Reproducibility and regional variations of an optimized gagCEST protocol for the in vivo evaluation of knee cartilage at 7 Tesla
Markus Matthias Schreiner1,2, Stefan Zbyn2, Benjamin Schmitt3, Stephan Domayer1, Reinhard Windhager1, Siegfried Trattnig2, and Vladimir Mlynarik2

1Department of Orthopaedic Surgery, Medical University of Vienna, Vienna, Austria, 2Department of Biomedical Imaging and Imag-Guided Therapy, High Field MR Centre, Medical University of Vienna, Vienna, Austria, 3Siemens Healthcare Pty Ltd, Macquarie Park, Australia


Early onset osteoarthritis is associated with ultrastructural and compositional changes of cartilage, in particular with a loss of glycosaminoglycans (GAGs) and disorganization of the collagen matrix. Both changes remain elusive to morphological MRI. GagCEST is a promising tool for the evaluation of glycosaminoglycan content in articular cartilage. However, it is affected by many variables, thus rendering its application challenging. The implementation of a novel saturation scheme combined with optimized fixation seems to improve the robustness of the technique as indicated by increased reproducibility. Our optimized protocol seems to be sensitive to regional differences in the GAG content.


Osteoarthritis is a major health issue in western countries. The inherently limited regenerative potential of articular cartilage renders timely diagnosis to be paramount for the possibility of successful conservative treatment. Similarly, a non-invasive method allowing for repetitive and reproducible assessment of cartilage quality would be valuable for interventional studies. It is assumed that even before morphological changes become apparent, early onset osteoarthritis goes along with changes in the biochemical composition of articular cartilage, notably with a decrease in GAG content.1 Hence, GAG specific MRI techniques, such as sodium imaging and gagCEST bear a high potential of catering to the aforementioned needs.2 The aim of this study was to establish an optimized gagCEST method that allows for robust assessment of GAG content in articular cartilage within a clinically feasible measurement time.

Subjects and Methods

Seven young and healthy volunteers (mean age 24, range 22-26; m:f = 5:2) were examined on a 7 Tesla MR System (Magnetom, Siemens, Erlangen). The physical integrity of the examined knee joint was assured by orthopaedic examination and assessment of the WOMAC score. Each volunteer was measured twice within one hour using a 28-channel knee array coil (Quality Electrodynamics LLC, Cleveland, OH). A custom-made fixation splint was used to address motion artefacts. A prototype segmented 3D RF-spoiled gradient-echo (GRE) sequence (TE = 3.1 ms, TR = 7.9 ms, resolution = 0.9 x 0.9 x 2.2 mm3, measurement time = 19:39 min) with selective RF presaturation using ten 60 - ms hs2 pulses with variable frequencies (± 10, ± 20 Hz) in the saturation pulse train was applied.3 The images were measured for 19 saturation offsets with a step of 92 Hz around the water resonance. B1 for saturation was set to reach 80% of the specific absorption rate (SAR) limit. Consecutively, offline image registration using an elastic approach was carried out. The calculation of Z-spectra was performed on a pixel-by-pixel basis using spline interpolation of experimental points. Asymmetry of the Z-spectra (MTRasym) was calculated from integrals over the offset range ± δ = 0.6 – 1.8 ppm relative to the minimum of each individual Z-spectrum. Region-of-interest (ROI) analysis was carried out by one reader. For each region, i.e., weight bearing & non-weight bearing femoral cartilage, trochlear groove, patellar and tibial cartilage, ROIs were placed on three consecutive slices on morphological images and were consecutively transferred to gagCEST maps (Fig. 2). For assessing reproducibility, a two-way mixed intraclass correlation coefficient (ICC) was calculated. Differences in MTRasym between different regions were assessed using one way ANOVA. Subsequently, least significant distance Bonferroni test was applied.


Thin knee cartilage structures and its curved surfaces contribute significantly to B0 inhomogeneity, which hampers uniform saturation of exchangeable OH protons over the entire cartilage volume. Therefore, variation of the nominal frequency of the adiabatic pulses around the offset frequency in the saturation pulse train was performed, which increased the uniformity of saturation in the whole range of resonance frequencies of the OH protons.3 In addition, the custom-made fixation splint successfully addressed motion artefacts and increased patient comfort during measurements. Fig. 1 shows typical MTRasym values in a healthy volunteer obtained with the optimized protocol. Typical regions of interest selected in various cartilage structured are shown in Fig. 2 and the corresponding mean MTRasym are given in Fig. 3. There was good agreement between two consecutive measurements as demonstrated by an ICC of 0.82. While MTRasym values of a similar magnitude were found for weight bearing and non-weight bearing femoral cartilage (p = 1.0), lower values were observed for the trochlear groove (p = 0.006), patellar (p = 0.028) and tibial cartilage (p = 0.006) compared to weight bearing femoral cartilage (Fig. 2).


Combined implementation of the modified pulse sequence and optimized fixation allowed to obtain gagCEST maps showing expected distribution of GAG in knee cartilage of young healthy subjects. Significant differences in the mean MTRasym values were observed between different regions of knee cartilage. The sensitivity to regional differences in the GAG content suggest that the gagCEST method might be useful in examining various pathological conditions in patients.


The study was supported by a grant provided by Vienna Science and Technology Fund, Project WWTF-LS11-018.


1. Venn M and Maroudas A. Chemical composition and swelling of normal and osteoarthrotic femoral head cartilage. I. Chemical composition. Ann Rheum Dis. 1977;36:121-9.

2. Ling W, Regatte RR, Navon G and Jerschow A. Assessment of glycosaminoglycan concentration in vivo by chemical exchange-dependent saturation transfer (gagCEST). Proc Natl Acad Sci U S A. 2008;105:2266-70.

3. Mlynarik V et al. An improved saturation scheme for measuring gagCEST in human knee at 7 T. Proc Intl Soc Mag Reson Med 23, 4231 (2015).


Figure 1: Right knee joint of a 26-year-old healthy female at 7T: sagittal gagCEST map superimposed on a proton density weighted turbo spin echo sequence image.

Figure 2: An example of the selection of regions of interests (ROIs) for the evaluation of MTRasym in weight bearing and non-weight bearing femoral cartilage, tibial and patellar cartilage.

Figure 3: Differences in MTRasym according to cartilage region. Two consecutive measurements per volunteer were included (n = 14).

Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)