Paramagnetic contrast agents in nuclear magnetic resonance medical imaging

Relaxation time differences are the sources of most of the contrast observed in proton NMR images, not only among normal organs and tissues but between lesions and the adjacent tissue. Although these differences are often large, there are low-contrast situations in which it would be desirable to increase the visibility of an organ or region. The study of time-dependent phenomena would also be aided by the ability to change selected relaxation times deliberately. One way to achieve these goals is to administer substances that change proton relaxation times in tissues without causing significant toxic effects or other physiologic changes. Paramagnetic ions and molecules, those with unpaired electrons, may be useful for this purpose because the very large magnetic effects associated with such electrons can drastically decrease water proton relaxation times at concentrations of the order of 100 to 1000 microM, which may be reached in certain organs after doses of 10 to 100 microM/kg. The general characteristics of such paramagnetic substances are described, and specific animal experiments with manganous ion and its complexes, and with stable nitroxide free radicals and molecular oxygen, are reviewed. The paramagnetic contrast agents already studied are effective, and many more are potentially possible, but the most important questions to be answered are whether acute and chronic toxicity are low enough to permit research and diagnosis on humans.     

Proton relaxation enhancement associated with iodinated contrast agents in MR imaging of the CNS.

PURPOSE: To study the effects of iodinated radiographic contrast agents on proton relaxation in MR imaging. PATIENTS AND METHODS: Two patients were evaluated after the intrathecal administration of an iodinated nonionic contrast agent (Isovue) and five subjects with cranial tumors following the intravenous administration of an iodinated ionic contrast medium (Renografin). RESULTS: Both patients with subarachnoid iodinated contrast media demonstrated a relative reduction in T1 and/or T2 times using a spin-echo sequence, while four of five of the subjects with intracranial tumors (one glioma, one dural metastasis, three meningiomas) and intravenous enhancement revealed a visible MR effect. Confirmation of these in vivo observations was obtained by in vitro measurement of T1 and T2 while varying the concentration of the contrast media in saline. All iodinated contrast media showed progressively reduced relaxation times (T1 and T2) as the concentration of the agent was increased. The largest contributing relaxation mechanism is probably due to the binding and exchange of the surrounding water with the contrast molecules. CONCLUSION: The observed T1/T2 effects suggest that administration of iodinated contrast media in the period immediately prior to MR scanning may be contraindicated in selected cases due to the demonstrated alteration of MR signal intensity that may lead to diagnostic inaccuracies.     

Intrathecal administration of nitroxides as potential contrast agents for MR imaging

The diagnosis of various disorders of the cerebrospinal fluid (CSF) with magnetic resonance (MR) imaging may require the intrathecal administration of a paramagnetic contrast agent. Furthermore, the CSF route provides direct access to the brain, circumventing the blood-brain barrier. Three nitroxides, two charged and one uncharged, were administered intrathecally to dogs to assess their potential as contrast agents for MR imaging of the CSF. Nitroxide concentrations and proton T1 values were measured in samples of CSF removed at various times after nitroxide administration, and pharmacokinetic curves were constructed. The charged nitroxides had considerably longer half-lives than the uncharged compound. On in vivo MR imaging of the CSF (surrounding the upper cervical cord and brain stem) in one dog, use of a charged nitroxide as contrast agent led to considerably higher CSF signal intensity than was observed in the nonenhanced, baseline T1-weighted images. This effect was achieved at low doses (20 mumol) and sustained for at least 90 minutes. The intrathecal use of nitroxides as contrast agents for MR imaging warrants continued investigation.     

Gadolinium phosphonates as MR imaging contrast agents: Physiologic effects in rabbit hearts

The hemodynamic effects of the diphosphonate terminus of a new infarct-avid magnetic resonance (MR) imaging agent, gadolinium-DTPA (diethylenetriamine-pentaacetic acid) HPDP (1-hydroxo-3-aminopropane-1,1-diphosphonate), and HEDP (hydroxyethyl-1,1-diphosphonate) (a simple diphosphonate terminus model) have been evaluated at MR imaging doses in both isolated and intact rabbit hearts. Rapid injections of the sodium salt of the diphosphonates reversibly depressed left ventricular developed pressure and its first derivative (dP/df) but did not affect the in vivo heart rate. Hemodynamic depression was prevented by the co-administration of two equivalents of calcium ion per diphosphonate terminus in the isolated heart and by either slow infusion or co-administration of one equivalent of calcium ion per diphosphonate terminus in the in vivo heart. Therefore, if these agents are to be used in MR imaging of acute myocardial infarction, appropriate measures should be taken to prevent negative inotropic effects.     

Preprocedural MR imaging for percutaneous vertebroplasty: special interest in contrast enhancement

PURPOSE: The success of percutaneous vertebroplasty (PVP) depends greatly on preprocedural evaluation of the patients. The purpose of this study was to evaluate the efficacy of preprocedural magnetic resonance imaging (MRI) for the indications of PVP. MATERIALS AND METHODS: A retrospective review of 122 osteoporotic compression fractures in 63 patients who underwent preprocedural gadolinium-enhanced MRI and PVP was performed. Based on the extent of contrast enhancement on preprocedural MRI, each case was classified into one of two groups: group 1, which represented more than 50% of the vertebral body enhanced; and group 2, which represented less than 50% of the vertebral body enhanced. The most enhancing level was evaluated in multilevel PVP sessions. We evaluated the difference of pre- and postprocedural pain scales between groups 1 and 2 using Mann-Whitney's U-test. RESULTS: There was a trend toward higher preoperative pain score in group 1, but it was not statistically significant (P = 0.0537). In addition, the postoperative pain score in group 2 was significantly higher than that in group 1 (P = 0.0007). The difference between the pre- and postoperative pain scores was significantly higher in group 1 than in group 2 (P = 0.0001). CONCLUSION: Contrast enhancement on MRI indicates a painful lesion and extensive contrast enhancement predicts better pain relief after PVP.     

Evaluation of Gd-DTPA-labeled dextran as an intravascular MR contrast agent: imaging characteristics in normal rat tissues.

Dextran covalently linked to moieties of gadolinium diethylenetriamine pentaacetic acid (DTPA), for use as a macromolecular, intravascular blood pool marker for contrast material-enhanced magnetic resonance (MR) imaging was characterized by means of physicochemical and relaxivity measurements and MR imaging in healthy rats. Dextran labeled with 15 Gd-DTPA moities (molecular weight of approximately 75,000 d) had a T1 relaxivity at 0.25 T and 37 degrees C of 157.1 mmol-1.sec-1 per molecule and 10.5 mmol-1.sec-1 per gadolinium atom, more than twice that of unbound Gd-DTPA. Osmolality was 300-350 mOsm/kg at a gadolinium concentration of 0.01 mmol/L. Tissue enhancement was essentially linearly related to injected dose in the gadolinium dose range of 0.01-0.05 mmol/kg of body weight. Approximate typical enhancement values over baseline for normal tissues at 10 minutes after a gadolinium dose of 0.05 mmol/kg were as follows: cardiac muscle, adrenal gland, and liver, 40%-50%; lungs, 160%-200%; renal cortex, 130%; renal medulla, 240%; spleen, 75%; muscle, 15%; and brain, 5%-10%. Projection-subtraction images showed that dextran-(Gd-DTPA)15 remained intravascular for at least 1 hour after injection. The prolonged and easily appreciated levels of tissue enhancement with dextran-(Gd-DTPA)15, at a gadolinium dose less than that routinely used in Gd-DTPA, indicate further evaluation of this macromolecular marker.     

Grading diffuse gliomas without intense contrast enhancement by amide proton transfer MR imaging: comparisons with diffusion- and perfusion-weighted imaging

Objectives

To investigate whether amide proton transfer (APT) MR imaging can differentiate high-grade gliomas (HGGs) from low-grade gliomas (LGGs) among gliomas without intense contrast enhancement (CE).

Methods

This retrospective study evaluated 34 patients (22 males, 12 females; age 36.0?±?11.3 years) including 20 with LGGs and 14 with HGGs, all scanned on a 3T MR scanner. Only tumours without intense CE were included. Two neuroradiologists independently performed histogram analyses to measure the 90th-percentile (APT₉₀) and mean (APT_mean) of the tumours’ APT signals. The apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) were also measured. The parameters were compared between the groups with Student’s t-test. Diagnostic performance was evaluated with receiver operating characteristic (ROC) analysis.

Results

The APT₉₀ (2.80?±?0.59 % in LGGs, 3.72?±?0.89 in HGGs, P?=?0.001) and APT_mean (1.87?±?0.49 % in LGGs, 2.70?±?0.58 in HGGs, P?=?0.0001) were significantly larger in the HGGs compared to the LGGs. The ADC and rCBV values were not significantly different between the groups. Both the APT₉₀ and APT_mean showed medium diagnostic performance in this discrimination.

Conclusions

APT imaging is useful in discriminating HGGs from LGGs among diffuse gliomas without intense CE.

Key Points

? Amide proton transfer (APT) imaging helps in grading non-enhancing gliomas ? High-grade gliomas showed higher APT signal than low-grade gliomas ? APT imaging showed better diagnostic performance than diffusion- and perfusion-weighted imaging

     

MR imaging in chronic partial epilepsy: role of contrast enhancement

Gadopentetate dimeglumine was administered prospectively to 150 consecutive patients who had had partial epilepsy for longer than 1 year to determine whether it is routinely indicated for the diagnosis of this disorder. MR abnormalities correlating with clinical or electroencephalographically documented seizure foci were detected in 69 cases (46%). Contrast enhancement was seen in 33 of these lesions, but the presence of enhancement altered the original radiologic diagnosis in only 17 (11%) of 150 cases. In only two cases (1%) did contrast administration reveal lesions that were not definitely apparent on the unenhanced images. The utility of contrast administration could not be predicted on the basis of seizure type (simple or complex) or the presence of secondary generalization. Gadopentetate dimeglumine does not appear to be routinely required in the MR workup of patients with chronic partial epilepsy. It should be used selectively to clarify or better define the nature of abnormalities encountered on unenhanced images.     

Intraluminal contrast agents for MR imaging of the abdomen and pelvis

Magnetic resonance (MR) imaging of the abdomen and pelvis with use of gastrointestinal (GI) contrast agents is slowly emerging as a valuable diagnostic tool. In the past few years, considerable effort has been expended on developing an oral contrast agent to serve as a bowel marker during abdominal and pelvic imaging. Four major categories of agents have been studied: compounds with positive contrast-enhancing characteristics (ie, which increase signal intensity), which may be either miscible or immiscible with bowel contents, and compounds with negative contrast-enhancing characteristics (ie, which decrease signal intensity), which also may be miscible or immiscible. Compared with precontrast images, MR images acquired after administration of GI contrast agents have shown increased anatomic delineation of the bowel lumen, pancreas, and paraaortic nodes, allowing increased detection of pancreatic lesions, improved assessment of bowel wall lesions, and distinction between intrahepatic and extrahepatic lesions. This review focuses on the general physics and requirements for intraluminal GI contrast media for MR imaging, the currently used intraluminal agents and their regulatory status, current and near-future availability, and cost considerations.     

Liposomes as MR contrast agents: pros and cons.

Liposomes are generally thought of as being useful for entrapping drugs within their internal aqueous space. When used with MR contrast agents, this has the drawback that water flux across the membrane bilayer is limiting to contrast enhancement. This can be partially overcome by making the liposomes very small, such that surface area is relatively great compared to internal volume, thereby facilitating water exchange. Alternatively the membranes can be designed to be permeable to water but this may render the vesicles unstable in serum. Another approach is to incorporate the contrast agents into the lipid bilayer. By designing novel complexes of manganese with the ligands incorporated onto dual acyl chains, we have achieved R1 and R2 values of over 20/mmol sec-1 or more than five times higher than Gd-DTPA. Hepatic metastasis detection is significantly improved in rats at doses of only 10 mumol/kg manganese. Membrane-bound manganese complexes function as highly effective liver imaging agents and merit further study for development as agents to undergo human clinical trials.     

An aqueous gastrointestinal contrast agent for use in echo-planar MR imaging.

Four volunteers were imaged with echo-planar imaging before and after ingesting a dilute barium preparation. The contrast material improved bowel visibility by increasing lumen signal intensity, without increasing noise. Long T2 gastrointestinal contrast material can be used in T2-weighted imaging when motion artifacts are suppressed by ultrashort acquisitions.     

Evaluation of superparamagnetic iron oxide for MR imaging of liver injury: proton relaxation mechanisms and optimal MR imaging parameters.

PURPOSE: To investigate the proton relaxation mechanisms and the optimal MR imaging parameters in superparamagnetic iron oxide (SPIO)-enhanced MR imaging of liver injury. METHODS: A liver injury model was created in the rat using carbon tetrachloride. The T1 and T2 relaxation effects of SPIO in normal and injured liver were estimated by ex vivo relaxometry. In vivo laser confocal microscopy of the liver was performed to simulate the distribution and clustering of SPIO particles in the hepatic macrophages. SPIO-enhanced MR imaging (1.5T) of normal and diseased rats was performed with variable parameters. The liver specimens were prepared for histopathological examination. RESULTS: Histopathological and laser confocal microscopic findings showed diffuse macrophage distribution but decreased intracellular clustering of SPIO in injured liver. Ex vivo relaxometry showed sustained T1 and T2 relaxation effects of SPIO in liver injury. On MR images obtained with moderate echo time (spin echo [SE] 2000/40 and gradient echo [GRE] 130/9.0/60 degrees), injured liver showed significantly lower decrease in signal-to-noise ratio (SNR) than the normal liver, whereas little difference in SNR was found between the normal and injured liver on heavily T2-(SE 2000/80) and T1-weighted (SE 300/11 and GRE 130/2.0/90 degrees) MR images. CONCLUSION: Pulse sequences with a moderately long echo time (TE) may be more appropriate than heavily T1- or T2-weighted images for distinguishing normal and injured liver in SPIO-enhanced MR imaging because of the maintained T1 and T2 relaxation effect but decreased T2* relaxation effect of SPIO in injured liver.     

Bone and soft tissue tumors: the role of contrast agents for MR imaging

Magnetic resonance imaging is an important modality for the imaging evaluation of musculoskeletal tumors. Although there is general agreement on the value of unenhanced MR in detection, diagnosis and staging, intravenous use of gadolinium-contrast media (gd-CM) is indicated in selected cases. The purpose of this article is to review the basic pharmacokinetic principles and imaging techniques for static and dynamic contrast-enhanced MR imaging and to highlight the most important indications for administration of gd-CM in patients with musculsokeletal tumors and tumor-like lesions: adding specificity in tissue characterization, staging of local extent and biopsy planning, monitoring preoperative chemotherapy and detection of recurrence.     

Magnetic resonance imaging enhancement of normal tissues and tumors using macromolecular Gd-based cascade polymer contrast agents: preclinical evaluations

OBJECTIVES: We sought to compare magnetic resonance imaging (MRI) enhancement using 4 novel macromolecular polyethyleneglycol (PEG)-based cascade-polymer gadolinium contrast agents (macromolecular contrast media) in normal soft tissues and a breast cancer model. MATERIALS AND METHODS: Four candidate PEG cascade polymers with effective molecular weights of 74, 82, 106, and 132 kDa, respectively, and T1-relaxivities of 8.1, 9.1, 9.7, and 10.0, respectively (at 2 Tesla and 37 degrees C in HEPES buffer), initially were used to characterize liver and kidney MRI-enhancement patterns in normal Sprague-Dawley rats (n = 4-5 per contrast agent). Kinetic analysis of dynamic MRI enhancement was used in 8 nude rats bearing MDA-MB 435 breast cancers to estimate fractional plasma volume and apparent endothelial leakiness (K) in tumors and muscle. RESULTS: Soft-tissue enhancement patterns followed closely the blood enhancement over the course of 30-50 minutes with estimated blood half-lives between 23 and 73 minutes, which varied with effective molecular weights. The 2 smaller compounds yielded measurable leaks in normal muscle [K = 204 and 56 microL/(min.100 cm), respectively], whereas the 2 larger molecules did not leak in muscle [K = 0 microL/(min.100 cm)]; however, MRI-assayed leakiness of tumor vessels with respect to those 2 larger macromolecular contrast media was 68 +/- 27 and 16 +/- 8 microL/(min.100 cm), respectively. CONCLUSIONS: Two relatively large (effective molecular weight >82 kDa) PEG-based cascade polymer contrast agents were well-suited for MRI quantification of tissue plasma volume and for differentiating leaky cancer microvessels from nonleaky normal vessels.     

Superparamagnetic iron oxide contrast agents: physicochemical characteristics and applications in MR imaging

Superparamagnetic iron oxide MR imaging contrast agents have been the subjects of extensive research over the past decade. The iron oxide particle size of these contrast agents varies widely, and influences their physicochemical and pharmacokinetic properties, and thus clinical application. Superparamagnetic agents enhance both T1 and T2/T2* relaxation. In most situations it is their significant capacity to reduce the T2/T2* relaxation time to be utilized. The T1 relaxivity can be improved (and the T2/T2* effect can be reduced) using small particles and T1-weighted imaging sequences. Large iron oxide particles are used for bowel contrast [AMI-121 (i.e. Lumirem and Gastromark) and OMP (i.e. Abdoscan), mean diameter no less than 300 nm] and liver/spleen imaging [AMI-25 (i.e. Endorem and Feridex IV, diameter 80-150 nm); SHU 555A (i.e. Resovist, mean diameter 60 nm)]. Smaller iron oxide particles are selected for lymph node imaging [AMI-227 (i.e. Sinerem and Combidex, diameter 20-40 nm)], bone marrow imaging (AMI-227), perfusion imaging [NC100150 (i.e. Clariscan, mean diameter 20 nm)] and MR angiography (NC100150). Even smaller monocrystalline iron oxide nanoparticles are under research for receptor-directed MR imaging and magnetically labeled cell probe MR imaging. Iron oxide particles for bowel contrast are coated with insoluble material, and all iron oxide particles for intravenous injection are biodegradable. Superparamagnetic agents open up an important field for research in MR imaging.     

Diagnostic challenges and pitfalls in MR imaging with hepatocyte-specific contrast agents

The use of gadolinium-based hepatocyte-specific contrast agents (HSCAs) has increased markedly since their introduction, and hepatocellular phase imaging performed with an HSCA is now a key part of the standard magnetic resonance (MR) imaging work-up for focal liver lesions. An understanding of the mechanisms of action of HSCAs helps ensure their effective use. The optimal delay for hepatocellular phase image acquisition differs between the two currently available HSCAs, gadoxetic acid and gadobenate dimeglumine, and MR imaging protocols must be adjusted accordingly. In addition, familiarity with typical and atypical appearances of benign and malignant focal liver lesions at HSCA-enhanced hepatocellular phase MR imaging, along with knowledge of the processes that are most likely to produce atypical appearances, is required to achieve optimal diagnostic accuracy.     

Receptor-directed contrast agents for MR imaging: preclinical evaluation with affinity assays.

In this study, the target-specific behavior of magnetic resonance (MR) imaging contrast agents directed at human hepatic asialoglycoprotein (ASG) receptors was evaluated in vitro with use of two novel assays: relaxation time measurements of incubated human cell membrane solutions and iron staining of biopsy samples. Specific uptake of ASG receptor-directed agents was demonstrated in human samples of normal liver tissue, areas of hepatitis, regenerating nodules, areas of focal nodular hyperplasia, and hepatic adenomas. A conventional iron oxide preparation not directed at ASG receptors failed to demonstrate specific uptake in these tissues. Attachment of the ASG receptor-directed agents was competitively blocked with a receptor agonist (D(+)-galactose) in these tissues. No attachment of conventional or receptor agents was seen in areas of hepatocellular carcinoma, cholangiocarcinoma, or liver metastases. The studies indicate that in vitro receptor assays are useful in predicting the affinity of new receptor-directed MR imaging contrast agents in human tissue prior to clinical trials.