Stephan A. Schmitz

Superparamagnetic iron oxide-enhanced MRI of atherosclerotic plaques in Watanabe hereditable hyperlipidemic rabbits

RATIONALE AND OBJECTIVES Inflammatory atherosclerotic plaques are characterized by increased endothelial permeability and multiple macrophages. Blood-pool MRI contrast agents like superparamagnetic iron oxide (SPIO) have an affinity for the monocyte-macrophage system and thus, may label inflammatory plaques. The objective was to demonstrate SPIO uptake in plaques of atherosclerotic rabbits by MRI and histology. METHODS Aortas of anesthetized Watanabe hereditable hyperlipidemic rabbits were studied with a moderately T2*-weighted gradient-echo sequence at 1.5 T. Four groups of five animals each were studied: (1) without ultrasmall SPIO (carboxydextran coating; particle size, 25 nm; estimated plasma half-life, 6 hours) or with imaging after intravenous injection of SPIO at a dose (micromol Fe/kg) and postcontrast time delay (hours) of 50/8 (2), 50/24 (3), or 200/48 (4). In vivo MRI was compared with corresponding ex vivo histological iron stains. RESULTS Animals receiving 200 micromol Fe/kg demonstrated areas of focal signal loss clearly confined to the aortic wall on a mean of 24 +/- 9 (31% +/- 11%) of 76 +/- 5 images compared with 0 +/- 0 of 76 +/- 5 images in controls (P = 0.009). The number of images with this finding in groups 2 and 3 was not significantly different compared with controls. By microscopy, SPIO-iron was seen in the endothelial cells and subendothelial intimal macrophages of atherosclerosis-prone aortic wall segments. Atherosclerotic lesions demonstrating iron uptake also showed a high macrophage content. CONCLUSIONS SPIO accumulates in aortic plaques of atherosclerotic rabbits, producing a characteristic MRI finding. As SPIO accumulates in plaques with increased endothelial permeability and a high macrophage content, two established features of plaque inflammation, it may have a potential for noninvasive assessment of inflammatory atherosclerotic plaques.

Magnetic resonance imaging of atherosclerotic plaques using superparamagnetic iron oxide particles

Experimental data show accumulation of superparamagnetic iron oxide (SPIO) particles in atherosclerotic plaques. SPIO uptake occurred in plaques, suggesting an increased endothelial permeability and macrophage infiltrates as signs of inflammatory plaque activity. We incidentally observed SPIO uptake in aortic and arterial wall segments in patients who had originally received the magnetic resonance (MR) contrast agent for staging lymph node metastases. Twenty patients (19 male, 1 female; mean age, 64; range, 41–78 years) with bladder or prostate cancer underwent MR imaging (MRI) using a T2*‐weighted high‐resolution gradient‐echo sequence prior to and 24–36 hours after intravenous injection of 2.6 mg of Fe/kg of SPIO (Sinerem®). The aorta, both common external and internal iliac, as well as both superficial femoral arteries, were retrospectively analyzed for atherosclerotic wall changes. One patient was excluded. A positive finding was defined as an area of pronounced signal loss on postcontrast images clearly confined to the arterial wall, which was absent in the precontrast examination or increased in size. Such a finding was observed in one to three arteries in 7 of the 19 patients. The pronounced signal loss in the wall of the aorta and pelvic arteries seen in part of an elderly patient population after intravenous SPIO administration strongly suggests that this contrast agent accumulates in human atherosclerotic plaques. J. Magn. Reson. Imaging 2001;14:355–361.

Liver fat content and T2*: simultaneous measurement by using breath-hold multiecho MR imaging at 3.0 T--feasibility.

Research ethics committee approval was obtained for this study, and written informed consent was obtained from all participants. The purpose was to prospectively evaluate the feasibility of breath-hold multiecho in- and out-of-phase magnetic resonance (MR) imaging for simultaneous lipid quantification and T2* measurement. A spoiled gradient-echo sequence with seven echo times alternately in phase and out of phase was used at 3.0 T. Imaging was performed in a lipid phantom, in five healthy volunteers (all men; mean age, 37 years), and in five obese individuals with hyperlipidemia or diabetes (four men, one woman; mean age, 53 years). A biexponential curve-fitting model was used to derive the relative signal contributions from fat and water, and these results were compared with results of liver proton MR spectroscopy, the reference standard. There was a significant correlation between multiecho and spectroscopic measurements of hepatic lipid concentration (r(2) = 0.99, P < .001). In vivo, the T2* of water was consistently longer than that of fat and reliably enabled the signal components to be correctly assigned. In the lipid phantom, the multiecho method could be used to determine the fat-to-water ratio and the T2* values of fat and water throughout the entire range of fat concentrations. Multiecho imaging shows promise as a method of simultaneous fat and T2* quantification.

A new concept for melatonin deficit: on pineal calcification and melatonin excretion.

Even though exogenous melatonin has proven to influence sleep and circadian parameters, low endogenous melatonin is not related to sleep disturbances, nor does it predict response to melatonin replacement therapy. In this manuscript, we present a new concept towards a definition of a melatonin deficit. The purpose of the study was to introduce a marker for an intra-individual decrease in melatonin production. Therefore, we developed a method to quantify the degree of pineal calcification (DOC) using cranial computed tomography. Combining pineal DOC with the organss size, we estimated the uncalcified pineal gland volume. This estimation was positively and significantly associated with 6-sulfatoxymelatonin (aMT6s), collected over 24 hours in urine, in 26 subjects. Data yielded evidence that the decline in aMT6s excretion with age can be sufficiently explained by an increased pineal calcification. These results suggest that DOC might be useful as an indicator of an intra-individual, decreased capability of the pineal gland to produce melatonin. DOC might prove to be a response-marker for melatonin replacement therapy and a vulnerability marker of the circadian timing system.

Use of contrast-enhanced MR imaging to detect sacroiliitis in children.

Abstract Purpose. To verify the diagnostic value of contrast-enhanced MR imaging compared with conventional radiography in the diagnosis of sacroiliitis in children. Design and patients. Radiography and MR imaging of the sacroiliac joints were performed in 185 children subdivided into the following groups according to the modified European Spondyloarthropathy (SpA) Study Group (ESSG) criteria: group 1, undifferentiated spondyloarthropathy (uSpA) (n=53, 94.5% HLA-B27+); group 2, differentiated SpA (n=45, 93.3% HLA-B27+); group 3, patients with no signs of SpA other than oligoarthritis (n=39, 92.3% HLA-B27+); group 4, HLA-B27+ controls with various other non-SpA diagnoses (n=22); and group 5, HLA-B27– controls with various other non-SpA diagnoses (n=26). Radiographs were evaluated on the basis of the modified New York criteria independently by three experienced radiologists masked to the clinical data. In a second step, the same radiologists independently evaluated the MR images without knowledge of the clinical data and radiographic findings using the recently published criteria developed by our group. These criteria allow differentiation of acute and chronic inflammatory changes. Results. Radiography demonstrated sacroiliitis in 18 patients: 4 of 53 in group 1 (7.5%), 14 of 45 in group 2 (31%), but none in groups 3, 4 and 5. In contrast, MR imaging demonstrated acute and/or chronic sacroiliitis in 44 patients: 18 of 53 in group 1 (34%), 21 of 45 in group 2 (46.7%) and 5 of 39 in group 3 (12.8%), but none in groups 4 and 5. The percentage of sacroiliitis detected by MR imaging was significantly higher than that detected by radiography (P<0.001). Conclusion. Contrast-enhanced MR imaging is a useful method for detecting sacroiliitis in children. Advantages of contrast-enhanced MR imaging compared with conventional radiography are a higher sensitivity due to the ability to document early and acute changes and the absence of radiation exposure.

Iron-oxide-enhanced magnetic resonance imaging of atherosclerotic plaques: postmortem analysis of accuracy, inter-observer agreement, and pitfalls.

Schmitz SA, Taupitz M, Wagner S, et al. Iron-oxide-enhanced magnetic resonance imaging of atherosclerotic plaques: postmortem analysis of accuracy, inter-observer agreement, and pitfalls. Invest Radiol 2002;37:405–411. introduction. Contrast-enhanced magnetic resonance (MR) imaging using ultra small superparamagnetic iron oxide (USPIO) particles is a new noninvasive modality for imaging inflammatory atherosclerotic plaques. We determined the accuracy, interobserver agreement, and potential sources of error of this technique by means of postmortem MR imaging of aortic preparations. material and methods.Anesthetized atherosclerotic Watanabe heritable hyperlipidemic (WHHL) rabbits were studied after administration of different dosages of intravenous USPIO (DDM 43/34, IDF Berlin, Germany) and different postcontrast time intervals. A (n = 5) received 0 &mgr;mol Fe/kg. B (n = 5) received 50 &mgr;mol Fe/kg, 8-hour postcontrast interval. C (n = 5) received 50 &mgr;mol, 24 hours. D received 200 &mgr;mol, 48 hours. The aortas were removed and 3-mm segments prepared for postmortem examination by MR imaging using a T2-weighted gradient-echo sequence (TR/TE/FA; 41 milliseconds/11 milliseconds/15°), radiography (mammography), and histology (iron staining). USPIO accumulation was defined as the presence of 20 iron-positive cells per microscopic view (×100 magnification). Two independent readers analyzed the MR images and rated their confidence level for a positive MRI finding, defined as a focal signal loss, on a 5-point scale. The results were evaluated by receiver-operator characteristic (ROC) analysis. results. Of a total of 621 vessel segments technically acceptable for evaluation, 534 were histologically negative and 87 positive. Accuracy, expressed as the area under the ROC curve, was 0.85 for reader 1 and 0.88 for reader 2. Interobserver agreement was 0.67. False-positive findings were established by at least one reader for 121 of the 621 segments, false-negative findings for only 15 segments. Calcifications and mural thrombi were identified as potential sources of error of the method. conclusion. Postmortem USPIO-enhanced MR imaging of atherosclerotic plaques showed a high accuracy and good interobserver agreement in the animal model used here. Further optimization of the method should aim at reducing the rather high percentage of false-positive results.

Functional hepatobiliary imaging with gadolinium-EOB-DTPA. A comparison of magnetic resonance imaging and 153gadolinium-EOB-DTPA scintigraphy in rats.

RATIONALE AND OBJECTIVES Gadolinium-EOB-DTPA (Gd-EOB-DTPA) is a hepatobiliary magnetic resonance (MR) imaging contrast medium designed to detect focal liver lesions. The objective of this study was to evaluate dynamic Gd-EOB-DTPA-enhanced MR imaging as a new method for assessing liver excretory function and to compare it with a scintigraphic method, the gold standard. METHODS Changes in scintigraphic liver activity or MR liver signal intensity were intraindividually monitored over time after intravenous injection of 50 mumol Gd/kg of Gd-EOB-DTPA in controls and rats with common bile duct obstruction or L-ethionine-induced fatty liver (n = 6). RESULTS A comparison of liver scintigraphy and MR imaging revealed that elimination half-lives of Gd-EOB-DTPA were significantly longer in rats with common bile duct obstruction (scintigraphy: 100 +/- 27 minutes; MR imaging: 59 +/- 18 minutes) or fatty liver (scintigraphy: 94 +/- 30 minutes; MR imaging: 72 +/- 32 minutes) than in controls (scintigraphy: 20 +/- 2 minutes; MR imaging: 18 +/- 3) (P < 0.05). CONCLUSIONS Like liver scintigraphy, functional MR liver imaging using Gd-EOB-DTPA is feasible and can differentiate normal controls from models of biliary and hepatocyte disease.

Neurovascular Contact of Cranial Nerve IX and X Root-Entry Zone in Hypertensive Patients

Neurovascular contact of the left rostral ventrolateral medulla has been implicated in the pathogenesis of “essential” hypertension, and recent intervention studies suggest that surgical decompression of the ventrolateral medulla lowers blood pressure in these patients. We assessed the prevalence of this vascular anomaly in patients with essential hypertension by using an advanced MRI technique. We performed MRI of the brain stem in 125 hypertensive patients and in 105 age-matched, sex-matched, and body mass index–matched normotensive control subjects. Imaging of the root-entry zone of cranial nerves IX and X was performed by combining a high-resolution 3D constructive interference in steady-state sequence with a flow-sensitive time-of-flight technique, and images were independently assessed by 4 readers using predefined criteria. Left-sided neurovascular contact was found in 23% of the hypertensive patients and in 16% of the normotensive individuals (P =0.12). Blood pressure level, heart rate, and number of antihypertensive medications in treated hypertensive patients were similar among patients with positive, borderline, and negative brain stem findings. Our findings cast doubt on the importance of left-sided neurovascular contact as a frequent cause of essential hypertension or as a major factor determining the severity of hypertension in patients with this anomaly.

EVALUATION OF GADOBUTROL IN A RABBIT MODEL AS A NEW LANTHANIDE CONTRAST AGENT FOR COMPUTED TOMOGRAPHY

RATIONALE AND OBJECTIVES.The efficacy of the neutral lanthanide contrast agent gadobutrol was compared to that of the iodinated contrast agent iopromide in rabbits. METHODS.The computed tomography (CT) attenuation of increasing concentrations of gadolinium (Gd) (gadobutrol) and iodine (I) (iopromide) was measured in Hounsfield units (HU) in aqueous solution at 80,120, and 137 kV. The peak enhancement (net increase in CT attenuation compared with baseline) and the time-enhancement product in the aorta and in the renal parenchyma of the outer and inner cortex were measured in rabbits over a 5-minute period after the animals were given single intravenous injections of 0.7,1.0, and 1.5 mmol Gd/kg of gadobutrol and 1.0 and 2.4 mmol I/kg of iopromide. RESULTS.In vitro, the CT attenuation of gadolinium was 40% higher than that of iodine at equivalent mass concentrations (120 kV). The mean peak enhancements in the aorta after the injections of 0.7,1.0, and 1.5 mmol Gd/kg and 1.0 and 2.4 mmol I/kg were 216,313,591, 224, and 498 HU, respectively. In addition, a 30-second injection of the high dose of gadobutrol resulted in an attenuation profile that was suitable for a three-dimensional reconstruction of the aorta and the renal vasculature. CONCLUSIONS.Because of the higher CT attenuation of gadolinium compared with that of iodine, the neutral macrocyclic chelate gadobutrol is a more effective contrast agent than iopromide for CT at lower doses of the imaging atom.

x-f choice: Reconstruction of undersampled dynamic MRI by data-driven alias rejection applied to contrast-enhanced angiography

A technique for reconstructing dynamic undersampled MRI data, termed “x‐f choice,” was developed and applied to dynamic contrast‐enhanced MR angiography (DCE‐MRA). Regular undersampling in k‐t space (a hybrid of k‐space and time) creates aliasing in the conjugate x‐f space that must be resolved. When regions in the object containing fast dynamic change are sparse, as in DCE‐MRA, signal overlap caused by aliasing is often much less than the undersample factor would imply. x‐f Choice reconstruction identifies overlapping signals using a model of the full non‐aliased x‐f space that is automatically generated from the undersampled data, and applies parallel imaging (PI) to separate them. No extra reference scans are required to generate either the model or the coil sensitivity maps. At each location in the reconstructed images, g‐factor noise amplification is compared with predicted reconstruction errors to obtain an optimized solution. Acceleration factors greater than the number of receiver coils are possible, but are limited by the sparseness of the dynamic content and the signal‐to‐noise ratio (SNR) (in DCE‐MRA the latter is dominant). Temporal fidelity was validated for up to a factor 10 speed‐up using retrospectively undersampled data from a six‐coil array. The method was tested on volunteers using fivefold prospective undersampling. Magn Reson Med, 2006.