e83. 97. Li W, Scheidegger R, Wu Y, Edelman RR, Farley M, Krishnan N, et al. Delayed contrast-enhanced MRI of cartilage: comparison of nonionic and ionic contrast agents. Magn Reson Med 2010;64:1267e73. 98. Owman H, Ericsson YB, Englund M, Tiderius CJ, Tjornstrand J, Roos EM, et al. Association between delayed gadoliniumenhanced MRI of cartilage (dGEMRIC) and joint space narrowing and osteophytes: a cohort study in patients with partial meniscectomy with 11 years of follow-up. Osteoarthritis Cartilage 2014;22:1537e41. 99. Owman H, Tiderius CJ, Ericsson YB, Dahlberg LE. Long-term effect of removal of knee joint loading on cartilage quality evaluated by delayed gadolinium-enhanced magnetic resonance imaging of cartilage. Osteoarthritis Cartilage 2014;22: 928e32. 100. Owman H, Tiderius CJ, Neuman P, Nyquist F, Dahlberg LE. Association between findings on delayed gadoliniumenhanced magnetic resonance imaging of cartilage and future knee osteoarthritis. Arthritis Rheum 2008;58: 1727e30. 101. Crema MD, Hunter DJ, Burstein D, Roemer FW, Li L, Eckstein F, et al. Association of changes in delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) with changes in cartilage thickness in the medial tibiofemoral compartment of the knee: a 2 year follow-up study using 3.0 T MRI. Ann Rheum Dis 2014;73:1935e41. 102. Crema MD, Hunter DJ, Burstein D, Roemer FW, Li L, Krishnan N, et al. Delayed gadolinium-enhanced magnetic resonance imaging of medial tibiofemoral cartilage and its relationship with meniscal pathology: a longitudinal study using 3.0T magnetic resonance imaging. Arthritis Rheum 2014;66:1517e24. 103. Crema MDHD, Burstein D, Roemer FW, Krishnan N, Hellio Le Graverand MP, Guermazi A. The relationship between the Kellgren-Lawrence grade of radiographic knee osteoarthritis and delayed gadolinium-enhanced MRI of medial tibiofemoral cartilage (dGEMRIC): a 1-year follow-up study. Osteoarthritis Cartilage 2013;21. 104. Lattanzi R, Petchprapa C, Ascani D, Babb JS, Chu D, Davidovitch RI, et al. Detection of cartilage damage in femoroacetabular impingement with standardized dGEMRIC at 3 T. Osteoarthritis Cartilage 2014;22:447e56. 105. Kim YJ, Jaramillo D, Millis MB, Gray ML, Burstein D. Assessment of early osteoarthritis in hip dysplasia with delayed gadolinium-enhanced magnetic resonance imaging of cartilage. J Bone Joint Surg Am 2003;85-A:1987e92. 106. Anandacoomarasamy A, Leibman S, Smith G, Caterson I, Giuffre B, Fransen M, et al. Weight loss in obese people has

107.

108. 109.

110.

111.

112.

113.

114. 115.

116.

117.

118.

119.

120.

121.

122.

123.

structure-modifying effects on medial but not on lateral knee articular cartilage. Ann Rheum Dis 2012;71:26e32. van Tiel J, Reijman M, Bos PK, Hermans J, van Buul GM, Bron EE, et al. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) shows no change in cartilage structural composition after viscosupplementation in patients with early-stage knee osteoarthritis. PLoS One 2013;8:e79785. Madelin G, Regatte RR. Biomedical applications of sodium MRI in vivo. J Magn Reson Imaging 2013;38:511e29. Wheaton AJ, Borthakur A, Shapiro EM, Regatte RR, Akella SV, Kneeland JB, et al. Proteoglycan loss in human knee cartilage: quantitation with sodium MR imaging e feasibility study. Radiology 2004;231:900e5. Madelin G, Jerscow A, Regatte RR. Sodium relaxation times in the knee joint in vivo at 7T. NMR Biomed 2012;25: 530e7. Madelin G, Babb J, Xia D, Chang G, Krasnokutsky S, Abramson SB, et al. Articular cartilage: evaluation with fluidsuppressed 7.0-T sodium MR imaging in subjects with and subjects without osteoarthritis. Radiology 2013;268:481e91. Madelin G, Babb JS, Xia D, Chang G, Jerschow A, Regatte RR. Reproducibility and repeatability of quantitative sodium magnetic resonance imaging in vivo in articular cartilage at 3 T and 7 T. Magn Reson Med 2012;68:841e9. Lesperance LM, Gray ML, Burstein D. Determination of fixed charge density in cartilage using nuclear magnetic resonance. J Orthop Res 1992;10:1e13. Freeman R. Magnetic Resonance in Chemistry and Medicine. Oxford, UK: Oxford University Press; 2003. Mattiello J, Basser PJ, Lebihan D. Analytical expressions for the b-matrix in NMR diffusion imaging and spectroscopy. J Magn Reson Ser A 1994;108:131e41. Burstein D, Gray ML, Hartman AL, Gipe R, Foy BD. Diffusion of small solutes in cartilage as measured by nuclear magnetic resonance (NMR) spectroscopy and imaging. J Orthop Res 1993;11:465e78 [PubMed]. rik V, Sulzbacher I, Bittsanský M, Fuiko R, Trattnig S. Mlyna Investigation of apparent diffusion constant as an indicator of early degenerative disease in articular cartilage. J Magn Reson Imaging 2003;17:440e4. Deoni SC, Peters TM, Rutt BK. Quantitative diffusion imaging with steady-state free precession. Magn Reson Med 2004;51: 428e33. Bieri O, Ganter C, Scheffler K. Quantitative in vivo diffusion imaging of cartilage using double echo steady-state free precession. Magn Reson Med 2012;68:720e9. Miller KL, Hargreaves BA, Gold GE, Pauly JM. Steady-state diffusion-weighted imaging of in vivo knee cartilage. Magn Reson Med 2004;51:394e8. Trattnig S, Domayer S, Welsch G, Mosher T, Eckstein F. MR imaging of cartilage and its repair in the kneeda review. Eur Radiol 2009;19:1582e94. Mamisch TC, Menzel MI, Welsch GH, Bittersohl B, Salomonowitz E, Szomolanyi P, et al. Steady-state diffusion imaging for MR in-vivo evaluation of reparative cartilage after matrix-associated autologous chondrocyte transplantation at 3 tesladpreliminary results. Eur J Radiol 2008;65:72e9. Friedrich KM, Mamisch TC, Plank C, Langs G, Marlovits S, Salomonowitz E, et al. Diffusion-weighted imaging for the follow-up of patients after matrix-associated autologous chondrocyte transplantation. Eur J Radiol 2010;73: 622e8.

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15

124. Raya JG, Melkus G, Adam-Neumair S, Dietrich O, Mützel E, Reiser MF, et al. Diffusion-tensor imaging of human articular cartilage specimens with early signs of cartilage damage. Radiology 2013;266:831e41. 125. Raya JG, Dettmann E, Notohamiprodjo M, Krasnokutsky S, Abramson S, Glaser C. Feasibility of in vivo diffusion tensor imaging of articular cartilage with coverage of all cartilage regions. Eur Radiol 2014;24:1700e6. 126. Raya JG, Horng A, Dietrich O, Krasnokutsky S, Beltran LS, Storey P, et al. Articular cartilage: in vivo diffusion-tensor imaging. Radiology 2012;262:550e9. 127. Regatte RR, Akella SV, Reddy R. Depth-dependent proton magnetization transfer in articular cartilage. J Magn Reson Imaging 2005;22:318e23. 128. Yao WW, Qu N, Lu ZH, Yang SX. The application of T1 and T2 relaxation time and magnetization transfer ratios to the early diagnosis of patellar cartilage osteoarthritis. Skeletal Radiol 2009;38:1055e62.

15

129. Ling W, Regatte RR, Navon G, Jerschow A. Assessment of glycosaminoglycan concentration in vivo by chemical exchange-dependent saturation transfer (gagCEST). Proc Natl Acad Sci USA 2008;105:2266e70. 130. Rehnitz C, Kupfer J, Streich NA, Burkholder I, Schmitt B, Lauer L, et al. Comparison of biochemical cartilage imaging techniques at 3 T MRI. Osteoarthritis Cartilage 2014;22: 1732e42. 131. Lee JS, Parasoglou P, Xia D, Jerschow A, Regatte RR. Uniform magnetization transfer in chemical exchange saturation transfer magnetic resonance imaging. Sci Rep 2013;3:1707. 132. Liebl H, Joseph G, Nevitt MC, Singh N, Heilmeier U, Subburaj K, et al. Early T2 changes predict onset of radiographic knee osteoarthritis: data from the osteoarthritis initiative. Ann Rheum Dis 2014 Mar 10, http://dx.doi.org/10.1136/annrheumdis-2013-204157. pii: annrheumdis-2013e204157 [Epub ahead of print].

Please cite this article in press as: Guermazi A, et al., Compositional MRI techniques for evaluation of cartilage degeneration in osteoarthritis, Osteoarthritis and Cartilage (2015), http://dx.doi.org/10.1016/j.joca.2015.05.026