Physicians, radiologists and clinical pharmacologists interested in the pathophysiology of cartilage diseases and monitoring of the repair process.

Cartilage degeneration or defective repair after an injury is typically associated with changes in the macromolecular composition and bi-layer organization. Thus, roughening of the articular surface results from cartilage fibrillation, a process involving denaturation of the collagen fibrils and fragmentation of the collagen network. Glycosaminoglycans (GAG), which contribute to tissue stiffness through hydration of the extracellular matrix, are also lost prior to early visible signs of degeneration, leading to an impaired biomechanical support function, which itself contributes to degradation of cartilage. Any repair of the defect is challenging to monitor and a non-invasive comprehensive MRI approach may then be considered as a good alternative to cartilage biopsies.

T2 mapping appears well adapted for collagen network evaluation. Thus, a lack of T2 variation across cartilage sub-layers may reflect a low degree of collagen fibril organization¹. Meanwhile, GAG levels, as measured by GAG chemical exchange saturation transfer (gagCEST) MRI at 7T², were found to agree well with (²³Na)-MRI results³. However, gagCEST performance at 3T is still not clearly demonstrated and the optimal use of biomarkers to monitor changes in cartilage quality at 3T or 7T requires further characterization.

Here we show preliminary results obtained from an observational study in which T2 and gagCEST measurements were combined to investigate how reliably damage progression can be detected in patients with acute cartilage injury and additional risk factors for further cartilage destruction.

Imaging sessions were performed on 7 patients with cartilage defect(s) in the knee joint (ICRS 1/2) as well as high risk factors for further progression into ICRS 3/4. Cartilage T2 and gagCEST images were obtained for all patients at 7T and 3T. T2 maps were reconstructed from images obtained using a 3D-Triple Echo Steady State sequence (3D-TESS: TR/TE 11.14/5.06 ms, resolution 0.25x0.25x3 mm³). For gagCEST imaging, a series of ten 60-ms adiabatic full passage hs2 RF pulses followed by spoiling gradients in all 3 directions with interpulse delays of 20 ms preceded the 3D RF-spoiled GRE sequence (TR/TE 7.9/3.15 ms, resolution 0.9x0.9x2.2 mm³). Nineteen scans with equidistant (92 Hz and 39 Hz at 7T and 3T, respectively) offsets in the range of ±2.8 ppm around the water resonance and a scan without saturation were collected. Then, Z-spectra were constructed from registered images on a pixel-by-pixel basis and asymmetry of the Z-spectra calculated from integrals over the offset range ±∂=0.6–1.8ppm relative to the minimum of each individual Z-spectrum. Regions-of-interest were defined from 2D-TSE morphological images in the suspicious regions for defective and normal appearing cartilage, and transferred to T2 and gagCEST images for quantitative analysis. All measurements were repeated 8 days later for variability assessment.Cartilage damage could clearly be identified in the tibio-femoral region from T2map and gagCEST images, but not from morphological MR images (Fig.1). At 7T, gagCEST asymmetry values (N=5, preliminary data) appeared to be ~28% lower in the defective vs healthy cartilage regions (3.06±2.18% vs 4.27±1.61%, NS), however were associated with substantial inter-individual variability. These results could not be confirmed from gagCEST measurements at 3T, which in some cases generated negative asymmetry values. (Superficial/Deep)T2 ratios also showed ~20% greater (NS) values in the defective vs healthy cartilage regions, both at 7T and 3T (7T: 0.81±0.22 vs 0.68±0.10; 3T: 0.75±0.18 vs 0.67±0.07). These T2 measurements showed high reproducibility between baseline and day-8 (ICCs at 7T: 0.82 to 0.69, and at 3T: 0.67 to 0.60 depending on the cartilage layer). Good reproducibility was also observed for gagCEST measurements at 7T. Test-retest results showed that T2 mapping may be reproducible and precise enough to monitor small changes in the collagen fibril network at 7 T and 3T. Similar changes in GAG concentration appear to be more challenging to detect, especially at 3T. In accordance with a previous study⁴, asymmetry values from gagCEST measurements at 3 T were found to be very low, with negative values most likely reflecting contribution of a larger exchange-relayed NOE through the aliphatic protons resonating upfield from water⁵. Alternatively, the gagCEST method could be replaced by sodium MRI, despite the need for specialized hardware and software. Yet, these preliminary results support the use of a comprehensive MRI approach to differentiate early formation of hyaline from fibrotic cartilage, and eventually monitor beneficial effects of new cartilage regenerating drugs, without resorting to serial biopsies. Given the serious pitfalls of gagCEST at 3T and the difficulty to access high field scanners, the conduct of multiple-site studies at 7T may however still be challenging.