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In vivo T and T2 mapping of articular cartilage in osteoarthritis of the knee using 3T MRI

      Summary

      Objective

      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 (T) and T2 mapping to detect cartilage matrix degeneration between normal and early OA patients.

      Method

      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 T and T2 values were compared between normal and OA patients. The relationship between T and T2 values, and Kellgren–Lawrence scores based on plain radiographs and the cartilage lesion grading based on MR images were studied.

      Results

      The average T 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 T, and 39.63±2.69 ms vs 34.74±2.48 ms with P=0.001 for T2). Increased T and T2 values were correlated with increased severity in radiographic and MR grading of OA. T has a larger range and higher effect size than T2, 3.7 vs 3.0.

      Conclusion

      Our results suggest that both in vivo T and T2 relaxation times increase with the degree of cartilage degeneration. T 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.

      Key words

      Introduction

      Osteoarthritis (OA) is a heterogeneous and multifactorial disease characterized primarily by the progressive loss of hyaline articular cartilage
      . 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
      • Rogers J.
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      A comparison of the visual and radiographic detection of bony changes at the knee joint.
      . 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
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      Osteoarthritis of the knee: comparison of radiography, CT, and MR imaging to assess extent and severity.
      .
      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
      • Gray M.L.
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      Toward imaging biomarkers for osteoarthritis.
      . Early events in the development of cartilage matrix breakdown include the loss of PGs, changes in water content, and molecular level changes in collagen
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      • Liem R.S.
      The structure, biochemistry, and metabolism of osteoarthritic cartilage: a review of the literature.
      . 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
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      Diffusion and relaxation mapping of cartilage-bone plugs and excised disks using microscopic magnetic resonance imaging.
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      Human articular cartilage: influence of aging and early symptomatic degeneration on the spatial variation of T2—preliminary findings at 3 T.
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      T2 relaxation time measurements in osteoarthritis.
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      • Lu Y.
      • Jin H.
      • Ries M.D.
      • Majumdar S.
      T2 relaxation time of cartilage at MR imaging: comparison with severity of knee osteoarthritis.
      . Elevated T2 values were observed in patients with OA
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      • Dardzinski B.J.
      • Smith M.B.
      Human articular cartilage: influence of aging and early symptomatic degeneration on the spatial variation of T2—preliminary findings at 3 T.
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      • Lu Y.
      • Jin H.
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      T2 relaxation time of cartilage at MR imaging: comparison with severity of knee osteoarthritis.
      . T1rho (T) relaxation time has recently been proposed as an attractive alternative parameter to probe biochemical changes in cartilage
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      T1rho-relaxation in articular cartilage: effects of enzymatic degradation.
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      T1rho imaging using magnetization-prepared projection encoding (MaPPE).
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      • et al.
      Proteoglycan-induced changes in T1rho-relaxation of articular cartilage at 4T.
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      Proton exchange as a relaxation mechanism for T1 in the rotating frame in native and immobilized protein solutions.
      • Mlynarik V.
      • Szomolanyi P.
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      • Vittur F.
      • Trattnig S.
      Transverse relaxation mechanisms in articular cartilage.
      . The T parameter describes the spin–lattice relaxation in the rotating frame
      • Redfield A.G.
      Nuclear spin thermodynamics in the rotating frame.
      . 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 T. Initial studies in human subjects showed elevated T values in patients with OA
      • Duvvuri U.
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      • Rizi R.
      • et al.
      Human knee: in vivo T1(rho)-weighted MR imaging at 1.5 T—preliminary experience.
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      • et al.
      3D-T1rho-relaxation mapping of articular cartilage: in vivo assessment of early degenerative changes in symptomatic osteoarthritic subjects.
      • Li X.
      • Han E.
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      • Link T.
      • Newitt D.
      • Majumdar S.
      In vivo 3T spiral imaging based multi-slice T(1rho) mapping of knee cartilage in osteoarthritis.
      . Although both T and T2 can probe slow motion of water protons, they are parameters describing different MR relaxation mechanisms. T 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
      • Hangody L.
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      Autologous osteochondral mosaicplasty for the treatment of full-thickness defects of weight-bearing joints: ten years of experimental and clinical experience.
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      • Rodkey W.
      Outcomes of microfracture for traumatic chondral defects of the knee: average 11-year follow-up.
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      • et al.
      Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial.
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      • Mazzuca S.
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      • Yocum D.
      • et al.
      Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial.
      . In this study, we investigated the changes in T and T2 relaxation times in normal and osteoarthritic patients using 3 T MRI. Our hypothesis was that there would be an increase in both T and T2 values in cartilage in osteoarthritic patients compared to normal controls. We further hypothesized that the amount of T and T2 elevation would be related to the severity of OA.

      Materials and methods

      Subjects

      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 T and T2 mapping, while in the remaining six volunteers only T mapping was obtained. In all the patients standard radiographs were obtained in addition to both T and T2 MR examinations. The study was approved by the Committee for Human Research at our institution and all the subjects gave informed consent.

      Imaging protocol

      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 T-weighted and T2-weighted images.
      The multi-slice T-weighted images were obtained using the sequence we previously developed based on spin-lock techniques and spiral image acquisition
      • Li X.
      • Han E.
      • Ma C.
      • Link T.
      • Newitt D.
      • Majumdar S.
      In vivo 3T spiral imaging based multi-slice T(1rho) mapping of knee cartilage in osteoarthritis.
      . 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 T-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
      • Brittain J.H.
      • Hu B.S.
      • Wright G.A.
      • Meyer C.H.
      • Macovski A.
      • Nishimura D.G.
      Coronary angiography with magnetization-prepared T2 contrast.
      • Oh J.
      • Cha S.
      • Aiken A.H.
      • Han E.T.
      • Crane J.C.
      • Stainsby J.A.
      • et al.
      Quantitative apparent diffusion coefficients and T2 relaxation times in characterizing contrast enhancing brain tumors and regions of peritumoral edema.
      with TR/TE=2000/6.7, 12, 28, 60 ms. All other prescription parameters of the T2 sequence were the same as the T sequence, with a total acquisition time of approximately 11 min. The T2 quantification was acquired subsequently and covered the same region as the T 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
      • Kellgren J.
      • Lawrence J.
      Radiologic assessment of osteoarthritis.
      • Hart D.
      • Spector T.
      Assessment of changes in joint tissues in patients treated with a disease-modifying osteoarthritis drug (DMOAD): monitoring outcomes.
      . 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
      • Link T.M.
      • Steinbach L.S.
      • Ghosh S.
      • Ries M.
      • Lu Y.
      • Lane N.
      • et al.
      Osteoarthritis: MR imaging findings in different stages of disease and correlation with clinical findings.
      : 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 T 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
      • Blumenkrantz G.
      • Lindsey C.T.
      • Dunn T.C.
      • Jin H.
      • Ries M.D.
      • Link T.M.
      • et al.
      A pilot, two-year longitudinal study of the interrelationship between trabecular bone and articular cartilage in the osteoarthritic knee.
      . 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 T 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:
      S(TSL)exp(TSL/T1ρ)


      T-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
      • Rueckert D.
      • Sonoda L.I.
      • Hayes C.
      • Hill D.L.
      • Leach M.O.
      • Hawkes D.J.
      Nonrigid registration using free-form deformations: application to breast MR images.
      . The transformation matrix was applied to the reconstructed T 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 T map. Similarly, The T2 map was reconstructed by fitting the image intensity pixel-by-pixel to the equation S(TE)exp(TE/T2). 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 T or T2 maps were manually removed from the data used for quantification.

      Statistical analysis

      A nonparametric rank test was used to compare volume, average thickness, average T and T2 values between control subjects and OA patients. A Spearman rank correlation was performed to study the relationship between average T 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 T and T2 values using the equation below:
      Effect size=Δmean/SD


      where Δmean is the mean difference between control and OA, and SD is the pooled standard deviation of these two groups defined as
      SD=(n11)SD12+(n21)SD22/(n1+n22)


      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.

      Results

      T and T2 quantification for control subjects and OA patients

      The average T 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 T and T2 maps for a healthy control. Fig. 2, Fig. 3 present T 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 T and T2 values correlated significantly (R2=86.0%, P<0.0001). T values had a higher effect size than T2 values (3.7 vs 3.0), indicating T may be more sensitive than T2 for distinguishing OA from controls.
      Table IRadiological findings based on radiographs and anatomic MR images
      Patient IDKL scoreCartilage thinningOsteophytesBME
      MFCLFCMTLTPF–TF–PCenter
      12100021100
      21110001100
      32010111112
      43202022212
      53303021102
      61100011103
      74323232112
      83232231102
      92000000100
      104303013202
      F–T: femoral–tibial joint; F–P: femoral–patellar joint.
      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.
      Figure thumbnail gr1
      Fig. 1T1-weighted water excitation SPGR image (a), T map (b) and T2 map (c) for a healthy control (male, 30). No radiographs were obtained, as the subject is a healthy asymptomatic control. No cartilage thinning, osteophytes and other OA symptoms were seen in MR images. The average T value was 40.1±11.4 ms and the average T2 value was 33.3±10.5 ms in cartilage.
      Figure thumbnail gr2
      Fig. 2Radiographs (a), T1-weighted water excitation SPGR image (b), T map (c) and T2 map (d) for a patient with mild OA (male, 66). From radiographs, no significant joint space narrowing was seen, but minimal osteophytes were observed in femoro-tibial joint and minimal to mild osteophytes were observed in femoro-patellar joint, resulting in a KL score of 1. From MR images, minimal osteophytes were also seen in femoro-tibial and femoro-patellar joints. The cartilage in medial femur and femoro-patellar compartment had grade 1 thinning. The average T value was 45.5±14.5 ms and the average T2 value was 35.0±10.9 ms in cartilage.
      Figure thumbnail gr3
      Fig. 3Radiographs (a), T1-weighted water excitation SPGR image (b), T map (c) and T2 map (d) for a patient with advanced OA (male, 46). Based on radiographs, the patient had joint space narrowing with 1 mm in medial compartment and 3 mm in lateral compartment, and significant osteophytes in both femoro-tibial and femoro-patellar joints, resulting in a KL score of 4. In MR images, significant osteophytes were seen in both femoro-tibial and femoro-patellar joints. The cartilage had a grade 3 thinning in medial femur, medial tibia and femoro-patellar compartments, and grade 2 thinning in lateral femur and LT compartments. The average T value was 55.4±26.0 ms and the average T2 value was 43.8±11.1 ms in cartilage.
      The average T 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).
      Figure thumbnail gr4
      Fig. 4Distribution of T values vs age in healthy volunteers. The correlation is moderate but significant with R2=58.3% and P=0.018.

      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
      PMFCLFCMTLT
      Controls2.17±0.621.51±0.351.51±0.381.23±0.491.88±0.28
      OA patients2.04±0.531.65±0.201.86±0.401.51±0.261.94±0.49
      Table IIbCartilage volume (normalized by epicondylar length, in cm3/cm, mean±SD) in each compartment
      PMFCLFCMTLT
      Controls0.23±0.070.27±0.050.43±0.140.15±0.040.19±0.04
      OA patients0.33±0.150.33±0.130.49±0.210.18±0.050.21±0.09
      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 IIIT and T2 values (in ms, mean±SD) in healthy controls and osteoarthritic subjects
      ControlsOAP valueEffect size
      T45.53±3.2852.04±2.970.00023.7
      T234.74±2.4839.63±2.690.0013.0

      Relationship between radiological findings and T and T2 quantification

      The average T 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 IVaT and T2 values (in ms, mean±SD) in subjects vs KL scores evaluated on plain radiographs
      KL score0 (n=10)I (n=2)II (n=3)III (n=3)IV (n=2)
      T45.5±3.347.6±3.051.8±0.752.9±0.955.6±0.4
      T234.7±2.535.9±1.439.8±2.440.0±0.243.0±1.0
      The average T 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 T, 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 T and T2 values and cartilage volumes and thickness (P>0.05).
      Table IVbT and T2 values (in ms, mean±SD) in subjects vs cartilage thinning grades evaluated on MR images
      Cartilage thinning grading0 (n=11)I (n=3)II (n=2)III (n=4)
      T46.1±3.648.9±3.052.4±0.254.4±1.5
      T235.0±2.537.7±3.140.3±1.341.4±2.0
      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 T 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%.

      Discussion

      In this study, we have demonstrated that both T and T2 cartilage values were significantly increased in patients with OA when compared with healthy controls. T 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
      • Mosher T.J.
      • Dardzinski B.J.
      • Smith M.B.
      Human articular cartilage: influence of aging and early symptomatic degeneration on the spatial variation of T2—preliminary findings at 3 T.
      • Dunn T.C.
      • Lu Y.
      • Jin H.
      • Ries M.D.
      • Majumdar S.
      T2 relaxation time of cartilage at MR imaging: comparison with severity of knee osteoarthritis.
      • Mosher T.
      • Dardzinski B.
      Cartilage MRI T2 relaxation time mapping: overview and applications.
      . 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
      • Regatte R.R.
      • Akella S.V.
      • Borthakur A.
      • Kneeland J.B.
      • Reddy R.
      Proteoglycan depletion-induced changes in transverse relaxation maps of cartilage: comparison of T2 and T1rho.
      • Toffanin R.
      • Mlynarik V.
      • Russo S.
      • Szomolanyi P.
      • Piras A.
      • Vittur F.
      Proteoglycan depletion and magnetic resonance parameters of articular cartilage.
      , and PG cleavage did not affect T2 values significantly
      • Nieminen M.T.
      • Toyras J.
      • Rieppo J.
      • Hakumaki J.M.
      • Silvennoinen J.
      • Helminen H.J.
      • et al.
      Quantitative MR microscopy of enzymatically degraded articular cartilage.
      . Instead, T2 can be affected mainly by collagen content and orientation and/or water content
      • Duvvuri U.
      • Reddy R.
      • Patel S.D.
      • Kaufman J.H.
      • Kneeland J.B.
      • Leigh J.S.
      T1rho-relaxation in articular cartilage: effects of enzymatic degradation.
      • Gray M.
      • Burstein D.
      • Xia Y.
      Biochemical (and functional) imaging of articular cartilage.
      . It has been observed that loss of PG is an initiating event in early OA, while neither the content nor the type of collagen is altered in early OA
      • Dijkgraaf L.C.
      • de Bont L.G.
      • Boering G.
      • Liem R.S.
      The structure, biochemistry, and metabolism of osteoarthritic cartilage: a review of the literature.
      . 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
      • Xia Y.
      Relaxation anisotropy in cartilage by NMR microscopy (muMRI) at 14-micron resolution.
      .
      T has been recently proposed as an attractive alternative to evaluate biochemical changes in cartilage matrix noninvasively. T relaxation rate (1/T) has been shown to decrease linearly with decreasing PG content in ex vivo bovine patellae
      • Duvvuri U.
      • Reddy R.
      • Patel S.D.
      • Kaufman J.H.
      • Kneeland J.B.
      • Leigh J.S.
      T1rho-relaxation in articular cartilage: effects of enzymatic degradation.
      and has been proposed as a more specific indicator of PG content than T2 relaxation in trypsinized cartilage
      • Regatte R.R.
      • Akella S.V.
      • Borthakur A.
      • Kneeland J.B.
      • Reddy R.
      Proteoglycan depletion-induced changes in transverse relaxation maps of cartilage: comparison of T2 and T1rho.
      and in human cartilage specimens obtained from patients with severe OA who underwent total knee replacement
      • Regatte R.
      • Akella S.
      • Lonner J.
      • Kneeland J.
      • Reddy R.
      T1rho relaxation mapping in human osteoarthritis (OA) cartilage: comparison of T1rho with T2.
      . Makela et al.
      • Makela H.I.
      • Grohn O.H.
      • Kettunen M.I.
      • Kauppinen R.A.
      Proton exchange as a relaxation mechanism for T1 in the rotating frame in native and immobilized protein solutions.
      and Duvvuri et al.
      • Duvvuri U.
      • Goldberg A.D.
      • Kranz J.K.
      • Hoang L.
      • Reddy R.
      • Wehrli F.W.
      • et al.
      Water magnetic relaxation dispersion in biological systems: the contribution of proton exchange and implications for the noninvasive detection of cartilage degradation.
      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 T relaxation. Therefore T may be specific to changes of PG in cartilage matrix during early stages of OA. Furthermore, T relaxation times do not seem to be affected by the orientation of collagen that can affect T2 relaxation techniques
      • Akella S.V.
      • Regatte R.R.
      • Wheaton A.J.
      • Borthakur A.
      • Reddy R.
      Reduction of residual dipolar interaction in cartilage by spin-lock technique.
      . Preliminary in vivo studies have also shown increased cartilage T values for patients with OA vs healthy controls
      • Duvvuri U.
      • Charagundla S.R.
      • Kudchodkar S.B.
      • Kaufman J.H.
      • Kneeland J.B.
      • Rizi R.
      • et al.
      Human knee: in vivo T1(rho)-weighted MR imaging at 1.5 T—preliminary experience.
      • Regatte R.R.
      • Akella S.V.
      • Wheaton A.J.
      • Lech G.
      • Borthakur A.
      • Kneeland J.B.
      • et al.
      3D-T1rho-relaxation mapping of articular cartilage: in vivo assessment of early degenerative changes in symptomatic osteoarthritic subjects.
      • Li X.
      • Han E.
      • Ma C.
      • Link T.
      • Newitt D.
      • Majumdar S.
      In vivo 3T spiral imaging based multi-slice T(1rho) mapping of knee cartilage in osteoarthritis.
      . Our results also suggested that the mean T values exhibit similar changes with age as seen in previous studies on T2 relaxation times
      • Mosher T.J.
      • Dardzinski B.J.
      • Smith M.B.
      Human articular cartilage: influence of aging and early symptomatic degeneration on the spatial variation of T2—preliminary findings at 3 T.
      • Mosher T.
      • Liu Y.
      • Yang Q.
      • Yao J.
      • Smith R.
      • Dardzinski B.
      • et al.
      Age dependency of cartilage magnetic resonance imaging T2 relaxation times in asymptomatic women.
      .
      The results of our comparison study demonstrated that both T and T2 techniques can be sensitive to cartilage degeneration. However, there is a larger range and effect size for T vs T2 values, which may indicate a more sensitive method of detecting cartilage degeneration. Furthermore, although there is a significant correlation between the average T 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 T and T2 values in future studies. We believe that since T 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, T 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.
      • Dunn T.C.
      • Lu Y.
      • Jin H.
      • Ries M.D.
      • Majumdar S.
      T2 relaxation time of cartilage at MR imaging: comparison with severity of knee osteoarthritis.
      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 T 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 (grade1), six had ‘spared’ compartments with cartilage thinning grade 0 on the clinical MR images. The average T 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 T 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 T and T2 values.
      Figure thumbnail gr5
      Fig. 5Segmented femoral and tibial cartilage in medial compartments of a healthy control (a, male, 30) and an OA patient (b, male, 66). The average thickness (in mm) is 1.68 vs 1.84 (control vs OA) in MFC, and 1.63 vs 1.71 (control vs OA) in MT. The volume (normalized by epicondylar length, in cm3/cm) is 0.31 vs 0.35 (control vs OA) in MFC, and 0.20 vs 0.19 (control vs OA) in MT. The slightly increased cartilage volume and thickness may due to the increase of water content and consequently swelling of the cartilage in the early stages of OA.
      T 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
      • Reddy R.
      • Insko E.K.
      • Noyszewski E.A.
      • Dandora R.
      • Kneeland J.B.
      • Leigh J.S.
      Sodium MRI of human articular cartilage in vivo.
      • Shapiro E.M.
      • Borthakur A.
      • Gougoutas A.
      • Reddy R.
      23Na MRI accurately measures fixed charge density in articular cartilage.
      and delayed gadolinium enhanced MRI of cartilage (dGEMRIC)
      • Bashir A.
      • Gray M.L.
      • Burstein D.
      Gd-DTPA2− as a measure of cartilage degradation.
      • Bashir A.
      • Gray M.L.
      • Hartke J.
      • Burstein D.
      Nondestructive imaging of human cartilage glycosaminoglycan concentration by MRI.
      • Nieminen M.T.
      • Rieppo J.
      • Silvennoinen J.
      • Toyras J.
      • Hakumaki J.M.
      • Hyttinen M.M.
      • et al.
      Spatial assessment of articular cartilage proteoglycans with Gd-DTPA-enhanced T1 imaging.
      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).
      T 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 T-weighted MR images can be easily obtained on more readily available 1.5 T scanners
      • Borthakur A.
      • Wheaton A.
      • Charagundla S.R.
      • Shapiro E.M.
      • Regatte R.R.
      • Akella S.V.
      • et al.
      Three-dimensional T1rho-weighted MRI at 1.5 Tesla.
      .
      A potential limitation of this study was that average T 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
      • Smith H.E.
      • Mosher T.J.
      • Dardzinski B.J.
      • Collins B.G.
      • Collins C.M.
      • Yang Q.X.
      • et al.
      Spatial variation in cartilage T2 of the knee.
      . It may be helpful to further investigate the spatial variation of T 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 T 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
      • Lozano J.
      • Li X.
      • Link T.
      • Safran M.
      • Majumdar S.
      • Ma C.
      Detection of posttraumatic cartilage injury using quantitative T1rho magnetic resonance imaging. A report of two cases with arthroscopic findings.
      . 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.

      Acknowledgments

      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.

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