John W. Wells

Update: Safety, New Applications, New MR Agents

In the last decade, i.v. contrast media use in magnetic resonance imaging (MRI) of the central nervous system has become well established. Three agents are currently available in the United States: gadopentetate dimeglumine (Magnevist), gadodiamide (Omniscan), and gadoteridol (ProHance). At a dose of 0.1 mmol/kg, for which all three agents are approved, the contrast effect is equivalent. The agents differ on the basis of stability in vivo, osmolality, and charge. A single agent (ProHance) is approved for high-dose administration (0.3 mmol/kg). The basis of this approval is due in part to the high stability of the agent and thus lower potential for toxicity from long-term heavy metal deposition. Clinical experience, combined with new developments in MR technology, continue to expand applications for these agents. Improved detection of metastatic disease to the brain has been demonstrated in multiple clinical trials with high-dose contrast administration. High dose may also play an important role in brain infection and infarction, providing improved recognition of blood-brain barrier disruption and thus disease activity. First-pass studies make possible the evaluation of regional cerebral blood volume with high intrinsic spatial resolution. The availability of new instrumentation, together with the use of high contrast dose, have improved the quality and clinical utility of these studies. Research is ongoing in the development of new agents, both with greater tissue selectivity and improved safety profile. Chelates of dysprosium, in addition to gadolinium, are receiving attention for potential clinical application in first-pass imaging.

DETECTABILITY OF EARLY BRAIN MENINGITIS WITH MAGNETIC RESONANCE IMAGING

RATIONALE AND OBJECTIVESThe ability of high-field (1.5 T) magnetic resonance imaging (MRI) to detect early brain meningitis was evaluated in a canine model. Contrast dose, timing postinjection, and imaging technique (specifically the use of magnetization transfer) were assessed. METHODSImaging of five canines was performed at 1.5 T 24 hours after injection of Cowans staphylococcus into the cisterna magna. Two control animals also were imaged using the same protocol, with one animal receiving a cisternal injection of nutrient broth only and the other no injection. Contrast doses of 0.1, 0.3, and 0.8 mmol/kg gadotcridol (Gd HP-DO3A or Pro- Hance) were compared. Scans were performed at 2, 12, and 22 minutes after an initial injection of 0.1 mmol/kg. At each time point, paired T1 -weighted scans with and without magnetization transfer (MT) were acquired. Thirty minutes after the initial injection of contrast, a supplemental dose of 0.2 mmol/kg was given (for a cumulative dose of 0.3 mmol/kg). Scans were then repeated at 2, 12, and 22 minutes after this dose was administered. A second supplemental contrast injection of 0.5 mmol/kg (for a cumulative dose of 0.8 mmol/kg) was given at 70 minutes, and immediate postinjection scans with and without MT were acquired. RESULTSIn the animals receiving a cisternal injection of bacteria, the degree of meningcal enhancement was greatest at 0.8 mmol/kg, intermediate at 0.3 mmol/kg, and least at 0.1 mmol/kg. These conclusions were constant whether imaging was performed with or without MT. Scans in control studies did not demonstrate abnormal meningeal enhancement. Highcontrast dose, MT, and acquisition of immediate postcontrast scans all resulted in statistically significant improvement. On masked film review, abnormal meningcal enhancement was noted in only 2 of 5 experimental dogs at a dose of 0.1 mmol/kg (regardless of the use of MT) compared with all animals at a dose of 0.3 mmol/kg. In 18 of 37 dogs (paired scans with and without MT), when abnormal enhancement was noted, the use of MT improved the visualization of abnormal meningcal enhancement. CONCLUSIONSIn early brain meningitis, high-contrast dose (0.3 mmol/kg), MT, and scanning immediately after injection improve detection of abnormal meningeal enhancement, thus facilitating the diagnosis of meningitis. Of these factors, contrast dose is the most important.

EVALUATION OF THE TEMPORAL EVOLUTION OF ACUTE SPINAL CORD INJURY

RATIONALE AND OBJECTIVES After receiving a controlled injury to the thoracic cord, five rats were examined on a 1.5-T magnetic resonance (MR) imaging system at regular intervals over 1 month to assess evolution of the injury. METHODS After the rats received pentobarbital anesthesia, a T10 laminectomy was performed on them, which exposed the dura over the dorsal surface of the spinal cord. With the animal placed in a New York University weight-drop device, a 10-g rod with a flat brass tip was dropped (free-fall) from a height of 50 mm to impact the cord. After injury, the incision was closed with suture material. Each animal was imaged on the day of injury, and at 7, 14, and 28 days after injury. Before contrast injection was administered, sagittal sections were obtained with T2 fast-spin echo and T1-spin echo technique. Each rat then received 0.3-mmol/kg gadoteridol (Gd HP-DO3A or ProHance) intravenously, with the T1 scan repeated. At 28 days, the animals were killed, and the cord was fixed and embedded in paraffin for histologic evaluation. RESULTS The intensity of cord enhancement in the region of injury, after intravenous (i.v.) contrast injection, was at a maximum on the day of injury, and it decreased in a steady fashion thereafter. The intensity was 11.7 +/- 0.6 on the day of injury, 9.7 +/- 2.6 on day 7, 6.3 +/- 5.3 on day 14, and 0.0 +/- 2.3 on day 28. The results on day 0 and 7 were statistically significant in terms of a difference from that on day 28, with a P value < 0.001. The length of cord injury, assessed postcontrast, also decreased in a steady fashion from the day of injury. The length of injury (in cm) was 1.1 +/- 0.1 on the day of injury, 0.5 +/- 0.2 on day 7, 0.3 +/- 0.1 on day 14, and 0.1 +/- 0.1 on day 28. The results on day 0 and 14 were statistically significant in terms of a difference from those at the next time point, with P values from < 0.01 to < 0.001. Visually, on T2 images, substantial edema was noted on day 0, with progression to focal cord atrophy and gliosis by day 28. CONCLUSIONS Acute spinal cord injury in a rat model is well visualized on pre- and postcontrast MR scans at 1.5 T. Observation of T2 changes and disruption of the blood-spinal cord barrier provide markers for temporal assessment of spinal cord injury in the rat model.

Evaluation of Gadolinium 2,5-BPA-DO3A, a New Macrocyclic Hepatobiliary Chelate, in Normal Liver and Metastatic Disease on High Field Magnetic Resonance Imaging

RATIONALE AND OBJECTIVES A new hepatobiliary gadolinium chelate, gadolinium (Gd) 2,5-BPA-DO3A, was compared in two animal species with Gd HP-DO3A (gadoteridol), a clinically approved extracellular contrast agent, and Gd Cy2-DOTA, a second hepatobiliary chelate in preclinical development. The ligand in Gd 2,5-BPA-DO3A is macrocyclic in nature, as opposed to the linear structure of Gd DTPA. Gadolinium 2,5-BPA-DO3A was evaluated on magnetic resonance imaging at 1.5 T, examining specifically liver parenchymal enhancement and lesion delineation, the latter in metastatic disease. METHODS Gadolinium 2,5-BPA-DO3A was evaluated in five normal rhesus monkeys and four New Zealand White rabbits with implanted VX-2 liver tumors. These studies were compared with magnetic resonance exams in the same animals using Gd HP-DO3A and Gd Cy2-DOTA. A contrast dose of 0.1 mmol/kg intravenous was employed in each instance, with the sequence of administration (for the three agents) randomized and at least 72 hours between injections. Spin echo breathhold T1-weighted scans were obtained before and at multiple times after contrast administration. Postcontrast scans were acquired from 1 to 60 minutes after injection in the monkeys and from 1 to 240 minutes in the rabbits. RESULTS Enhancement of normal liver parenchyma was markedly superior with Gd 2,5-BPA-DO3A compared with Gd HP-DO3A and Gd Cy2-DOTA in both monkeys and rabbits. At 2 and 60 minutes after contrast administration, the liver signal intensity in the monkey was 452 +/- 56 and 440 +/- 69 with Gd 2,5-BPA-DO3A compared with 295 +/- 34 and 256 +/- 38 with Gd HP-DO3A. The difference between agents was statistically significant at all postcontrast time points in the rhesus monkey. Excretion of contrast into the gall bladder was consistently observed after Gd 2,5-BPA-DO3A injection in both animal species. Maximum lesion conspicuity occurred in the rabbit at 45 minutes after Gd 2,5-BPA-DO3A administration. At 45 minutes postinjection, liver-lesion contrast was 0.60 +/- 0.15 with Gd 2,5-BPA-DO3A, 0.35 +/- 0.11 with Gd Cy2-DOTA, and 0.12 +/- 0.04 with Gd HP-DO3A, with the differences between agents being statistically significant. CONCLUSIONS Gadolinium 2,5-BPA-DO3A is superior to both Gd Cy2-DOTA and Gd HP-DO3A in the degree of enhancement of normal liver parenchyma achieved after intravenous injection. This leads to improved liver lesion delineation with Gd 2,5-BPA-DO3A on delayed postcontrast magnetic resonance scans.

MAGNETIZATION TRANSFER AND HIGH-DOSE CONTRAST IN EARLY BRAIN INFECTION ON MAGNETIC RESONANCE

RATIONALE AND OBJECTIVES.The authors studied the effect of contrast dose, use of magnetization transfer (IMT), and temporal delay on the visualization of contrast enhancement with gadotcridol (Gd HP-DO3A) in a canine brain abscess model. METHODS.Alpha streptococcus brain abscesses were studied in five dogs at 1.5 tesla (T) 1 and 5 days after implantation. Scans were performed 1,11, and 21 minutes after contrast was administered, using an initial dose of 0.1 mmol/kg. A. supplemental contrast injection of 0.2 mmol/kg was given (for a cumulative dose of 0.3 mmol/kg), with scans repeated at 31,41, and 51 minutes. RESULTS.Lesion conspicuity on day 1 was greater at highcontrast doses (0.3 mmol/kg) compared with standard doses (0.1 mmol/kg), regardless of whether imaging was performed without (0.89 ± 0.02 compared with 0.26 ± 0.08) or with (0.97 ± 0.04 compared with 0.28 ± 0.06) MT. High-dose, NT, and a delay after contrast was injected all produced a statistically significant improvement. On blinded review of films obtained 11 and 14 minutes after injection, enhancement of the lesion could not be identified with certainty in two of five dogs at a dose of 0.1 mmol/kg, regardless of whether MT was used. Enhancement was seen consistently in all lesions at 0.3 mmol/kg, On day 5, results were comparable, with greater absolute enhancement. CONCLUSIONS.In early brain infection, high-contrast doses (0.3 mmol/kg), MT, and a moderate delay after injection all improve visualization of lesion enhancement.

RENAL METASTASIS DETECTION AND CHARACTERIZATION ON ENHANCED MAGNETIC RESONANCE IMAGING USING AN ANIMAL MODEL

RATIONALE AND OBJECTIVES A new animal model was developed in rabbits (renal metastasis using the VX-2 tumor line), and magnetic resonance (MR) imaging performed before and after intravenous gadoteridol injection to assess lesion conspicuity and characterization. METHODS Six New Zealand White rabbits with renal metastases were studied on a 1.5-tesla Siemens Vision MR unit. Iodinated contrast was given intravenously to the rabbits, before implantation, to visualize the kidneys under fluoroscopy. Using a 5/8-inch 25-gauge needle, 0.1 mL of minced, screened VX-2 tumor was injected percutaneously into each kidney at the corticomedullary junction. Animals were studied on day 7 after implantation. Baseline fast low-angle shot (FLASH) T1-weighted and fast spin echo T2-weighted breathhold scans were first obtained. Then, an additional precontrast turbo-FLASH T1-weighted scan was acquired. After these scans, 0.1 mmol/kg gadoteridol (gadolinium HP-D03A; ProHance) was injected intravenously at a rate of 1.5 mL/second. Dynamic breathhold turbo-FLASH T1 images were then obtained at 0, 6, 12, 19, 25, and 31 seconds after injection and at 1, 2, and 10 minutes after injection. The T1 multislice FLASH two-dimensional scan was repeated at 10 minutes after contrast. Imaging results were analyzed by region of interest measurement and correlated with tissue pathology. RESULTS On dynamic T1-weighted turbo-FLASH scans, lesion conspicuity, specifically (SI(kidney)-SI(tumor)/noise), increased from 7 +/- 7 signal intensity precontrast to a maximum of 14 +/- 8 at 1 minute after contrast. This increase was statistically significant (P = 0.002). An initial rapid increase in tumor conspicuity occurred within the first 30 seconds after contrast, with the curve flattening thereafter. Lesion conspicuity on the precontrast T2-weighted scans was 9 +/- 10, not statistically different from results with either of the precontrast T1-weighted scan techniques. Using T1-weighted FLASH technique, lesion conspicuity increased from 10 +/- 5 precontrast to 31 +/- 12 postcontrast. As with turbo-FLASH, the improvement in tumor conspicuity after contrast on FLASH scans was statistically significant (P = 0.02). The difference between postcontrast FLASH scans and precontrast T2-weighted scans also was statistically significant, with postcontrast scans superior for lesion conspicuity (P = 0.01). Each tumor was confirmed on pathologic exam. CONCLUSIONS This research establishes a model of metastasis to the kidney for use in imaging studies. The conspicuity of a small renal metastasis is shown to be improved on early dynamic imaging, as well as at 10 minutes after intravenous injection of 0.1 mmol/kg gadoteridol. Observation of dynamic signal intensity changes provides additional information regarding lesion characterization, supplementing that from precontrast scans.

Choice of metal ion and formulation concentration for first-pass brain perfusion studies with magnetic resonance imaging at 1.5 tesla.

RATIONALE AND OBJECTIVES Gadolinium (Gd) and dysprosium (Dy) analogues, chelated with HP-DO3A, were compared at both 0.5- and 1.0-mol/L concentrations for efficacy in first-pass brain studies on magnetic resonance (MR) imaging at 1.5 tesla (T). METHODS Ten healthy cats were examined with a dose of 0.3 mmol/kg, using two concentrations of each agent (0.5 mol/L and 1.0 mol/L, 20 examinations). Gadolinium-HP-DO3A (gadoteridol or ProHance) or Dy-HP-DO3A was injected at 9 mL/second, with acquisition of 64 sequential steady-state free precession (SSFP) images at a rate of one each 0.6 second. RESULTS The change in white matter signal intensity, at the peak of the first pass of the contrast agent bolus in the brain, was -231 +/- 68 for the 0.5-mol/L formulation of Gd-HP-DO3A, compared with -267 +/- 57 for the 1.0-mol/L formulation. Using the 0.5-mol/L formulation of Dy-HP-DO3A, the change at peak was -318 +/- 42, a result statistically improved compared with both the 0.5-mol/L (P < 0.02) and 1.0-mol/L (P < 0.04) Gd-HP-DO3A formulations. A further improvement was observed with the 1.0-mol/L Dy-HP-DO3A formulation, with the change being -368 +/- 33. CONCLUSIONS First-pass brain MR studies at 1.5 T are improved by use of higher concentration Gd chelate formulations (1.0 versus 0.5 mol/L) and by substitution of the Dy ion for the Gd ion in the chelate. Injection of higher-concentration formulations results in higher initial arterial metal ion concentration. Incomplete blood mixing on transit during first pass causes the higher initial concentration, which then results in a greater susceptibility effect on imaging. The superiority of the Dy formulation compared with the Gd formulation is anticipated because of the higher magnetic moment of Dy. The curves for tissue signal intensity versus time during first pass return artifactually to near baseline after Gd chelate injection (when SSFP imaging techniques are used), a differentiating feature from results with the Dy chelate. This difference can be explained by a substantial T1 effect of the Gd chelate, despite acquisition of images that are predominantly susceptibility weighted.

The use of gadolinium-BOPTA on magnetic resonance imaging in brain infection.

RATIONALE AND OBJECTIVES The use of gadolinium (Gd)-BOPTA as a magnetic resonance contrast agent for central nervous system disease was studied in a canine brain abscess model. METHODS A Streptococcus faecalis brain abscess was evaluated in five dogs at 1.5T. Imaging was performed during the late cerebritis stage, at 5 to 7 days after surgery. Magnetic resonance scans were acquired before and at 1, 5, 15, 30, 45, and 60 minutes after contrast administration, using a dose of 0.1 mmol/kg. Scans also were acquired both before and after contrast injection with the implementation of magnetization transfer. RESULTS Lesion enhancement, quantified by region-of-interest measurement, peaked at 5 minutes after contrast injection. Both the increase in lesion enhancement from 1 to 5 minutes after injection and the decrease from 5 to 15 minutes after injection, although small, were statistically significant (P < 0.004 and P < 0.03, respectively). The application of magnetization transfer improved lesion enhancement, as measured by signal difference/noise, by 39%. This result also was statistically significant (P < 0.001). CONCLUSIONS In intraparenchymal brain infection, Gd-BOPTA provides effective lesion enhancement when used at a dose of 0.1 mmol/kg. Further research is needed to compare the magnitude of enhancement achieved with Gd-BOPTA, which has weak protein binding and both hepatobiliary and renal excretion, with that with Gd chelates, which have pure renal excretion.

Magnetic resonance imaging of an experimental model of intracranial metastatic disease. A study of lesion detectability.

RATIONALE AND OBJECTIVES.The detectability of brain metastases was evaluated in a rabbit model, with attention to magnetic resonance contrast dose and timing of image acquisition after injection of contrast medium. METHODS.Five New Zealand white rabbits were studied at 1.5 T 6 to 7 days and 11 to 12 days after surgical implantation of an adenocarcinoma tumor nidus. T l - and T2-wcighted spinecho images (0.9 X 0.9 X 2 mm3 voxel size) were obtained before administration of contrast medium. Tl-weighted images were repeated 5,15, and 30 minutes after intravenous injection of 0.1 mmol/kg gadoteridol. At 40 minutes, a supplemental dose of 0.2 mmol/kg (0.3 mmol/kg cumulative dose) was administered, with Tl-weighted images repeated at 5,15, and 30 minutes after the second injection. RESULTS.Six to 7 days after tumor implantation, lesion enhancement (percent change, with normalization to baseline and equilibrium values) was 42 ± 9% at 5 minutes, 48 ± 9% at 15 minutes, and 42 ± 10% at 30 minutes after administration of 0.1 mmol/kg gadoteridol. After administration of 0.3 mmol/kg gadoteridol, lesion enhancement was 111 ± 13% at 5 minutes, 116 ± 8% at 15 minutes, and 100% at 30 minutes. On film review, 2 of 5 lesions were not detectable at 6 to 7 days after tumor implantation with 0.1 mmol/kg gadoteridol. Administration of 0.3 mmol/kg gadoteridol provided for lesion identification in each instance. Eleven to 12 days after tumor implantation, one lesion was not detectable with 0.1 mmol/kg gadoteridol. Administration of 0.3 mmol/kg gadoteridol again provided for lesion identification in all cases. Mean lesion enhancement increased from 39 ± 15% to 104 ± 10%. CONCLUSIONS.The administration of 0.3 mmol/kg gadoteridol (high dose) compared with 0.1 mmol/kg gadoteridol (conventional dose) improves metastatic lesion detectability in the brain. The lesions identified only at high dose were confirmed by histopathology. Smaller lesions were not detected at a dose ofO.l mmol/kg.

Hepatic abscesses. Magnetic resonance imaging findings using gadolinium-BOPTA.

RATIONALE AND OBJECTIVES Gadolinium (Gd)-BOPTA was evaluated in a rabbit liver abscess model and compared with Gd-HP-DO3A, examining lesion conspicuity and characterization. METHODS Five New Zealand White rabbits with a liver abscess were studied on a 1.5-tesla Siemens Vision magnetic resonance unit. The disease model was created by surgically implanting a gel capsule filled with fusobacterium into the central or left lobe of the liver. For imaging, the animals were ventilated using a Harvard pump. Pancuronium bromide (0.12 mg/kg) was administered to allow acquisition of breath-hold scans. Magnetic resonance scans were obtained in each animal on days 2 and 3 after surgery. Every animal was studied twice, once after intravenous injection of 0.3 mmol/kg Gd-HP-DO3A (gadoteridol; ProHance) and once after intravenous injection of 0.1 mmol/kg Gd-BOPTA (gadobenate dimeglumine; MultiHance). The order of injection for the two agents was randomized with the two studies in each animal, separated by 24 hours to permit clearance. Image acquisition was performed in each instance with respiration suspended. Baseline two-dimensional spin-echo T1-weighted and fast spin-echo T2-weighted breath-hold scans were obtained first. The voxel dimensions were 5 x 0.8 x 0.8 mm3. Imaging times were 23 seconds for the T1-weighted scan and 26 seconds for the T2-weighted scan. Postcontrast scans, using spin-echo T1-weighted technique, were obtained at 1, 3, 5, and 15 minutes after contrast injection, whether Gd-HP-DO3A or Gd-BOPTA was used. Additional scans were obtained at 30, 45, and 60 minutes after Gd-BOPTA administration. At the completion of imaging on day 3, each animal was killed and the liver was removed and taken to a veterinary pathologist at the Universitys animal disease diagnostic lab for gross and histologic examination. RESULTS The enhancement of normal liver parenchyma, assessed by region of interest measurement and specifically as (SI(t) - SI0)/SI0 x 100, peaked at 119 +/- 37% 1 minute after injection of 0.3 mmol/kg Gd-HP-DO3A and at 126 +/- 30% 30 minutes after injection of 0.1 mmol/kg Gd-BOPTA. The difference in enhancement achieved, comparing results at each time point, was statistically significant only at 1 and 3 minutes postcontrast (P = 0.003 and 0.03). Lesion conspicuity, specifically (SIliver - SIlesion/noise), increased from 272 +/- 29 precontrast to a maximum of 639 +/- 73 at 30 minutes postcontrast using a dose of 0.1 mmol/kg Gd-BOPTA, with the improvement statistically significant (P = 0.0003). Lesion conspicuity on the T2-weighted scan was 137 +/- , with the Gd-BOPTA scan markedly superior (P = 0.00004). On scans at 45 and 60 minutes after Gd-BOPTA administration, a progressive increase in signal intensity in the central necrotic portion of the lesion was observed. This was most consistent with gradual diffusion of the agent from the adjacent liver into the lesion. Using Gd-HP-DO3A at 0.3 mmol/kg (three times the dose for Gd-BOPTA), lesion conspicuity increase from 305 +/- 37 precontrast to a maximum of 701 +/- 92 at 1 minute postcontrast, with this difference also statistically significant (P = 0.0004). The abscess rim exhibited moderate contrast enhancement, greater than that of normal liver parenchyma, on early postcontrast images with Gd-HP-DO3A. CONCLUSIONS The conspicuity of an early liver abscess is improved markedly on delayed imaging after administration of 0.1 mmol/kg Gd-BOPTA. Although a similar magnitude of parenchymal enhancement can be obtained after the administration of an extracellular agent, such as Gd-HP-DO3A, high-contrast dose (0.3 mmol/kg) and early dynamic imaging are required. The appearance of a liver abscess on late scans (45 to 60 minutes) after Gd-BOPTA injection is distinct from that of nonnecrotic metastases, with diffusion of the agent into the lesion noted.