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.

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.

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.

MR imaging of cartilage and its repair in the knee--a review.

Chondral injuries are common lesions of the knee joint, and many patients could benefit from cartilage repair. Widespread cartilage repair techniques require sophisticated noninvasive follow-up using MRI. In addition to the precise morphological assessment of this area of cartilage repair, the cartilage's biochemical constitution can be determined using biochemical MRI techniques. The combination of the clinical outcome after cartilage repair together with the morphological and biochemical description of the cartilage repair tissue as well as the surrounding cartilage can lead to an optimal follow-up evaluation. The present article on MR imaging techniques of cartilage repair focuses on morphological description and scoring using techniques from conventional 2D through advanced isotropic 3D MRI sequences. Furthermore the ultrastructure of the repair tissue and the surrounding cartilage is evaluated in-vivo by biochemical T1-delayed gadolinium enhanced MRI of cartilage (dGEMRIC), T2 relaxation, and diffusion-weighted imaging techniques.

Hydrogen ion concentration is not the sole determinant of muscle metaboreceptor responses in humans.

We examined the effects of exercise conditioning on muscle sympathetic nerve activity (MSNA) during handgrip and posthandgrip circulatory arrest (PHG-CA). Two conditioning stimuli were studied: forearm dominance and bodybuilding. Static handgrip at 30% maximal voluntary contraction followed by PHG-CA led to a rise in MSNA smaller in dominant than in nondominant forearms (99% vs. 222%; P less than 0.02) and in body builders than in normal volunteers (28% vs. 244%; P less than 0.01). Separate 31P NMR experiments showed no effect of dominance on forearm pH but a pH in bodybuilders higher (6.88) than in normal volunteers (6.79; P less than 0.02) during PHG-CA. Our second goal was to determine if factors besides attenuated [H+] contribute to this conditioning effect. If differences in MSNA during exercise were noted at the same pH, then other mechanisms must contribute to the training effect. We measured MSNA during ischemic fatiguing handgrip. No dominance or bodybuilding effect on pH was noted. However, we noted increases in MSNA smaller in dominant than nondominant forearms (212% vs. 322%; P less than 0.02) and in bodybuilders than in normal volunteers (161% vs. 334%; P less than 0.01). In summary, MSNA responses were less during exercise of conditioned limbs. Factors aside from a lessening of muscle acidosis contribute to this effect.

Aversive stimulus properties of the 5-HT2C receptor agonist WAY 161503 in rats.

Serotonin2C (5-HT2C) receptors may influence motivation and reward through effects on the mesocorticolimbic dopamine (DA) system. Previous work from this laboratory indicated that 5-HT2C receptor stimulation does not induce place conditioning when animals are tested in a drug-free state, but does result in decreased locomotor activity and increased frequency thresholds for electrical self-stimulation of the ventral tegmental area (VTA). The present study was conducted to determine whether the 5-HT2C receptor agonist WAY 161503 may induce place conditioning in a state-dependent manner and also whether this compound will induce gustatory avoidance conditioning in the conditioned taste aversion (CTA) paradigm. The effects of the 5-HT2C receptor agonist WAY 161503 in the place conditioning and CTA (two-bottle choice test) paradigms were assessed in male Sprague-Dawley rats. Administration of WAY 161503 (3.0 mg/kg) induced a state-dependent conditioned place aversion and a CTA to saccharin. The differential state dependency of 5-HT2C receptor agonists' effects in place conditioning (state dependent) and CTA (non-state dependent) is consistent with the activation of different brain systems in these two paradigms. The state-dependent effects in place conditioning underscore the need to include controls for state dependency in studies of 5-HT receptor related compounds.

Muscle acidosis during static exercise is associated with calf vasoconstriction.

In this study we measured (n = 6) the phosphocreatine-to-inorganic phosphate ratio (PCr/Pi), Pi, and pH with 31P-nuclear magnetic resonance (31P-NMR) in the human forearm during static work at 30% of maximal voluntary contraction (MVC) for 2 min followed immediately by 3 min of circulatory arrest (forearm arterial occlusion). Static exercise, with its central volitional and skeletal muscle metabolic and mechanical afferent components, caused a rise in heart rate (HR, 32%), blood pressure (BP, 29%), and calf vascular resistance (calf R, 30%). During forearm occlusion after static exercise, HR returned to base line, the increase in BP was attenuated by 30%, and calf R remained elevated and unchanged. The percent change in calf R was correlated with forearm cellular pH (R = 0.56, P less than 0.001) but only weakly associated with PCr/Pi (R = 0.33, P less than 0.042). 30% MVC for 1 min followed by arterial occlusion (3 min) reduced PCr/Pi by 65% and pH by 0.16 U (P less than 0.05). Calf R was unchanged. Circulatory arrest alone (20 min) caused no change in either pH or calf R but large changes in PCr/Pi (50% reduction). We conclude that 1) there is an association between forearm cellular acidosis and calf vasconstriction during static forearm exercise and 2) large changes in PCr/Pi without concomitant changes in pH are not associated with changes in calf R.

The cadmium-induced disruption of tight junctions in LLC-PK1 cells does not result from apoptosis.

Exposure of LLC-PK1 cells to low micromolar concentrations of Cd2+ for 1-4 hours causes the disruption of the adhering and occluding junctions between the cells, whereas exposure to higher concentrations of Cd2+ for longer periods of time causes more severe toxic effects and cell death. The objective of the present studies was to determine whether or not the junctional effects of Cd2+ might be a consequence of apoptotic injury. LLC-PK1 cells on cell culture inserts were exposed to either Cd2+ or tumor necrosis factor (TNF-alpha) plus cycloheximide, a treatment that has recently been shown to cause apoptosis in LLC-PK1 cells. The results showed that at the time the Cd2(+)-induced junctional changes were occurring, there was no increase in the number of apoptotic cells or evidence of DNA fragmentation. By contrast, TNF-alpha plus cycloheximide induced changes that were characteristic of apoptosis. These results indicate that the disruption of intercellular junctions by Cd2+ in the LLC-PK1 cell line occurs independently of apoptosis.

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.

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.

Proposal for a nomenclature for magnetic resonance imaging based measures of articular cartilage in osteoarthritis.

OBJECTIVE: Magnetic resonance imaging (MRI) of articular cartilage has evolved to be an important tool in research on cartilage (patho)physiology and osteoarthritis (OA). MRI provides a wealth of novel and quantitative information, but there exists no commonly accepted terminology for reporting these metrics. The objective of this initiative was to propose a nomenclature for definitions and names to be used in scientific communications and to give recommendations as to which minimal methodological information should be provided when reporting MRI-based measures of articular cartilage in OA. METHODS: An international group of experts with direct experience in MRI measurement of cartilage morphology or composition reviewed the existing literature. Through an iterative process that included a meeting with a larger group of scientists and clinicians (December 2nd, 2004, Chicago, IL, USA), they discussed, refined, and proposed a nomenclature for MRI-based measures of articular cartilage in OA. RESULTS: The group proposes a nomenclature that describes: (1) the anatomical location and (2) the structural feature being measured, each name consisting of a metric variable combined with a tissue label. In addition, the group recommends minimal methodological information that should be described. CONCLUSIONS: Utilization of this nomenclature should facilitate communication within the scientific community. Further, the uniform adoption of comprehensive nomenclature to describe quantitative MRI- features of articular cartilage should strengthen epidemiological, clinical, and pharmacological studies in OA.

Magnetic susceptibility measurement using a double-DANTE tagging (DDT) sequence.

Preliminary results are presented for the nuclear magnetic resonance (NMR) measurement of field gradients generated by differences in magnetic susceptibility. The DDT technique maps the resonant frequency throughout the sample in a single image. Regions of paramagnetic and diamagnetic susceptibility are differentiated with a single magnitude-calculated image.

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.

A DANTE tagging sequence for the evaluation of translational sample motion.

A magnetic resonance imaging sequence that is sensitive to translational motion such as that seen with cardiac contraction is presented. The sequence employs DANTE radio-frequency excitation with a continuous magnetic field gradient to generate a grid pattern of lines. There is improved line resolution and reduced eddy-current formation over current techniques.