OARSI Clinical Trials Recommendations: Knee imaging in clinical trials in osteoarthritis.

Significant advances have occurred in our understanding of the pathogenesis of knee osteoarthritis (OA) and some recent trials have demonstrated the potential for modification of the disease course. The purpose of this expert opinion, consensus driven exercise is to provide detail on how one might use and apply knee imaging in knee OA trials. It includes information on acquisition methods/techniques (including guidance on positioning for radiography, sequence/protocol recommendations/hardware for magnetic resonance imaging (MRI)); commonly encountered problems (including positioning, hardware and coil failures, sequences artifacts); quality assurance (QA)/control procedures; measurement methods; measurement performance (reliability, responsiveness, validity); recommendations for trials; and research recommendations.

Osteoarthritis year 2013 in review: imaging.

PURPOSE: To review recent original research publications related to imaging of osteoarthritis (OA) and identify emerging trends and significant advances. METHODS: Relevant articles were identified through a search of the PubMed database using the query terms "OA" in combination with "imaging", "radiography", "MRI", "ultrasound", "computed tomography", and "nuclear medicine"; either published or in press between March 2012 and March 2013. Abstracts were reviewed to exclude review articles, case reports, and studies not focused on imaging using routine clinical imaging measures. RESULTS: Initial query yielded 932 references, which were reduced to 328 citations following the initial review. MRI (118 references) and radiography (129 refs) remain the primary imaging modalities in OA studies, with fewer reports using computed tomography (CT) (35 refs) and ultrasound (23 refs). MRI parametric mapping techniques remain an active research area (33 refs) with growth in T2*- and T1-rho mapping publications compared to prior years. Although the knee is the major joint studied (210 refs) there is interest in the hip (106 refs) and hand (29 refs). Imaging continues to focus on evaluation of cartilage (173 refs) and bone (119 refs). CONCLUSION: Imaging plays a major role in OA research with publications continuing along traditional lines of investigation. Translational and clinical research application of compositional MRI techniques is becoming more common driven in part by the availability of T2 mapping data from the Osteoarthritis Initiative (OAI). New imaging techniques continue to be developed with a goal of identifying methods with greater specificity and responsiveness to changes in the joint, and novel functional neuroimaging techniques to study central pain. Publications related to imaging of OA continue to be heavily focused on quantitative and semiquantitative MRI evaluation of the knee with increasing application of compositional MRI techniques in the hip.

T2 texture index of cartilage can predict early symptomatic OA progression: data from the osteoarthritis initiative.

OBJECTIVE: There is an interest in using Magnetic Resonance Imaging (MRI) to identify pre-radiographic changes in osteoarthritis (OA) and features that indicate risk for disease progression. The purpose of this study is to identify image features derived from MRI T2 maps that can accurately predict onset of OA symptoms in subjects at risk for incident knee OA. METHODS: Patients were selected from the Osteoarthritis Initiative (OAI) control cohort and incidence cohort and stratified based on the change in total Western Ontario and McMaster Universities Arthritis (WOMAC) score from baseline to 3-year follow-up (80 non-OA progression and 88 symptomatic OA progression patients). For each patient, a series of image texture features were measured from the baseline cartilage T2 map. A linear discriminant function and feature reduction method was then trained to quantify a texture metric, the T2 texture index of cartilage (TIC), based on 22 image features, to identify a composite marker of T2 heterogeneity. RESULTS: Statistically significant differences were seen in the baseline T2 TIC between the non-progression and symptomatic OA progression populations. The baseline T2 TIC differentiates subjects that develop worsening of their WOMAC score OA with an accuracy between 71% and 76%. The T2 TIC differences were predominantly localized to a dominant knee compartment that correlated with the mechanical axis of the knee. CONCLUSION: Baseline heterogeneity in cartilage T2 as measured with the T2 TIC index is able to differentiate and predict individuals that will develop worsening of their WOMAC score at 3-year follow-up.

Definition of osteoarthritis on MRI: results of a Delphi exercise.

OBJECTIVE: Despite a growing body of Magnetic Resonance Imaging (MRI) literature in osteoarthritis (OA), there is little uniformity in its diagnostic application. We envisage in the first instance the definition requiring further validation and testing in the research setting before considering implementation/feasibility testing in the clinical setting. The objective of our research was to develop an MRI definition of structural OA. METHODS: We undertook a multistage process consisting of a number of different steps. The intent was to develop testable definitions of OA (knee, hip and/or hand) on MRI. This was an evidence driven approach with results of a systematic review provided to the group prior to a Delphi exercise. Each participant of the steering group was allowed to submit independently up to five propositions related to key aspects in MRI diagnosis of knee OA. The steering group then participated in a Delphi exercise to reach consensus on which propositions we would recommend for a definition of structural OA on MRI. For each round of voting, ≥60% votes led to include and ≤20% votes led to exclude a proposition. After developing the proposition one of the definitions developed was tested for its validity against radiographic OA in an extant database. RESULTS: For the systematic review we identified 25 studies which met all of our inclusion criteria and contained relevant diagnostic measure and performance data. At the completion of the Delphi voting exercise 11 propositions were accepted for definition of structural OA on MRI. We assessed the diagnostic performance of the tibiofemoral MRI definition against a radiographic reference standard. The diagnostic performance for individual features was: osteophyte C statistic=0.61, for cartilage loss C statistic=0.73, for bone marrow lesions C statistic=0.72 and for meniscus tear in any region C statistic=0.78. The overall composite model for these four features was a C statistic=0.59. We detected good specificity (1) but less optimal sensitivity (0.46) likely due to detection of disease earlier on MRI. CONCLUSION: We have developed MRI definition of knee OA that requires further formal testing with regards their diagnostic performance (especially in datasets of persons with early disease), before they are more widely used. Our current analysis suggests that further testing should focus on comparisons other than the radiograph, that may capture later stage disease and thus nullify the potential for detecting early disease that MRI may afford. The propositions are not to detract from, nor to discourage the use of traditional means of diagnosing OA.

What semi-quantitative scoring instrument for knee OA MRI should you use?

Multiple techniques have been used to assess synovial morphology and change on MRI in OA. Broadly speaking these methods are divided into quantitative and semi-quantitative methods. Quantitative measurements use computer-aided image processing to assess joint quantification (cartilage morphometry, bone volume, bone marrow lesion volume, meniscal position and volume, synovial volume, etc). In contrast to quantitative measures, semi-quantitative image analysis is typically much more observer dependent and generates grades or scales rather than truly continuous output. Multiple methods for semi-quantitative multi-feature assessment of the knee using conventional MRI acquisitions exist. These instruments provide for broad assessment of the whole joint and derive from knowledge from reading as to what joint features are morphologically abnormal. They are labour- and expertise-intensive compared to more automated methodologies. As a consequence of their reader dependence, precision and reliability results have not been as favourable for these instruments as their quantitative cousins. These instruments are generally based on past perceptions of what should be considered an important feature and therefore can bias future research. This said they do provide an important tool especially when quantitative methodologies are lacking or have their own inherent limitations.

Functional cartilage MRI T2 mapping: evaluating the effect of age and training on knee cartilage response to running.

OBJECTIVE: To characterize effects of age and physical activity level on cartilage thickness and T2 response immediately after running. DESIGN: Institutional review board approval was obtained and all subjects provided informed consent prior to study participation. Cartilage thickness and magnetic resonance imaging (MRI) T2 values of 22 marathon runners and 15 sedentary controls were compared before and after 30 min of running. Runner and control groups were stratified by ageor=46 years. Multi-echo [(Time to Repetition (TR)/Time to Echo (TE) 1500 ms/9-109 ms)] MR images obtained using a 3.0 T scanner were used to calculate thickness and T2 values from the central femoral and tibial cartilage. Baseline cartilage T2 values, and change in cartilage thickness and T2 values after running were compared between the four groups using one-way analysis of variance (ANOVA). RESULTS: After running MRI T2 values decreased in superficial femoral (2 ms-4 ms) and tibial (1 ms-3 ms) cartilage along with a decrease in cartilage thickness: (femoral: 4%-8%, tibial: 0%-12%). Smaller decrease in cartilage T2 values were observed in the middle zone of cartilage, and no change was observed in the deepest layer. There was no difference cartilage deformation or T2 response to running as a function of age or level of physical activity. CONCLUSIONS: Running results in a measurable decrease in cartilage thickness and MRI T2 values of superficial cartilage consistent with greater compressibility of the superficial cartilage layer. Age and level of physical activity did not alter the T2 response to running.

1H magnetic resonance spectroscopy of nanomelic chicken cartilage: effect of aggrecan depletion on cartilage T2.

OBJECTIVE: To determine the effect of proteoglycan depletion on cartilage proton magnetic resonance (MR) spectroscopy T2 using nanomelic chicken cartilage, a genetic mutant that completely lacks aggrecan. DESIGN: Proton MR spectroscopic T2 measurements of normal embryonic and nanomelic femoral epiphyseal cartilage were obtained using a 96-echo pulse sequence with inter-echo delay times increased logarithmically over the TE period of 60 micros to 1.7 s. The relative intensity and distribution of cartilage T2 components were determined by fitting signal decay curves to a multi-exponential function. The number of T2 components in the signal decay curves was determined by the degree of freedom limited r2 of the fit. RESULTS: For normal fetal chicken cartilage, 97.6 +/- 0.2% (mean +/- 95% confidence interval) of the total signal comprises a long T2 component (179.1 +/- 1.3 ms) with a relatively small short T2 component (0.5 +/- 0.4 ms). The T2 distribution for nanomelic cartilage is more heterogeneous with four components identified: two short T2 components (0.5 +/- 0.02 and 7.3 +/- 0.6 ms), a large intermediate component (56.4 +/- 5.6 ms), and a broadly distributed long component (137.5 +/- 16.6 ms). In nanomelic cartilage there is greater heterogeneity of cartilage T2 indicating greater variation in water proton mobility and exchange of water with the extracellular matrix. CONCLUSION: Absence of aggrecan in the extracellular cartilage matrix produces greater heterogeneity in cartilage T2, but will not increase T2 as has been previously reported with degenerative change of the collagen matrix.

Lumbar spine mechanical response to axial compression load in vivo.

STUDY DESIGN: Lumbar spine kinematic response to a 1.0 body weight compressive load was measured in vivo by comparison of relaxed and loaded magnetic resonance image sets in the sagittal plane. OBJECTIVES: To identify and measure acute response mechanisms of the lumbar spine during compression loading. SUMMARY OF BACKGROUND DATA: The isolated ligamentous spine buckles under small loads (88 N); yet, the spine supports >10 times that load in daily activities. Mechanical function of the lumbar spine in vivo is not well understood, and only a few studies examined the spine during in vivo loading. METHODS: Magnetic resonance imaging scans of subjects were taken while subjects were relaxed and while supporting a 1.0 body weight compressive load. Vertebral bodies and disc perimeters were digitized, and relative centroid positions were measured and compared between conditions. Lumbar rotation, bending, compression, and disc translation were determined. Two parameter ensembles were analyzed to describe mechanisms of "spine shrinkage" (decrease of projected spine length) and lumbosacral response. RESULTS: All subjects underwent spine shrinkage (-3.9 +/- 1.2 mm) dominated by cumulative bending, except in three subjects where the rotation component dominated. Levels L2-L4 extended, while L5 flexed, and dL2 through dL4 translated anterior, while dL5 translated posterior. Significant segmental deformations were as follows: L3 extension (-3.3 +/- 3.1 degrees ), dL5 disc translation (-1.4 +/- 1.4 mm), and posterior sacral rotation (3.2 +/- 4.7 degrees ). CONCLUSIONS: Spine shrinkage occurred mainly from spine bending and rotation, with only small contribution from spine compression (shortening along the spine curvature). Response pattern groupings indicated at least two unique subgroups, but the cause remains to be determined.

MR imaging and T2 mapping of femoral cartilage: in vivo determination of the magic angle effect.

OBJECTIVE: The purpose of this study was to perform a quantitative evaluation of the effect of static magnetic field orientation on cartilage transverse (T2) relaxation time in the intact living joint and to determine the magnitude of the magic angle effect on in vivo femoral cartilage. MATERIALS AND METHODS: Quantitative T2 maps of the femoral-tibial joint were obtained in eight asymptomatic male volunteers using a 3-T magnet. Cartilage T2 profiles (T2 vs normalized distance from subchondral bone) were evaluated as a function of orientation of the radial zone of cartilage with the applied static magnetic field (B(0)). RESULTS: At a normalized distance of 0.3 from bone, cartilage T2 is 8.6% longer in cartilage oriented 55 degrees to B(0) compared with cartilage oriented parallel with B(0). Greater orientation variation is observed in more superficial cartilage. At a normalized distance of 0.6, cartilage T2 is 18.3% longer. The greatest orientation effect is observed near the articular surface where T2 is 29.1% longer at 55 degrees. CONCLUSION: The effect of orientation on cartilage T2 is substantially less than that predicted from prior ex vivo studies. The greatest variation in cartilage T2 is observed in the superficial 20% of cartilage. Given the small orientation effect, it is unlikely that the "magic angle effect" accounts for regional differences in cartilage signal intensity observed in clinical imaging. We hypothesize that regional differences in the degree of cartilage compression are primarily responsible for the observed regional differences in cartilage T2.

Spatial variation in cartilage T2 of the knee.

Technical limitations imposed by resolution and B1 homogeneity have thus far limited quantitative in vivo T2 mapping of cartilage to the patella. The purpose of this study is to develop T2 mapping of the femoral/tibial joint and assess regional variability of cartilage T2 in the knee. Quantitative in vivo T2 mapping of the knee was performed on 15 asymptomatic adults (age, 22-44) using a 3T MR scanner. There is a consistent pattern of spatial variation in cartilage T2 with longer values near the articular surface. The greatest variation occurs in the patella, where T2 increases from 45.3 +/- 2.5 msec at a normalized distance of 0.33-67 +/- 5.5 msec at a distance of 1.0. These results demonstrate feasibility of performing in vivo T2 mapping of femoral tibial cartilage. Except for the superficial 15% where T2 values are lower, the spatial variation in T2 of femoral and tibial cartilage is similar to patellar cartilage.

Human articular cartilage: influence of aging and early symptomatic degeneration on the spatial variation of T2--preliminary findings at 3 T.

PURPOSE: To determine if age and early symptomatic degeneration alter the spatial dependency of cartilage T2. MATERIALS AND METHODS: In 25 asymptomatic volunteers and six volunteers with symptoms of patellar chondromalacia, quantitative T2 maps of patellar cartilage were obtained with a multiecho, spin-echo magnetic resonance imaging sequence at 3.0 T. Spatial variation in T2 was evaluated as a function of participant age and symptoms. RESULTS: All asymptomatic volunteers demonstrated a continuous increase in T2 from the radial zone to the articular surface. In the population aged 46-60 years compared with younger volunteers, there was a statistically significant (P < .05) increase in T2 of the transitional zone. In symptomatic volunteers, the increase in T2 was larger in magnitude and focal in distribution. In five of the six symptomatic volunteers, the increase in T2 was greater than the 95% prediction interval determined from data in the corresponding age-matched asymptomatic population. CONCLUSION: Aging is associated with an asymptomatic increase in T2 of the transitional zone of articular cartilage. Preliminary results indicate this diffuse increase in T2 in senescent cartilage is different in appearance than the focally increased T2 observed in damaged articular cartilage.

Iron and manganese homeostasis in chronic liver disease: relationship to pallidal T1-weighted magnetic resonance signal hyperintensity.

The hyperintense signal in the globus pallidus of cirrhotic patients on T1-weighted magnetic resonance (MR) imaging has been postulated to arise from deposition of paramagnetic manganese2+ (Mn). Intestinal absorption of both iron and Mn are increased in iron deficiency; iron deficiency may therefore increase susceptibility to Mn neurotoxicity. To investigate the relationships between MR signal abnormalities and Mn and Fe status, 21 patients with chronic liver disease were enrolled (alcoholic liver disease, 5; primary biliary cirrhosis, 9; primary sclerosing cholangitis, 3; hepatitis B virus, 2; hepatitis C virus, 1; alpha1-antitrypsin deficiency, 1). Signal hyperintensity in the pallidum on axial T1 weighted images (repetition time/evolution time: 500 ms/15 ms) was observed in 13 of 21 subjects: four patients had mild hyperintensity, three moderate, and six exhibited marked hyperintensity. Erythrocyte Mn concentrations were positively correlated with the degree of the MR hyperintensity (Kendall's tau-b=0.52, P<0.005). The log of erythrocyte Mn concentration was also inversely correlated with all measures of iron status: hemoglobin (Pearson's R=-0.73, P<0.0005); hematocrit (R=-0.62, P<0.005); serum Fe concentrations (R=-0.65, P<0.005); and TIBC saturation (R=-0.62, P<0.005). These findings confirm the association of Mn with the development of pallidal hyperintensity in patients with liver disease. We further found that iron deficiency is an exacerbating factor, probably because of increased intestinal absorption of Mn. We therefore recommend that patients with chronic liver disease avoid Mn supplements without concurrent iron supplementation.

Magnetic resonance imaging of superficial cartilage lesions: role of contrast in lesion detection.

Excised patellar cartilage phantoms with artificial surface lesions were imaged in a 2 g/dl albumin solution to determine the effect of cartilage/fluid contrast on detection of early degenerative change. Surface lesions consisted of full-thickness holes, superficial grooves, and coarse abrasion. Phantoms were imaged with a T1-weighted fast low-angle shot (FLASH) and T2*-weighted dual-echo in the steady state (DESS) sequence. Although both sequences were able to identify full-thickness holes, they underestimated the presence of superficial grooves and extent of fibrillation. Despite greater bulk tissue contrast between cartilage and fluid for the FLASH sequence, detection of fibrillation was poorer compared with the DESS images. The results of this study suggest that surface properties of fibrillated cartilage contribute significantly to the insensitivity of magnetic resonance imaging in detecting superficial lesions. In contrast to previous papers suggesting that T1-weighted spoiled gradient-echo imaging provides the greatest accuracy for lesion detection, our results indicate that, in the presence of joint fluid, T2*-weighted imaging increases detection of superficial lesions. J. Magn. Reson. Imaging 1999;10:178-182.

Advanced MR imaging techniques for evaluation of the heart and great vessels.

A "one-stop shop" for evaluating cardiac disease with magnetic resonance (MR) imaging is progressing toward clinical reality and promises to have a major effect on the care of patients with cardiac disease. T1-weighted conventional spin-echo imaging gated to the cardiac cycle yields good anatomic detail but requires long imaging times and provides only static images of a single cardiac phase. Fast MR imaging with electrocardiographically (ECG) gated, low-flip-angle, segmented k-space gradient-recalled-echo (GRE) sequences provides excellent image quality with sufficiently high temporal resolution to "freeze" cardiac motion. Segmented k-space sequences improve on standard ECG-gated GRE sequences by allowing many cardiac phases, or frames of a cine sequence, to be imaged in a single breath hold with prospective cardiac gating. As commercial implementations of segmented k-space imaging become more widely available, the applications of this technique are expanding from research protocols to include many clinical applications in the heart and great vessels. Such applications include evaluation of vascular anatomy (coronary angiography, aortic disease, aberrant vessels, vascular access), cardiac anatomy (congenital anomalies, right ventricular dysplasia, constrictive pericarditis, valvular function), myocardial perfusion, and myocardial wall motion.

Removal of local field gradient artifacts in T2*-weighted images at high fields by gradient-echo slice excitation profile imaging.

Development of high magnetic field MRI techniques is hampered by the significant artifacts produced by B0 field inhomogeneities in the excited slices. A technique, gradient-echo slice excitation profile imaging (GESEPI), is presented for recovering the signal lost caused by intravoxel phase dispersion in T2*-weighted images. This technique superimposes an incremental gradient offset on the slice refocusing gradient to sample k-space over the full range of spatial frequencies of the excitation profile. A third Fourier transform of the initial two-dimensional image set generates an image set in which the artifacts produced by the low-order B0 inhomogeneity field gradients in the sample are separated and removed from the high-order microscopic field gradients responsible for T2* contrast. Application to high field brain imaging, at 3.0 T for human and at 9.4 T for immature rat imaging demonstrates the significant improvement in quality of the T2*-weighted contrast images.

Renal medullary cystic disease: assessment by MRI.

Medullary cystic disease is an important cause of renal failure in adolescent patients. Imaging plays a primary role in the diagnosis of this entity as cysts are characteristically seen in the renal medulla and corticomedullary junction with normal to small sized kidneys. Imaging studies that do not use intravenous contrast or ionizing radiation are particularly useful given the young age of these patients and presence of renal failure. In this case, we demonstrate the imaging findings of medullary cystic disease by MRI.

Spatial variation of T2 in human articular cartilage.

PURPOSE: To determine the spatial variation of in vivo cartilage T2 in young asymptomatic adults. MATERIALS AND METHODS: Quantitative T2 maps of seven asymptomatic young male adults and one male volunteer with a history of previous intraarticular chondroid fragments were calculated by using a multiecho, spin-echo magnetic resonance imaging sequence at 3.0 T. The T2 maps were bilinearly interpolated to generate T2 profiles across the thickness of cartilage. RESULTS: All seven asymptomatic volunteers demonstrated a monotonic increase in T2, which increased from 32 msec +/- 1 in the deep radial zone and 48 msec +/- 1 in the deep transitional zone to 67 msec +/- 2 in the outer transitional superficial zone. The T2 profile of the volunteer with superficial fibrillation observed at arthroscopy demonstrated marked spatial heterogeneity and a statistically significant increase in cartilage T2. CONCLUSION: There is a reproducible pattern of increasing T2 that is proportional to the known spatial variation in cartilage water and is inversely proportional to the distribution of proteoglycans. The authors postulate that these regional T2 differences are secondary to the restricted mobility of cartilage water within an anisotropic solid matrix.

Thoracic spiral CT: delivery of contrast material pushed with injectable saline solution in a power injector.

A method of power injection of contrast material pushed with injectable saline solution during thoracic computed tomography (CT) was evaluated in 75 patients to help decrease the amount of contrast material necessary. Patients received 50-125 mL of 60% nonionic contrast material alone or pushed with 50 mL of saline. A volume of 75 mL of contrast material pushed with saline provided enhancement of the thoracic vasculature equal to that provided by a 125-mL volume of contrast material administered alone (P < .001) and caused significantly less beam-hardening artifact (P < .01).