A monoclonal antibody to α4-integrin reverses the MR-detectable signs of experimental allergic encephalomyelitis in the Guinea pig

Experimental allergic encephalomyelitis (EAE) is a T cell-mediated autoimmune disease of the CNS characterized by blood-brain barrier breakdown. cerebral edema formation, lymphocyte infiltration, and demy-elination, and is used as an animal model of multiple sclerosis (MS). MR imaging is important for the diagnosis of MS and for the evaluation of potential new therapier. In this study, T2-weighted and T1-weighted contrast-enhanced MR imaging was used to evaluate the effectiveness of an antiadhesion therapy in EAE. Leukocyte-endothelial adhesion at the blood-brain barrier is considered an essential step in the mediation of CNS leukocyte infiltration in EAE. AN100226m. a monoclonal antibody to α4 integrin has been previously shown to reverse the clinical and histologic signs of EAE by blocking this interaction. In the present study, AN100226m treatment in acute EAE significantly decreased contrast enhancement of the CNS parenchyma indicating closure of the blood-brain barrier. The percentage of pixele due to leakage of contrast material in T1-weighted images decreased to <4% in AN100226m-treated animals whereas it was increased to 15% in control animal (P <.05. Mann-Whitney rank sum test). A decrease in CNS abnormalities associated with cerebral edema and inflammation was also obsaved on T2-weighted images (P < _-05, Mann-Whitney rank sum test). Thus, an antibody to α4 integrin reversed the blood-brain barrier permeability changes characteristic of acute EAE. In addition, the further accumulation of innammatory edema was prevented and preexisting edema was resolved.     

Gd-enhanced MR imaging of acute and chronic experimental demyelinating lesions

Experimental allergic encephalomyelitis, a demyelinating disease with marked similarity to multiple sclerosis, was produced in two of 12 dogs. All dogs were studied with serial MR imaging. T1- and T2-weighted MR images were obtained both before and after IV Gd-DTPA. Multiple, new periventricular white matter demyelinating lesions were observed after each clinical episode of the disease. Like multiple sclerosis, the acute lesions of experimental allergic encephalomyelitis on T2-weighted MR images were indistinguishable from the older, more chronic lesions. However, after Gd-DTPA, there was bright paramagnetic enhancement of the acute lesions and, in one animal, no enhancement of the chronic lesions on T1-weighted MR images. At necropsy, the differences in the MR paramagnetic enhancement correlated well with the relative histologic age of the demyelinating lesions. Our results suggest that MR with Gd-DTPA may be used to differentiate acute, active demyelinating lesions from the more chronic, inactive lesions in this animal model.     

Diffusion imaging of experimental allergic encephalomyelitis

Diffusion-weighted magnetic resonance imaging (MRI) was compared with T₂-weighted MRI in longitudinal studies of experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis, in five monkeys (Macaca fascicularis). In a region of the brain that had highly directional myelinated fibers (internal capsule) sequential changes were identified on diffusion-weighted images on and before the day these changes were detected on conventional T₂-weighted images. Changes were also identified on diffusion-weighted images in brain areas that did not develop T₂-weighted abnormalities. This result suggests that diffusion-weighted image intensities are sensitive to pathologic conditions of the brain that can not be seen on T₂-weighted images.     

In vivo visualization of myelin water in brain by magnetic resonance

We exploit the intrinsic difference in magnetic resonance spin-spin relaxation time, T₂, between water associated with myelin sheaths and water in other central nervous system tissue in order to measure myelin water content within any region of an image or to generate indirectly a myelin map of the brain. In normal volunteers, myelin water maps give the expected myelin distribution. In multiple sclerosis patients, lesions exhibit different myelin water contents providing insight into the de-myelination process unavailable from conventional magnetic resonance images. In vivo myelin measurement has important applications in the clinical management of multiple sclerosis and other white matter diseases.     

Magnetization transfer effects in MR-detected multiple sclerosis lesions: comparison with gadolinium-enhanced spin-echo images and nonenhanced T1-weighted images.

PURPOSETo define the relationship between magnetization transfer and blood-brain-barrier breakdown in multiple sclerosis lesions using gadolinium enhancement as an index of the latter.METHODSTwo hundred twenty lesions (high-signal abnormalities on T2-weighted images) in 35 multiple sclerosis patients were studied with gadolinium-enhanced spin-echo imaging and magnetization transfer. Lesions were divided into groups having nodular or uniform enhancement, ring enhancement, or no enhancement after gadolinium administration. For 133 lesions, T1-weighted images without contrast enhancement were also analyzed. These lesions were categorized as isointense or hypointense based on their appearance on the unenhanced T1-weighted images.RESULTSThere was no difference between the magnetization transfer ratio (MTR) of lesions as a function of enhancement. MTR of hypointense lesions on unenhanced T1-weighted images was, however, lower than the MTR of isointense lesions.CONCLUSIONWe speculate that diminished MTR may reflect diminished myelin content and that hypointensity on T1-weighted images corresponds to demyelination. Central regions of ring-enhancing lesions had a lower MTR than the periphery, suggesting that demyelination in multiple sclerosis lesions occurs centrifugally. In addition, the short-repetition-time pulse sequence seems useful in the evaluation of myelin loss in patients with multiple sclerosis.     

Reperfused ischemia of the rat intestine: Detection by MR imaging with polylysine-Gd-DTPA enhancement

To detect reperfused ischemia of the rat intestine, T₂-weighted spin-echo images were acquired, followed by T₁-weighted images before and after administration of polylysine-Gd-DTPA or Gd-DTPA. Before administration of the contrast agent, the reperfused intestine was hyperintense on T₂-weighted images, and to a lesser extent on T₁-weighted images. After administration of polylysine-Gd-DTPA, the reperfused intestine enhanced more than the normal one, giving a significantly better contrast-to-noise (CNR) ratio than on unenhanced images. Gd-DTPA induced the same enhancement of the reperfused and the normal intestine and the CNR was lower than on unenhanced T₂-weighted images. Reperfused intestinal ischemia could thus be better detected on polylysine-Gd-DTPA-enhanced MR images than on unenhanced images or on Gd-DTPA- enhanced images.     

Lysolecithin-induced demyelination in primates: preliminary in vivo study with MR and magnetization transfer.

PURPOSETo study bystander demyelination in multiple sclerosis with an experimental in vivo model of toxic demyelination.METHODSToxic demyelinating lesions were created in two monkeys by injection of lysophosphatidylcholine in the centrum semiovale. Follow-up was done clinically and with serial MR studies, including T2-weighted and gadolinium-enhanced T1-weighted images and measurement of magnetization transfer ratio, until the animals were killed at days 14 and 34, respectively. Light and electron microscopy analysis was compared with MR data.RESULTSInterval measurement of magnetization transfer ratio during the course of the experiment revealed a maximum decrease at day 7 to day 8, associated with the greatest clinical manifestations. The lowest values of magnetization transfer ratio correlated with histopathologic findings of myelin and axon destruction. Magnetization transfer ratio measurements appear to be sensitive to macromolecular destruction and specifically to membrane disorganization. At no time was gadolinium enhancement observed in this model of toxic demyelination.CONCLUSIONPreliminary results of this study indicated that magnetization transfer is a good technique to follow in vivo matrix destruction in brain parenchyma lesions. The results suggest also that phases of toxic demyelination in multiple sclerosis might not show gadolinium enhancement. Differentiation between demyelinating activity and associated inflammation in multiple sclerosis lesions should be considered in further in vivo work.     

MR imaging of relapsing multiple sclerosis patients using ultra-small-particle iron oxide and compared with gadolinium

BACKGROUND AND PURPOSE: Inflammatory multiple sclerosis (MS) lesions are characterized by microglia activation and infiltration of T cells, B cells, and macrophages across the blood-brain barrier (BBB). In the experimental autoimmune encephalomyelitis (EAE) rat model of MS, previous MR imaging investigations with a new contrast agent ultra-small-particle iron oxide (USPIO) that accumulates in phagocytic cells revealed in vivo the presence of macrophage brain infiltration. The goal of this study was to characterize MS lesions with the use of this contrast agent. METHODS: A prospective MR imaging study of 10 patients with MS in acute relapses was achieved by using USPIO and gadolinium. RESULTS: Twenty-four hours after USPIO injection, 33 acute MS lesions in 9 patients showed USPIO uptake. Lesions were seen as high signal intensities on T1-weighted images and low signal intensities on T2-weighted images. Gadolinium enhancement was seen in 31 of these lesions in 7 patients. These 7 patients presented 24 gadolinium-enhanced lesions that did not enhance with USPIO. Two patients showed USPIO-enhanced lesions but no gadolinium-enhanced lesions. CONCLUSION: Taken together with earlier findings obtained in experimental models or in human stroke, the visualization of macrophage activity in vivo with USPIO characterize a distinct cellular and inflammatory event of the dynamic process of MS lesion formation. The macrophage activity information obtained with USPIO is distinct and complementary to the increased BBB permeability seen with gadolinium.     

Magnetic resonance imaging of peripheral soft tissue hemangiomas

Ten patients with soft tissue hemangiomas outside the central nervous system were studied with MR imaging. Eight patients were studied at 1.5 Tesla (T) with T₁-weighted and triple echo T₂-weighted sequences. Two additional patients were imaged on a 0.5-T system. The MR images were correlated with images from other modalities. Histologie diagnosis was obtained in all cases. It was found that prolonged T₂-weighted imaging together with standard spin echo T₁ and T₂ pulse sequences is a good substitute for contrast-enhanced CT and arteriographic evaluation of soft tissue hemangiomas.     

Multiple sclerosis: gadolinium enhancement in MR imaging

Magnetic resonance (MR) images--both nonenhanced and enhanced with gadolinium DTPA/dimeglumine (Gd)--were compared with high-iodine (88.1 g I) computed tomographic (HICT) scans in demonstrating lesions in 15 patients known to have multiple sclerosis (MS). T1-weighted, mixed (T1, proton density, and T2), and T2-weighted MR pulse sequences were used. More than 20 lesions in each of 14 patients were demonstrated by pre-Gd mixed images and T2WI. Nine patients had clinical symptoms of active disease. Gd-enhanced T1WI showed at least one lesion that appeared to correspond with newly reported symptoms or signs. In addition, three clinically stable patients showed enhancement. Enhancement was best seen on 3-minute T1WI. HICT scans showed enhancement in four of the nine patients with active disease and in none of five clinically stable patients. Gd-enhanced MR imaging appears to be more sensitive than HICT in the detection of the transient abnormalities of the blood-brain barrier that occur in patients with active MS and appears capable of distinguishing active lesions that may correspond to the anatomic regions responsible for abnormal clinical findings.     

Detection and characterization of primary liver cancer in rats by MS-264-enhanced MRI

A new MR contrast agent, MS-264 (Gd(1 RS)-1-(p-butylbenzyl)-DTPA), was developed to achieve hepatobiliary specificity and its potential evaluated for detecting and characterizing liver tumors in rats with chemically induced hepatocellular carcinoma (HCC). In seven rats with 66 HCC lesions, enhancements of different abdominal organs and tumors were compared on T₁-weighted images after intravenous administration of Gd-DTPA (0.3 mmol/kg) and MS-264 (0.05 mmol/kg). MR images were correlated with postmortem microangiographic and histological findings. An overall enhancement of different organs, which normalized within 24 h, was observed after Gd-DTPA and MS-264 injection. MS-264 caused a higher relative enhancement (RE) in liver (60%), compared with that of Gd-DTPA (40%), which resulted in a prompt negative contrast enhancement in 59 of 66 HCCs. All were moderately to poorly differentiated (Grades II–IV) tumors. Six of these 59 negative contrast-enhancing lesions showed a positively enhanced peritumoral rim, which corresponded histologically to malignant infiltration (n = 2) or compression (n = 4). On the other hand, six well differentiated HCCs showed prolonged positive enhancement. However, one well differentiated HCC was not positively enhanced by MS-264, probably due to poor access of the agent to the lesion. In comparison to that of the pre-contrast images, enhancement with Gd-DTPA and MS-264 increased the number of detected lesions by 22 and 42%, respectively. In this animal study, MS-264 proved to be useful in detection and characterization of primary liver cancers.     

Patterns of lesion development in multiple sclerosis: longitudinal observations with T1-weighted spin-echo and magnetization transfer MR.

PURPOSEWe evaluated the appearance of enhancing multiple sclerosis (MS) lesions on unenhanced T1-weighted MR images and the natural course of enhancing MS lesions on serial unenhanced T1-weighted and magnetization transfer (MT) MR images.METHODSOne hundred twenty-six enhancing lesions were followed up monthly for 6 to 12 months to determine their signal intensity on unenhanced T1-weighted and MT MR images. At the time of initial enhancement, the size of the lesion and the contrast ratio of enhancement were calculated for each enhancing lesion. During follow-up, the contrast ratio on the corresponding unenhanced T1-weighted image was measured, and an MT ratio (MTR) was calculated.RESULTSTwenty-five enhancing lesions (20%) appeared isointense and 101 lesions (80%) appeared hypointense relative to normal-appearing white matter on unenhanced T1-weighted images. During 6 months of follow-up, four MR patterns of active lesions were detected: initially isointense lesions remained isointense (15%); initially isointense lesions became hypointense (5%, most of which reenhanced); initially hypointense lesions became isointense (44%); and initially hypointense lesions remained hypointense (36%). MTR was significantly lower for hypointense lesions as compared with isointense lesions at the time of initial enhancement. For lesions that changed from hypointense to isointense, MTR increased significantly during 6 months of follow-up. Multiple regression analysis showed that strongly decreased MTR at the time of initial enhancement and enhancement duration of more than one scan were predictive of a hypointense appearance on unenhanced T1-weighted images at 6 months'' follow-up. Ring enhancement was found to be the only (weak) predictor of persistently hypointense signal intensity.CONCLUSIONMost enhancing lesions appear slightly to significantly hypointense on unenhanced T1-weighted images. Although most hypointensities are reversible, only those lesions that fail to recover on unenhanced T1-weighted and MT images may have considerable irreversible structural changes.     

Rapidly enhancing hepatic hemangiomas at MRI: Distinction from malignancies with T2-weighted images

The purpose of this study is to describe a subset of atypical hepatic hemangiomas that enhance rapidly and diffusely and to determine whether heavily T2-weighted images could distinguish between atypically enhancing liver hemangiomas and hypervascular malignancies. A retrospective search of MR records identified seven patients with liver hemangiomas that demonstrated diffuse early enhancement and 23 patients with biopsy-proven malignant liver lesions that were hypervascular on dynamic gadolinium-enhanced MR images. Quantitative analysis of signal intensity measurements was performed on the T2-weighted images, heavily T2-weighted (TE < 140), and dynamic gadolinium-enhanced images. Blinded reader comparison of the T2-weighted images and gadolinium-enhanced images was performed. Hypervascular hemangiomas enhanced to a greater degree than hypervascular malignant liver lesions on the early phase gadolinium-enhanced images. Perilesional parenchymal enhancement was demonstrated in five cases of rapidly enhancing hemangiomas. Signal intensity and contrast-to-noise ratios on the heavily T2-weighted images of the hemangiomas were significantly greater than that of the hypervascular malignant lesions (P < .05). Hemangiomas were differentiated from the hypervascular malignant liver lesions with high accuracy (97–100%) by three blinded readers based on the T2-weighted images. A subset of hemangiomas have atypical rapid diffuse enhancement on dynamic gadolinium-enhanced images. These atypical hemangiomas can be distinguished from hypervascular malignant liver lesions on T2-weighted MR images.     

Quantitative Analysis of Dynamic Gd-DTPA Enhancement in Breast Tumors Using a Permeability Model

The MRI signal enhancement in a breast tumor, measured as a function of time after a bolus injection of Gd-DTPA, may contain enough information to differentiate malignant from benign tissue. We find a physiological model for measuring capillary permeability and leakage space (P. S. Tofts, A. G. Kermode, measurement of the blood-brain barrier permeability and leakage space using dynamic MR imaging. 1. Fundamental concepts. Magn. Reson. Med. 17, 357–367 (1991)) fits the data well. The enhancement curve is particularly sensitive to the preinjection T₁, of the tumor, the dose, and the time of injection. This model may provide a means of characterizing the pathophysiology of breast tumors from the Gd-DTPA enhancement curve.     

Late radiation injury to the temporal lobes: morphologic evaluation at MR imaging

PURPOSE: To study the morphologic characteristics of late radiation injury to the temporal lobes of the brain on magnetic resonance (MR) images. MATERIALS AND METHODS: This was a prospective study involving 34 patients (age range, 37-72 years) with known radiation injury to the temporal lobes from radiation therapy administered 2-10 years previously for nasopharyngeal carcinoma MR imaging was performed with T2-weighted gradient- and spin-echo, gradient-recalled echo, T1-weighted spin-echo, fluid-attenuated inversion-recovery, and T1-weighted postcontrast spin-echo sequences. RESULTS: Radiation injury was present in 57 of the 68 temporal lobes. The white matter lesions in radiation-induced injury were predominantly hyperintense on T2-weighted images, but in 37 (65%) of the 57 lobes, foci with heterogeneous signal intensity consistent with necrosis were detected. In the 57 involved lobes, gray matter lesions were detected in 50 (88%); blood-brain barrier disruption based on parenchymal contrast enhancement, in 51 (89%); and hemosiderin deposits, in 30 (53%). There was a significant correlation between white matter necrosis, gray matter lesions, and blood-brain barrier disruption, all of which were located mainly in the inferior temporal lobes that received the highest radiation dose. CONCLUSION: The lesion components of radiation-induced injury to the temporal lobes at MR imaging were more varied than have been previously described. In addition to the classic white matter lesions, gray matter lesions, blood-brain barrier disruption, and hemosiderin deposition also were frequently seen.     

MR imaging of acute cerebral infarction: experimental study with Gd-DTPA

To evaluate the sensitivity of MR imaging for acute cerebral infarction and the effectiveness of MR enhancement with Gd-DTPA, we created a canine model of cerebral infarction by transarterial embolization (TAE). The external and internal carotid arteries were embolized respectively through a transfemoral catheter. MR imaging was performed with the Yokogawa Medical System prototype superconducting MR machine "Resona" operating at 0.35 Tesla. MR enhancement was done with 0.4 mmol/kg of Gd-DTPA. Early detectability without Gd-DTPA was 60% (3/5) two hours after TAE and 67% (4/6) at three hours. MR imaging showed high-intensity lesions on the T2-weighted sequence (SE 2000/100). The T1-weighted sequence (SR 250-600/25-35) did not reveal any lesions four hours after TAE. Five animals which received Gd-DTPA showed abnormal enhancement in the brain parenchyma within 30 min after Gd injection on the T1 weighted sequence. Gd-DTPA enhancement not only improved early sensitivity for acute cerebral infarction when MR imaging without Gd-DTPA was negative, but also enhanced the size and number of lesions compared with SE 2000/100 images without enhancement. The breakdown of the blood-brain barrier was suggested to be an important factor in Gd-DTPA enhancement.     

Single-dose gadolinium with magnetization transfer versus triple-dose gadolinium in the MR detection of multiple sclerosis lesions.

PURPOSETo compare the efficacy of single-dose gadolinium with magnetization transfer contrast (MTC) with that of triple-dose gadolinium in detecting enhancing multiple sclerosis lesions.METHODSTwenty-one patients with multiple sclerosis were examined with MR imaging first with 0.1 mmol/kg gadolinium (single dose) and then, after 24 to 72 hours, with 0.3 mmol/kg gadolinium (triple dose). T2-weighted fast spin-echo and T1-weighted spin-echo MR images with and without MTC were obtained before contrast administration followed by either T1-weighted spin-echo images with MTC (single dose) or conventional T1-weighted spin-echo images (triple dose), starting 5, 17, and 29 minutes after contrast administration. All images were evaluated in a blinded fashion and scored in random order by two readers. Outcome parameters included number of enhancing lesions, number of active MR examinations (those containing at least one enhancing lesion), contrast ratio (signal intensity of enhancing lesion divided by signal intensity of normal-appearing white matter), and size of enhancing lesions.RESULTSEighty-one percent more enhancing lesions and 49% more active MR examinations were detected when a triple dose of gadolinium was used as compared with a single dose. The level of agreement between readers as to the number of enhancing lesions was significantly higher for triple-dose than for single-dose gadolinium. With triple-dose gadolinium, contrast ratios and areas of enhancement increased by 10% and 33%, respectively. Delayed imaging increased the size of the lesion by 11% on single-dose MTC images and by 18% on triple-dose images.CONCLUSIONTriple-dose gadolinium is more effective (higher sensitivity and interobserver agreement) than single-dose gadolinium in combination with MTC in detecting enhancing multiple sclerosis lesions.     

Efficacy of nonionic low-osmolar gadodiamide injection in animals with intracranial mass lesions.

Gadodiamide injection is a nonionic, low-osmolar formulation of a paramagnetic metal chelate complex consisting of gadodiamide and caldiamide sodium. The efficacy of gadodiamide injection as a magnetic resonance (MR) imaging enhancement medium was evaluated by imaging intracranial 9L-glioma lesions induced in rats and naturally occurring lesions in dogs. T1- and T2-weighted spin-echo images were obtained before and after administration of gadodiamide injection at doses of 0.1 and 0.2 mmol/kg. On the precontrast T1-weighted images, the intracranial lesions were not well seen, appearing isointense to normal brain parenchyma. Although the presence of disease was shown unequivocally on the T2-weighted images, the margins of the masses could not be delineated. Postcontrast T1-weighted images were characterized by marked enhancement of the tumor, with no change in signal intensity in the surrounding edematous brain tissue. Gadodiamide injection was efficacious in identifying areas of blood-brain barrier breakdown associated with intracranial masses.     

MR contrast enhancement of intracranial lesions with Gd-DTPA

Gd-DTPA is a paramagnetic contrast agent for MR that produces enhancement of lesions on T1-weighted images. Since it does not cross the intact blood-brain barrier (BBB), Gd-DTPA enhances only those pathologic processes that are associated with breakdown of the BBB and structures or lesions that are devoid of a BBB. Gd-DTPA improves conspicuity, helps characterize and delineate the extent of lesions, and increases the sensitivity for detection of cerebral abnormalities.     

Magnetic resonance imaging findings of proliferating trichilemmal tumor

We report the magnetic resonance (MR) imaging findings of proliferative trichilemmal tumor (PTT), a rare benign tumor of the scalp. MR imaging showed a well-margined mass with isointense signal on T₁-weighted images and heterogeneous mixed intensity signal on T₂-weighted images After i.v. administration of contrast material, the mass showed significant enhancement, with small portions remaining unenhanced. It was considered that these findings reflected the pathological characteristics of PTT, which consists of solid lobules and cystic cavities.