David L. White

Osteoarthritis, magnetic resonance imaging, and biochemical markers: a one year prospective study

Objective: To investigate the relation between biochemical markers of bone, cartilage, and synovial remodelling and the structural progression of knee osteoarthritis. Methods: 62 patients of both sexes with knee osteoarthritis were followed prospectively for one year. From magnetic resonance imaging (MRI), done at baseline and after one year, the volume and thickness of cartilage of the femur, the medial tibia, and the lateral tibia were assessed. A whole organ magnetic resonance imaging score (WORMS) of the knee was calculated for each patient at baseline and at the one year visits. This score consists in a validated, semiquantitative scoring system for whole organ assessment of the knee in osteoarthritis using MRI. Biochemical markers (serum hyaluronic acid, osteocalcin, cartilage glycoprotein 39 (YKL-40), cartilage oligomeric matrix protein (COMP), and C-telopeptide of type I collagen (CTX-I), and urine C-telopeptide of type II collagen (CTX-II)) were measured at baseline and after three months. Results: Baseline markers were not correlated with one year changes observed in cartilage volume and thickness. However, an increase in CTX-II after three months was significantly correlated with a one year decrease in mean thickness of medial tibial and lateral tibial cartilage. Patients in the highest quartile of three month changes in CTX-II experienced a mean loss of 0.07 (0.08) mm of their medial thickness, compared with a mean increase of 0.05 (0.19) mm for patients in the lowest quartile (p = 0.04) Multiple regression analysis showed that high baseline levels of hyaluronic acid are predictive of a worsening in WORMS (p = 0.004). Conclusions: These results suggest that a single measurement of serum hyaluronic acid or short term changes in urine CTX-II could identify patients at greatest risk of progression of osteoarthritis.

Vascular Mapping using Albumin-(Gd-DTPA), an Intravascular MR Contrast Agent, and Projection MR Imaging

An intravascular magnetic resonance (MR) contrast agent is valuable for vascular mapping of tissues when used in combination with projection spin-echo MR imaging. The primary advantage of using projection imaging lies in its global depiction of anatomy. Also, relatively short echo time values can be readily achieved, reducing flow dephasing signal losses from blood and increasing overall signal-to-noise. These advantages, coupled with the reduction of blood pool T1 values due to the presence of the intravascular contrast agent, allow for detailed spatial mapping of slow-flow vascular structures using MR.

Contrast-enhanced MRI of tumors. Comparison of Gd-DTPA and a macromolecular agent.

The study aim was to define potential differences and advantages in magnetic resonance (MR) patterns of tumoral contrast enhancement using either a small molecular, extracellular fluid contrast enhancer [Gd-DTPA] or a macromolecular agent [albumin-(Gd-DTPA)20], designed for primary intravascular biodistribution. MR images of 25 mice with implanted fibrosarcomas were obtained before and repeatedly for up to 120 minutes after injection of either Gd-DTPA [0.2 mmol/kg, n = 11] or albumin-(Gd-DTPA) [0.0029 mmol/kg, n = 14]. Histologically, this hypovascular tumor contained zones of viable tissue and non-viable, necrotic tissue. Using either type of contrast media, the viable portions enhanced strongly, up to 152% and the necrotic portions enhanced poorly, less than 31%. However, the time-course of enhancement differed between contrast agents. Gd-DTPA tended to provide maximal enhancement soon after administration with no significant changes over two hours. Enhancement from albumin-(Gd-DTPA) was weak initially, corresponding to tumor hypovascularity, but over two hours the signal of the viable tumor zones progressively increased in intensity. This gradual tumoral accumulation of the macromolecular agent within the tumor was considered to reflect abnormal capillary permeability, associated with neovascularity. Thus, the increasing intensity within the neoplastic tissues over time, reflecting abnormal capillary permeability for macromolecules, may serve as a useful, albeit indirect, marker of neoplasia.

Hepatic metastases: Rat models for imaging research

Improved rat liver tumor models with solitary or multiple metastatic tumors were developed for radiological imaging research. Unlike previous studies which employed trocar inoculation of tumor fragments, an enzymatically disaggregated cell suspension of mammary cancer was injected by fine needle either directly into the liver to produce solitary cancer nodules, or indirectly via the spleen or mesenteric vein to produce multiple liver metastases. Tumor size was proportional to the time elapsed after implantation. The operative mortality of direct liver, splenic parenchymal, and mesenteric inoculations were 8%, 4%, and 27%, respectively. MR tissue characteristics, image contrast, and pharmaceutical enhancement of these tumors closely resembles human hepatic metastases. The availability of reproducible, inexpensive animal models of metastatic cancer allows efficient evaluation of new liver imaging techniques.

Electric current density imaging of bone by MRI

Current density imaging (CDI) has been shown to be a feasible method to map spatial distribution of electric currents through bone structures and for studying osteoporosis and bone fracture models. For the osteoporosis model, bone sample was moistened in a solution of a sodium salt of ethylendiamintetraacetic acid (EDTA) which causes chemical reaction with hydroxyapatite Ca2+ ions and lowers the mineralisation degree of the solid bone. This enables clear visualisation of conventional magnetic resonance imaging and CDI. Sensitivity of conventional magnetic resonance and CD images of bone was improved by immersing the bone samples into physiological saline containing contrast agent Gd-DTPA prior to imaging. To stimulate effects of bone fracture on electric current conductivity through bone, a transverse cut was made through the bone, and the resulting gap was filled with an insulator. Electric current density images under these conditions have shown that regions of strong conductivity can be distinguished from regions of no conductivity at the site where the insulator restricts electric current. Real bone fracture was imaged as well. To demonstrate influence of electrolyte concentration on electric current spatial distribution, the bone samples were imaged after being immersed in various saline concentrations. The same contrast in current density images was produced with the combinations of higher electrolyte concentrations and lower voltages. Our observations demonstrate the feasibility of the method in mapping current density in bone structures, which could have implications in understanding and monitoring the effects of the electrical stimulation.

Hepatobiliary magnetic resonance contrast agents assessed by gadolinium-153 scintigraphy.

A simple method to test new gadolinium complexes potentially useful as enhancement agents for magnetic resonance imaging was developed. Healthy rats underwent scintigraphy with two potential hepatobiliary agents, diethyl IDA and diisopropyl IDA complexed with gadolinium-153. Control products included 153Gd DTPA, 153GdCl3 and technetium-99m diethyl IDA. As shown scintigraphically, 153Gd IDA complexes were partially excreted by urinary and hepatobiliary excretion early after administration. These findings paralleled significant reduction in 1H T1 values of excised livers. However, these agents exhibited prolonged 153Gd whole-body retention. The prolonged tissue distribution of 153Gd activity in animals given 153Gd diethyl IDA did not differ significantly from that observed in animals given GdCl3, and could be attributed to chemical instability or reticuloendothelial uptake. The scintigraphic method permits screening of gadolinium complexes in animals by showing mass balance, kinetics, distribution, and effective stability. Biologic effects of tracer or pharmacologic levels can be compared with those of carrier-free and carrier-added pharmaceuticals.

Stereoscopic MR imaging.

The visual fusion of two projection or slice-selective magnetic resonance (MR) images taken at two oblique angles imparts three-dimensional (3D) information within the projection or slice. This approach to 3D MR is rapid and straightforward, requiring only two oblique images and, at most, only a simple optical stereoscope for viewing. Stereoscopic images of the vascular system of a rat were obtained using the intravascular contrast agent albumin-(Gd-diethylenetriaminepentaacetic acid). Stereoscopic images of the human head showing CSF distribution were acquired using a long echo time sequence. These images illustrate the potential clinical applications of this technique.

Ascorbate-induced cancellation of nitroxide contrast media enhancement of MR images.

Ascorbate (Vitamin C), a naturally occurring reducing substance, was tested as an in vivo chemical agent to cancel magnetic resonance imaging (MRI) tissue contrast enhancement induced by a nitroxide spin label contrast agent. Paramagnetic nitroxide compounds can be reduced in vitro by ascorbate to nonparamagnetic hydroxylamine derivatives. A nitroxide agent, TES, was injected intravenously, 2 mmol/kg, in 11 anesthetized rats. Renal cortical and hepatic intensities were monitored by serial T1-weighted images (TR/TE 310/15) acquired precontrast and postcontrast. Fourteen minutes after TES administration, ascorbate (1 mmol/kg) was injected in 6 rats, and saline in 5 control rats. At twenty-nine minutes postcontrast, a second TES-injection was given to all rats. The initial TES-injection resulted in a marked enhancement of kidney cortex and liver. Ascorbate administration immediately cancelled this enhancement. Contrast enhancement could be successfully reinduced by a repeat administration of TES. Results indicate that in vivo administration of reducing agents can be used to immediately cancel enhancement induced by nitroxide contrast media, thus nonenhanced images could be obtained after enhanced images without lengthy delays for contrast media elimination.

A Method to Monitor Local Changes in MR Signal Intensity in Articular Cartilage: A Potential Marker for Cartilage Degeneration in Osteoarthritis

Osteoarthritis (OA) involves changes in the composition and ultimately the loss of cartilage from articulating joints. MRI has the ability to non-invasively probe the compositional integrity of cartilage, thereby potentially identifying dis- eased cartilage before loss occurs. In this study we have developed a technique to compare local changes in signal intensity over time in fat suppressed 3D gradient echo MR images of articular cartilage in patients with OA. We have used an Ac- tive Appearance Model (AAM) based image registration to correspond locations within the cartilage in the same individual at different times. We have applied the technique to data taken over periods of 1 and 3 years in two groups of patients with established OA of the knee. In both these studies, no significant change in total cartilage volume could be detected but we were able to observe some significant changes in signal intensity. We conclude that in a study of cartilage structure the technique can provide additional information without the overhead of extra scans.

MRI-SPECT image registration using multiple MR pulse sequences to examine osteoarthritis of the knee

We have examined whether automated image registration can be used to combine metabolic information from SPECT knee scans with anatomical information from MRI. Ten patients, at risk of developing OA due to meniscal surgery, were examined. 99mTc methyldiphosphonate SPECT, T2-weighted fast spin echo (FSE) MRI, and T1-weighted, 3D fat-suppressed gradient recalled echo (SPGR) MRI images were obtained. Registration was performed using normalized mutual information. For each patient, FSE data was registered to SPGR data, providing a composite MRI image with each voxel represented by two intensities (ISPGR, IFSE). Modifications to the registration algorithm were made to allow registration of SPECT data (one intensity per voxel) to composite MRI data (2 intensities per voxel). Registration sources was assessed by visual inspection of uptake localization over expected anatomical locations, and the absence of uptake over unlikely sites. Three patients were discarded from SPECT-MRI registration tests since they had metallic artifacts that prevented co-registration of MR data. Registration of SPECT to SPGR or FSE data alone proved unreliable, with less than 50% of attempts succeeding. The modified algorithm, treating co-registered SPGR and FSE data as a two-value-per-voxel image, proved most reliable, allowing registration of all patients with no metallic artifacts on MRI.