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Original Report |
1 Department of Radiology, Beth Israel Deaconess Medical Center, 4 Blackfan
Cir., Rm. 147, Boston, MA 02115.
2 Division of Rheumatology, Northwestern University Medical School, 300 E
Superior St., Tarry 3-713, Chicago, IL 60611.
3 Division of Sports Medicine, Children's Hospital Boston, 319 Longwood Ave.,
Sixth Floor, Boston, MA 02115.
4 Department of Orthopedic Surgery, New England Baptist Hospital, ProSports
Orthopedics, 840 Winter St., Waltham, MA 02451.
Received April 10, 2003;
accepted after revision July 30, 2003.
Address correspondence to D. Burstein.
Abstract
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CONCLUSION. The index of glycosaminoglycan distribution, T1Gd, can exceed 500 msec (denoting high glycosaminoglycan) or can be less than 300 msec, with focal areas as low as 240 msec. Compartmental differences, as well as focal defects within the knee, were observed in patients who had sustained injuries to the ligaments and menisci of the knee or who had chronic osteoarthritis. Overall, these results suggest the need for further research into the biochemical changes seen during disease progression and the effects of therapeutic interventions.
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MRI can play a critical role in the evaluation of morphologic cartilage abnormalities and also has potential use in the evaluation of the molecular status of cartilage. In this report, we focus on one of several molecular imaging techniques under development—delayed gadolinium-enhanced MRI of cartilage (dGEMRIC)—as a tool for estimating glycosaminoglycan distribution in cartilage. The term "delayed" in the name of the technique refers to the time required for the gadolinium agent to penetrate the cartilage tissue.
Because of the abundance of charged side chains on the glycosaminoglycan molecules, the distribution of the mobile ions reflects the glycosaminoglycan concentration in the cartilage, when allowed sufficient time to distribute in the cartilage. One of the most common MRI contrast agents, gadopentetate dimeglumine (Magnevist, Berlex, Wayne, NJ), which is sometimes referred to as Gd-DTPA2–, has a negative charge. Given time to penetrate into cartilage, this gadolinium agent is distributed in higher concentrations in areas of cartilage in which the glycosaminoglycan content is relatively low and in lower concentrations in regions rich in glycosaminoglycans. Because the gadolinium inversely affects the MRI parameter T1, measurement of T1 after full penetration of the contrast agent (T1Gd) is used as an index of concentration of the contrast agent in the cartilage and is proportional to the glycosaminoglycan concentration in the tissue. A low level of glycosaminoglycans is associated with a high concentration of gadolinium and results in a measurement of low T1Gd value. Therefore, the T1Gd index varies directly with glycosaminoglycan concentration.
The dGEMRIC technique has been validated in both basic scientific and clinical studies as reflecting the glycosaminoglycan concentration in cartilage [2–7]. The potential of this technique to reveal clinically relevant information has begun to emerge through several recent reports of focused pilot studies of dose-response and compartmental differences in asymptomatic individuals [8], autologous chondrocyte transplants [9], arthroscopically determined cartilage softening [10], and hip dysplasia [11].
These reports have led to the performance of larger clinical trials to better delineate the usefulness of dGEMRIC. Previous studies have reported a mean T1Gd index for the area of interest in the cartilage or have covered focused clinical conditions, but designing large trials requires a better understanding of the range of values expected under different conditions and within joints. Through a series of case studies, we sought to determine a dynamic range of T1Gd index values seen in several individuals, the level of heterogeneity that can be observed within the joint of a given individual, and the levels of changes that might be seen over time. These case studies also provide the basis for hypotheses regarding physiologic and pathologic data that might be addressed in future studies.
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A series of T1-weighted images was acquired using a fast inversion recovery spin-echo sequence with five to seven inversion delays ranging from 25 to 1,680 msec (TR/TE, 1,800/14). Coronal, sagittal, or axial views were collected in a 512 x 512 matrix with an in-plane resolution of 275–350 µm. Sections were 3 mm thick. The scanning time was 15 min per image.
We used Matlab software (The MathWorks, Natick, MA) to generate T1Gd maps depicting areas determined by hand segmentation to be cartilage, using a pixel-by-pixel three-parameter T1 fit and a custom-designed interface [13]. The color-coded (Fig. 1) T1Gd-calculated maps were then superimposed on one of the inversion recovery images for display. The T1Gd index was taken as an average of the T1Gd values in a given region of interest; unless otherwise stated, the region of interest for a compartment in a sagittal image was that of the weight-bearing femoral cartilage and all of the tibial cartilage (Fig. 2A). In the coronal image, the region of interest consisted of all of the cartilage in that view (Fig. 2B).
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Striking heterogeneity can also be observed within the cartilage tissue. Figure 4A was obtained in a patient in whom the medial patellar cartilage was denuded. The remaining cartilage on the lateral side has an area of focally low T1Gd values and an area of mid-range T1Gd values. Similarly, Figure 4B shows the lateral compartment in a patient with medial osteoarthritis. Although the cartilage in the lateral compartment was relatively intact anatomically, focal areas had T1Gd values 35% lower than surrounding cartilage.
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We monitored several individuals longitudinally. The variation within the T1Gd index in four asymptomatic volunteers during a 6-month period was found to be less than 10%. T1Gd was also monitored in 10 volunteers taking a supplement containing glucosamine and chondroitin sulfate (CosaminDS, Nutramax Laboratories, Edgewood, MD). Four volunteers who are professional dancers (those reported in the discussion of T1Gd index in patient imaged in Fig. 2A) took the supplements and showed no change after 6 months. Increases of 13% and 19% were seen in two volunteers who took the supplements while recovering from arthroscopic surgery (Fig. 5A). The T1Gd index in three other volunteers recovering from arthroscopic surgery did not change significantly. The T1Gd index in one volunteer with a history of knee injuries (patellar fracture and meniscectomy) decreased 9%; he reported that he had stopped running while taking the supplements. These results are summarized in Figure 6. Long-term changes in the T1Gd index in focal areas of an osteoarticular transfer system procedure were also observed (Fig. 7A, 7B). The T1Gd index increased 20% at the implant site during the period of 7–20 months after the transplantation, whereas the index at the harvest sites decreased 20–25% during the same period.
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The dynamic range and heterogeneity that we found indicate a need for
grading schemes that take these factors into account. For example, the mean
value of a compartment may be a useful metric of the overall biochemical
status of that compartment (e.g., Fig.
2A,
2B,
2C), whereas a metric of
heterogeneity or the number of voxels below a certain T1Gd cutoff,
as a metric of lesions (e.g., Fig.
4A,
4B), may differentiate segments
of cartilage similar in overall biochenical status. Large clinical studies can
be used retrospectively to better define the combination of metrics best
suited for the clinical question under investigation. This technique can be
implemented in any MRI center because the pulse sequences are available on any
standard clinical scanner, and the analysis could be run on most standard
computer systems. Segmentation of the cartilage area within an imaging section
is currently the only step requiring user
interaction.
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The cases that we presented point to several areas of potential further
investigation. Our findings of high levels of glycosaminoglycans in the
professional dancers is consistent with the results of a recent study that
reported that individuals who exercise regularly have higher T1Gd
indexes (denoting higher glycosaminoglycan levels) than individuals who are
sedentary (Tiderius CJ et al., presented at the Orthopaedic Research Society
meeting, 2003). Similarly, the decrease in the T1Gd index that we
found in the volunteer taking supplements who had stopped running might be an
indication of the effects of activity. Further studies can be designed to
investigate the effect of starting exercise regimens on short- and long-term
T1Gd indexes.
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Other researchers have found lower medial T1Gd values in an asymptomatic population [8]. In our study, we found severe medial degradation in a patient 10 years after medial meniscectomy and a reversal of this pattern, with lower T1Gd values seen laterally, in patients after an injury of the anterior cruciate ligament. Collectively, these findings warrant longitudinal studies of the effects of differing biomechanical environments on cartilage.
T1Gd indexes found in patients with early osteoarthritis were correlated with arthroscopic findings in an earlier study [10] in which global values of the T1Gd index were reported. Our images show more detail regarding the biochemical status of the tissue across the joint. The heterogeneities, with focal lesions as exhibiting indexes as low as 240 msec, may represent areas potentially amenable to disease-modifying interventions to halt or reverse the biochemical degradation. These focal lesions have been documented previously in T1Gd and histologic studies of excised human knee joint samples [3]
We found the T1Gd indexes in asymptomatic individuals in our study were stable (within 10%) during a 6-month period. Among volunteers taking nutritional supplements, two individuals had increases in T1Gd values and one had a decrease. The reason for these changes is not known and may or may not be attributable to the supplements, surgery, change in mobility of the joint, or other factors. We found it interesting that the increases were seen in those with low initial values, suggesting that the individuals with low T1Gd indexes may be more likely to benefit from such interventions. The fact that any change was observed suggests that dGEMRIC may be useful for monitoring the effects of various pharmacologic interventions in controlled trials.
In a cross-sectional study of patients who had received autologous chondrocyte transplants, researchers found that during the initial postoperative period, the tissue had filled in but had a low T1Gd index, suggesting that little glycosaminoglycan had accumulated in the transplants. By 12–18 months after the transplantation, the transplants, with one exception, showed T1Gd indexes that were approximately the same as those of the surrounding cartilage [9]. Another study noted low glycosaminoglycan concentration as measured by T1Gd in a series of patients with transplants; these findings were confirmed through biochemical analysis after biopsy (Dahlberg L et al., presented at the Orthopaedic Research Society meeting, 2003). Findings in our patient who had undergone osteoarticular transfer and in the previous studies indicate the need for a prospective study to determine if T1Gd might be useful as a predictor of successful implantation. The T1Gd images suggest that the dGEMRIC technique could be useful for noninvasively monitoring the long-term progress of patients who have undergone osteoarticular transfer and other cartilage therapies.
In summary, the delineation of dynamic ranges that can be expected clinically with T1Gd will help to determine sequence parameters necessary to quantitate T1Gd indexes in longitudinal studies. Likewise, the heterogeneity and levels of changes observed will aid in the planning of future studies and the determination of applications for which the dGEMRIC technique may be appropriate. Although the potentially clinically relevant observations of the individuals in our study have yet to be confirmed in larger studies, our findings underscore the opportunity provided by this noninvasive technique to monitor changes in glycosaminoglycan concentration and to better understand the biomechanical and biochemical mediators of cartilage homeostasis and alterations in disease.
Acknowledgments
We thank Wei Li for assistance with the MRI scanning.
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