Nitya Krishnan’s research while affiliated with Harvard University and other places

Objective: To evaluate the relationship between medial meniscal pathology and cartilage matrix status using delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) in medial tibiofemoral cartilage in a sample of middle-aged women. Methods: A total of 148 women ages ≥40 years were included, and 3.0T MRI of the knee was performed at baseline and at 1 year. T2-weighted, fat-suppressed and 3-dimensional inversion recovery-prepared spoiled gradient-recalled echo sequences were acquired 90 minutes after gadolinium injection. Baseline medial meniscal pathology was scored on a scale of 0-3, where 0 = normal, 1 = intrasubstance meniscal signal change, 2 = single tears, and 3 = complex tears/maceration. The central medial femur, the medial tibial plateau, and the posterior medial femur were subjected to dGEMRIC at baseline and at 1 year. Analysis of covariance was used to examine whether baseline and 1-year dGEMRIC indices in the same regions were related to the severity of meniscal damage at baseline, using normal medial menisci (grade 0) as the reference. Results: Medial compartments with grade 3 lesions showed significantly lower dGEMRIC indices (less proteoglycan content) at the central medial femur region compared with compartments with normal menisci. Mean ± SEM differences in dGEMRIC indices between grade 3 and grade 0 menisci at the central medial femur were -119.1 ± 34.2 msec at baseline (P = 0.03) and -120.3 ± 35.2 msec at followup (P = 0.04). Conclusion: High-grade damage of the medial meniscus showed significant associations with lower dGEMRIC indices. The dGEMRIC technique may be a useful tool in detecting early degenerative changes of cartilage when meniscal function is lost.

To determine the association between changes in the delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) index over 2 years as a measure of cartilage proteoglycan concentration, with changes in cartilage thickness in the medial tibiofemoral compartment of knees in middle-aged women. One hundred and forty-eight women (one knee for each subject) aged ≥40 years were included. 3.0 T MR images of the knee were acquired at baseline, 1 year and 2 years. Three-dimensional (3D) spoiled gradient recalled echo (SPGR) sequences (for cartilage thickness) and 3D inversion recovery-prepared SPGR sequences after dGEMRIC were acquired. Segmentation was performed in the medial central (weight-bearing) femur and tibia to determine cartilage proteoglycan concentration and thickness. The association of change in the dGEMRIC indices between baseline and 1-year follow-up with (a) concomitant changes in cartilage thickness and (b) change in cartilage thickness between 1 and 2 years was assessed using linear regression. In the whole-sample model, a decrease in dGEMRIC indices over time at the central medial femur significantly predicted an increase in cartilage thickness at both the central medial femur (p=0.008) and the medial tibia (p=0.04). A decrease in dGEMRIC indices was associated with an increase in cartilage thickness in the medial compartment. Our results suggest that an increase in cartilage thickness may also be related to a decrease in proteoglycan concentration, which may represent swelling of cartilage in early stages of degeneration.

To determine whether either of two magnetic resonance imaging approaches - delayed gadolinium enhanced magnetic resonance imaging of cartilage (dGEMRIC), or T2 mapping - can detect short-term changes in knee hyaline cartilage among individuals taking a formulation of collagen hydrolysate. Single center, prospective, randomized, placebo-controlled, double-blind, pilot trial of collagen hydrolysate for mild knee osteoarthritis (OA). Participants were allowed to continue the prior analgesic use. The primary outcome was change in dGEMRIC T1 relaxation time in the cartilage regions of interest at the 24-week timepoint. Secondary endpoints included the change in dGEMRIC T1 relaxation time between baseline and 48 weeks, the change in T2 relaxation time at 0, 24 and 48 weeks, the symptom and functional measures obtained at each of the visits, and overall analgesic use. Among a sample of 30 randomized subjects the dGEMRIC score increased in the medial and lateral tibial regions of interest (median increase of 29 and 41 ms respectively) in participants assigned to collagen hydrolysate but decreased (median decline 37 and 36 ms respectively) in the placebo arm with the changes between the two groups at 24 weeks reaching significance. No other significant changes between the two groups were seen in the other four regions, or in any of the T2 values or in the clinical outcomes. These preliminary results suggest that the dGEMRIC technique may be able to detect change in proteoglycan content in knee cartilage among individuals taking collagen hydrolysate after 24 weeks.

The objective of this study was to evaluate if cartilage fixed charge density is the only factor determining the distribution of the measured delayed gadolinium-enhanced magnetic resonance imaging of cartilage index, T(1) (Gd-DTPA(2-) ), across cartilage in the clinical delayed gadolinium-enhanced magnetic resonance imaging of cartilage protocol. Nineteen subjects with osteoarthritis and 14 controls were included. Cartilage T(1) (Gd) was measured following administration of 0.2 mmol kg(-1) of nonionic (Gd-DTPA-BMA) and, at a different date, anionic (Gd-DTPA(2-). T(1) (Gd-DTPA-BMA) was plotted against T(1) (Gd-DTPA(2-); a slope of 0 would indicate domination by charge effects; a nonzero slope would suggest that other factors influence T(1) (Gd-DTPA-BMA), and hence potentially T(1) (Gd-DTPA(2-). The low slope of the curve found in osteoarthritis subjects (0.31) indicates that Gd-DTPA-BMA penetrated most osteoarthritis cartilage to the same extent, and T(1) (Gd-DTPA-BMA) did not differentiate cartilages, which were differentiated by T(1) (Gd-DTPA(2-). The higher slopes in control subjects (0.88) are possibly due to inhibited transport of contrast agent into healthier cartilage, potentially exaggerated by the fast body clearance of the nonionic contrast agent. Overall, the use of anionic Gd-DTPA(2-) for delayed gadolinium-enhanced magnetic resonance imaging of cartilage is indicated for better discrimination of the health status of cartilage. Future studies could be designed to use contrast-enhanced dynamics to understand the transport properties of tissues in the joint and to evaluate the concentration of tissue constituents.

Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) is based on the theory that Gd-DTPA(2-) will distribute in inverse relation to cartilage glycosaminoglycan (GAG). T(1Gd) (T(1) after penetration of a 0.2 mmol/kg dose of Gd-DTPA(2-)) has been used as the dGEMRIC index, although (1/T(1Gd)-1/T(1o)) should be more representative of Gd-DTPA(2-) concentration (where T(1o) = T(1) before contrast). T(1o) and T(1Gd) were measured in 20 volunteers at both 1.5T and 3T and the correlation between the metrics of T(1Gd) and (1/T(1Gd)-1/T(1o)) was calculated. There was a high correlation coefficient between the two metrics at both field strengths, with R = 0.94, 0.93, and 0.90 for central medial femur, posterior medial femur, and medial tibia, respectively, at 1.5T and 0.87, 0.94, 0.96 at 3T. In all cases P < 0.0001. Therefore, these data suggest that, for native cartilage, the current practice of measuring T(1Gd) (but not also T(1o)) is adequate at both 1.5T and 3T.

Much attention has been focused recently on the need for a better understanding of the mechanisms and natural progression of knee osteoarthritis (OA), particularly in its early stages. One technique that has been used to investigate early OA is delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC), where T1(Gd) (T1 value after penetration of the MRI contrast agent gadopentate dimeglumine [Gd-DTPA(2-)]) is used as an index of the molecular status of articular cartilage. The goal of this study was to explore T1(Gd) in the meniscus and its relationship with articular cartilage T1(Gd) in knee dGEMRIC image data sets. T1(Gd) maps of the meniscus and articular cartilage were made from knee dGEMRIC images obtained from prior studies of dGEMRIC of the knee in 21 asymptomatic subjects and 9 patients with self-reported OA. T1(Gd) of the meniscus covered a range of values (247-515 msec) and patterns (homogeneous and focal variations). In addition, T1(Gd) of the meniscus correlated with that of articular cartilage (R = 0.38, P = 0.037; R = 0.57, P = 0.001 for correlations of the medial posterior meniscus with the medial femoral and tibial cartilage, respectively; T1[Gd] of the anterior meniscus and lateral compartments also correlated, with R > 0.38 and P < 0.037), potentially demonstrating parallel degradative processes in the knee. While the biophysical basis for the T1(Gd) results relative to meniscus molecular structure needs investigation, these findings introduce a potential means of examining the time course of meniscal tissue change in the development and progression of arthritis.