If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Address correspondence and reprint requests to: Dr Xiaojuan Li, Ph.D., Department of Radiology, University of California at San Francisco, 185 Berry Street, Suite 350, San Francisco, CA 94107, USA. Tel: 1-415-353-4909; Fax: 1-415-353-3438.
Musculo-skeletal Quantitative Imaging Research (MQIR), Department of Radiology, University of California at San Francisco (UCSF), San Francisco, CA, USADepartment of Orthopaedic Surgery, UCSF, San Francisco, CA, USA
Evaluation and treatment of patients with early stages of osteoarthritis (OA) is dependent upon an accurate assessment of the cartilage lesions. However, standard cartilage dedicated magnetic resonance (MR) techniques are inconclusive in quantifying early degenerative changes. The objective of this study was to determine the ability of MR T1rho (T1ρ) and T2 mapping to detect cartilage matrix degeneration between normal and early OA patients.
Sixteen healthy volunteers (mean age 41.3) without clinical or radiological evidence of OA and 10 patients (mean age 55.9) with OA were scanned using a 3 Tesla (3 T) MR scanner. Cartilage volume and thickness, and T1ρ and T2 values were compared between normal and OA patients. The relationship between T1ρ and T2 values, and Kellgren–Lawrence scores based on plain radiographs and the cartilage lesion grading based on MR images were studied.
The average T1ρ and T2 values were significantly increased in OA patients compared with controls (52.04±2.97 ms vs 45.53±3.28 ms with P=0.0002 for T1ρ, and 39.63±2.69 ms vs 34.74±2.48 ms with P=0.001 for T2). Increased T1ρ and T2 values were correlated with increased severity in radiographic and MR grading of OA. T1ρ has a larger range and higher effect size than T2, 3.7 vs 3.0.
Our results suggest that both in vivo T1ρ and T2 relaxation times increase with the degree of cartilage degeneration. T1ρ relaxation time may be a more sensitive indicator for early cartilage degeneration than T2. The ability to detect early cartilage degeneration prior to morphologic changes may allow us to critically monitor the course of OA and injury progression, and to evaluate the success of treatment to patients with early stages of OA.
. Plain radiographs have been used primarily in the evaluation of OA, which depict only narrowing of the joint space or gross osseous changes that tend to occur late in the disease. Early changes in the articular cartilage may not be visible on plain radiographs. Cartilage loss can only be indirectly inferred by the development of joint space narrowing, which can be highly unreliable even with careful attention to proper technique
. In addition, plain radiographs are insensitive to focal cartilage loss, and widening of the joint space despite significant cartilage loss can occur in one compartment of the knee simply as a result of narrowing in the other compartment
Magnetic resonance imaging (MRI) has been found useful to visualize cartilage directly yet morphologic imaging shows damage at a stage when cartilage is already irreversibly lost. Standard cartilage dedicated magnetic resonance (MR) techniques include fat-saturated T2-weighted, proton density-weighted fast spin echo (FSE) sequences and T1-weighted spoiled gradient echo (SPGR) sequences. These sequences, however, are inconclusive in quantifying early degenerative changes of the cartilage matrix, especially biochemical changes such as proteoglycan (PG) loss
. Early diagnosis of cartilage injury would require the ability to noninvasively detect changes in PG concentration and collagen integrity before gross morphologic changes occur.
T2 relaxation reflects the ability of free water proton molecules to move and to exchange energy inside the cartilaginous matrix. Damage to collagen—PG matrix and increase of water content in degenerating cartilage may increase T2 relaxation times. In vivo T2 relaxation times have been derived by several groups
. It probes the slow motion interactions between motion-restricted water molecules and their local macromolecular environment. The extracellular matrix in the articular cartilage provides a motion-restricted environment to water molecules. Changes to the extracellular matrix, such as PG loss, therefore may be reflected in measurements of T1ρ. Initial studies in human subjects showed elevated T1ρ values in patients with OA
. Although both T1ρ and T2 can probe slow motion of water protons, they are parameters describing different MR relaxation mechanisms. T1ρ is spin–lattice relaxation related with the energy changes between proton spins and the environment, while T2 is spin–spin relaxation related with the energy changes between proton spins themselves. Therefore, these two parameters may provide complementary information regarding macromolecular changes in cartilage.
With the improvement in cartilage resurfacing procedures and development of disease modifying drugs for OA, there is a need to develop a noninvasive method to monitor early cartilage degeneration or restoration
. In this study, we investigated the changes in T1ρ and T2 relaxation times in normal and osteoarthritic patients using 3 T MRI. Our hypothesis was that there would be an increase in both T1ρ and T2 values in cartilage in osteoarthritic patients compared to normal controls. We further hypothesized that the amount of T1ρ and T2 elevation would be related to the severity of OA.
Materials and methods
Sixteen healthy volunteers (eight females and eight males, ranging in age from 22 to 74 years, with an average age of 41.3 years) and 10 patients with clinical OA symptoms and radiological findings (three females and seven males, ranging in age from 37 to 72 years, with an average age of 55.9 years) were studied. Among them 10 healthy volunteers (four females and six males, ranging in age from 28 to 74 years, with an average age of 41.0 years) were scanned for both T1ρ and T2 mapping, while in the remaining six volunteers only T1ρ mapping was obtained. In all the patients standard radiographs were obtained in addition to both T1ρ and T2 MR examinations. The study was approved by the Committee for Human Research at our institution and all the subjects gave informed consent.
In the patients, the standard knee radiographic protocol included (1) bilateral standing flexion weight-bearing view, (2) 30° flexion lateral, and (3) bilateral patellofemoral, sunrise views.
All MR exams were implemented on a 3 T GE Excite Signa MR scanner using a quadrature transmit/receive knee coil. The protocol included six sequences: sagittal T1-weighted spin echo (SE) imaging (time of repetition (TR)/time of echo (TE)=700/13.5 ms, field of view (FOV)=16 cm, matrix=288×224, bandwidth=15.63 kHz, number of excitations [NEX]=2), sagittal and axial three-dimensional (3D) water excitation high-resolution SPGR imaging (TR/TE=15/6.7 ms, flip angle=12°, FOV=16 cm, matrix=512×512, slice thickness=1 mm, bandwidth=31.25 kHz, NEX=0.75), sagittal fat-saturated T2-weighted FSE images (TR/TE=3700/68 ms, FOV=14 cm, matrix=288×224, slice thickness=3 mm, echo train length [ETL]=8, bandwidth=16.5 kHz, NEX=2), and axial T1ρ-weighted and T2-weighted images.
The multi-slice T1ρ-weighted images were obtained using the sequence we previously developed based on spin-lock techniques and spiral image acquisition
. The acquisition parameters were as follows: 14 interleaves/slice, 4096 points/interleaf, FOV=16 cm, effective in-plane spatial resolution=0.6×0.6 mm, slice thickness=3 mm, skip=1 mm, number of slices=14–16, TR/TE=2000/5.8 ms, time of spin-lock (TSL)=20/40/60/80 ms, and spin-lock frequency=500 Hz. The total acquisition time was approximately 13 min. The axial T1ρ-weighted images were prescribed on sagittal SPGR images, covering regions from the top of the patellar cartilage to the femoral–tibial cartilage. The T2 quantification sequence was also based on spiral sequence
with TR/TE=2000/6.7, 12, 28, 60 ms. All other prescription parameters of the T2 sequence were the same as the T1ρ sequence, with a total acquisition time of approximately 11 min. The T2 quantification was acquired subsequently and covered the same region as the T1ρ sequence.
Plain radiographic and clinical diagnostic MR images' assessment
All radiographs and clinical MR images (SPGR, T1- and T2-weighted fat-saturated sequences) were reviewed by a radiologist (TML). The radiographic findings were scored according to the Kellgren–Lawrence (KL) scale, which is a standard grading system for OA
. Osteophytes at the joint margins, narrowing of the joint spaces and subchondral sclerosis have been considered as radiological features of OA. Based on these features, the following KL scores were defined
: 0, no features of OA; 1, doubtful OA, with minute osteophytes of doubtful importance; 2, minimal OA, with definite osteophytes but unimpaired joint space; 3, moderate OA, with osteophytes and moderate diminution of joint space; and 4, severe OA, with greatly impaired joint space and sclerosis of subchondral bone.
The MR images were analyzed regarding cartilage lesions, joint effusion, popliteal cysts, ligaments and menisci. Additional features included reactive bone marrow changes, osteophytes, subchondral cysts and loose bodies. Five compartments were defined in each subject: patella (P), medial femoral condyle (MFC), lateral femoral condyle (LFC), medial tibia (MT) and lateral tibia (LT). Cartilage thinning was defined in each of the compartments based on T2-weighted FSE and T1-weighted SPGR images as follows: 0, no obvious thinning; 1, <50% thinning; 2, >50% thinning; and 3, full thickness loss of cartilage. Each patient was given an overall grade based on the most severe cartilage lesion in each of the five compartments. The bone marrow edema (BME) pattern was defined as high signal intensity in the T2-weighted fat-saturated FSE images and graded as follows: 0, no obvious BME; 1, mild edema with less than 1 cm diameter in the long axis; 2, moderate edema with diameter between 1 and 3 cm in the long axis; and 3, severe edema with diameter larger than 3 cm in the long axis. Osteophytes were classified as follows: 0, no obvious osteophytes; 1, mild when they were located in the joint margins and were less than 0.5 cm in diameter; and 2, severe when osteophytes were larger than 0.5 cm in diameter.
MR images post-processing
MR images were transferred to a Sun workstation (Sun Microsystems, Palo Alto, CA) for off-line quantification of cartilage volume and thickness, and for quantification of T1ρ and T2 relaxation times.
Cartilage was segmented semiautomatically in sagittal SPGR images using an in-house developed program with MATLAB based on edge detection and Bezier splines
Carballido-Gamio J, Bauer JS, Lee KY, Krause S, Majumdar S. Combined image processing techniques for characterization of MRI cartilage of the knee. 27th Annual Conference IEEE Engineering in Medicine and Biology Society (EMBS) 2005 Sep 1–4; Shanghai, China.
. Five compartments were defined as mentioned above in each subject: P, MFC, LFC, MT and LT. An iterative minimization process was used to calculate total cartilage volume and average thickness for each region. Following segmentation, a medial line was generated in each region of the cartilage. The cartilage thickness was determined by calculating the minimum distance from each point on the medial line to a cartilage boundary. The average thickness was calculated for each slice and then averaged for all the slices. The cartilage volume was determined by multiplying the total number of voxels encompassing the cartilage by the volume of each voxel. The root mean square coefficient of variation for intra-observer reproducibility of this algorithm was between 2.4% and 3.69% as reported previously
. Finally to minimize volumetric variations due to the size of the knee, the cartilage volume was normalized by the epicondylar distance determined from axial SPGR images.
The T1ρ map was reconstructed by fitting the image intensity pixel-by-pixel to the equation below using a Levenberg–Marquardt mono-exponential fitting algorithm developed in-house:
T1ρ-weighted images with the shortest TSL (therefore with highest signal to noise ratio) were rigidly registered to high-resolution T1-weighted SPGR images acquired in the same exam using the VTK CISG Registration Toolkit
. The transformation matrix was applied to the reconstructed T1ρ map. Different regions of the knee cartilage—patellar, trochlea, medial and lateral compartments—were segmented automatically based on axial high-resolution SPGR images using the same algorithm used for sagittal segmentation. The segmentation was corrected manually to avoid synovial fluid or other surrounding tissue. 3D cartilage contours were generated and overlaid on the registered T1ρ map. Similarly, The T2 map was reconstructed by fitting the image intensity pixel-by-pixel to the equation . T2-weighted images with the shortest TE were rigidly registered to the SPGR images, and the transformation matrix was applied to T2 maps using the VTK CISG Registration Toolkit. The cartilage contours generated previously from the SPGR images were also overlaid on the registered T2 map. To reduce artifacts caused by partial volume effects with synovial fluid, regions with relaxation time greater than 150 ms in T1ρ or T2 maps were manually removed from the data used for quantification.
A nonparametric rank test was used to compare volume, average thickness, average T1ρ and T2 values between control subjects and OA patients. A Spearman rank correlation was performed to study the relationship between average T1ρ and T2 values, between these relaxation times and ages, and between these relaxation times and cartilage thickness and volumes. The effect size was calculated to compare the discrimination power of T1ρ and T2 values using the equation below:
where Δmean is the mean difference between control and OA, and SD is the pooled standard deviation of these two groups defined as
where n1 and n2 are the sample sizes of these two groups, respectively, and SD1 and SD2 are the standard deviations of these two groups, respectively.
T1ρ and T2 quantification for control subjects and OA patients
The average T1ρ values were significantly higher in OA subjects compared with healthy controls (52.04±2.97 ms vs 45.53±3.28 ms, P=0.0002), as shown in Table I. The average T2 values were also increased significantly in patients with OA (39.63±2.69 ms vs 34.74±2.48 ms, P=0.001, Table I). Figure 1 shows T1ρ and T2 maps for a healthy control. Fig. 2, Fig. 3 present T1ρ and T2 maps of a patient with mild OA with KL score=1, and a patient with advanced OA with KL score=4, respectively. The average T1ρ and T2 values correlated significantly (R2=86.0%, P<0.0001). T1ρ values had a higher effect size than T2 values (3.7 vs 3.0), indicating T1ρ may be more sensitive than T2 for distinguishing OA from controls.
Table IRadiological findings based on radiographs and anatomic MR images
Cartilage thinning grading: 1, <50% thinning; 2, >50% thinning; and 3, full thinning (loss) of cartilage.
BME grading: 0, no obvious BME; 1, mild edema with less than 1 cm diameter in the long axis; 2, moderate edema with diameter between 1 and 3 cm in the long axis; 3, severe edema with diameter larger than 3 cm in the long axis.
The average T1ρ values increased with age in the 16 healthy controls, with a significant but moderate correlation (R2=58.3%, P=0.018), as shown in Fig. 4. In the 10 controls who also had T2 quantification, T2 values also increased with ages, but the correlation was not significant (R2=41.5%, P=0.233).
KL scores and MR findings based on anatomic MR images
Based on radiographs, two patients had a KL score=1, three had a KL score=2, three had a KL score=3 and two had a KL score=4. Cartilage lesions were classified as grade 0 for one patient, 1 for three patients, 2 for two patients and 3 for four patients. Table IIa, Table IIb illustrate the main findings based on radiographs and clinical MR images for the 10 patients, including KL score, cartilage lesion grade in each compartment, osteophytes in the femoro-tibial joint, femoro-patellar joint and the joint center, as well as BME. Among the 10 OA patients, six patients had more severe cartilage lesions at the medial compartments than at the lateral compartments, two had more severe lesions at the lateral compartments, and two had the same lesion grade at both compartments.
Table IIaCartilage thickness (in mm, mean±SD) in each compartment
There were no significant difference in the total volume and average thickness of cartilage in OA patients and control subjects (1.53±0.42 cm3/cm vs 1.27±0.29 cm3/cm for volume normalized by epicondyle length, and 1.78±0.31 mm vs 1.65±0.32 mm for thickness) (P=0.13 and P=0.37, respectively). Table III presents the mean and SD of cartilage volumes and thickness in each compartment for control subjects and OA patients. There were no significant differences in either cartilage volume or thickness for any compartment between these two groups.
Table IIIT1ρ and T2 values (in ms, mean±SD) in healthy controls and osteoarthritic subjects
Relationship between radiological findings and T1ρ and T2 quantification
The average T1ρ value increased as KL score increased based on radiographs, with 45.5±3.3 ms, 47.6±3.0 ms, 51.8±0.7 ms, 52.4±0.2 ms and 55.6±0.4 ms for KL=0 (healthy controls), 1, 2, 3, and 4, respectively [Table IV(a)]. The same trend was found between average T2 values and KL scores, with T2 values of 34.7±2.5 ms for grade 0, 35.9±1.4 ms for grade 1, 39.8±2.4 ms for grade 2, 39.6±0.3 ms for grade 3 and 43.0±1.0 ms for grade 4, as shown in Table IV(a).
Table IVaT1ρ and T2 values (in ms, mean±SD) in subjects vs KL scores evaluated on plain radiographs
The average T1ρ and T2 values increased as the overall cartilage lesion grades increased from 0 to 3 [from 46.1±3.6 ms to 54.4±1.5 ms for T1ρ, and from 35.0±2.5 ms to 41.4±2.0 ms for T2 as presented in Table IV(b)]. No significant correlation was found between T1ρ and T2 values and cartilage volumes and thickness (P>0.05).
Table IVbT1ρ and T2 values (in ms, mean±SD) in subjects vs cartilage thinning grades evaluated on MR images
Based on the cartilage lesion grading, we regrouped the 50 compartments for the 10 OA patients into two groups: mild OA with grades 0 and 1, and advanced OA with grades 2 and 3. The average T1ρ values were significantly increased in compartments with advanced OA compared with the ones with mild OA (54.3±6.1 ms vs 48.4±5.6 ms, P=0.0012). The increase in percentage was 12.2%. The T2 values were also elevated in the compartments with advanced OA (41.0±4.5 ms vs 38.0±4.8 ms, P=0.030), but with an increased percentage of only 7.9%.
In this study, we have demonstrated that both T1ρ and T2 cartilage values were significantly increased in patients with OA when compared with healthy controls. T1ρ and T2 values also increased with more severe radiographic OA and MR grades of cartilage degeneration.
Increased T2 values were reported previously in degenerated cartilage in both animal models and in human subjects
. The values obtained in our study are consistent with the reported values, with a range from 31.3 ms to 38.7 ms for healthy controls and from 35.0 ms to 43.8 ms for patients with OA. In an effort to correlate the T2 relaxation times with biochemical changes in cartilage, previous in vitro studies have reported that T2 correlated poorly with PG content
. Therefore lack of specificity to quantify PG loss may make T2 less appealing for early detection of cartilage degeneration. In addition, the angular dependency of T2 values with respect to the external magnetic field B0 have made it difficult to define a ‘normal’ appearance of T2 maps. As a result, it is difficult to apply T2 values to quantify cartilage degeneration longitudinally, and the clinical results obtained with T2 quantification remain inconclusive. This angular dependency, however, as shown in an in vitro study using high field (8.6 T) microscopic MRI (μMRI), can provide specific information about the collagen ultra-structure
T1ρ has been recently proposed as an attractive alternative to evaluate biochemical changes in cartilage matrix noninvasively. T1ρ relaxation rate (1/T1ρ) has been shown to decrease linearly with decreasing PG content in ex vivo bovine patellae
have suggested that proton exchange between chemically shifted NH and OH groups of PG and the tissue water could be an important relaxation mechanism contributing to T1ρ relaxation. Therefore T1ρ may be specific to changes of PG in cartilage matrix during early stages of OA. Furthermore, T1ρ relaxation times do not seem to be affected by the orientation of collagen that can affect T2 relaxation techniques
The results of our comparison study demonstrated that both T1ρ and T2 techniques can be sensitive to cartilage degeneration. However, there is a larger range and effect size for T1ρ vs T2 values, which may indicate a more sensitive method of detecting cartilage degeneration. Furthermore, although there is a significant correlation between the average T1ρ and T2 values, the spatial distribution of the elevation of these two parameters can be different in OA patients, as clearly seen in Fig. 3. We will investigate the spatial correlation between T1ρ and T2 values in future studies. We believe that since T1ρ and T2 represent two relaxation mechanisms in tissues, they may provide complementary information on cartilage degeneration. Combining this information may enhance our ability to detect early cartilage degeneration, as well as to distinguish between different stages of degeneration.
In this study, T1ρ and T2 increased with KL scores based on radiographs and overall cartilage lesion grade based on analysis of clinical MR sequences. However, due to the small sample size, we could not test the statistical significance of this correlation. In a previous study correlating in vivo T2 values and OA disease severity as defined by KL scores, Dunn et al.
showed that the T2 values were elevated significantly in mild OA (KL=1, 2, n=20) compared with healthy controls. Although there was an increasing trend of T2 values from mild OA to severe OA (KL=3, 4, n=28), this difference was not significant. The authors proposed that with the limitations of KL grading system, in particular the emphasis on the presence of osteophytes, significant changes in T2 values for cartilage with different KL scores are not necessarily expected. Interestingly in this study, significant differences were observed in both T1ρ and T2 values between mild OA compartments (with cartilage thinning grades 0 and 1) and advanced OA compartments (with cartilage thinning grades 2 and 3) after we regrouped all the 50 compartments according to cartilage lesion grade.
Furthermore, among the patients with cartilage thinning observed in MR images (grade≥1), six had ‘spared’ compartments with cartilage thinning grade 0 on the clinical MR images. The average T1ρ and T2 values for these ‘spared’ compartments were 50.8±5.4 ms and 39.4±3.8 ms, respectively. These values were significantly higher than those found in the cartilage of healthy controls (P=0.029 and P=0.004 for T1ρ and T2, respectively). These results suggest that cartilage degeneration, or the biochemical change, can take place in these compartments even if no morphologic changes are yet visualized.
In this study, we did not find a significant difference in cartilage volume or thickness between the healthy control and OA groups. We attribute the lack of volumetric differences to the fact that early osteoarthritic patients with less structural cartilage wear were examined and to the varying severity of OA in the disease group. The cartilage volume and thickness were slightly higher in the osteoarthritic subjects. This may be due to the increase of water content and consequently swelling of the cartilage in the early stages of OA. One example of segmented cartilage in medial compartments in a control (male, 30 years) vs an OA patient (male, 66 years) is shown in Fig. 5. Our findings also indicate that physical measures such as cartilage thickness and volume may lag behind biochemical and molecular changes which can be measured quantitatively with T1ρ and T2 values.
T1ρ and T2 imaging are one of the techniques that have shown the potential of MR imaging to reflect changes in the biochemical composition of cartilage with early OA. Other techniques, including sodium 23 (23Na) MRI
have also shown promising results in imaging cartilage biochemistry. All these techniques are complementary to standardized cartilage sensitive images and may provide information about cartilage changes (either PG or collagen) that may exist prior to structural changes in cartilage thickness or surface morphology. However, some of the techniques may have requirements that can limit their clinical use. The dGEMRIC technique, which has been validated in multiple studies to allow assessment of the PG component of articular cartilage, requires a several hour wait after either an intravenous or intraarticular injection of the contrast agent (Gadopentetic acid) for effective penetration. 23Na MR imaging, which uses sodium concentrations as a marker for PG loss, is of limited clinical use because of the inherent low sensitivity of sodium signal and the limited availability of sodium MRI (requires special coils and hardware).
T1ρ and T2 mapping does not require the use of special hardware, coils or contrast. Our study was implemented on a 3 T MR scanner because of the advantages afforded by using a higher field strength (such as increased signal to noise ratio and higher resolution), but T1ρ-weighted MR images can be easily obtained on more readily available 1.5 T scanners
A potential limitation of this study was that average T1ρ and T2 values were quantified within the entire cartilage surface or in a specific compartment of the knee. Mosher and coworkers have developed techniques examining the spatial variation of T2 within cartilage and reported changes in different layers with age and with cartilage degeneration
. It may be helpful to further investigate the spatial variation of T1ρ in different layers and compare it with that of T2 values in both healthy controls and osteoarthritic subjects to better localize areas of cartilage degeneration.
In conclusion, in vivo T1ρ and T2 mapping techniques have demonstrated feasibility in detecting cartilage degeneration. Quantitative cartilage imaging may enhance our ability to detect subtle, early matrix changes associated with cartilage injuries when used in conjunction with standardized cartilage sensitive imaging. We are currently investigating the ability of quantitative imaging to detect cartilage injuries associated with ligament tears
. Development of noninvasive methods to assess early cartilage matrix changes is potentially important to initiate early treatment, monitor disease progression and to follow-up operative cartilage repair and resurfacing.
The authors would like to thank Dr Robert Stahl for his help with the radiograph data. The research was supported by NIH RO1 AG17762, RO1 AR46905 and K25 AR053633.
Brandt K.D. Doherty M. Lohmander L.S. Osteoarthritis. Oxford University Press Inc,
Carballido-Gamio J, Bauer JS, Lee KY, Krause S, Majumdar S. Combined image processing techniques for characterization of MRI cartilage of the knee. 27th Annual Conference IEEE Engineering in Medicine and Biology Society (EMBS) 2005 Sep 1–4; Shanghai, China.