Characterisation of the guinea pig model of osteoarthritis by in vivo three-dimensional magnetic resonance imaging.

OBJECTIVE: To characterise longitudinal changes in joint integrity and cartilage volume in vivo in the guinea pig spontaneous osteoarthritis (OA) model by magnetic resonance imaging (MRI). METHODS: Guinea pigs knee were imaged in vivo by high-resolution three-dimensional (3D) MRI between the ages of 3 and 12 months. Image analysis was performed to assess qualitative knee joint changes between 3 and 12 months (n=16) and quantitative volumetric changes of the medial tibial cartilage between 9 and 12 months (n=7). After imaging, animals were killed and knees were assessed macroscopically and histologically. RESULTS: From 3 to 6 months qualitative observation by MRI and histopathology indicated localised cartilage swelling on the medial tibial plateau. At 6 months, bone cysts had developed in the epiphysis. At 9 months, we observed by MRI and histopathology, fragmentation of the medial tibial cartilage in areas not protected by the meniscus. Cartilage degeneration had intensified at 12 months with evidence of widespread loss of cartilage throughout the tibial plateau. Segmentation of the MR cartilage images showed a 36% loss of volume between 9 and 12 months. CONCLUSIONS: We have achieved 3D image acquisition and segmentation of knee cartilage in a guinea pig model of chronic OA, which permits measurements previously only possible in man. High resolution and short acquisition time allowed qualitative longitudinal characterisation of the entire knee joint and enabled us to quantify for the first time longitudinal tibial cartilage volume loss associated with disease progression.

Use of dynamic contrast-enhanced MRI to evaluate acute treatment with ZD6474, a VEGF signalling inhibitor, in PC-3 prostate tumours.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), using gadopentetate dimeglumine, was used to monitor acute effects on tumour vascular permeability following inhibition of vascular endothelial growth factor-A (VEGF-A) signal transduction. Mice bearing PC-3 human prostate adenocarcinoma xenografts were treated with ZD6474, a VEGF receptor-2 (KDR) tyrosine kinase inhibitor. The pharmacokinetic parameter K(trans) was obtained, which reflects vascular permeability and perfusion. Mice were imaged immediately before, and following, acute treatment with ZD6474 (12.5-100 mg x kg(-1) orally). Whole tumours were analysed to obtain mean K(trans) values, and a histogram approach was used to examine intratumour heterogeneity. Reproducibility of K(trans) measurements gave inter- and intra-animal coefficients of variation of 40 and 18%, respectively. Dose-related reductions in K(trans) were evident following acute ZD6474 treatment. A K(trans) reduction of approximately 30% (P<0.001) was evident with 50 and 100 mg x kg(-1) ZD6474, a reduction of 12.5% (P<0.05) at 25 mg x kg(-1), and a reduction that did not reach statistical significance at 12.5 mg kg(-1). A correlation between this dose response and the growth inhibitory effect of ZD6474 following chronic treatment was also observed. The histogram analysis of the data indicated that ZD6474-induced a K(trans) reduction in both the most enhancing rim and the core of PC-3 tumours. Dynamic contrast-enhanced magnetic resonance imaging may have a role in assessing the acute effects of VEGF signalling inhibition, in clinical dose-ranging studies.

Tumour dose response to the antivascular agent ZD6126 assessed by magnetic resonance imaging.

ZD6126 is a vascular targeting agent that disrupts the tubulin cytoskeleton of proliferating neo-endothelial cells. This leads to the selective destruction and congestion of tumour blood vessels in experimental tumours, resulting in extensive haemorrhagic necrosis. In this study, the dose-dependent activity of ZD6126 in rat GH3 prolactinomas and murine RIF-1 fibrosarcomas was assessed using two magnetic resonance imaging (MRI) methods. Dynamic contrast-enhanced (DCE) MRI, quantified by an initial area under the time-concentration product curve (IAUC) method, gives values related to tumour perfusion and vascular permeability. Multigradient recalled echo MRI measures the transverse relaxation rate T(2)*, which is sensitive to tissue (deoxyhaemoglobin). Tumour IAUC and R(2)* (=1/T(2)*) decreased post-treatment with ZD6126 in a dose-dependent manner. In the rat model, lower doses of ZD6126 reduced the IAUC close to zero within restricted areas of the tumour, typically in the centre, while the highest dose reduced the IAUC to zero over the majority of the tumour. A decrease in both MRI end points was associated with the induction of massive central tumour necrosis measured histologically, which increased in a dose-dependent manner. Magnetic resonance imaging may be of value in evaluation of the acute clinical effects of ZD6126 in solid tumours. In particular, measurement of IAUC by DCE MRI should provide an unambiguous measure of biological activity of antivascular therapies for clinical trial.

Reproducibility of quantitative dynamic contrast-enhanced MRI in newly presenting glioma.

We have investigated the reproducibility of dynamic contrast enhanced imaging techniques in nine patients with cerebral glioma. Patients were imaged twice with a 2 day interval between scans. Maps were produced of the time taken to achieve 90% enhancement (T90), the maximal intensity change per time interval ratio (MITR), the volume transfer coefficient between plasma and the extravascular extracellular space (K(trans)) and the extravascular extracellular contrast distribution volume, v(e). Measurements of K(trans) greater than 1.2 min(-1) were used to exclude pixels where first pass perfusion effects dominated the measurement. Measures of the test-retest coefficient of variation (CoV) and intraclass correlation coefficients were used to assess reproducibility for measurements from a volume of interest containing enhancing tissue from the whole tumour. MITR showed poor reproducibility (mean CoV 17.9%, 95% confidence limits for group comparisons 20.2%). T90 showed good reproducibility (mean CoV 7.1%, 95% confidence limits for group comparisons 5.2%). Calculated values of K(trans) and v(e) also showed good reproducibility (mean CoV 7.7% and 6.2% respectively, 95% confidence limits for group comparisons 6.2% and 4.8%, respectively). We conclude that the measurements of K(trans) and v(e) derived from pharmacokinetic analysis are sufficiently reproducible to support their use as a biological markers in therapeutic trials.

Simultaneous mapping of blood volume and endothelial permeability surface area product in gliomas using iterative analysis of first-pass dynamic contrast enhanced MRI data.

We describe a novel method for the calculation of endothelial permeability surface area product from dynamic contrast enhanced MRI. The technique uses iterative estimation to automatically decompose tissue residue function into intravascular and extravascular components, which are subsequently used to generate tumour blood volume, which is equal to relative cerebral blood volume calculated from T(1) weighted images and corrected for contamination by contrast agent leakage (rCBV(T1)(corrected), and endothelial permeability (k(fp)) maps. The technique was assessed in patients with cerebral glioma (n=5) by examining the reproducibility of endothelial permeability and rCBV(T1)(corrected) between two separate examinations conducted with a 2-day interval. The technique produces maps of endothelial permeability that appear to be free of any contribution from intravascular contrast agent. Maps of rCBV(T1)(corrected) show close correlation with maps of blood volume calculated from independently acquired dynamic susceptibility weighted MRI examinations, with no evidence of residual permeability effects. The results were highly reproducible with strong intra-class correlation between the two examinations for mean values and for 97.5 percentiles of endothelial permeability and rCBV(T1)(corrected). The excellent reproducibility of this technique and the ability to calculate endothelial permeability and rCBV(T1)(corrected) values from rapidly acquired data sets offer considerable advantages over conventional approaches and support the use of this methodology for therapeutic monitoring or trials of novel therapeutic agents.

Quantification of endothelial permeability, leakage space, and blood volume in brain tumors using combined T1 and T2* contrast-enhanced dynamic MR imaging.

This study describes a method for imaging brain tumors that combines T1-weighted (T1W) and T2*-weighted (T2*W) dynamic contrast-enhanced acquisitions. Several technical improvements have been made to produce high-quality three-dimensional mapping of endothelial permeability surface area product (k) and leakage space (vl), based on T1W data. Tumor blood volume maps are obtained from T2*W images with a complete removal of residual relaxivity effects. The method was employed in 15 patients with brain tumors (5 gliomas, 5 meningioma, and 5 acoustic schwannoma). Mean values of vl were significantly greater in acoustic schwannomas (53% +/- 9%) than in meningiomas (34% +/- 7%) or gliomas (22% +/- 4%). Mean values of vl in meningioma were significantly greater than those of gliomas. Mean values of rCBV correlated closely with k. There was also a positive correlation between k and vl for pixels with low k values. This relationship was weaker in areas of high k. The highest mean ratios of k to vl (k(ep)) were seen in two patients with glioblastoma, one patient with transitional cell meningioma, and one patient with angioblastic meningioma. Pixel-by-pixel comparison showed a strong correlation between rCBV and k in 11 of 15 patients. However, decoupling between pixel-wise rCBV and k was found in four patients who had lesions with moderate k and vl elevation but no increase of rCBV. Results from this study suggest that in assessing the angiogenic activities in brain tumors it is advisable to monitor simultaneously changes in tumor blood volume, vessel permeability, and leakage space of tumor neovasculature.

The characterisation of fluid transport in porous solids by means of pulsed magnetic field gradient NMR.

The determination, by pulsed field gradient (PFG) nuclear magnetic resonance (NMR), of the probability distributions (propagators) of displacements for fluids undergoing transport by both flow and self-diffusion within porous solids is outlined. The nature of the observed propagator, P delta (Z), for the transport of a single aqueous phase through an outcrop sandstone (Fontainebleau) is described. Recent measurements of the propagators for both aqueous and oil phase flow in the limiting saturation states of irreducible water (Swi) and residual oil (Sor) in the same sample are illustrated through the use of difference propagators. These are shown to emphasise the regions of the propagators most affected by the presence of the second, stationary, phases in these limiting saturation conditions. Measurement of the propagators for both oil and aqueous phases undergoing simultaneous flow are also described for the same sandstone sample and the effect of increasing Swi on the nature of the oil flow is briefly discussed. Finally, a new two-dimensional (2-D) experiment is introduced which measures the propagator P delta (X, Z). This is the joint probability for displacements X and Z in time delta. Some preliminary observations of these two-dimensional propagators are shown for single-phase flow in the Fontainebleau sandstone sample, where Z and X are, respectively, displacements in the axial and radial direction for the cylindrical sample for which the pressure gradient is along Z and where bulk radial flow is constrained to be zero.

Interpretation of magnetization transfer and proton cross-relaxation spectra of biological tissues.

Magnetization-transfer (MT) experiments have been performed at 300 MHz on agar gels, solutions of sodium alginate, bovine nasal cartilage, and postmortem porcine muscle. The experimental results elucidate MT mechanisms between mobile macromolecules (correlation time TC on the order of 10(-8) s) and water, and demonstrate the need to incorporate their effects in the characterization of biological samples. In addition, the results obtained confirm a recently published three-spin-bath theoretical treatment for proton magnetization transfer.