Quantitative Imaging Biomarkers of Knee Cartilage Composition

For a long time, radiography and subsequently conventional magnetic resonance imaging (MRI) were used as imaging biomarkers for evaluating cartilage morphological disease state in osteoarthritis (OA). Because research is switching its focus towards disease modification or even prevention to target OA at an early stage, imaging techniques that measure cartilage composition rather than its morphology became of interest. Several MRI and computed tomography (CT) based quantitative imaging biomarkers for cartilage composition were developed. These techniques were advocated to allow a quantitative measure of the sulphated glycosaminoglycan (sGAG) content, an important composite of the cartilage extracellular matrix. The main aims of this thesis is based have been divided between MRI and CT based quantitative imaging biomarkers since their different stage of application in research. MRI has already been applied in human OA research, whereas CT was still to be translated and implemented in clinical research. The first part of this thesis focused on MRI based techniques and aimed at optimization of image post processing, assessing reproducibility, comparison of different MRI sequences and application in clinical OA research. Since accurate image post processing is of utmost importance to generate reliable and robust quantitative MRI outcomes, an imaging post processing tool was developed and described in chapter 2. This tool corrects for intra-sequence patient motion during acquisition of quantitative MR images, by applying image registration reducing errors and incorrect outcomes. This resulted in 6-14% improvement in accuracy of delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) T1 relaxation time. Using image registration, the tool also allows assessment of the same cartilage region throughout multiple MRI acquisitions, which makes analyses less time consuming. Finally, the algorithm also involves a fitting technique which corrects for unreliable quantitative MRI biomarker data by calculating a weighted mean outcome for all voxels in a specific cartilage region based on the inaccuracy of each voxel. Because of these abilities and the fact that this tool could be used in any quantitative MRI biomarker, e.g. T1rho-mapping or T2-mapping, the image post processing tool was used in all chapters in this thesis where MRI based measures were used for cartilage sGAG content. Along with robust image processing tools, the outcomes of the MRI exam itself should also be reproducible in order to be able to apply the particular technique in cross-sectional or longitudinal study designs. Therefore, chapter 3 described a reproducibility study of dGEMRIC acquired at 3 Tesla in early stage knee OA patient. It was shown that dGEMRIC is highly reproducible in terms of results in large cartilage regions, as well as for differentiating between spatial distributions of diverse cartilage quality within a single slice. dGEMRIC can therefore be used as an imaging biomarker in cross-sectional and longitudinal study designs. In addition, a threshold for defining significant changes in dGEMRIC results for longitudinal follow-up was determined. T1rho-mapping has been proposed as a non-contrast-enhanced alternative to dGEMRIC for sGAG quantification in clinical studies. However, no thorough validation has been performed comparing both techniques within the same OA patients using a reference standard for cartilage sGAG. Therefore, in chapter 4 an in vivo comparison and validation study assessing the capability of dGEMRIC and T1rho-mapping was performed. In knee OA patients, dGEMRIC results strongly correlate with cartilage sGAG content, whereas T1rho-mapping did not. Therefore, it appears that T1rho-mapping cannot be regarded as an alternative for dGEMRIC to measure cartilage sGAG content in clinical OA research. It was also shown that resu

Has the reporting quality of published randomised controlled trial protocols improved since the SPIRIT statement? A methodological study

OBJECTIVES: To determine the reporting quality of published randomised controlled trial (RCT) protocols before and after the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) statemen

Quantitative in vivo CT arthrography of the human osteoarthritic knee to estimate cartilage sulphated glycosaminoglycan content: Correlation with ex-vivo reference standards

Objective: Recently, computed tomography arthrography (CTa) was introduced as quantitative imaging biomarker to estimate cartilage sulphated glycosaminoglycan (sGAG) content in human cadaveric knees. Our aim was to assess the correlation between in vivo CTa in human osteoarthritis (OA) knees and ex vivo reference standards for sGAG and collagen content. Design: In this prospective observational study 11 knee OA patients underwent CTa before total knee replacement (TKR). Cartilage X-ray attenuation was determined in six cartilage regions. Femoral and tibial cartilage specimens harvested during TKR were re-scanned using equilibrium partitioning of an ionic contrast agent with micro-CT (EPIC-μCT), which served as reference standard for sGAG. Next, cartilage sGAG and collagen content were determined using dimethylmethylene blue (DMMB) and hydroxyproline assays. The correlation between CTa X-ray attenuation, EPIC-μCT X-ray attenuation, sGAG content and collagen content was assessed. Results: CTa X-ray attenuation correlated well with EPIC-μCT (r = 0.76, 95% credibility interval (95%CI) 0.64 to 0.85). CTa correlated moderately with the DMMB assay (sGAG content) (r = -0.66, 95%CI -0.87 to -0.49) and to lesser extent with the hydroxyproline assay (collagen content) (r = -0.56, 95%CI -0.70 to -0.36). Conclusions: Outcomes of in vivo CTa in human OA knees correlate well with sGAG content. Outcomes of CTa also slightly correlate with cartilage collagen content. Since outcomes of CTa are mainly sGAG dependent and despite the fact that further validation using hyaline cartilage of other joints with different biochemical composition should be conducted, CTa may be suitable as quantitative imaging biomarker to estimate cartilage sGAG content in future clinical OA research

Quantitative subchondral bone perfusion imaging in knee osteoarthritis using dynamic contrast enhanced MRI

Objective: Subchondral bone changes, characterized by increased bone turnover and vascularity, are believed to stimulate progression and pain in knee osteoarthritis (OA). The objective of this study was to evaluate the bone perfusion in knee OA using quantitative dynamic contrast enhanced MRI (DCE-MRI). Design: Unicompartmental knee OA patients were included and underwent 3 Tesla DCE-MRI and T2-weighted MRI. Quantitative DCE-MRI analysis of Ktrans and Kep, representing perfusion parameters, was performed to evaluate differences between the most and least affected knee compartment. First, DCE-MRI parameter differences between epimetaphyseal and subchondral bone in both femur and tibia were assessed. Second, DCE-MRI parameters in subchondral bone marrow lesions (BMLs) were compared to surrounding subchondral bone without BMLs. Results: Twenty-three patients were analyzed. Median Ktrans and Kep in epimetaphyseal bone were significantly higher (p < 0.05) in the most affected (Ktrans: 0.014; Kep: 0.054 min−1) compared to least affected (Ktrans: 0.010; Kep: 0.016 min−1) compartment. For subchondral bone, DCE-MRI parameters were significantly higher (p < 0.05) in the most affected (Ktrans: 0.019; Kep: 0.091 min−1) compared to least affected (Ktrans: 0.014; Kep: 0.058 min−1) compartment as well. Subchondral BMLs detected on fat-saturated T2-weighted images were present in all patients. Median Ktrans (0.091 vs 0.000 min−1) and Kep (0.258 vs 0.000 min−1) were significantly higher within subchondral BMLs compared to surrounding subchondral bone without BMLs (p < 0.001). Conclusions: Increased perfusion parameters in epimetaphyseal bone, subchondral bone and BMLs are observed in unicompartmental knee OA. BMLs likely account for most of the effect of the higher bone perfusion in knee OA

T-2 mapping of the meniscus is a biomarker for early osteoarthritis

Purpose To evaluate in vivo T2 mapping as quantitative, imaging-based biomarker for meniscal degeneration in humans, by studying the correlation between T2 relaxation time and degree of histological degeneration as reference standard. Methods In this prospective validation study, 13 menisci from seven patients with radiographic knee osteoarthritis (median age 67 years, three males) were included. Menisci were obtained during total knee replacement surgery. All patients underwent preoperative magnetic resonance imaging using a 3-T MR scanner which included a T2 mapping pulse sequence with multiple echoes. Histological analysis of the collected menisci was performed using the Pauli score, involving surface integrity, cellularity, matrix organization, and staining intensity. Mean T2 relaxation times were calculated in meniscal regions of interest corresponding with the areas scored histologically, using a multi-slice multi-echo postprocessing algorithm. Correlation between T2 mapping and histology was assessed using a generalized least squares model fit by maximum likelihood. Results The mean T2 relaxation time was 22.4 ± 2.7 ms (range 18.5–27). The median histological score was 10, IQR 7–11 (range 4–13). A strong correlation between T2 relaxation time and histological score was found (rs = 0.84, CI 95% 0.64–0.93). Conclusion In vivo T2 mapping of the human meniscus correlates strongly with histological degeneration, suggesting that T2 mapping enables the detection and quantification of early compositional changes of the meniscus in knee OA

Quantitative measurement of articular cartilage quality using MRI

'Delayed gadolinium-enhanced MRI of cartilage' (dGEMRIC) and 'T2 mapping' are novel MRI techniques to quantitatively measure the quality of articular cartilage. The advantage of these novel techniques is that they are able to detect the loss of important composites of cartilage before damage to and deformities of the cartilage become visibleon radiographs or on conventional MRI. These novel MRI techniques can be used to investigate the effectiveness of potentially preventative or disease-modifying therapy at an early stage of cartilage disease, e.g. in osteoarthritis. It is possible that in the future dGEMRIC and T2 mapping will be used in routine clinical practice to diagnose osteoarthritis at an earlier stage and to predict disease progression. However, much more research is still needed. At the Erasmus Medical Center in Rotterdam, the Netherlands, work is being carried out on the validation, implementation and translation into clinicalpractice of these and other novel techniques of quantitative measurement of cartilage quality.</p

Quantitative measurement of articular cartilage quality using MRI

'Delayed gadolinium-enhanced MRI of cartilage' (dGEMRIC) and 'T2 mapping' are novel MRI techniques to quantitatively measure the quality of articular cartilage. The advantage of these novel techniques is that they are able to detect the loss of important composites of cartilage before damage to and deformities of the cartilage become visibleon radiographs or on conventional MRI. These novel MRI techniques can be used to investigate the effectiveness of potentially preventative or disease-modifying therapy at an early stage of cartilage disease, e.g. in osteoarthritis. It is possible that in the future dGEMRIC and T2 mapping will be used in routine clinical practice to diagnose osteoarthritis at an earlier stage and to predict disease progression. However, much more research is still needed. At the Erasmus Medical Center in Rotterdam, the Netherlands, work is being carried out on the validation, implementation and translation into clinicalpractice of these and other novel techniques of quantitative measurement of cartilage quality.</p