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Deborah Burstein

Publications and source records attributed to Deborah Burstein.

At least 19 recordsLinked to original sources
PubMed2006

MRI of articular cartilage in OA: novel pulse sequences and compositional/functional markers.

Osteoarthritis (OA) is a leading cause of disability worldwide. Magnetic resonance imaging (MRI), with its unique ability to image and characterize soft tissue non-invasively, has proven valuable in assessing cartilage in OA. The development of new, fast imaging methods with high contrast show promise to improve the magnetic resonance (MR) evaluation of this disease. In addition to morphologic MRI methods, MRI contrast mechanisms under development may reveal detailed information about the physiology of cartilage. It is anticipated that these and other MRI techniques will play an increasingly important role in assessing the success or failure of therapies for OA. On December 5 and 6, 2002, OMERACT (Outcome Measures in Rheumatology Clinical Trials) and OARSI (Osteoarthritis Research Society International) held a workshop in Bethesda, MD aiming at providing a state-of-the-art review of imaging outcome measures for OA of the knee to help guide scientists and pharmaceutical companies in the use of MRI in multi-site studies of OA. Applications of MRI were initially reviewed by a multidisciplinary, international panel of expert scientists and physicians from academia, the pharmaceutical industry and regulatory agencies. The findings of the panel were then presented to a wider group of participants for open discussion. The following report summarizes the results of these discussions with respect to novel MRI pulse sequences for evaluating articular cartilage of the knee in OA and notes any additional advances that have been made since.

Cartilage, Articular↗
PubMed2006

Three-dimensional delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) at 1.5T and 3.0T.

PURPOSE: To implement and validate a three-dimensional (3D) T1 measurement technique that is suitable for delayed gadolinium (Gd)-enhanced MRI of cartilage (dGEMRIC) and can be easily implemented with clinically available pulse sequences at 1.5T and 3.0T. MATERIALS AND METHODS: A 3D inversion-recovery prepared spoiled gradient-echo (IR-SPGR) imaging pulse sequence with variable TR was used to implement a 3D T1 measurement protocol. The 3D T1 measurements were validated against a gold-standard single-slice 2D IR T1 measurement protocol in both phantoms and in vivo, in both asymptomatic volunteers and volunteers with osteoarthritis (OA). RESULTS: T1 measurements in phantoms showed a statistically significant correlation between the 2D and 3D measurements at 1.5T (R2=0.993, P<0.001) and 3.0T (R2=0.996, P<0.001). In vivo application demonstrated the feasibility of using this 3D IR-SPGR sequence to evaluate the molecular status of articular cartilage throughout the knee joint with 0.63x0.63x3.0 mm spatial resolution within a 20-minute acquisition, even with the measurement parameters set for the higher T1(Gd) of cartilage at 3T (range=400-900 msec mean T1 within a region of interest (ROI) in cartilage, compared to 200-600 msec mean T1 at 1.5T). CONCLUSION: This 3D T1 measurement protocol may prove useful for the evaluation and follow-up of cartilage dGEMRIC indices in clinical studies of OA.

Cartilage, Articular↗
PubMed2006

Quantitative MRI of cartilage and bone: degenerative changes in osteoarthritis.

Magnetic resonance imaging (MRI) and quantitative image analysis technology has recently started to generate a great wealth of quantitative information on articular cartilage and bone physiology, pathophysiology and degenerative changes in osteoarthritis. This paper reviews semiquantitative scoring of changes of articular tissues (e.g. WORMS = whole-organ MRI scoring or KOSS = knee osteoarthritis scoring system), quantification of cartilage morphology (e.g. volume and thickness), quantitative measurements of cartilage composition (e.g. T2, T1rho, T1Gd = dGEMRIC index) and quantitative measurement of bone structure (e.g. app. BV/TV, app. TbTh, app. Tb.N, app. Tb.Sp) in osteoarthritis. For each of these fields we describe the hardware and MRI sequences available, the image analysis systems and techniques used to derive semiquantitative and quantitative parameters, the technical accuracy and precision of the measurements reported to date and current results from cross-sectional and longitudinal studies in osteoarthritis. Moreover, the paper summarizes studies that have compared MRI-based measurements with radiography and discusses future perspectives of quantitative MRI in osteoarthritis. In summary, the above methodologies show great promise for elucidating the pathophysiology of various tissues and identifying risk factors of osteoarthritis, for developing structure modifying drugs (DMOADs) and for combating osteoarthritis with new and better therapy.

Animals↗
PubMed2006

MRI for development of disease-modifying osteoarthritis drugs.

MRI has advantages as an imaging modality for drug development through its potential to provide information regarding localized morphological parameters, in addition to metrics of the structural and molecular state of cartilage. These metrics have the potential to provide earlier indications of pathology and may progress more rapidly than radiographic measures. These combined scans of localized morphology and matrix parameters will most likely provide a fuller assessment of cartilage state and will improve the cost and practicality of an overall evaluation of cartilage status by MRI. In the first part of this review, the relevant parameters are presented in terms of the information content they might provide in the drug development process. In the second part, applications of the MRI parameters in preclinical and clinical drug development are presented.

Animals↗
PubMed2006

Three-dimensional T1 mapping for dGEMRIC at 3.0 T using the Look Locker method.

OBJECTIVE: The objective of this study was to implement a three-dimensional (3-D) T1 mapping sequence (3DLL) at 3.0 T for dGEMRIC based on the Look Locker scheme. MATERIALS AND METHODS: Because all current reports on dGEMRIC are at 1.5 T and mostly using 2-D IR fast spin echo (FSE), data were acquired at 1.5 T and 3.0 T with both 3DLL and 2-D IR-FSE sequence. Phantoms with different concentrations of Gd(DTPA) were used and seven subjects (three asymptomatic, four symptomatic) were scanned using the dGEMRIC technique. RESULTS: The T1 measurements obtained on the phantom with 3DLL show very good agreement with those acquired with 2-D IR-FSE. Using a two-tailed paired t test, the T1 (Gd) measurements in two sections obtained in all subjects with both sequences were found to be statistically indistinguishable at either field strength (P = 0.07 at 1.5 T and P = 0.07 at 3.0 T). CONCLUSIONS: The preliminary data presented here suggest that the 3DLL sequence provides accurate T1 values with sufficient in-plane resolution and allows full joint coverage in less than 10 minutes.

Adult↗
PubMed2005

Delayed gadolinium-enhanced magnetic resonance imaging of cartilage in knee osteoarthritis: findings at different radiographic stages of disease and relationship to malalignment.

OBJECTIVE: Delayed gadolinium-enhanced magnetic resonance imaging (MRI) of cartilage (dGEMRIC) is used to examine the distribution of glycosaminoglycan in cartilage. This study sought to characterize dGEMRIC in the evaluation of knee osteoarthritis (OA) according to various radiographically determined disease parameters, and to examine the relationship between alignment of the knee joint and the lateral:medial dGEMRIC ratio. METHODS: Thirty-one patients with knee OA underwent MRI with a dGEMRIC protocol at 1.5T. Semiflexed knee radiographs and full-limb radiographs were also obtained for assessment of alignment. RESULTS: Compartments of the knee joint without joint space narrowing had a higher dGEMRIC index than those with any level of narrowing (mean 408 msec versus 365 msec; P = 0.001). In knees with 1 unnarrowed (spared) and 1 narrowed (diseased) compartment, the dGEMRIC index was greater in the spared versus the diseased compartment (mean 395 msec versus 369 msec; P = 0.001). In spared compartments, there was a trend toward a lower dGEMRIC index with increasing Kellgren/Lawrence (K/L) radiographic severity grade; the spared compartments of knees with a K/L grade 2 had a higher dGEMRIC index than those of knees with a K/L grade 4 (mean 425 msec versus 371 msec; P < 0.05). There was a range of dGEMRIC values in the spared compartments within a given K/L grade, demonstrating biochemical differentiation of disease in radiographically comparable compartments. Almost all compartments with narrowing had dGEMRIC indices of <400 msec. Valgus-aligned knees tended to have lower dGEMRIC values laterally, and varus-aligned knees tended to have lower dGEMRIC values medially; as a continuous variable, alignment correlated with the lateral:medial dGEMRIC ratio (Pearson's R = 0.43, P = 0.02). CONCLUSION: The biochemical information provided by dGEMRIC scans may augment radiography by improving the differentiation of disease status within a given radiographic grade, especially in early OA.

Aged↗
PubMed2005

Spatially-localized correlation of dGEMRIC-measured GAG distribution and mechanical stiffness in the human tibial plateau.

The concentration of glycosaminoglycan (GAG) in articular cartilage is known to be an important determinant of tissue mechanical properties based on numerous studies relating bulk GAG and mechanical properties. To date limited information exists regarding the relationship between GAG and mechanical properties on a spatially-localized basis in intact samples of native tissue. This relation can now be explored by using delayed gadolinium-enhanced MRI of cartilage (dGEMRIC--a recently available non-destructive magnetic resonance imaging method for measuring glycosaminoglycan concentration) combined with non-destructive mechanical indentation testing. In this study, three tibial plateaus from patients undergoing total knee arthroplasty were imaged by dGEMRIC. At 33-44 test locations for each tibial plateau, the load response to focal indentation was measured as an index of cartilage stiffness. Overall, a high correlation was found between the dGEMRIC index (T(1Gd)) and local stiffness (Pearson correlation coefficients r = 0.90, 0.64, 0.81; p < 0.0001) when the GAG at each test location was averaged over a depth of tissue comparable to that affected by the indentation. When GAG was averaged over larger depths, the correlations were generally lower. In addition, the correlations improved when the central and peripheral (submeniscal) areas of the tibial plateau were analyzed separately, suggesting that a factor other than GAG concentration is also contributing to indentation stiffness. The results demonstrate the importance of MRI in yielding spatial localization of GAG concentration in the evaluation of cartilage mechanical properties when heterogeneous samples are involved and suggest the possibility that the evaluation of mechanical properties may be improved further by adding other MRI parameters sensitive to the collagen component of cartilage.

Aged↗
PubMed2004

T2 and T1rho MRI in articular cartilage systems.

T2 and T1rho have potential to nondestructively detect cartilage degeneration. However, reports in the literature regarding their diagnostic interpretation are conflicting. In this study, T2 and T1rho were measured at 8.5 T in several systems: 1) Molecular suspensions of collagen and GAG (pure concentration effects): T2 and T1rho demonstrated an exponential decrease with increasing [collagen] and [GAG], with [collagen] dominating. T2 varied from 90 to 35 ms and T1rho from 125 to 55 ms in the range of 15-20% [collagen], indicating that hydration may be a more important contributor to these parameters than previously appreciated. 2) Macromolecules in an unoriented matrix (young bovine cartilage): In collagen matrices (trypsinized cartilage) T2 and T1rho values were consistent with the expected [collagen], suggesting that the matrix per se does not dominate relaxation effects. Collagen/GAG matrices (native cartilage) had 13% lower T2 and 17% lower T1rho than collagen matrices, consistent with their higher macromolecular concentration. Complex matrix degradation (interleukin-1 treatment) showed lower T2 and unchanged T1rho relative to native tissue, consistent with competing effects of concentration and molecular-level changes. In addition, the heterogeneous GAG profile in these samples was not reflected in T2 or T1rho. 3) Macromolecules in an oriented matrix (mature human tissue): An oriented collagen matrix (GAG-depleted human cartilage) showed T2 and T(1rho) variation with depth consistent with 16-21% [collagen] and/or fibril orientation (magic angle effects) seen on polarized light microscopy, suggesting that both hydration and structure comprise important factors. In other human cartilage regions, T2 and T1rho abnormalities were observed unrelated to GAG or collagen orientation differences, demonstrating that hydration and/or molecular-level changes are important. Overall, these studies illustrate that T2 and T1rho are sensitive to biologically meaningful changes in cartilage. However, contrary to some previous reports, they are not specific to any one inherent tissue parameter.

Animals↗
PubMed2004

Perfusion MRI of U87 brain tumors in a mouse model.

Continuous arterial spin labeling (CASL) was used to obtain an index of cerebral blood flow (ICBF) in the normal mouse brain and in an orthotopic mouse model of human U87 high-grade glioma at 8.5 T. Under the assumption of a constant tissue:blood partition coefficient for water in different tissues, the mean ICBF (n = 14) was found to be 50 +/- 9 mL/100g/min for tumor core and 209 +/- 11 mL/100g/min for normal tissue. The apparent T(1) (T(1app)) was 2.01 +/- 0.06 sec for tumor core and 1.66 +/- 0.03 sec for normal tissue. The ICBF and the T(1app) values were significantly different (P < 0.001) between these two regions. The detailed changes of ICBF and T(1app) in the transition from the tumor core through the tumor periphery to surrounding tissue were studied. Immunohistochemistry indicated that tumor vascularity was not uniform, with microvessel density highest in normal brain and the tissue surrounding the tumor and lowest in the tumor core. The large difference in ICBF between the tumor core and normal tissue suggests that this index might be useful for the assessment of the efficacy of antiangiogenic therapy.

Animals↗
PubMed2004

T2 of articular cartilage in the presence of Gd-DTPA2-.

T(2) information and delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) are both used to characterize articular cartilage. They are currently obtained in separate studies because Gd-DTPA(2-) (which is needed for dGEMRIC) affects the inherent T(2) information. In this study, T(2) was simulated and then measured at 8.45 T in 20 sections from two human osteochondral samples equilibrated with and without Gd-DTPA(2-). Both the simulations and data demonstrated that Gd-DTPA(2-) provides a non-negligible mechanism for relaxation, especially with higher (1 mM) equilibrating Gd-DTPA(2-) concentrations, and in areas of tissue with high T(2) (due to weak inherent T(2) mechanisms) and high tissue Gd-DTPA(2-) (due to a low glycosaminoglycan concentration). Nonetheless, T(2)-weighted images of cartilage equilibrated in 1 mM Gd-DTPA(2-) showed similar T(2) contrast with and without Gd-DTPA(2-), demonstrating that the impact on T(2) was not great enough to affect identification of T(2) lesions. However, T(2) maps of the same samples showed loss of conspicuity of T(2) abnormalities. We back-calculated inherent T(2)'s (T(2,bc)) using a T(2)-relaxivity value from a 20% protein phantom (r(2) = 9.27 +/- 0.09 mM(-1)s(-1)) and the Gd-DTPA(2-) concentration calculated from T(1,Gd). The back-calculation restored the inherent T(2) conspicuity, and a correlation between T(2) and T(2,bc) of r = 0.934 (P < 0.0001) was found for 80 regions of interest (ROIs) in the sections. Back-calculation of T(2) is therefore a viable technique for obtaining T(2) maps at high equilibrating Gd-DTPA(2-) concentrations. With T(2)-weighted images and/or low equilibrating Gd-DTPA(2-) concentrations, it may be feasible to obtain both T(2) and dGEMRIC information in the presence of Gd-DTPA(2-) without such corrections. These conditions can be designed into ex vivo studies of cartilage. They appear to be applicable for clinical T(2) studies, since pilot clinical data at 1.5 T from three volunteers demonstrated that calculated T(2) maps are comparable before and after "double dose" Gd-DTPA(2-) (as utilized in clinical dGEMRIC studies). Therefore, it may be possible to perform a comprehensive clinical examination of dGEMRIC, T(2), and cartilage volume in one scanning session without T(2) data correction.

Cartilage, Articular↗
PubMed2004

In vivo MRI of embryonic stem cells in a mouse model of myocardial infarction.

The therapeutic potential of administering stem cells to promote angiogenesis and myocardial tissue regeneration after infarction has recently been demonstrated. Given the advantages of using embryonic stem cells and mouse models of myocardial infarction for furthering the development of this therapeutic approach, the purpose of this study was to determine if embryonic stem cells could be loaded with superparamagnetic iron oxide (SPIO) particles and imaged in a mouse model of myocardial infarction over time using MRI. Mouse embryonic stem cells were labeled with SPIO particles. When incubated with 11.2, 22.4, and 44.8 microg Fe/ml of SPIO particles, cells took up increasing amounts of iron oxide. Embryonic stem cells loaded with SPIO compared to unlabeled cells had similar viability and proliferation profiles for up to 14 days. Free SPIO injected into infarcted myocardium was not observable within 12 hr after injection. After injection of three 10-microl aliquots of 10(7) SPIO-loaded cells/ml into infarcted myocardium, MRI demonstrated that the mouse embryonic stem cells were observable and could be seen for at least 5 weeks after injection. These findings support the ability of MRI to test the long-term therapeutic potential of embryonic stem cells in small animals in the setting of myocardial infarction.

Animals↗
PubMed2004

Src blockade stabilizes a Flk/cadherin complex, reducing edema and tissue injury following myocardial infarction.

Ischemia resulting from myocardial infarction (MI) promotes VEGF expression, leading to vascular permeability (VP) and edema, a process that we show here contributes to tissue injury throughout the ventricle. This permeability/edema can be assessed noninvasively by MRI and can be observed at the ultrastructural level as gaps between adjacent endothelial cells. Many of these gaps contain activated platelets adhering to exposed basement membrane, reducing vessel patency. Following MI, genetic or pharmacological blockade of Src preserves endothelial cell barrier function, suppressing VP and infarct volume, providing long-term improvement in cardiac function, fibrosis, and survival. To our surprise, an intravascular injection of VEGF into healthy animals, but not those deficient in Src, induced similar endothelial gaps, VP, platelet plugs, and some myocyte damage. Mechanistically, we show that quiescent blood vessels contain a complex involving Flk, VE-cadherin, and beta-catenin that is transiently disrupted by VEGF injection. Blockade of Src prevents disassociation of this complex with the same kinetics with which it prevents VEGF-mediated VP/edema. These findings define a molecular mechanism to account for the Src requirement in VEGF-mediated permeability and provide a basis for Src inhibition as a therapeutic option for patients with acute MI.

Animals↗
PubMed2004

Glycosaminoglycan distribution in cartilage as determined by delayed gadolinium-enhanced MRI of cartilage (dGEMRIC): potential clinical applications.

OBJECTIVE: We sought to describe a range of in vivo observations of glycosaminoglycan distribution in knee cartilage using the delayed gadolinium-enhanced MRI of cartilage technique. CONCLUSION: The index of glycosaminoglycan distribution, T1(Gd), can exceed 500 msec (denoting high glycosaminoglycan) or can be less than 300 msec, with focal areas as low as 240 msec. Compartmental differences, as well as focal defects within the knee, were observed in patients who had sustained injuries to the ligaments and menisci of the knee or who had chronic osteoarthritis. Overall, these results suggest the need for further research into the biochemical changes seen during disease progression and the effects of therapeutic interventions.

Adult↗
PubMed2003

Differential recovery of glycosaminoglycan after IL-1-induced degradation of bovine articular cartilage depends on degree of degradation.

In the present study we examined cartilage matrix repair following IL-1-induced matrix depletion. Previous data indicated that, in some cases, chondrocytes can synthesize macromolecules to establish a functional extracellular matrix in response to a matrix-damaging insult or when placed in a three-dimensional environment with inadequate matrix. However, the conditions under which such 'repair' can occur are not entirely clear. Prior studies have shown that chondrocytes in trypsin-depleted young bovine articular cartilage can replenish tissue glycosaminoglycan (GAG) and that the rate of replenishment is relatively uniform throughout the tissue, suggesting that all chondrocytes have similar capacity for repair. In the present study we used the characteristic heterogeneous distribution of matrix depletion in response to IL-1 exposure in order to investigate whether the severity of depletion influenced the rate of GAG replenishment. We used the delayed Gadolinium-Enhanced Magnetic Resonance Imaging of Cartilage (dGEMRIC) method to monitor the spatial and temporal evolution of tissue GAG concentration ([GAG]). For both mild (n=4) and moderate (n=10) IL-1-induced GAG depletion, we observed partial recovery of GAG (80% and 50% of baseline values, respectively) over a 3-week recovery period. During the first 2 weeks of recovery, [GAG] increased homogeneously at 10-15 mg/ml per week. However, during the third week the regions most severely depleted following IL-1 exposure showed negligible [GAG] accumulation, whereas those regions affected the least by IL-1 demonstrated the greatest accumulation. This finding could suggest that the most severely degraded regions do not recover fully, possibly because of more severe collagen damage; this possibility requires further examination.

Animals↗
PubMed2003

Magnetic resonance imaging of patched heterozygous and xenografted mouse brain tumors.

Experimental mouse models are emerging as useful systems for the study of human brain tumors. Nuclear magnetic resonance imaging (MRI) methods can noninvasively provide images of complex heterogeneous tissues such as experimental brain tumors. The current report demonstrates the feasibility of longitudinal high-resolution MRI in two mouse brain tumor models: patched heterozygous (ptc +/-) mice with spontaneously arising posterior fossa tumors that resemble human medulloblastoma, and homozygous nude mice implanted with intracerebral xenografts of human medulloblastoma cell lines. Methods were optimized to achieve favorable volumetric comparison with histologic methods and sub-millimeter resolution, improved by contrast enhancement with intravenous administration of a gadolinium-based agent. Results also show that experimental mice, even symptomatic mice, tolerate repeated serial imaging studies over weeks to months to follow tumor progression and to visualize placement of an intracerebral drug delivery system.

Animals↗
PubMed2003

Assessment of early osteoarthritis in hip dysplasia with delayed gadolinium-enhanced magnetic resonance imaging of cartilage.

BACKGROUND: The efficacy of surgical and medical treatment of osteoarthritis is difficult to assess because of the lack of a noninvasive, sensitive measure of cartilage integrity. Delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) was designed to specifically examine glycosaminoglycan changes in articular cartilage that occur during the development of osteoarthritis. Our primary goal was to compare this technique with measurement of the joint space width on conventional radiographs in patients with hip dysplasia. We performed this comparison by assessing the correlation between the findings of each technique and clinically important factors such as pain, severity of dysplasia, and age. METHODS: Sixty-eight hips in forty-three patients were included in the study. Clinical symptoms were assessed with use of the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) questionnaire. The width of the joint space as well as the lateral center-edge angle of Wiberg (as a measure of the severity of the dysplasia) was measured on standard standing radiographs. Magnetic resonance imaging maps of glycosaminoglycan distribution were made with T1-calculated images after administration of gadopentetate (2-) (Gd-DTPA (2-) ). The dGEMRIC index was calculated as the average of the T1 values for the acetabular and femoral head cartilages. RESULTS: The dGEMRIC index correlated with both pain (rs = -0.50, p < 0.0001) and the lateral center-edge angle (rs = 0.52, p < 0.0001), whereas the joint space width did not correlate with either, with the numbers available. There was a correlation between the dGEMRIC index and pain whether or not a labral tear was present. The dGEMRIC index was significantly different (p < 0.0001) among three groups of hips classified according to whether they had mild, moderate, or severe dysplasia, whereas the joint space width did not differ significantly among these three groups. There was no significant correlation between age and any of the other parameters. CONCLUSIONS: We demonstrated that, in patients with hip dysplasia, the dGEMRIC index-a measure of the biochemical integrity of cartilage-correlates with pain and the severity of the dysplasia and is significantly different among groups of hips with mild, moderate, and severe dysplasia, suggesting that it may be a sensitive measure of early osteoarthritis. Additional studies are needed to determine whether dGEMRIC can be used to predict disease progression in different situations and/or demonstrate responses to therapeutic interventions.

Adolescent↗