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Angela Ariza de Schellenberger,1 Harald Kratz,1 Tracy D Farr,2,3 Norbert Löwa,4 Ralf Hauptmann,1 Susanne Wagner,1 Matthias Taupitz,1 Jörg Schnorr,1 Eyk A Schellenberger1 1Department of Radiology, 2Department of Experimental Neurology, Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, Berlin, Germany; 3School of Life Sciences, University of Nottingham, Medical School, Nottingham, UK; 4Department of Biomagnetic Signals, Physikalisch-Technische Bundesanstalt Berlin, Berlin, Germany Abstract: Sensitive cell detection by magnetic resonance imaging (MRI) is an important tool for the development of cell therapies. However, clinically approved contrast agents that allow single-cell detection are currently not available. Therefore, we compared very small iron oxide nanoparticles (VSOP) and new multicore carboxymethyl dextran-coated iron oxide nanoparticles (multicore particles, MCP) designed by our department for magnetic particle imaging (MPI) with discontinued Resovist® regarding their suitability for detection of single mesenchymal stem cells (MSC) by MRI. We achieved an average intracellular nanoparticle (NP) load of >10 pg Fe per cell without the use of transfection agents. NP loading did not lead to significantly different results in proliferation, colony formation, and multilineage in vitro differentiation assays in comparison to controls. MRI allowed single-cell detection using VSOP, MCP, and Resovist® in conjunction with high-resolution T2*-weighted imaging at 7 T with postprocessing of phase images in agarose cell phantoms and in vivo after delivery of 2,000 NP-labeled MSC into mouse brains via the left carotid artery. With optimized labeling conditions, a detection rate of ~45% was achieved; however, the experiments were limited by nonhomogeneous NP loading of the MSC population. Attempts should be made to achieve better cell separation for homogeneous NP loading and to thus improve NP-uptake-dependent biocompatibility studies and cell detection by MRI and future MPI. Additionally, using a 7 T MR imager equipped with a cryocoil resulted in approximately two times higher detection. In conclusion, we established labeling conditions for new high-relaxivity MCP, VSOP, and Resovist® for improved MRI of MSC with single-cell sensitivity. Keywords: magnetic field microdistortions, single-cell imaging, mesenchymal stem cells, VSOP, MCP, Resovist®

Susanne Wagner,1 Jörg Schnorr,1 Antje Ludwig,2 Verena Stangl,2 Monika Ebert,1 Bernd Hamm,1 Matthias Taupitz11Department of Radiology, Section of Experimental Radiology, Charité – Universitätsmedizin Berlin, Campus Charité Mitte, and Campus Benjamin Franklin, Berlin, Germany; 2Department of Cardiology, Section of Experimental Cardiology, Charité – Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, GermanyObjective: To evaluate the suitability of citrate-coated very small superparamagnetic iron oxide particles (VSOP) as a contrast agent for identifying inflammation in atherosclerotic lesions using magnetic resonance imaging (MRI).Methods and results: VSOP, which have already been evaluated as a blood pool contrast agent for MR angiography in human clinical trials, were investigated in Watanabe heritable hyperlipidemic rabbits to determine to what extent their accumulation in atherosclerotic lesions is a function of macrophage density and other characteristics of progressive atherosclerotic plaques. In advanced atherosclerotic lesions, a significant MRI signal loss was found within 1 hour after intravenous administration of VSOP at the intended clinical dose of 0.05 mmol Fe/kg. Histological examinations confirmed correlations between the loss of MRI signal in the vessel wall and the presence of Prussian blue-stained iron colocalized with macrophages in the plaque cap, but surprisingly also with calcifying microvesicles at the intimomedial interface. Critical electrolyte magnesium chloride concentration in combination with Alcian blue stain indicates that highly sulfated glycosaminoglycans are a major constituent of these calcifying microvesicles, which may serve as the key molecules for binding VSOP due to their highly complexing properties.Conclusion: Calcifying microvesicles and macrophages are the targets for intravenously injected VSOP in atherosclerotic plaques, suggesting that VSOP-enhanced MRI may render clinically relevant information on the composition and inflammatory activity of progressive atherosclerotic lesions at risk of destabilization.Keywords: atherosclerosis, inflammation, magnetic resonance imaging, iron oxide nanoparticles, glycosaminoglycans, calcifying microvesicles

We investigated the 2H nuclear magnetic resonance (NMR) line shape of deuterated benzene and hexamethylbenzene as guest molecules in organic glasses in the temperature range of 10–150 K. A broad distribution G(ln τ) of correlation times determines the slowing down of the molecular reorientation around the sixfold symmetry axis of the guests. The line shape is described by a superposition of temperature-dependent fractions F(T) of only two subspectra corresponding to fast and slowly rotating molecules; no spectra characteristic for intermediate mobility as found in crystal matrices are observed. Assuming a thermally activated motional process, the temperature dependence of G(ln τ) comes from a temperature-independent distribution of activation energies g(E). In this case, the derivative of the fraction dF(T)/dT yields directly the distribution g(E). Using this method an asymmetric distribution g(E) with its maximum at the low energy side is found for the glasses. While the general shape of g(E) is similar for different matrices, the mean activation energy differs significantly. We used the same approach to discuss similar ‘‘two-phase’’ spectra for the isotropic reorientation of toluene in polystyrene below the glass transition of the mixed system. Here, an alternative explanation is offered considering a distribution of glass transition points Tg for the dynamics of toluene in the mixed system. [ABSTRACT FROM AUTHOR]

Deuterated hexamethylbenzene (HMB) is used as a probe molecule for 2H NMR studies of the crystalline state of hexachlorobenzene and of several organic glasses. By measuring the spin–lattice relaxation and the line shape in the temperature range of 4–300 K the dynamical parameters of the molecular reorientation are investigated. For the system HMB/hexachlorobenzene, we find exponential relaxation and for the corresponding T1 an increase of its activation energy by a factor of 2 in comparison to the neat HMB. A homogeneous mixing of the guest and host molecules is found at least for guest concentrations up to 7%. In contrast, nonexponential spin–lattice relaxation is characteristic for all glass matrices, indicating motional heterogeneities. A log–Gauss distribution for the corresponding motional correlation times gives a good fit of the data. Its width parameter decreases linearly with temperature, while the mean correlation times are described by an Arrhenius law. The mean activation energy is reduced by a factor of about 3.5 as compared to neat HMB, demonstrating a loose packing of the molecules in the glass matrices. [ABSTRACT FROM AUTHOR]

Objectives: To compare 0.15 mmol/kg gadobutrol for late gadolinium enhancement (LGE) imaging of chronic myocardial infarction with a relaxivity-adjusted dose of gadoterate meglumine (Gd-DOTA).Methods: Seventeen patients with suspected chronic myocardial infarction underwent LGE imaging at 1.5 T, acquiring an inversion-recovery-prepared gradient echo sequence 15 min after contrast agent administration. Each patient underwent LGE imaging twice, once after administration of 0.15 mmol/kg gadobutrol (r1 = 5.2 l mmol(-1) s(-1)) and after 0.22 mmol/kg Gd-DOTA (r1 = 3.6 l mmol(-1) s(-1)). Two readers independently determined infarct size and contrast-to-noise ratios of infarcted myocardium to remote myocardium (CNR(remote)) and to the left ventricular lumen (CNR(lumen)).Results: LGE was present in 14 patients. Infarct sizes determined after administration of gadobutrol [23.4 ml; 95 % CI (14.4; 32.5)] and Gd-DOTA [22.1 ml; 95 % CI (13.0; 31.1)] were not statistically different (P = 0.22). The CNR(remote) of LGE in infarcted myocardium on gadobutrol- and Gd-DOTA-enhanced images was 44.1 [95 % CI (31.0; 57.1)] and 45.2 [95 % CI (32.2; 58.3)], respectively (P = 0.73). CNR(lumen) was significantly higher on gadobutrol-enhanced LGE images [12.7; 95 % CI (2.5; 23.0) versus 6.8; 95 % CI (-3.5; 17.0); P = 0.02].Conclusion: At relaxivity-adjusted doses, gadobutrol and Gd-DOTA yielded similar infarct sizes with superior contrast between infarcted myocardium and left ventricular lumen on gadobutrol-enhanced images. [ABSTRACT FROM AUTHOR]

Objective: To assess active myocardial inflammation by cardiovascular magnetic resonance (CMR) and endomyocardial biopsy (EMB) amongst adult patients with dilated cardiomyopathy (DCM).Methods: We evaluated 23 adults with chronic DCM, who had successfully undergone both CMR and EMB within 3.5 ± 2.6 days. EMB was considered the gold standard. CMR assessment of myocardial inflammation used the following parameters as recommended by the recently published "Lake Louise Criteria": global myocardial oedema, global relative enhancement (RE), and late gadolinium enhancement (LGE). According to "Lake Louise Criteria", myocardial inflammation was diagnosed if two or more of the three above-mentioned parameters were positive.Results: Myocardial inflammation was confirmed by immunohistology in 12 patients (52.2%). Sensitivity, specificity, and diagnostic accuracy of CMR to detect immunohistologically confirmed myocardial inflammation were 75.0%, 72.7%, and 73.9%, respectively. Sensitivity, specificity, and diagnostic accuracy of the individual CMR parameters to detect myocardial inflammation were as follows: global myocardial oedema, 91.7%, 81.8%, and 87.0%, respectively; global RE, 58.3%, 63.6%, and 60.9%, respectively; LGE, 58.3%, 45.4%, and 52.2%, respectively.Conclusion: Global myocardial oedema was identified as a promising CMR parameter for assessment of myocardial inflammation in patients with DCM. In these patients, global myocardial oedema yielded superior diagnostic performance compared to "Lake Louise Criteria". [ABSTRACT FROM AUTHOR]

The peripheral washout sign was first described in delayed dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) using a small molecular contrast medium in solid lesions of the human breast and liver. It was found to be 100% specific for malignant lesions and could therefore potentially be used as an additional noninvasive diagnostic tool differentiating malignant from benign lesions. The origin of this phenomenon has not yet been explained. The objective of this study was to translate the peripheral washout sign as seen in solid tumours in delayed DCE-MRI in human onto an animal model for further assessment of DCE-MRI characteristics and histological analysis. Small molecular contrast medium DCE-MRI was performed over 42 min in experimental colon carcinoma grown subcutaneously in rats. Qualitative and quantitative analyses for evaluation of presence and characteristics of the peripheral washout sign were accomplished, defining four centripetally distributed tumour zones (central, intermediate, peripheral and marginal). One hundred per cent of the carcinomas demonstrated a peripheral washout sign in DCE-MRI starting at 20 min after bolus injection. Histomorphological analysis was performed for tissue classification and evaluation of microvasculature. Quantitative analysis revealed different enhancement profiles of the four tumour zones. Histology indicated centripetally asymmetric vascularization and vascular endothelial growth factor VEGF/VEGF receptor 2 expression within the tumour tissue. Thus, peripheral washout sign can be translated to an animal model. However, comparison of small molecular contrast medium DCE-MRI with histology revealed that histology alone does not explain the occurrence of the peripheral washout. [ABSTRACT FROM AUTHOR]

Background: Respiratory triggering allows the acquisition of high-resolution magnetic resonance (MR) images of the upper abdomen. However, the depiction of organs close to the gastrointestinal tract can be considerably impaired by ghosting artifacts and blurring caused by bowel peristalsis. Purpose: To evaluate the effect of gastrointestinal motion suppression by intramuscular butylscopolamine administration on the image quality of a respiratory-triggered T2-weighted turbo spin-echo (T2w TSE) sequence of the upper abdomen. Material and Methods: Images of 46 patients were retrospectively analyzed. Twenty-four patients had received intramuscular injection of 40 mg butylscopolamine immediately before MR imaging. Fourteen of the 24 patients in the butylscopolamine group underwent repeat imaging after a mean of 29 min. Quantitative analysis of the ghosting artifacts was done by measuring signal intensities in regions of interest placed in air anterior to the patient. In addition, image quality was assessed qualitatively by two radiologists by consensus. Results: Spasmolytic medication with butylscopolamine reduced ghosting artifacts and significantly improved image quality of the respiratory-triggered T2w TSE sequence. The most pronounced effect of butylscopolamine administration on image quality was found for the pancreas and the left hepatic lobe. The rate of examinations with excellent or good depiction of the pancreas and the left hepatic lobe in the group without premedication and in the butylscopolamine group was 55% vs. 96% (pancreatic head), 35% vs. 88% (pancreatic body), 43% vs. 96% (pancreatic tail), and 45% vs. 83% (left hepatic lobe), respectively. Regarding the duration of the effect of intramuscular butylscopolamine, repeat imaging after a mean of 29 min did not result in a significant deterioration of image quality. Conclusion: Intramuscular butylscopolamine administration significantly improves image quality of respiratory-triggered T2-weighted abdominal MR imaging by persistent reduction of peristaltic artifacts. MR imaging of the liver and pancreas in particular benefits from the suppression of gastrointestinal peristalsis by butylscopolamine. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate several substances regarding small bowel distension and contrast on balanced steady‐state free precession (bSSFP) cine magnetic resonance (MR) images.Material and Methods: Luminal contrast was evaluated in 24 volunteers after oral application of two different contrast agent groups leading to either bright lumen (pineapple, blueberry juice) or dark lumen (tap water, orange juice) on T1‐weighted images. Bowel distension was evaluated in 30 patients ingesting either methylcellulose or mannitol solution for limiting intestinal absorption. Fifteen patients with duodeno‐jejunal intubation served as the control. Quantitative evaluation included measurement of luminal signal intensities and diameters of four bowel segments, qualitative evaluation assessed luminal contrast and distension on a five‐point scale.Results: Quantitative and qualitative evaluation of the four contrast agents revealed no significant differences regarding luminal contrast on bSSFP images. Quantitative evaluation revealed significantly lower (P<0.05) small bowel distension for three out of four segments (qualitative evaluation: two out of four segments) for methylcellulose in comparison to the control. Mannitol was found to be equal to the control.Conclusion: Oral ingestion of tap water or orange juice in combination with mannitol is recommended for cine MR imaging of the small bowel regarding luminal contrast and small bowel distension on bSSFP sequences. [ABSTRACT FROM AUTHOR]

We present a pattern classification method that combines the classical Perceptron algorithm with simulated annealing. For a sample set S of n-dimensional patterns labeled as positive and negative, our algorithm computes threshold circuits of small depth where the linear threshold functions of the first layer are calculated by simulated annealing with the logarithmic cooling schedule c(k) = Γ(k)/ln (k + 2). The parameter F depends on the sample set and changes in time, and the neighborhood relation is determined by the Perceptron algorithm. We apply the approach to the recognition of focal liver tumours. From 400 positive (focal liver tumour) and 400 negative (normal liver tissue) examples a depth-six threshold circuit is calculated. The examples are of size n = 14 161 = 119 × 119 and they are presented in the DICOM format. On test sets of 100 + 100 examples (disjoint from the learning set) we obtain a correct classification of more than 98%. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess a possible association between breast malignancy and ipsilateral higher vascularity on gadolinium-enhanced MR angiography. One hundred six patients were examined by dynamic gadolinium-enhanced 3D MR imaging. Magnetic resonance angiographic views were generated by image subtraction and maximum intensity projection. The study included 85 patients with unilateral malignant breast neoplasms and 21 with unilateral benign lesions. Three blinded readers independently reviewed the MR angiograms after masking the lesions and the corresponding contralateral sites. The readers were asked to determine whether vascularity was higher on the right side, higher on the left side, or equal on both sides. The results were analyzed by the Kappa statistic and Pearson's chi-square test. The blood vessels of the breasts were clearly seen in all cases. There was good agreement among the observers (kappa > 0.54) in assessing vascularity on both sides. Breasts harboring malignant neoplasms were found to have a higher vascularity than the contralateral breasts (p < 0.005). This sign of malignancy had a sensitivity of 76.5%, a specificity of 57%, and an accuracy of 72.6%. Blood vessels of the breast can be depicted by MR angiography. Unilateral malignant neoplasms are associated with a higher ipsilateral vascularity. In conjunction with other indications of malignancy on gadolinium-enhanced MR images, a higher ipsilateral vascularity may serve as an additional sign of malignancy. [ABSTRACT FROM AUTHOR]

Abstract Background Gadopentate dimeglumine (Gd-DTPA) enhanced magnetic resonance imaging (MRI) is widely applied for the visualization of blood brain barrier (BBB) breakdown in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Recently, the potential of magnetic nanoparticles to detect macrophage infiltration by MRI was demonstrated. We here investigated a new class of very small superparamagnetic iron oxide particles (VSOP) as novel contrast medium in murine adoptive-transfer EAE. Methods EAE was induced in 17 mice via transfer of proteolipid protein specific T cells. MR images were obtained before and after application of Gd-DTPA and VSOP on a 7 Tesla rodent MR scanner. The enhancement pattern of the two contrast agents was compared, and correlated to histology, including Prussian Blue staining for VSOP detection and immunofluorescent staining against IBA-1 to identify macrophages/microglia. Results Both contrast media depicted BBB breakdown in 42 lesions, although differing in plaques appearances and shapes. Furthermore, 13 lesions could be exclusively visualized by VSOP. In the subsequent histological analysis, VSOP was localized to microglia/macrophages, and also diffusely dispersed within the extracellular matrix. Conclusion VSOP showed a higher sensitivity in detecting BBB alterations compared to Gd-DTPA enhanced MRI, providing complementary information of macrophage/microglia activity in inflammatory plaques that has not been visualized by conventional means.

Background: Gadopentate dimeglumine (Gd-DTPA) enhanced magnetic resonance imaging (MRI) is widely applied for the visualization of blood brain barrier (BBB) breakdown in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). Recently, the potential of magnetic nanoparticles to detect macrophage infiltration by MRI was demonstrated. We here investigated a new class of very small superparamagnetic iron oxide particles (VSOP) as novel contrast medium in murine adoptive-transfer EAE.Methods: EAE was induced in 17 mice via transfer of proteolipid protein specific T cells. MR images were obtained before and after application of Gd-DTPA and VSOP on a 7 Tesla rodent MR scanner. The enhancement pattern of the two contrast agents was compared, and correlated to histology, including Prussian Blue staining for VSOP detection and immunofluorescent staining against IBA-1 to identify macrophages/microglia.Results: Both contrast media depicted BBB breakdown in 42 lesions, although differing in plaques appearances and shapes. Furthermore, 13 lesions could be exclusively visualized by VSOP. In the subsequent histological analysis, VSOP was localized to microglia/macrophages, and also diffusely dispersed within the extracellular matrix.Conclusion: VSOP showed a higher sensitivity in detecting BBB alterations compared to Gd-DTPA enhanced MRI, providing complementary information of macrophage/microglia activity in inflammatory plaques that has not been visualized by conventional means. [ABSTRACT FROM AUTHOR]