Glycosaminoglycan Chemical Exchange Saturation Transfer Research Articles

Non-Invasive Monitoring of Increased Fibrotic Tissue and Hyaluronan Deposition in the Tumor Microenvironment in the Advanced Stages of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinomas are characterized by a complex and robust tumor microenvironment (TME) consisting of fibrotic tissue, excessive levels of hyaluronan (HA), and immune cells. We utilized quantitative multi-parametric magnetic resonance imaging (mp-MRI) methods at 14 Tesla in a genetically engineered KPC (KrasLSL-G12D/+, Trp53LSL-R172H/+, Cre) mouse model to assess the complex TME in advanced stages of tumor development. The whole tumor, excluding cystic areas, was selected as the region of interest for data analysis and subsequent statistical analysis. Pearson correlation was used for statistical inference. There was a significant correlation between tumor volume and T2 (r = -0.66), magnetization transfer ratio (MTR) (r = 0.60), apparent diffusion coefficient (ADC) (r = 0.48), and Glycosaminoglycan-chemical exchange saturation transfer (GagCEST) (r = 0.51). A subset of mice was randomly selected for histological analysis. There were positive correlations between tumor volume and fibrosis (0.92), and HA (r = 0.76); GagCEST and HA (r = 0.81); and MTR and CD31 (r = 0.48). We found a negative correlation between ADC low-b (perfusion) and Ki67 (r = -0.82). Strong correlations between mp-MRI and histology results suggest that mp-MRI can be used as a non-invasive tool to monitor the tumor microenvironment.

Imaging of exercise-induced spinal remodeling in elite rowers

ObjectivesAs in-vivo knowledge of training-induced remodeling of intervertebral discs (IVD) is scarce, this study assessed how lumbar IVDs change as a function of long-term training in elite athletes and age-matched controls using compositional Magnetic Resonance Imaging (MRI). DesignProspective case-control study. MethodsProspectively, lumbar spines of 17 elite rowers (ERs) of the German national rowing team (mean age: 23.9 ± 3.3 years) were imaged on a clinical 3.0 T MRI scanner. ERs were imaged twice during the annual training cycle, i.e., at training intensive preseason preparations (t0) and 6 months later during post-competition recovery (t1). Controls (n = 22, mean age: 26.3 ± 1.9 years) were imaged once at corresponding time points (t0: n = 11; t1: n = 11). Segment-wise, the glycosaminoglycan (GAG) content of lumbar IVDs (n = 195) was determined using glycosaminoglycan chemical exchange saturation transfer (gagCEST). Linear mixed models were set up to assess the influence of cohort and other variables on GAG content. ResultsDuring preseason, IVD GAG values of ERs were significantly higher than those of controls (ERs(t0): 2.58 ± 0.27% (mean ± standard deviations); controls(t0): 1.43 ± 0.36%; p ≤ 0.001), while during post-competition recovery, such differences were not present anymore (ERs(t1): 2.11 ± 0.18%; controls(t1): 1.89 ± 0.24%; p = 0.362). ConclusionsProfessional elite-level rowing is transiently associated with significantly higher gagCEST values, which indicate increased lumbar IVD-GAG content and strong remodeling effects in response to training. Beyond professional rowing, core-strengthening full-body exercise may help to enhance the resilience of the lumbar spine as a potential therapeutic target in treating back pain.

Evaluating Lumbar Intervertebral Disc Degeneration on a Compositional Level Using Chemical Exchange Saturation Transfer: Preliminary Results in Patients with Adolescent Idiopathic Scoliosis.

Lumbar intervertebral disc (IVD) degeneration is characterized by structural and compositional changes. This study aimed to assess the glycosaminoglycan (GAG) content of IVDs of patients with adolescent idiopathic scoliosis (AIS) and healthy controls using GAG chemical exchange saturation transfer (gagCEST) imaging. Ten AIS patients (mean age 18.3 ± 8.2 years) and 16 healthy controls (mean age 25.5 ± 1.7 years) were included. Clinical standard morphologic MR images (T1w-, T2w-, and STIR-sequences), to rule out further spinal disorders and assess IVD degeneration using the Pfirrmann score, and compositional gagCEST sequences were acquired on a 3T MRI. In AIS patients, the most distal scoliotic curve was determined on whole-spine conventional radiographs and morphological MRI and IVDs were divided as to whether they were affected by scoliotic deformity, i.e., proximal (affected, aIVDs) or distal (unaffected, uaIVDs) to the stable vertebra of the most distal scoliotic curve. Linear mixed models were used to compare mean gagCEST-values. Over all segments, AIS-patients’ IVDs exhibited significantly lower gagCEST-values than the controls: 2.76 [2.32, 3.20]% (AIS), 3.51 [3.16, 3.86]% (Control); p = 0.005. Meanwhile, no significant differences were found for gagCEST values comparing aIVDs with uaIVDs. In conclusion, as a powerful diagnostic adjunct, gagCEST imaging may be prospectively applied to detect early compositional degenerative changes in patients suffering from AIS.

OP0109 CARTILAGE LESIONS OF THE KNEE: GAGCEST IMAGING AT 3 T MRI AND INTRAOPERATIVE VALIDATION

Background:Morphological Magnetic Resonance Imaging (MRI) has become the accepted diagnostic tool for non-invasive evaluation of cartilage lesions1. Emerging techniques including chemical exchange saturation transfer (CEST) can be used to visualize microstructural and biochemical changes to the cartilage matrix even before morphological damage is visible2,3. CEST is a promising technique based on detecting the chemical exchange between bulk water protons and protons bound to solutes. This technique renders the possibility to function as a biomarker for glycosaminoglycan (GAG/gag) content for instance in cartilage of joints.Objectives:The aim of the study was to compare glycosaminoglycan chemical exchange saturation transfer (gagCEST) of knee cartilage with intraoperative results for the assessment of early osteoarthritis (OA) and to define gagCEST values for the differentiation between healthy and degenerated cartilage.Methods:Patients with cartilage lesions or moderate OA were preoperatively examined using 3T Magnetic Resonance Imaging (MRI). In this prospective study, regions of interest (ROIs) were examined by a sagittal gagCEST analysis and a morphological high-resolution three-dimensional, fat-saturated proton-density space sequence. Cartilage lesions were identified arthroscopically, graded by the International Cartilage Repair Society (ICRS) score in 42 defined ROIs per patient and consecutively compared with mean gagCEST values using analysis of variance and Spearman’s rank correlation test. Receiver operating characteristics (ROC) curves were applied to identify gagCEST threshold values to differentiate between the ICRS grades.aResults:Twenty-one patients with cartilage lesions or moderate OA were examined. The imaging assessment consisted of a total of 882 ROIs which were examined and graduated in ICRS score 0 (67.3%), 1 (25.2%), 2 (6.2%) and the merged ICRS 3 and 4 (1.0%). gagCEST values decreased with increasing grade of cartilage damage with a negative correlation between gagCEST values and ICRS scores. A gagCEST value threshold of 3.55% was identified to differentiate between ICRS score 0 (normal) and all other grades.Conclusion:Conclusions. gagCEST reflects the content of glycosaminoglycan and might provide a diagnostic tool for the detection of early knee-joint cartilage damage and for the non-invasive subtle differentiation between ICRS grades by MRI even at early stages in clinical practice.

GagCEST imaging at 3 T MRI in patients with articular cartilage lesions of the knee and intraoperative validation

The aim of this study was to compare glycosaminoglycan chemical exchange saturation transfer (gagCEST) of knee cartilage with intraoperative results for the assessment of early osteoarthritis (OA) and to define gagCEST values for the differentiation between healthy and degenerated cartilage. Twenty-one patients with cartilage lesions or moderate OA were examined using 3T Magnetic Resonance Imaging (MRI). In this prospective study, regions of interest (ROIs) were examined by a sagittal gagCEST analysis and a morphological high-resolution three-dimensional, fat-saturated proton-density space sequence. Cartilage lesions were identified arthroscopically, graded by the International Cartilage Repair Society (ICRS) score in 42 defined ROIs per patient and consecutively compared with mean gagCEST values using analysis of variance and Spearman's rank correlation test. Receiver operating characteristics (ROC) curves were applied to identify gagCEST threshold values to differentiate between the ICRS grades. A total of 882 ROIs were examined and graduated in ICRS score 0 (67.3%), 1 (25.2%), 2 (6.2%) and the merged ICRS 3 and 4 (1.0%). gagCEST values decreased with increasing grade of cartilage damage with a negative correlation between gagCEST values and ICRS scores. A gagCEST value threshold of 3.55% was identified to differentiate between ICRS score 0 (normal) and all other grades. gagCEST reflects the content of glycosaminoglycan and might provide a diagnostic tool for the detection of early knee-joint cartilage damage and for the non-invasive subtle differentiation between ICRS grades by MRI even at early stages in clinical practice.

Non-Specific Low Back Pain and Lumbar Radiculopathy: Comparison of Morphologic and Compositional MRI as Assessed by gagCEST Imaging at 3T.

Using glycosaminoglycan Chemical Exchange Saturation Transfer (gagCEST) magnetic resonance imaging (MRI), this study comparatively evaluated the GAG contents of lumbar intervertebral disks (IVDs) of patients with non-specific low back pain (nsLBP), radiculopathy, and asymptomatic volunteers to elucidate the association of clinical manifestation and compositional correlate. A total of 18 patients (mean age 57.5 ± 22.5 years) with radiculopathy, 16 age-matched patients with chronic nsLBP and 20 age-matched volunteers underwent standard morphologic and compositional gagCEST MRI on a 3T scanner. In all cohorts, GAG contents of lumbar IVDs were determined using gagCEST MRI. An assessment of morphologic IVD degeneration based on the Pfirrmann classification and T2-weighted sequences served as a reference. A linear mixed model adjusted for multiple confounders was used for statistical evaluation. IVDs of patients with nsLBP showed lower gagCEST values than those of volunteers (nsLBP: 1.3% [99% confidence intervals (CI): 1.0; 1.6] vs. volunteers: 1.9% [99% CI: 1.6; 2.2]). Yet, IVDs of patients with radiculopathy (1.8% [99% CI: 1.4; 2.1]) were not different from patients with nsLBP or volunteers. In patients with radiculopathy, IVDs directly adjacent to IVD extrusions demonstrated lower gagCEST values than distant IVDs (adjacent: 0.9% [99% CI: 0.3; 1.5], distant: 2.1% [99% CI: 1.7; 2.5]). Advanced GAG depletion in nsLBP and directly adjacent to IVD extrusions in radiculopathy indicates close interrelatedness of clinical pathology and compositional degeneration.

In vivo biochemical assessment of cartilage with gagCEST MRI: Correlation with cartilage properties.

To assess articular cartilage in vivo, a noninvasive measurement is proposed to evaluate damage of the cartilage. It is hypothesized that glycosaminoglycan chemical exchange saturation transfer (gagCEST) can be applied as a noninvasive imaging technique as it would relate to electromechanical indentation and GAG content as measured with biochemical assays. This pilot study applies gagCEST MRI in total knee arthroplasty (TKA) patients to assess substantially damaged articular cartilage. The outcome was verified against electromechanical indentation and biochemical assays to assess the potential of gagCEST MRI. Five TKA patients were scanned on a 7.0 T MRI with a gagCEST sequence. Articular resurfacing cuts after TKA were obtained for electromechanical and biochemical analyses. The gagCEST MRI measurements on the medial condyle showed a moderate correlation with the GAG content, although sensitivity on the lateral condyle was lacking. Additionally, a strong negative correlation of gagCEST MRI with the electromechanical measurements was observed in the regression analysis. Correlation of gagCEST MRI with electromechanical measurements was shown, but the correlation of gagCEST MRI with GAG content was not convincing. In conclusion, gagCEST could be a useful tool to assess the GAG content in articular cartilage noninvasively, although the mismatch in heterogeneity requires further investigation.

Functional MR imaging beyond structure and inflammation\u2014radiographic axial spondyloarthritis is associated with proteoglycan depletion of the lumbar spine

BackgroundTo compare the glycosaminoglycan (GAG) content of lumbar intervertebral disks (IVDs) of patients with ankylosing spondylitis (AS) and healthy volunteers and to investigate the association of GAG depletion and disease-related clinical and imaging features.MethodsLumbar spines of 50 AS patients (mean age 50 ± 10.5 years) and 30 age-matched volunteers were studied with 3-T magnetic resonance imaging (MRI) and conventional radiographs (CR). The MRI protocol included high-resolution morphological sequences and the compositional GAG chemical exchange saturation transfer imaging technique (gagCEST). Morphological images were analyzed by three raters for inflammatory activity, fat deposition, disk degeneration, and structural changes on CR. Clinical and serological measures included the Bath AS Disease Activity (BASDAI) and Bath AS Function (BASFI) Indices and C-reactive protein (CRP) levels. GagCEST values of both groups were compared using a linear mixed model. Kendall-Tau correlation analyses were performed.ResultsGagCEST values were significantly lower in AS patients (2.0 ± 1.7%) vs. healthy volunteers (2.4 ± 1.8%), p = 0.001. Small, yet significant correlations were found between gagCEST values and CRP levels (τ = − 0.14, p = 0.007), BASFI (τ = − 0.18, p < 0.001) and presence of syndesmophytes (τ = − 0.17, p = 0.001). No significant correlations were found with BASDAI, inflammation, and fat deposition MRI scores.ConclusionsLumbar spines of r-AS patients undergo significant GAG depletion, independently associated with syndesmophyte formation, functional disability, and increased serological inflammation markers. Beyond establishing a pathophysiological role of the cartilage in AS, these findings suggest that gagCEST imaging may have an adjunct confirmatory role in the assessment of disease-related pathological MRI findings in axial spondyloarthritis.Trial registration3980 (https://studienregister.med.uni-duesseldorf.de)

Detection of early cartilage degeneration in the tibiotalar joint using 3 T gagCEST imaging: a feasibility study

ObjectiveTo establish and optimize a stable 3 Tesla (T) glycosaminoglycan chemical exchange saturation transfer (gagCEST) imaging protocol for assessing the articular cartilage of the tibiotalar joint in healthy volunteers and patients after a sustained injury to the ankle.MethodsUsing Bloch–McConnell simulations, we optimized the sequence protocol for a 3 T MRI scanner for maximum gagCEST effect size within a clinically feasible time frame of less than 07:30 min. This protocol was then used to analyze the gagCEST effect of the articular cartilage of the tibiotalar joint of 17 healthy volunteers and five patients with osteochondral lesions of the talus following ankle trauma. Reproducibility was tested with the intraclass correlation coefficient.ResultsThe mean magnetization transfer ratio asymmetry (MTRasym), i.e., the gagCEST effect size, was significantly lower in patients than in healthy volunteers (0.34 ± 1.9% vs. 1.49 ± 0.11%; p < 0.001 [linear mixed model]). Intra- and inter-rater reproducibility was excellent with an average measure intraclass correlation coefficient (ICC) of 0.97 and a single measure ICC of 0.91 (p < 0.01).DiscussionIn this feasibility study, pre-morphological tibiotalar joint cartilage damage was quantitatively assessable on the basis of the optimized 3 T gagCEST imaging protocol that allowed stable quantification gagCEST effect sizes across a wide range of health and disease in clinically feasible acquisition times.

Magnetic resonance imaging biomarkers for pulsed focused ultrasound treatment of pancreatic ductal adenocarcinoma.

BACKGROUNDThe robust fibroinflammatory stroma characteristic of pancreatic ductal adenocarcinoma (PDA) impedes effective drug delivery. Pulsed focused ultrasound (pFUS) can disrupt this stroma and has improved survival in an early clinical trial. Non-invasive methods to characterize pFUS treatment effects are desirable for advancement of this promising treatment modality in larger clinical trials.AIMTo identify promising, non-invasive pre-clinical imaging methods to characterize acute pFUS treatment effects for in vivo models of PDA.METHODSWe utilized quantitative magnetic resonance imaging methods at 14 tesla in three mouse models of PDA (subcutaneous, orthotopic and transgenic - KrasLSL-G12D/+, Trp53LSL-R172H/+, Cre or “KPC”) to assess immediate tumor response to pFUS treatment (VIFU 2000 Alpinion Medical Systems; 475 W peak electric power, 1 ms pulse duration, 1 Hz, duty cycle 0.1%) vs sham therapy, and correlated our results with histochemical data. These pFUS treatment parameters were previously shown to enhance tumor permeability to chemotherapeutics. T1 and T2 relaxation maps, high (126, 180, 234, 340, 549) vs low (7, 47, 81) b-value apparent diffusion coefficient (ADC) maps, magnetization transfer ratio (MTR) maps, and chemical exchange saturation transfer (CEST) maps for the amide proton spectrum (3.5 parts per million or “ppm”) and the glycosaminoglycan spectrum (0.5-1.5 ppm) were generated and analyzed pre-treatment, and immediately post-treatment, using ImageJ. Animals were sacrificed immediately following post-treatment imaging. The whole-tumor was selected as the region of interest for data analysis and subsequent statistical analysis. T-tests and Pearson correlation were used for statistical inference.RESULTSMean high-b value ADC measurements increased significantly with pFUS treatment for all models. Mean glycosaminoglycan CEST and T2 measurements decreased significantly post-treatment for the KPC group. Mean MTR and amide CEST values increased significantly for the KPC group. Hyaluronic acid focal intensities in the treated regions were significantly lower following pFUS treatment for all animal models. The magnetic resonance imaging changes observed acutely following pFUS therapy likely reflect: (1) Sequelae of variable degrees of microcapillary hemorrhage (T1, MTR and amide CEST); (2) Lower PDA glycosaminoglycan content and associated water content (glycosaminoglycan CEST, T2 and hyaluronic acid focal intensity); and (3) Improved tumor diffusivity (ADC) post pFUS treatment.CONCLUSIONT2, glycosaminoglycan CEST, and ADC maps may provide reliable quantitation of acute pFUS treatment effects for patients with PDA.

The role of cartilage glycosaminoglycan structure in gagCEST.

Glycosaminoglycan (GAG) chemical exchange saturation transfer (gagCEST) is a potential method for cartilage quality assessment. The aim of this study was to investigate how the gagCEST effect depends on the types and molecular organization of GAG typically found in articular cartilage. gagCEST was performed on different concentrations of GAG in various forms: free chains of chondroitin sulfate (CS) of different types (-A and -C) and GAG bound to protein in aggregated and nonaggregated aggrecan extracted from calf articular cartilage. The measured magnetization transfer ratio asymmetry (MTRasym ) was compared with known GAG concentrations or GAG concentrations determined through biochemical analysis. The gagCEST effect was assessed through the linear regression coefficient with 95% confidence interval of MTRasym per GAG concentration. We observed a lower gagCEST effect in phantoms containing a mixture of CS-A and CS-C compared with phantoms containing mainly CS-A. The difference in response corresponds well to the difference in CS-A concentration. GAG bound in aggrecan from calf articular cartilage, where CS-A is assumed to be the major type of GAG, produed a similar gagCEST effect as that observed for free CS-A. The effect was also similar for aggregated (ie, bound to hyaluronic acid) and nonaggregated aggrecan. In conclusion, our results indicate that the aggrecan structure in itself does not impact the gagCEST effect, but that the effect is strongly dependent on GAG type. In phantoms, the current implementation of gagCEST is sensitive to CS-A while for CS-C, the main GAG component in mature human articular cartilage, the sensitivity is limited. This difference in gagCEST sensitivity between GAG types detected in phantoms is a strong motivation to also explore the possibility of a similar effect in vivo.

Non-Invasive Monitoring of Stromal Biophysics with Targeted Depletion of Hyaluronan in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is characterized by a pronounced fibroinflammatory stromal reaction consisting of inordinate levels of hyaluronan (HA), collagen, immune cells, and activated fibroblasts that work in concert to generate a robust physical barrier to the perfusion and diffusion of small molecule therapeutics. The targeted depletion of hyaluronan with a PEGylated recombinant human hyaluronidase (PEGPH20) lowers interstitial gel–fluid pressures and re-expands collapsed intratumoral vasculature, improving the delivery of concurrently administered agents. Here we report a non-invasive means of assessing biophysical responses to stromal intervention with quantitative multiparametric magnetic resonance imaging (MRI) at 14 Tesla (T). We found that spin-spin relaxation time T2 values and glycosaminoglycan chemical exchange saturation transfer (GagCEST) values decreased at 24 h, reflecting depletion of intratumoral HA content, and that these parameters recovered at 7 days concurrent with replenishment of intratumoral HA. This was also reflected in an increase in low-b apparent diffusion coefficient (ADC) at 24 h, consistent with improved tumor perfusion that again normalized at 7 days after treatment. Phantom imaging suggests that the GagCEST signal is driven by changes in HA versus other glycosaminoglycans. Thus, multiparametric magnetic resonance imaging (MRI) can be used as a non-invasive tool to assess therapeutic responses to targeted stromal therapy in PDA and likely other stroma-rich solid tumors that have high levels of hyaluronan and collagen.

Assessment of Glycosaminoglycan Content of Lumbar Intervertebral Discs in Patients with Radiculopathy

Objective: To assess glycosaminoglycan (GAG) content of lumbar intervertebral discs (IVDs) in patients with radiculopathy compared with healthy volunteers with glycosaminoglycan chemical exchange saturation transfer (gagCEST). Methods: The lumbar spines of 15 patients with radiculopathy (9 women, 6 men; mean age 45 years; range: 19 - 80 years) and 13 healthy controls (10 women, 3 men; mean age 29 years; range: 19 - 38 years) without lumbar back pain or previous spine surgery were examined at a 3 Tesla (T) magnetic resonance imaging (MRI) scanner in this prospective study. The MRI protocol included standard morphological, sagittal, and transverse T2-weighted (T2w) images of the five lumbar IVDs (L1-S1) to assess Pfirrmann score and to detect disc disorders according to the Combined Task Force classification. To analyze biochemically the lumbar IVDs, a gagCEST sequence was applied to measure the GAG content of the nucleus pulposus (NP) and annulus fibrosus (AF). Results: Patients with radiculopathy indicated significantly lower gagCEST values in NP than healthy volunteers (2.82% ± 3.12% vs. 4.09% ± 2.25%, P = 0.017). The GAG content of AF showed no significant difference between volunteers and patients (2.66% ± 2.01% vs. 1.92% ± 2.56%; P = 0.175). Conclusions. Patients with radiculopathy presented with lower GAG values than healthy volunteers in NP, indicating an association between pain and IVD degeneration. gagCEST of lumbar IVDs is a powerful, non-invasive tool to investigate early disc degeneration, which we could demonstrate in the NP in our study collective.

A Qualitative and Quantitative Correlation Study of Lumbar Intervertebral Disc Degeneration Using Glycosaminoglycan Chemical Exchange Saturation Transfer, Pfirrmann Grade, and T1-ρ.

Glycosaminoglycan chemical exchange saturation transfer (gagCEST) imaging allows the direct measurement and mapping of glycosaminoglycans. In this study, we aimed to evaluate the usefulness of gagCEST imaging in the quantitative assessment of intervertebral disc degeneration in a comparison with Pfirrmann grade and T1-ρ measurements. Ninety-six lumbar intervertebral discs in 24 volunteers (36.0 ± 8.5 years of age, 21 men and 3 women) were examined with both gagCEST imaging and T1-ρ measurements. The gagCEST imaging was performed at 3T with a saturation pulse with 1.0-second duration and the B1 amplitude of 0.8 μT followed by imaging by a 2D fast spin-echo sequence. The Z-spectra were obtained at 25 frequency offsets from -3 to +3 ppm (step, 0.25 ppm). A point-by-point B0 correction was performed with a B0 map. The gagCEST signal and T1-ρ values were measured in the nucleus pulposus in each intervertebral disc. The Pfirrmann grades were assessed on T2-weighted images. The gagCEST signal at grade I (5.36% ± 2.79%) was significantly higher than those at Pfirrmann grade II (3.15% ± 1.40%, P = .0006), grade III (0.14% ± 1.03%, P < .0001), grade IV (-1.75% ± 2.82%, P < .0001), and grade V (-1.47% ± 0.36%, P < .0001). The gagCEST signal at grade II was significantly higher than those of grade III (P < .0001), grade IV (P < .0001), and grade V (P < .0001). The gagCEST signal was significantly correlated negatively with Pfirrmann grade (P < .0001) and positively correlated with T1-ρ (P < .0001). GagCEST imaging could be a reliable and quantitative technique for assessing intervertebral disc degeneration.

Cartilage Imaging: Techniques and Developments.

Cartilage degeneration is one of the most common chronic age-related joint disorders leading to pain and reduced joint motion. The increasing prevalence of osteoarthritis requires accurate cartilage imaging, both clinically and in research. Detailed cartilage imaging is also necessary for traumatic cartilage lesions and for pre- and postoperative assessment of cartilage repair procedures. Although still widely used, conventional radiography bears significant limitations because it assesses cartilage indirectly by joint space width. Magnetic resonance imaging (MRI) enables direct visualization of cartilage damage along with other concomitantly affected joint tissues. Several semiquantitative grading systems and volumetric analysis methods exist to assess cartilage damage and cartilage repair on MRI. Quantification of hyaline and fibrocartilage biochemical composition is possible with novel MRI methods such as T2- and T1ρ-mapping, delayed gadolinium-enhanced MRI of cartilage, glycosaminoglycan chemical exchange saturation transfer, and sodium imaging, along with quantitative computed tomography arthrography. These techniques provide promising quantitative imaging biomarkers that can detect early cartilage changes before morphological alterations occur.

Relationship Between Quantitative MRI Biomarkers and Patient-Reported Outcome Measures After Cartilage Repair Surgery: A Systematic Review

Background:Treatment of articular cartilage injuries remains a clinical challenge, and the optimal tools to monitor and predict clinical outcomes are unclear. Quantitative magnetic resonance imaging (qMRI) allows for a noninvasive biochemical evaluation of cartilage and may offer advantages in monitoring outcomes after cartilage repair surgery.Hypothesis:qMRI sequences will correlate with early pain and functional measures.Study Design:Systematic review; Level of evidence, 3.Methods:A PubMed search was performed with the following search terms: knee AND (cartilage repair OR cartilage restoration OR cartilage surgery) AND (delayed gadolinium-enhanced MRI OR t1-rho OR T2 mapping OR dgemric OR sodium imaging OR quantitative imaging). Studies were included if correlation data were included on quantitative imaging results and patient outcome scores.Results:Fourteen articles were included in the analysis. Eight studies showed a significant relationship between quantitative cartilage imaging and patient outcome scores, while 6 showed no relationship. T2 mapping was examined in 11 studies, delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) in 4 studies, sodium imaging in 2 studies, glycosaminoglycan chemical exchange saturation transfer (gagCEST) in 1 study, and diffusion-weighted imaging in 1 study. Five studies on T2 mapping showed a correlation between T2 relaxation times and clinical outcome scores. Two dGEMRIC studies found a correlation between T1 relaxation times and clinical outcome scores.Conclusion:Multiple studies on T2 mapping, dGEMRIC, and diffusion-weighted imaging showed significant correlations with patient-reported outcome measures after cartilage repair surgery, although other studies showed no significant relationship. qMRI sequences may offer a noninvasive method to monitor cartilage repair tissue in a clinically meaningful way, but further refinements in imaging protocols and clinical interpretation are necessary to improve utility.

Detection of early cartilage damage: feasibility and potential of gagCEST imaging at 7T

ObjectivesThe purpose was to implement a fast 3D glycosaminoglycan Chemical Exchange Saturation Transfer (gagCEST) sequence at 7 T, test stability and reproducibility in cartilage in the knee in healthy volunteers, and evaluate clinical applicability in cartilage repair patients.MethodsExperiments were carried out on a 7-T scanner using a volume transmit coil and a 32-channel receiver wrap-around knee coil. The 3D gagCEST measurement had an acquisition time of 7 min. Signal stability and reproducibility of the GAG effect were assessed in eight healthy volunteers. Clinical applicability of the method was demonstrated in five patients before cartilage repair surgery.ResultsCoefficient of variation of the gagCEST signal was 1.9%. The reproducibility of the GAG effect measurements was good in the medial condyle (ICC = 0.87) and excellent in the lateral condyle (ICC = 0.97). GAG effect measurements in healthy cartilage ranged from 2.6%-12.4% compared with 1.3%-5.1% in damaged cartilage. Difference in GAG measurement between healthy cartilage and damaged cartilage was significant (p < 0.05).ConclusionsA fast 3D gagCEST sequence was applied at 7 T for use in cartilage in the knee, acquired within a clinically feasible scan time of 7 min. We demonstrated that the method has high stability, reproducibility and clinical applicability.Key Points• gagCEST measurements are stable and reproducible• A non-invasive GAG measurement with gagCEST can be acquired in 7 min• gagCEST is able to discriminate between healthy and damaged cartilage

Evaluating the cartilage adjacent to the site of repair surgery with glycosaminoglycan-specific magnetic resonance imaging

The glycosaminoglycan (GAG) chemical exchange saturation transfer (CEST) imaging method (gagCEST) makes it possible to assess and quantify the GAG concentration in human cartilage. This biochemical imaging technique facilitates detection of the loss of GAG in the course of osteoarthritis. The gagCEST technique was used to analyse the perilesional zone (PLZ) adjacent to repair tissue after cartilage repair surgery, to determine whether there are biochemical changes present in the sense of degeneration. Asymmetries in the PLZ of cartilage defects in 11 patients, who had been treated by microfracturing or matrix-associated autologous chondrocyte transplantation (MACT), were measured by gagCEST on a 7-T whole-body system. These results were correlated with gagCEST asymmetries of healthy reference cartilage (RC), measured anterior and posterior to the PLZ and to the repair tissue (RT). The mean gagCEST asymmetry for the anterior PLZ was 4.8% (±4.4), for the posterior PLZ 5.4% (±2.3), for the anterior RC 6.6% (±3.5) and 7.2% (±3.3) for the posterior RC and 4.5% (±2.3) for the RT. The difference between the anterior PLZ and the anterior RC (p = 0.019), the posterior PLZ and the posterior RC (p = 0.005), and the mean RC and the RT (p = 0.021) were all statistically significant. The measurements between RT and mean PLZ did not reveal significant results (p = 0.398). The gagCEST method provides a potentially useful biomarker for the loss of GAGs, indicating cartilage degeneration in the PLZ. Pre-operative and post-operative monitoring of the biomechanical state of the cartilage might influence intra-operative decision-making concerning the extent of cartilage resection or might give information of the success of the treatment post-operatively.

Prestructural cartilage assessment using MRI.

5 J. Magn. Reson. Imaging 2017;45:949-965.

Assessment of the patellofemoral cartilage: Correlation of knee pain score with magnetic resonance cartilage grading and magnetization transfer ratio asymmetry of glycosaminoglycan chemical exchange saturation transfer

PurposeBiochemical imaging of glycosaminoglycan chemical exchange saturation transfer (gagCEST) could predict the depletion of glycosaminoglycans (GAG) in early osteoarthritis. The purpose of this study was to evaluate the relationship between the magnetization transfer ratio asymmetry (MTRasym) of gagCEST images and visual analog scale (VAS) pain scores in the knee joint. Materials and methodsThis retrospective study was approved by the institutional review board. A phantom study was performed using hyaluronic acid to validate the MTRasym values of gagCEST images. Knee magnetic resonance (MR) images of 22 patients (male, 9; female, 13; mean age, 50.3years; age range; 25–79years) with knee pain were included in this study. The MR imaging (MRI) protocol involved standard knee MRI as well as gagCEST imaging, which allowed region-of-interest analyses of the patellar facet and femoral trochlea. The MTRasym at 1.0ppm was calculated at each region. The cartilages of the patellar facets and femoral trochlea were graded according to the Outerbridge classification system. Data regarding the VAS scores of knee pain were collected from the electronic medical records of the patients. Statistical analysis was performed using Spearman's correlation. ResultsThe results of the phantom study revealed excellent correlation between the MTRasym values and the concentration of GAGs (r=0.961; p=0.003). The cartilage grades on the MR images showed significant negative correlation with the MTRasym values in the patellar facet and femoral trochlea (r=−0.460; p=0.031 and r=−0.543; p=0.009, respectively). The VAS pain scores showed significant negative correlation with the MTRasym values in the patellar facet and femoral trochlea (r=−0.435; p=0.043 and r=−0.671; p=0.001, respectively). ConclusionThe pain scores were associated with the morphological and biochemical changes in articular cartilages visualized on knee MR images. The biochemical changes, visualized in terms of the MTRasym values of the gagCEST images, exhibited greater correlation with the pain scores than the morphological changes visualized on conventional MR images; these results provide evidence supporting the theory regarding the association of patellofemoral osteoarthritis with knee pain scores.