Compositional MRI Techniques for Evaluation of Cartilage Degeneration in Osteoarthritis

Review

Compositional MRI techniques for evaluation of cartilage degenerationin 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

¶ Department of Radiology, Hospital do Coraç~ao and Teleimagem, S~ao Paulo, Brazil

# 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

Article history:

Received 11 November 2014

Accepted 25 May 2015

Keywords:

Cartilage

Compositional imaging

MRI

Osteoarthritis

s u m m a r y

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 ultra-

structural 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.

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

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 particu-

larly 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

* 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: 1-617-638-

6616.

E-mail address: [email protected] (A. Guermazi).

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.

Osteoarthritis and Cartilage xxx (2015) 1e15

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

mailto:[email protected]




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 gadolinium-

enhanced 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 yiel-

ded 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 extra-

cellular 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 carti-

lage11. 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 concen-

tration is not appreciably affected in disease states12e14. A pro-

teoglycan 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 degen-

eration 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, spin-

echo, 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 echo-

time (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

appliedmagnetic 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 interac-

tion 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.

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e152


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 degener-

ation 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 measure-

ments 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, sug-

gesting 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 Initia-

tive found higher knee cartilage T2 values in obese subjects

compared to those with normal weight39. Serebrakian and col-

leagues 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, how-

ever, 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 compart-

ment42. The association of physical activity with cartilage degen-

eration 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 ac-

tivity 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 col-

leagues 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.

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 three-

dimensional (3D) cartilage evaluation. It is also easy to imple-

ment on clinical MRI systems, as pulse sequences and inline pro-

cessing 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 spin-

echo 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 signif-

icant 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 ~ 10e100ms. Therefore, T2mapping 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. Pre-

vious 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 degener-

ation64. 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-bearingmedial 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 pathol-

ogy70. More scientific evidence is needed to definitively determine

the meaning and clinical significance of T2* values and their cor-

relation 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

A. Guermazi et al. / Osteoarthritis and Cartilage xxx (2015) 1e15 3


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 frommultiple 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 theMHz range because of the dependence on

the static magnetic field (B0)11,71. T1rho values may reflect non-

specific changes in the cartilage ECM and proteoglycan con-

tent72,73. In vitro studies have demonstrated that depletion of pro-

teoglycan results in increased T1rho values, suggesting that T1rho

estimates proteoglycan content74. Specifically T1rho probes the

slow motion interactions between motion-restricted water mole-

cules 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 re-

quires 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 macro-

molecules 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 fac-

tors, 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

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 thosewithout 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, us-

ing 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 in-

juries87. The T1rho mapping technique has been shown to non-

invasively 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 there-

fore distributed in inverse proportion to the local proteoglycan

concentration. Gd-DTPA2� accumulates in areas of lowGAG content

and cartilage will consequently have a shorter T1 relaxation time in

these regions.

The ability to measure spatial variations in cartilage GAG con-

centration in vitrowith 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 be-

tween in vivo images of patients scheduled for total knee replace-

ment surgery and ex vivo images of the same joint after surgery95.

Similarly, when Gd(DTPA)2� was injected intravenously into pa-

tients 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 re-

sults79,96. 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 concen-

tration91. 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

dGEMRICwere 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

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.



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.)



cartilage thicknesses. Challenges in applying dGEMRIC in clinical

studies include the lack of standardization of patient physical ac-

tivity 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 de-

creases 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 pa-

tients 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 compart-

ment after 2 years, mainly in middle-aged women with no radio-

graphic 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 sur-

roundings, 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 vivowater proton concentration108. The combination of

all these factors results in a sodium MRI signal that is approxi-

mately 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 so-

dium 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 so-

diumMRI results. Tominimize the contamination of cartilage signal

Fig. 4. dGEMRIC assessment of the medial tibiofemoral compartment of an asymp-

tomatic 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).

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.



from synovial fluid or joint effusion, various techniques can be

employed such as inversion recovery preparation based fluid sup-

pression (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 or-

der 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 im-

aging to compare the cartilage of healthy subjects with subjects

with symptoms of early OA. They found a highermean 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 so-

dium 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 sodiumMRI 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 mo-

tion of water. Diffusion MRI techniques are sensitive to the

restriction of motion of water molecules bound within a macro-

molecular 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 al-

lows 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 diffusion-

weighted turbo spin echo (DW-TSE) and the diffusion-weighted

echo planar imaging (DW-EPI) sequences. The most useful

sequence for DWI of themusculoskeletal system is the reversed fast

imaging with steady precession with diffusion weighting (DW-

FISP), 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

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 weight-

bearing 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 su-

perficial zones of the central medial femoral cartilage (small white arrows) representing low GAG concentration.



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.)



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 diffi-

cult to implement in vivo.

Diffusion imagingmaysupplementotherquantitative 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

Fig. 8. 37-year-old manwith 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.)



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 carti-

lage 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 asso-

ciated 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 ex-

change can occur by either dipolar coupling or chemical exchange.

MTC can therefore estimate cartilage macromolecular concentra-

tion (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 mea-

surements 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 exchange-

able 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 toMTC. 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 gagC-

EST 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 degen-

eration at an earlier stage than is possible today using morphologic

sequences only. To date, however, the relevance of these techniques

to clinical or structural outcomes is unclear and there is a lack of

studies focusing on responsiveness. Although the different tech-

niques 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 un-

derstanding 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 stratifi-

cation 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.

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 non-

weight-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.



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 in-

tellectual 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)

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.

Acknowledgment

We thank S Pavol, MD, and D Hayashi, MD PhD, for their tech-

nical assistance with preparation of the revised manuscript and

figures.

References

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 osteoar-

thritis and the potential to develop personalised disease-

modifying 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 up-

date 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 osteoar-

thritis: 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 effi-

cacious 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:

Woo SLY, Buckwalter JA, Eds. Injury and Repair of the

Musculoskeletal Soft Tissues. Park Ridge, Ill: American Acad-

emy of Orthopaedic Surgeons; 1988:405e25.

11. Burstein D, Gray M, Mosher T, Dardzinski B. Composition and

structure in osteoarthritis. Radiol Clin North Am 2009;47:

675e86.

12. 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.

13. Buckwalter JA, Martin J. Degenerative joint disease. Clin

Symp 1995;47:1e32.

14. Maroudas AI. Balance between swelling pressure and

collagen tension in normal and degenerate cartilage. Nature

1976;260:808e9.

15. Buckwalter JA, Mankin HJ. Articular cartilage: degeneration

and osteoarthritis, repair, regeneration, and transplantation.

Instr Course Lect 1998;47:487e504.

16. 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.

17. Nissi MJ, Rieppo J, Toyras J, Laasanen MS, Kiviranta I,

Jurvelin JS, et al. T(2) relaxation time mapping reveals age-

and species-related diversity of collagen network architec-

ture in articular cartilage. Osteoarthritis Cartilage 2006;14:

1265e71.

18. 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.

19. 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 degenera-

tion of cartilage, meniscus, and bone marrow over 3

yearsedata from the Osteoarthritis Initiative. Osteoarthritis

Cartilage 2012;20:727e35.

20. Prasad AP, Nardo L, Schooler J, Joseph GB, Link TM. T(1)rho

and T(2) relaxation times predict progression of knee oste-

oarthritis. Osteoarthritis Cartilage 2013;21:69e76.

21. 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.

22. 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.

23. Baum T, Joseph GB, Karampinos DC, Jungmann PM, Link TM,

Bauer JS. Cartilage and meniscal T2 relaxation time as non-

invasive biomarker for knee osteoarthritis and cartilage

repair procedures. Osteoarthritis Cartilage 2013;21:1474e84.

24. 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 osteo-

arthritis initiative. Magn Reson Med 2010;63:465e72.

25. 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.

26. 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.





http://refhub.elsevier.com/S1063-4584(15)01183-8/sref1


































































































































27. Bae WC, Du J, Bydder GM, Chung CB. Conventional and ul-

trashort time-to-echo magnetic resonance imaging of artic-

ular 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 osteo-

chondral junction of the knee at 3 T: identification of

anatomic structures contributing to signal intensity. Radi-

ology 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 architec-

ture 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. Osteo-

arthritis 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. Orientation-

dependent changes in MR signal intensity of articular carti-

lage: 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]. Radi-

ology 1993;188:23e5.

35. Mosher TJ, Zhang Z, Reddy R, Boudhar S, Milestone BN,

Morrison WB, et al. Knee articular cartilage damage in oste-

oarthritis: 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 mea-

surements 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 Im-

aging 2004;19:323e8.

39. Baum T, Joseph GB, Nardo L, Virayavanich W, Arulanandan A,

Alizai H, et al. Correlation of magnetic resonance imaging-

based knee cartilage T2 measurements and focal knee le-

sions 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 pro-

gression 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 follow-

up. 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 assess-

ment: 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. JMagnReson 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.


































































































































































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. Oste-

oarthritis 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 Roent-

genol 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 eval-

uation 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:

comparison of T1rho with T2. J Magn Reson Imaging

2006;23:547e53.

76. Koskinen SK, Yla-Outinen H, Aho HJ, Komu ME. Magnetiza-

tion transfer and spin lock MR imaging of patellar cartilage

degeneration at 0.1 T. Acta Radiol 1997;38:1071e5.

77. Duvvuri U, Kudchodkar S, Reddy R, Leigh JS. T(1rho) relaxa-

tion can assess longitudinal proteoglycan loss from articular

cartilage in vitro. Osteoarthritis Cartilage 2002;10:838e44.

78. Menezes NM, Gray ML, Hartke JR, Burstein D. T2 and T1rho

MRI in articular cartilage systems. Magn Reson Med 2004;51:

503e9.

79. 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.

80. 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.

81. Wang L, Regatte RR. Quantitative mapping of human carti-

lage at 3.0T: parallel changes in T(2), T(1)rho, and dGEMRIC.

Acad Radiol 2014;21:463e71.

82. 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.

83. 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.

84. 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.

85. 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.

86. 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 osteo-

arthritis. Osteoarthritis Cartilage 2010;18:1408e16.

87. 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.

88. 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.

89. Li X, Kuo D, Theologis A, Carballido-Gamio J, Stehling C,

Link TM, et al. Cartilage in anterior cruciate Liga-

menteReconstructed Knees: MR imaging T1r and T2dInitial

experience with 1-year follow-up. Radiology 2011;258:

505e14.

90. Bashir A, Gray ML, Burstein D. Gd-DTPA2- as a measure of

cartilage degradation. Magn Reson Med 1996;36:665e73.

91. 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.

92. 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.

































































http://dx.doi.org/10.1002/jmri.24677










































































































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 glycosamino-

glycan replenishment in cartilage explants with gadolinium-

enhanced magnetic resonance imaging. J Orthop Res

1999;17:430e6.

95. Bashir A, Gray ML, Hartke J, Burstein D. Nondestructive im-

aging 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 Gd-

DTPA. 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 carti-

lage: 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 gadolinium-

enhanced MRI of cartilage (dGEMRIC) and joint space nar-

rowing and osteophytes: a cohort study in patients with

partial meniscectomy with 11 years of follow-up. Osteoar-

thritis 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 reso-

nance imaging of cartilage. Osteoarthritis Cartilage 2014;22:

928e32.

100. Owman H, Tiderius CJ, Neuman P, Nyquist F, Dahlberg LE.

Association between findings on delayed gadolinium-

enhanced 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 tibiofe-

moral cartilage (dGEMRIC): a 1-year follow-up study. Oste-

oarthritis Cartilage 2013;21.

104. Lattanzi R, Petchprapa C, Ascani D, Babb JS, Chu D,

Davidovitch RI, et al. Detection of cartilage damage in femo-

roacetabular impingement with standardized dGEMRIC at 3

T. Osteoarthritis Cartilage 2014;22:447e56.

105. Kim YJ, Jaramillo D, Millis MB, Gray ML, Burstein D. Assess-

ment of early osteoarthritis in hip dysplasia with delayed

gadolinium-enhanced magnetic resonance imaging of carti-

lage. 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

structure-modifying effects on medial but not on lateral knee

articular cartilage. Ann Rheum Dis 2012;71:26e32.

107. van Tiel J, ReijmanM, Bos PK, Hermans J, van Buul GM, Bron EE,

et al. Delayed gadolinium-enhanced MRI of cartilage (dGEM-

RIC) shows no change in cartilage structural composition after

viscosupplementation in patients with early-stage knee oste-

oarthritis. PLoS One 2013;8:e79785.

108. Madelin G, Regatte RR. Biomedical applications of sodium

MRI in vivo. J Magn Reson Imaging 2013;38:511e29.

109. 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.

110. Madelin G, Jerscow A, Regatte RR. Sodium relaxation times

in the knee joint in vivo at 7T. NMR Biomed 2012;25:

530e7.

111. Madelin G, Babb J, Xia D, Chang G, Krasnokutsky S,

Abramson SB, et al. Articular cartilage: evaluation with fluid-

suppressed 7.0-T sodium MR imaging in subjects with and

subjects without osteoarthritis. Radiology 2013;268:481e91.

112. 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.

113. Lesperance LM, Gray ML, Burstein D. Determination of fixed

charge density in cartilage using nuclear magnetic resonance.

J Orthop Res 1992;10:1e13.

114. Freeman R. Magnetic Resonance in Chemistry and Medicine.

Oxford, UK: Oxford University Press; 2003.

115. 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.

116. 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].

117. Mlyn�arik V, Sulzbacher I, Bitt�sanský M, Fuiko R, Trattnig S.

Investigation of apparent diffusion constant as an indicator of

early degenerative disease in articular cartilage. J Magn Reson

Imaging 2003;17:440e4.

118. Deoni SC, Peters TM, Rutt BK. Quantitative diffusion imaging

with steady-state free precession. Magn Reson Med 2004;51:

428e33.

119. 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.

120. Miller KL, Hargreaves BA, Gold GE, Pauly JM. Steady-state

diffusion-weighted imaging of in vivo knee cartilage. Magn

Reson Med 2004;51:394e8.

121. 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.

122. 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 trans-

plantation at 3 tesladpreliminary results. Eur J Radiol

2008;65:72e9.

123. 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 autolo-

gous chondrocyte transplantation. Eur J Radiol 2010;73:

622e8.




































































































































































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 T2relaxation time and magnetization transfer ratios to the early

diagnosis of patellar cartilage osteoarthritis. Skeletal Radiol

2009;38:1055e62.

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/annr-

heumdis-2013-204157. pii: annrheumdis-2013e204157

[Epub ahead of print].








































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