Ultrashort Echo Time Imaging of the Osteochondral Junction in Subjects with Knee Osteoarthritis and Age-matched Healthy Volunteers

SYNOPSIS We describe in vivo translation of ultrashort TE (UTE) imaging of the osteochondral junction (OCJ) at the knee in 9 subjects with osteoarthritis (OA) and 4 age-matched healthy volunteers. The OCJ plays an important role in onset and progression of OA. Our study demonstrates that UTE imaging of the OCJ is repeatable and demonstrates OCJ defects in OA subjects but not in healthy volunteers. Areas of OCJ damage commonly co-locate to other osteochondral pathology (bone marrow lesions and cartilage defects). UTE imaging of the OCJ may be a helpful tool for assessing OCJ damage in clinical studies of OA. INTRODUCTION Disruption of the osteochondral junction (OCJ) is thought to play an important role in the onset and progression of osteoarthritis (OA). Using conventional MR imaging, direct visualisation of the OCJ is not possible due to inherent short T1 and T2 relaxation times of the OCJ tissues. However, by achieving echo times (TEs) of < 1 ms, ultrashort echo time (UTE) MR imaging allows direct visualisation of the OCJ. The normal OCJ appears as an area of linear high signal intensity (SI) on UTE images at the bone-cartilage interface. In OA it has been shown that this area of linear high SI can become thinned or absent, compatible with histological findings of OCJ defects(1, 2). These findings have been described in a number of cadaveric MR studies, but there are limited in vivo data available(3-5). The aims of this study were to compare the in vivo appearance of the OCJ on UTE MR imaging between subjects with knee OA and age-matched healthy volunteers, to determine the relationship between OCJ defects and other osteochondral pathology, and to assess test-retest repeatability. METHODS We imaged 9 participants with mild-moderate knee osteoarthritis, characterised by radiographs with medial tibiofemoral compartment predominant disease and Kellgren-Lawrence grades 2-3, and 4 age-matched healthy volunteers. Participants were imaged at baseline and 1 month. MR studies were performed on a 3T system (GE 750, GE Healthcare). The MR protocol consisted of standard clinical sequences (coronal and sagittal intermediate-weighted fat-saturated fast spin echo (FSE) sequences plus a coronal T1-weighted FSE sequence) and a sagittal dual-echo UTE gradient echo sequence acquired using a 3D cones trajectory (research prototype; repetition time 15 ms, TE 0.03/4.5 ms, flip angle 13o, field-of-view 18 x 18 cm, matrix 430 x 430, slice thickness 2 mm, number of averages 1, acquisition time ~ 7.5 minutes). To increase conspicuity of short T2 tissues, we performed weighted digital image subtraction of the longer TE (4.5 ms) from the shorter TE images (0.03 ms)(6). The presence or absence of characteristic linear high SI at the OCJ was scored in 12 regions for each knee, corresponding to tibiofemoral subdivisions commonly used for semi-quantitative scoring. The presence of bone marrow lesions (BML) or cartilage defects in the same regions was also recorded. Assessment was performed by a single musculoskeletal radiologist with 5 years' experience in OA research, blinded to group assignment. We used descriptive statistics to compare the number of regions with OCJ defects in subjects with OA and healthy volunteers, and to assess the frequency with which OCJ defects co-located with BMLs or cartilage defects. Test-retest repeatability was evaluated using kappa statistics. RESULTS Participant characteristics are displayed in table 1. Six out of 9 OA participants (67%) had an OCJ defect in at least one region compared to 0 out of 4 controls (0%). The most commonly involved region was the central medial tibia (4 participants). OCJ defects commonly co-located to BMLs (7 out of 10 OCJ defects, 70%) and cartilage defects (6 out of 10 OCJ defects, 60%). Results are displayed in table 2. Sample images are displayed in figures 1 - 3. The kappa value for test-retest repeatability of OCJ assessment using UTE was 0.83 (95% confidence interval 0.64 to 1). DISCUSSION The appearances of OCJ defects in subjects with OA in vivo are in keeping with abnormalities predicted by cadaveric MR and histology studies(1, 3). The biological plausibility of the findings is enhanced by the frequency of co-location of OCJ damage to other osteochondral pathology (BMLs and cartilage defects). Our findings demonstrate in vivo translation of UTE imaging of the OCJ, and suggest that this is a useful tool for future studies of OA onset and progression. This may include predicting response to intervention, as equine studies have demonstrated that the presence or absence of OCJ damage is an important predictor of response to treatment of cartilage defects(7). Our results demonstrate that UTE imaging of the OCJ is repeatable with kappa values in keeping with 'near-perfect' test-retest repeatability for qualitative assessment(8). Previous in vivo studies have not used age-matched control subjects, therefore it has been unclear whether areas of OCJ damage are related to OA or normal ageing(4). The normal appearance of the OCJ in age-matched control subjects in this study suggests that the OCJ defects are not part of normal ageing, although at present the number of healthy volunteers imaged is small. CONCLUSION In vivo UTE MR imaging of the OCJ is repeatable and demonstrates OCJ defects in subjects with OA. OCJ defects commonly co-locate with other osteochondral pathology

Analysis of cardiac amyloidosis progression using model-based markers

Deposition of amyloid in the heart can lead to cardiac dilation and impair its pumping ability. This ultimately leads to heart failure with worsening symptoms of breathlessness and fatigue due to the progressive loss of elasticity of the myocardium. Biomarkers linked to clinical deterioration can be crucial in developing effective treatments. However, to date progression of cardiac amyloidosis is poorly characterized, and there is an urgent need to identify key features that can predict the disease progression and cardiac tissue function. In this proof of concept study, we estimate a group of new markers based on mathematical models of the left ventricle derived from routine clinical magnetic resonance imaging and follow-up scans from the National Amyloidosis Centre at the Royal Free in London. Using mechanical modelling and statistical classification, we show that it is possible to predict disease progression. Our predictions agree with clinical assessments in a double-blind test in six out of the seven sample cases studied. Importantly, we find that multiple factors need to be used in the classification, which includes mechanical, geometrical and shape features. No single marker can yield reliable prediction given the complexity of the growth and remodelling process of diseased hearts undergoing high-dimensional shape changes. Our approach is promising in terms of clinical translation but the results presented should be interpreted with caution due to the small sample size

Effectively Measuring Exercise-Related Variations in T1ρ and T2 Relaxation Times of Healthy Articular Cartilage.

BACKGROUND: Determining the compositional response of articular cartilage to dynamic joint-loading using MRI may be a more sensitive assessment of cartilage status than conventional static imaging. However, distinguishing the effects of joint-loading vs. inherent measurement variability remains difficult, as the repeatability of these quantitative methods is often not assessed or reported. PURPOSE: To assess exercise-induced changes in femoral, tibial, and patellar articular cartilage composition and compare these against measurement repeatability. STUDY TYPE: Prospective observational study. POPULATION: Phantom and 19 healthy participants. FIELD STRENGTH/SEQUENCE: 3T; 3D fat-saturated spoiled gradient recalled-echo; T1ρ - and T2 -prepared pseudosteady-state 3D fast spin echo. ASSESSMENT: The intrasessional repeatability of T1ρ and T2 relaxation mapping, with and without knee repositioning between two successive measurements, was determined in 10 knees. T1ρ and T2 relaxation mapping of nine knees was performed before and at multiple timepoints after a 5-minute repeated, joint-loading stepping activity. 3D surface models were created from patellar, femoral, and tibial articular cartilage. STATISTICAL TESTS: Repeatability was assessed using root-mean-squared-CV (RMS-CV). Using Bland-Altman analysis, thresholds defined as the smallest detectable difference (SDD) were determined from the repeatability data with knee repositioning. RESULTS: Without knee repositioning, both surface-averaged T1ρ and T2 were very repeatable on all cartilage surfaces, with RMS-CV SDD) average exercise-induced in T1ρ and T2 of femoral (-8.0% and -5.3%), lateral tibial (-6.9% and -5.9%), medial tibial (+5.8% and +2.9%), and patellar (-7.9% and +2.8%) cartilage were observed. DATA CONCLUSION: Joint-loading with a stepping activity resulted in T1ρ and T2 changes above background measurement error. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY STAGE: 1 J. MAGN. RESON. IMAGING 2020;52:1753-1764.GlaxoSmithKline National Institute of Health Research (NIHR) Cambridge Biomedical Research Centr

Manganese-Enhanced T₁ Mapping in the Myocardium of Normal and Infarcted Hearts

Background. Manganese-enhanced MRI (MEMRI) has the potential to identify viable myocardium and quantify calcium influx and handling. Two distinct manganese contrast media have been developed for clinical application, mangafodipir and EVP1001-1, employing different strategies to mitigate against adverse effects resulting from calcium-channel agonism. Mangafodipir delivers manganese ions as a chelate, and EVP1001-1 coadministers calcium gluconate. Using myocardial T1 mapping, we aimed to explore chelated and nonchelated manganese contrast agents, their mechanism of myocardial uptake, and their application to infarcted hearts. Methods. T1 mapping was performed in healthy adult male Sprague-Dawley rats using a 7T MRI scanner before and after nonchelated (EVP1001-1 or MnCl2 (22 μmol/kg)) or chelated (mangafodipir (22–44 μmol/kg)) manganese-based contrast media in the presence of calcium channel blockade (diltiazem (100–200 μmol/kg/min)) or sodium chloride (0.9%). A second cohort of rats underwent surgery to induce anterior myocardial infarction by permanent coronary artery ligation or sham surgery. Infarcted rats were imaged with standard gadolinium delayed enhancement MRI (DEMRI) with inversion recovery techniques (DEMRI inversion recovery) as well as DEMRI T1 mapping. A subsequent MEMRI scan was performed 48 h later using either nonchelated or chelated manganese and T1 mapping. Finally, animals were culled at 12 weeks, and infarct size was quantified histologically with Masson’s trichrome (MTC). Results. Both manganese agents induced concentration-dependent shortening of myocardial T1 values. This was greatest with nonchelated manganese, and could be inhibited by 30–43% with calcium-channel blockade. Manganese imaging successfully delineated the area of myocardial infarction. Indeed, irrespective of the manganese agent, there was good agreement between infarct size on MEMRI T1 mapping and histology (bias 1.4%, 95% CI −14.8 to 17.1 P&gt;0.05). In contrast, DEMRI inversion recovery overestimated infarct size (bias 11.4%, 95% CI −9.1 to 31.8 P=0.002), as did DEMRI T1 mapping (bias 8.2%, 95% CI −10.7 to 27.2 P=0.008). Increased manganese uptake was also observed in the remote myocardium, with remote myocardial ∆T1 inversely correlating with left ventricular ejection fraction after myocardial infarction (r=−0.61, P=0.022). Conclusions. MEMRI causes concentration and calcium channel-dependent myocardial T1 shortening. MEMRI with T1 mapping provides an accurate assessment of infarct size and can also identify changes in calcium handling in the remote myocardium. This technique has potential applications for the assessment of myocardial viability, remodelling, and regeneration.</jats:p

Segmentation of knee MRI data with convolutional neural networks for semi-automated three-dimensional surface-based analysis of cartilage morphology and composition

Objective: To assess automatic segmentations for surface-based analysis of cartilage morphology and composition on knee magnetic resonance (MR) images. Methods: 2D and 3D U-Nets were trained on double echo steady state (DESS) images from the publicly available Osteoarthritis Initiative (OAI) dataset with femoral and tibial bone and cartilage segmentations provided by the Zuse Institute Berlin (ZIB). The U-Nets were used to perform automatic segmentation of femoral and tibial bone-cartilage structures (bone and cartilage segmentations combined into one structure) from the DESS images. T2-weighted images from the OAI dataset were registered to the DESS images and used for T2 map calculation. Using the 3D cartilage surface mapping (3D-CaSM) method, surface-based analysis of cartilage morphology (thickness) and composition (T2) was performed using both manual and network-generated segmentations from OAI ZIB testing images. Bland-Altman analyses were performed to evaluate the accuracy of the extracted cartilage thickness and T2 measurements from both U-Nets compared to manual segmentations. Results: Bland-Altman analysis showed a mean bias [95% limits of agreement] for femoral and tibial cartilage thickness measurements ranging between -0.12 to 0.33 [-0.28, 0.96] mm with 2D U-Net and 0.07 to 0.14 [-0.14, 0.39] mm with 3D U-Net. For T2, the mean bias [95% limits of agreement] ranged between -0.16 to 1.32 [-4.71, 4.83] ms with 2D U-Net and -0.05 to 0.46 [-2.47, 3.39] ms with 3D U-Net. Conclusions: While both 2D and 3D U-Nets exemplified the time-efficiency benefit of using deep learning methods for generating the required segmentations, segmentations from 3D U-Nets demonstrated higher accuracy in the extracted thickness and T2 features using 3D-CaSM compared to the segmentations from 2D U-Nets

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.

BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018)

Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.

BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018)

Dynamic contrast-enhanced MRI of synovitis in knee osteoarthritis: repeatability, discrimination and sensitivity to change in a prospective experimental study

Abstract: Objectives: Evaluate test-retest repeatability, ability to discriminate between osteoarthritic and healthy participants, and sensitivity to change over 6 months, of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) biomarkers in knee OA. Methods: Fourteen individuals aged 40–60 with mild-moderate knee OA and 6 age-matched healthy volunteers (HV) underwent DCE-MRI at 3 T at baseline, 1 month and 6 months. Voxelwise pharmacokinetic modelling of dynamic data was used to calculate DCE-MRI biomarkers including Ktrans and IAUC60. Median DCE-MRI biomarker values were extracted for each participant at each study visit. Synovial segmentation was performed using both manual and semiautomatic methods with calculation of an additional biomarker, the volume of enhancing pannus (VEP). Test-retest repeatability was assessed using intraclass correlation coefficients (ICC). Smallest detectable differences (SDDs) were calculated from test-retest data. Discrimination between OA and HV was assessed via calculation of between-group standardised mean differences (SMD). Responsiveness was assessed via the number of OA participants with changes greater than the SDD at 6 months. Results: Ktrans demonstrated the best test-retest repeatability (Ktrans/IAUC60/VEP ICCs 0.90/0.84/0.40, SDDs as % of OA mean 33/71/76%), discrimination between OA and HV (SMDs 0.94/0.54/0.50) and responsiveness (5/1/1 out of 12 OA participants with 6-month change > SDD) when compared to IAUC60 and VEP. Biomarkers derived from semiautomatic segmentation outperformed those derived from manual segmentation across all domains. Conclusions: Ktrans demonstrated the best repeatability, discrimination and sensitivity to change suggesting that it is the optimal DCE-MRI biomarker for use in experimental medicine studies. Key Points: • Dynamic contrast-enhanced MRI (DCE-MRI) provides quantitative measures of synovitis in knee osteoarthritis which may permit early assessment of efficacy in experimental medicine studies. • This prospective observational study compared DCE-MRI biomarkers across domains relevant to experimental medicine: test-retest repeatability, discriminative validity and sensitivity to change. • The DCE-MRI biomarker Ktransdemonstrated the best performance across all three domains, suggesting that it is the optimal biomarker for use in future interventional studies

Quantifying disease activity in rheumatoid arthritis with the TSPO PET ligand 18 F-GE-180 and comparison with 18 F-FDG and DCE-MRI

Abstract: Purpose: While the aetiology of rheumatoid arthritis (RA) remains unclear, many of the inflammatory components are well characterised. For diagnosis and therapy evaluation, in vivo insight into these processes would be valuable. Various imaging probes have shown value including dynamic contrast-enhanced (DCE) MRI and PET/CT using 18F-fluorodeoxyglucose (18F-FDG) or tracers targeting the translocator protein (TSPO). To evaluate 18F-GE-180, a novel TSPO PET tracer, for detecting and quantifying disease activity in RA, we compared 18F-GE-180 uptake with that of 18F-FDG and DCE-MRI measures of inflammation. Methods: Eight RA patients with moderate-to-high, stable disease activity and active disease in at least one wrist were included in this study (NCT02350426). Participants underwent PET/CT examinations with 18F-GE-180 and 18F-FDG on separate visits, covering the shoulders and from the pelvis to the feet, including hands and wrists. DCE-MRI was performed on one affected hand. Uptake was compared visually between tracers as judged by an experienced radiologist and quantitatively using the maximum standardised uptake value (SUVmax). Uptake for both tracers was correlated with DCE-MRI parameters of inflammation, including the volume transfer coefficient Ktrans using Pearson correlation (r). Results: PET/CT imaging with 18F-GE-180 in RA patients showed marked extra-synovial uptake around the affected joints. Overall sensitivity for detecting clinically affected joints was low (14%). 18F-GE-180 uptake did not or only weakly correlate with DCE-MRI parameters in the wrist (r = 0.09–0.31). 18F-FDG showed higher sensitivity for detecting symptomatic joints (34%), as well as strong positive correlation with DCE-MRI parameters (SUVmax vs. Ktrans: r = 0.92 for wrist; r = 0.68 for metacarpophalangeal joints). Conclusions: The correlations between DCE-MRI parameters and 18F-FDG uptake support use of this PET tracer for quantification of inflammatory burden in RA. The TSPO tracer 18F-GE-180, however, has shown limited use for the investigation of RA due to its poor sensitivity and ability to quantify disease activity in RA

Effectively Measuring Exercise-Related Variations in T1ρ and T2 Relaxation Times of Healthy Articular Cartilage.

BACKGROUND: Determining the compositional response of articular cartilage to dynamic joint-loading using MRI may be a more sensitive assessment of cartilage status than conventional static imaging. However, distinguishing the effects of joint-loading vs. inherent measurement variability remains difficult, as the repeatability of these quantitative methods is often not assessed or reported. PURPOSE: To assess exercise-induced changes in femoral, tibial, and patellar articular cartilage composition and compare these against measurement repeatability. STUDY TYPE: Prospective observational study. POPULATION: Phantom and 19 healthy participants. FIELD STRENGTH/SEQUENCE: 3T; 3D fat-saturated spoiled gradient recalled-echo; T1ρ - and T2 -prepared pseudosteady-state 3D fast spin echo. ASSESSMENT: The intrasessional repeatability of T1ρ and T2 relaxation mapping, with and without knee repositioning between two successive measurements, was determined in 10 knees. T1ρ and T2 relaxation mapping of nine knees was performed before and at multiple timepoints after a 5-minute repeated, joint-loading stepping activity. 3D surface models were created from patellar, femoral, and tibial articular cartilage. STATISTICAL TESTS: Repeatability was assessed using root-mean-squared-CV (RMS-CV). Using Bland-Altman analysis, thresholds defined as the smallest detectable difference (SDD) were determined from the repeatability data with knee repositioning. RESULTS: Without knee repositioning, both surface-averaged T1ρ and T2 were very repeatable on all cartilage surfaces, with RMS-CV SDD) average exercise-induced in T1ρ and T2 of femoral (-8.0% and -5.3%), lateral tibial (-6.9% and -5.9%), medial tibial (+5.8% and +2.9%), and patellar (-7.9% and +2.8%) cartilage were observed. DATA CONCLUSION: Joint-loading with a stepping activity resulted in T1ρ and T2 changes above background measurement error. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY STAGE: 1 J. MAGN. RESON. IMAGING 2020;52:1753-1764.GlaxoSmithKline National Institute of Health Research (NIHR) Cambridge Biomedical Research Centr