Showing papers in "NMR in Biomedicine in 2004"
TL;DR: SPIO‐based cellular imaging has now become an established technique to label and detect the cells of interest and is aimed at obtaining a deeper insight into the dynamics of in vivo cell biology, including lymphocyte trafficking, and at monitoring therapies that are based on the use of stem cells and progenitors.
Abstract: Molecular and cellular MR imaging is a rapidly growing field that aims to visualize targeted macromolecules or cells in living organisms. In order to provide a different signal intensity of the target, gadolinium-based MR contrast agents can be employed although they suffer from an inherent high threshold of detectability. Superparamagnetic iron oxide (SPIO) particles can be detected at micromolar concentrations of iron, and offer sufficient sensitivity for T2(*)-weighted imaging. Over the past two decades, biocompatible particles have been linked to specific ligands for molecular imaging. However, due to their relatively large size and clearance by the reticuloendothelial system (RES), widespread biomedical molecular applications have yet to be implemented and few studies have been reproduced between different laboratories. SPIO-based cellular imaging, on the other hand, has now become an established technique to label and detect the cells of interest. Imaging of macrophage activity was the initial and still is the most significant application, in particular for tumor staging of the liver and lymph nodes, with several products either approved or in clinical trials. The ability to now also label non-phagocytic cells in culture using derivatized particles, followed by transplantation or transfusion in living organisms, has led to an active research interest to monitor the cellular biodistribution in vivo including cell migration and trafficking. While most of these studies to date have been mere of the ‘proof-of-principle’ type, further exploitation of this technique will be aimed at obtaining a deeper insight into the dynamics of in vivo cell biology, including lymphocyte trafficking, and at monitoring therapies that are based on the use of stem cells and progenitors. Copyright © 2004 John Wiley & Sons, Ltd.
1,444 citations
TL;DR: Repeat administration of Mn, or compounds that readily release Mn, may increase the risk of Mn‐induced toxicity, and chelation therapy with EDTA and supplementation with levodopa are the current treatment options.
Abstract: Manganese (Mn) is a required element and a metabolic byproduct of the contrast agent mangafodipir trisodium (MnDPDP). The Mn released from MnDPDP is initially sequestered by the liver for first-pass elimination, which allows an enhanced contrast for diagnostic imaging. The administration of intravenous Mn impacts its homeostatic balance in the human body and can lead to toxicity. Human Mn deficiency has been reported in patients on parenteral nutrition and in micronutrient studies. Mn toxicity has been reported through occupational (e.g. welder) and dietary overexposure and is evidenced primarily in the central nervous system, although lung, cardiac, liver, reproductive and fetal toxicity have been noted. Mn neurotoxicity results from an accumulation of the metal in brain tissue and results in a progressive disorder of the extrapyramidal system which is similar to Parkinson's disease. In order for Mn to distribute from blood into brain tissue, it must cross either the blood-brain barrier (BBB) or the blood-cerebrospinal fluid barrier (BCB). Brain import, with no evidence of export, would lead to brain Mn accumulation and neurotoxicity. The mechanism for the neurodegenerative damage specific to select brain regions is not clearly understood. Disturbances in iron homeostasis and the valence state of Mn have been implicated as key factors in contributing to Mn toxicity. Chelation therapy with EDTA and supplementation with levodopa are the current treatment options, which are mildly and transiently efficacious. In conclusion, repeated administration of Mn, or compounds that readily release Mn, may increase the risk of Mn-induced toxicity.
710 citations
TL;DR: In the present work the different approaches to MEMRI are reviewed from a practical standpoint and emphasis is given to the experimental methodology of how to achieve significant, yet safe, amounts of Mn2+ to the target areas of interest.
Abstract: Manganese-enhanced MRI (MEMRI) is being increasingly used for MRI in animals due to the unique T1 contrast that is sensitive to a number of biological processes. Three specific uses of MEMRI have been demonstrated: to visualize activity in the brain and the heart; to trace neuronal specific connections in the brain; and to enhance the brain cytoarchitecture after a systemic dose. Based on an ever-growing number of applications, MEMRI is proving useful as a new molecular imaging method to visualize functional neural circuits and anatomy as well as function in the brain in vivo. Paramount to the successful application of MEMRI is the ability to deliver Mn2+ to the site of interest at an appropriate dose and in a time-efficient manner. A major drawback to the use of Mn2+ as a contrast agent is its cellular toxicity. Therefore, it is critical to use as low a dose as possible. In the present work the different approaches to MEMRI are reviewed from a practical standpoint. Emphasis is given to the experimental methodology of how to achieve significant, yet safe, amounts of Mn2+ to the target areas of interest.
479 citations
TL;DR: This is the first report showingFeridex blocking of cellular differentiation down a specific pathway (while not affecting viability and proliferation), and caution should thus be exercised when using Feridex‐labeled MSCs for chondrogenic MR tracking studies.
Abstract: Magnetic resonance (MR) tracking of superparamagnetic iron oxide (SPIO)-labeled cells is a relatively new technique to non-invasively determine the biodistribution and migration of transplanted stem cells. A number of studies have recently reported encouraging results in the use of bone marrow-derived mesenchymal stem cells (MSCs) for repair of a variety of tissues. For MR tracking of SPIO-labeled MSCs, it is important to determine the effect that the magnetic labeling procedure may have on the differentiation capacity of labeled MSCs. Human MSCs were labeled with poly-L-lysine (PLL)-coated Feridex, with Feridex being an FDA-approved SPIO formulation in an off-label application, and assayed for cellular differentiation using five different assays. As compared with unlabeled controls, labeled MSCs exhibited an unaltered viability, proliferated similarly, and underwent normal adipogenic and osteogenic differentiation. However, there was a marked inhibition of chondrogenesis. The blocking of chondrogenic activity was mediated by the Feridex, rather than by the transfection agent (PLL). This is the first report showing Feridex blocking of cellular differentiation down a specific pathway (while not affecting viability and proliferation), and caution should thus be exercised when using Feridex-labeled MSCs for chondrogenic MR tracking studies. On the other hand, no detrimental effects of Feridex-labeling are anticipated for MR-guided osteogenic or adipogenic transplantation studies.
427 citations
TL;DR: This article aims to increase interest in issues of spectral quality and quality assessment, to start a larger debate on generally accepted criteria that spectra must fulfil to be clinically and scientifically acceptable, and to provide a sample gallery of artifacts, which can be used to raise awareness for potential pitfalls in MRS.
Abstract: In spite of the facts that magnetic resonance spectroscopy (MRS) is applied as clinical tool in non-specialized institutions and that semi-automatic acquisition and processing tools can be used to produce quantitative information from MRS exams without expert information, issues of spectral quality and quality assessment are neglected in the literature of MR spectroscopy. Even worse, there is no consensus among experts on concepts or detailed criteria of quality assessment for MR spectra. Furthermore, artifacts are not at all conspicuous in MRS and can easily be taken for true, interpretable features. This article aims to increase interest in issues of spectral quality and quality assessment, to start a larger debate on generally accepted criteria that spectra must fulfil to be clinically and scientifically acceptable, and to provide a sample gallery of artifacts, which can be used to raise awareness for potential pitfalls in MRS.
393 citations
TL;DR: Recent advances in the basic science of brain iron metabolism, the clinical understanding of neurodegenerative diseases and in MRI technology, suggest that iron‐dependent MR imaging may soon provide biomarkers capable of characterizing the presence and progression of important neurological disorders.
Abstract: The brain has an unusually high concentration of iron, which is distributed in an unusual pattern unlike that in any other organ. The physiological role of this iron and the reasons for this pattern of distribution are not yet understood. There is increasing evidence that several neurodegenerative diseases are associated with altered brain iron metabolism. Understanding these dysmetabolic conditions may provide important information for their diagnosis and treatment. For many years the iron distribution in the human brain could be studied effectively only under postmortem conditions. This situation was changed dramatically by the finding that T2-weighted MR imaging at high field strength (initially 1.5 T) appears to demonstrate the pattern of iron distribution in normal brains and that this imaging technique can detect changes in brain iron concentrations associated with disease states. Up to the present time this imaging capability has been utilized in many research applications but it has not yet been widely applied in the routine diagnosis and management of neurodegenerative disorders. However, recent advances in the basic science of brain iron metabolism, the clinical understanding of neurodegenerative diseases and in MRI technology, particularly in the availability of clinical scanners operating at the higher field strength of 3 T, suggest that iron-dependent MR imaging may soon provide biomarkers capable of characterizing the presence and progression of important neurological disorders. Such biomarkers may be of crucial assistance in the development and utilization of effective new therapies for Alzheimer's and Parkinson's diseases, multiple sclerosis and other iron-related CNS disorders which are difficult to diagnose and treat. Copyright © 2004 John Wiley & Sons, Ltd.
328 citations
TL;DR: This special issue of NMR in Biomedicine on manganese‐enhanced MRI (MEMRI) is aimed at providing the readers of this journal with an extensive review of some of the most prominent applications of MEMRI in biological systems.
Abstract: Manganese ion (Mn 2þ ) is an essential metal that participates as a cofactor in a number of critical biological functions, such as electron transport, detoxification of free radicals and synthesis of neurotransmitters. Mn 2þ can enter excitable cells using some of the same transport systems as Ca 2þ and it can bind to a number of intracellular sites because it has high affinity for Ca 2þ and Mg 2þ binding sites on proteins and nucleic acids. Paramagnetic forms of manganese ions are potent MRI relaxation agents. Indeed, Mn 2þ was the first contrast agent proposed for use in MRI. Recently, there has been renewed interest in combining the strong MRI relaxation effects of Mn 2þ with its unique biology, in order to further expand the already broad assortment of useful information that can be measured by MRI. Such an approach has been continuously developed in the past several years to provide unique tissue contrast, to assess tissue viability, to act as a surrogate marker of calcium influx into cells and to trace neuronal connections. This special issue of NMR in Biomedicine on manganese- enhanced MRI (MEMRI) is aimed at providing the readers of this journal with an extensive review of some of the most prominent applications of MEMRI in biological systems. Written by several of the leaders in the field, the reviews and original research articles featured in this special issue are likely to offer an exciting and inspiring view of the broad range of applications of MEMRI. Copyright # 2004 John Wiley & Sons, Ltd.
287 citations
TL;DR: This review paper attempts to provide an overview of the principles and techniques that are often termed electron paramagnetic resonance (EPR) oximetry, and illustrates they have been successfully applied to measure oxygen tension, an essential parameter of the tumor microenvironment.
Abstract: This review paper attempts to provide an overview of the principles and techniques that are often termed electron paramagnetic resonance (EPR) oximetry. The paper discusses the potential of such methods and illustrates they have been successfully applied to measure oxygen tension, an essential parameter of the tumor microenvironment. To help the reader understand the motivation for carrying out these measurements, the importance of tumor hypoxia is first discussed: the basic issues of why a tumor is hypoxic, why these hypoxic microenvironments promote processes driving malignant progression and why hypoxia dramatically influences the response of tumors to cytotoxic treatments will be explained. The different methods that have been used to estimate the oxygenation in tumors will be reviewed. To introduce the basics of EPR oximetry, the specificity of in vivo EPR will be discussed by comparing this technique with NMR and MRI. The different types of paramagnetic oxygen sensors will be presented, as well as the methods for recording the information (EPR spectroscopy, EPR imaging, dynamic nuclear polarization). Several applications of EPR for characterizing tumor oxygenation will be illustrated, with a special emphasis on pharmacological interventions that modulate the tumor microenvironment. Finally, the challenges for transposing the method into the clinic will also be discussed.
214 citations
TL;DR: This review will discuss the in vivo physical chemical relaxation properties of superparamagnetic iron oxide particles and applications usingIron oxide particles for vascular, perfusion and viability imaging as well as assessment of the inflammatory status of a given tissue.
Abstract: This review will discuss the in vivo physical chemical relaxation properties of superparamagnetic iron oxide particles. Various parameters such as size, magnetization, compartmentalization and water exchange effects and how these alter the behavior of the iron oxide particles in an in vitro vs an in vivo situation with special reference to the cardiovascular system will be exemplified. Furthermore, applications using iron oxide particles for vascular, perfusion and viability imaging as well as assessment of the inflammatory status of a given tissue will be discussed. Copyright © 2004 John Wiley & Sons, Ltd.
177 citations
TL;DR: This is the most detailed assignment of biochemical compounds obtained in intact human tissue, in particular in brain tumour tissue, which is comparable to that obtained on perchloric extracts.
Abstract: High-resolution magic angle spinning (HR-MAS) one- and two-dimensional 1H and 13C nuclear magnetic resonance (NMR) spectroscopy has been used to study intact glioblastoma (GBM) brain tumour tissue The results were compared with in vitro chemical extract and in vivo spectra The resolution of 1H one-dimensional, 1H TOCSY and 13C HSQC HR-MAS spectra is comparable to that obtained on perchloric extracts 13C HSQC HR-MAS spectra have been particularly useful for the identification of 37 different metabolites in intact biopsy tumours, excluding water and DSS components To our knowledge, this is the most detailed assignment of biochemical compounds obtained in intact human tissue, in particular in brain tumour tissue Tissue degradation during the recording of the NMR experiment was avoided by keeping the sample at a temperature of 4 degrees C Detailed metabolical compositions of 10 GBM (six primary, two secondary and two unclassified) were obtained A good correlation between ex vivo and in vivo MRS has been found
172 citations
TL;DR: MEMRI utilizes a combination of these properties of Mn2+ to trace neuronal pathways in an MRI‐detectable manner, and some of the current MEMRI tract‐tracing methodologies in mice and non‐human primates as well as biological applications of MEMRI tractor-tracing are detailed.
Abstract: It is well established that manganese ion (Mn2+) can access neurons through voltage-gated calcium (Ca2+) channels. Based upon this fundamental principle, Mn2+ has long been used in biomedical research as an indicator of Ca2+ influx in conjunction with fluorescent microscopy. Additionally, after entry into neurons, Mn2+ is transported down axons via microtubule based fast axonal transport. Furthermore, Mn2+ is paramagnetic, resulting in a shortening of the spin-lattice relaxation time-constant, T1, which yields positive contrast enhancement in T1-weighted MRI images, specific to tissues where the ion has accumulated. Manganese-enhanced MRI (MEMRI) utilizes a combination of these properties of Mn2+ to trace neuronal pathways in an MRI-detectable manner. The focus of this review will detail some of the current MEMRI tract-tracing methodologies in mice and non-human primates as well as biological applications of MEMRI tract-tracing.
TL;DR: The results suggested that the combination of voxel‐based diffusion tensor analysis and diffusion Tensor tractography might help determine the location of the affected neuronal tissues among ALS patients in a non‐invasive manner.
Abstract: The purpose of this study is to investigate whether the diffusional anisotropy of water molecules is disrupted in the pyramidal and extra-pyramidal regions in patients with amyotrophic lateral sclerosis (ALS). We studied seven patients with probable ALS (four women, mean age ± SD, 57.3 ± 6.2 years old) according to the criteria of the World Federation of Neurology. A control group consisted of 11 age- and sex-matched volunteers (six women, 57.1 ± 4.5) without disorders affecting the central nervous system. Voxel-based diffusion tensor analysis was made with statistical parametric mapping (SPM99). We also created the normalized corticospinal tractography from the diffusion tensor data. The significant fractional anisotropy (FA) decrease in the ALS group was found in the right frontal subgyral white matter and left frontal precentral white matter. These clusters with significant FA decrease corresponded well to the average group map of the corticospinal tract in a standard reference frame. These results suggested that the combination of voxel-based diffusion tensor analysis and diffusion tensor tractography might help determine the location of the affected neuronal tissues among ALS patients in a non-invasive manner. Copyright © 2004 John Wiley & Sons, Ltd.
TL;DR: The development and use of in vivo techniques for strictly experimental applications in animals has been very successful, and these results now have made possible some very attractive potential clinical applications, including oximetry, where EPR almost uniquely can make repeated and accurate measurements of pO2 in tissues.
Abstract: The development and use of in vivo techniques for strictly experimental applications in animals has been very successful, and these results now have made possible some very attractive potential clinical applications. The area with the most obvious immediate, effective and widespread clinical use is oximetry, where EPR almost uniquely can make repeated and accurate measurements of pO2 in tissues. Such measurements can provide clinicians with information that can impact directly on diagnosis and therapy, especially for oncology, peripheral vascular disease and wound healing. The other area of immediate and timely importance is the unique ability of in vivo EPR to measure clinically significant exposures to ionizing radiation ‘after-the-fact’, such as may occur due to accidents, terrorism or nuclear war. There are a number of other capabilities of in vivo EPR that also potentially could become extensively used in human subjects. In pharmacology the unique capabilities of in vivo EPR to detect and characterize free radicals could be applied to measure free radical intermediates from drugs and oxidative process. A closely related area of potential widespread applications is the use of EPR to measure nitric oxide. These often unique capabilities, combined with the sensitivity of EPR spectra to the immediate environment (e.g. pH, molecular motion, charge) have already resulted in some very productive applications in animals and these are likely to expand substantially in the near future. They should provide a continually developing base for extending clinical uses of in vivo EPR. The challenges for achieving full implementation include adapting the spectrometer for safe and comfortable measurements in human subjects, achieving sufficient sensitivity for measurements at the sites of the pathophysiological processes that are being measured, and establishing a consensus on the clinical value of the measurements. Copyright © 2004 John Wiley & Sons, Ltd.
TL;DR: This study yields new information regarding the expected variation in muscle elasticity in a healthy population, and also reveals the expected variability of the MRE technique in skeletal muscle.
Abstract: MR elastography (MRE) has been shown to be capable of non-invasively measuring tissue elasticity even in deep-lying regions. Although limited studies have already been published examining in vivo muscle elasticity, it is still not clear over what range the in vivo elasticity values vary. The present study intends to produce further information by examining four different skeletal muscles in a group of 12 healthy volunteers in the age range of 27-38 years. The examinations were performed in the biceps brachii, the flexor digitorum profundus, the soleus and the gastrocnemius. The average shear modulus was determined to be 17.9 (+/- 5.5), 8.7 (+/- 2.8), 12.5 (+/- 7.3) and 9.9 (+/- 6.8) kPa for each muscle, respectively. To ascertain the reproducibility of the examination, the stiffness measurements in two volunteers were repeated seven times for the biceps brachii. These examinations yielded a mean shear modulus of 11.3 +/-.7 and 13.3 +/- 4.7 kPa for the two subjects. For elasticity reconstruction, an automated reconstruction algorithm is introduced which eliminates variation due to subjective manual image analysis. This study yields new information regarding the expected variation in muscle elasticity in a healthy population, and also reveals the expected variability of the MRE technique in skeletal muscle.
TL;DR: A single‐spin‐echo methodology is described for the measurement and imaging of proton transverse relaxation rates (R2) in iron‐loaded and normal human liver tissue in vivo to enable reliable extraction of relaxation times from tissues with very short T2 values.
Abstract: A single-spin-echo methodology is described for the measurement and imaging of proton transverse relaxation rates (R2) in iron-loaded and normal human liver tissue in vivo. The methodology brings together previously reported techniques dealing with (i) the changes in gain between each spin-echo acquisition, (ii) signal level offset due to background noise, (iii) estimation of signal intensities in decay curves at time zero to enable reliable extraction of relaxation times from tissues with very short T2 values, (iv) bi-exponential modelling of decay curves with a small number of data points, and (v) reduction of respiratory motion artefacts. The accuracy of the technique is tested on aqueous manganese chloride solutions yielding a relaxivity of 74.1+/-0.3 s-1 (mM)-1, consistent with previous reports. The precision of the in vivo measurement of mean liver R2 values is tested through duplicate measurements on 10 human subjects with mean liver R2 values ranging from 26 to 220 s-1. The random uncertainty on the measurement of mean liver R2 was found to be 7.7%.
TL;DR: The main relaxation properties of ferritin in solution and in tissue are presented together with a discussion of the possible reasons for the faster transverse relaxation observed in tissues.
Abstract: Ferritin, the iron storing protein, is known to darken T2-weighted MRI This darkening can be used to non- invasively measure iron content However, ferritin's behavior is not the same in tissue as in solution, a discrepancy that remains unexplained by the recently developed theory matching the NMR properties of ferritin solutions A better understanding of the relaxation induced by ferritin in tissue could help for the development of new MRI protocols of iron quantification In this short review, the main relaxation properties of ferritin in solution and in tissue are presented together with a discussion of the possible reasons for the faster transverse relaxation observed in tissues Copyright # 2004 John Wiley & Sons, Ltd
TL;DR: Two main applications of AIM, mapping brain activation in rat somatosensory cortex, as well stroke research based on the well‐established middle cerebral artery occlusion model, are described in detail.
Abstract: Divalent manganese ion (Mn2+) has been reported to be a useful contrast agent for functional MRI, through a technique named activity-induced manganese-dependent MRI (AIM). In AIM, signal enhancement is related to functional increases in calcium influx, and therefore AIM is, thus far, the only MRI method able to map brain activation in vivo independently of the surrogate hemodynamic changes used in functional MRI. Because of its high signal-to-noise ratio (SNR) and high sensitivity, AIM allows the use of multi-slice or three-dimensional MRI techniques to map functional activity at high spatial resolution. In the present review, we define AIM as a functional MRI tool based on the administration of divalent ionized manganese through an open or disrupted blood-brain barrier (BBB). The adequacy and efficacy of AIM in detecting neural activation is described in light of supporting experiments on inhibition of calcium channels, FOS expression, and on direct comparison to BOLD- and perfusion-based functional MRI. Two main applications of AIM, mapping brain activation in rat somatosensory cortex, as well stroke research based on the well-established middle cerebral artery occlusion model, are described in detail. Methodological problems associated with a strong dependence on anesthetic conditions, potential corruption due to disruption of the BBB, and unspecific increase of the baseline signal due to acoustical noise are discussed. Finally, recommended preparation methods and experimental protocols for AIM are introduced.
TL;DR: It turns out that intravitreal and intrahippocampal injections of MnCl2 emerge as useful tools for a delineation of major axonal connections in the intact central nervous system.
Abstract: This work presents three-dimensional MRI studies of rodent brain in vivo after focal and systemic administration of MnCl2. Particular emphasis is paid to the morphology and dynamics of Mn2+-induced MRI signal enhancements, and the physiological mechanisms underlying cerebral Mn2+ uptake and distribution. It turns out that intravitreal and intrahippocampal injections of MnCl2 emerge as useful tools for a delineation of major axonal connections in the intact central nervous system. Subcutaneous administrations may be exploited to highlight regions involved in fundamental brain functions such as the olfactory bulb, inferior colliculus, cerebellum and hippocampal formation. Specific insights into the processes supporting cerebral Mn2+ accumulation may be obtained by intraventricular MnCl2 injection as well as by pharmacologic modulation of, for example, hippocampal function. Taken together, Mn2+-enhanced MRI opens new ways for mapping functioning pathways in animal brain in vivo with applications ranging from assessments of transgenic animals to follow-up studies of animal models of human brain disorders. Copyright © 2004 John Wiley & Sons, Ltd.
TL;DR: D‐MEMRI, combined with other MRI techniques, clearly harbors potential for unraveling seasonal, hormonal, pharmacological or even genetically driven changes in a neuronal circuit, by simultaneously measuring changes in morphology, activity and connectivity.
Abstract: The song control system of song birds is an excellent model for studying brain plasticity and has thus far been extensively analyzed by histological and electrophysiological methods However, these approaches do not provide a global view of the brain and/or do not allow repeated measures, which are necessary to establish correlations between alterations in neural substrate and behavior Application of in vivo manganese-enhanced MRI enabled us for the first time to visualize the song control system repeatedly in the same bird, making it possible to quantify dynamically the volume changes in this circuit as a function of seasonal and hormonal influences In this review, we introduce and explore the song control system of song birds as a natural model for brain plasticity to validate a new cutting edge technique, which we called ‘repeated dynamic manganese enhanced MRI’ or D-MEMRI This technique is based on the use of implanted permanent cannulae—for accurate repeated manganese injections in a defined target area—and the subsequent MRI acquisition of the dynamics of the accumulation of manganese in projection brain targets A compilation of the D-MEMRI data obtained thus far in this system demonstrates the usefulness of this new method for studying brain plasticity In particular it is shown to be a perfect tool for long-term studies of morphological and functional responses of specific brain circuits to changes in endocrine conditions The method was also successfully applied to obtain quantitative measures of changes in activity as a function of auditory stimuli in different neuronal populations of a same nucleus that project to different targets D-MEMRI, combined with other MRI techniques, clearly harbors potential for unraveling seasonal, hormonal, pharmacological or even genetically driven changes in a neuronal circuit, by simultaneously measuring changes in morphology, activity and connectivity Copyright © 2004 John Wiley & Sons, Ltd
TL;DR: Electron paramagnetic resonance (EPR) imaging in the continuous wave (CW) and time‐domain modes, as well as Overhauser‐enhanced magnetic resonance imaging in vivo is described, and the relative merits of these methods for functional in vivo imaging of small animals to assess hypoxia and tissue redox status are described.
Abstract: Electron paramagnetic resonance (EPR) imaging in the continuous wave (CW) and time-domain modes, as well as Overhauser-enhanced magnetic resonance imaging in vivo is described. The review is based mainly on the CW and time-domain EPR instrumentation at 300 MHz developed in our laboratory, and the relative merits of these methods for functional in vivo imaging of small animals to assess hypoxia and tissue redox status are described. Overhauser imaging of small animals at magnetic fields in the range 10–15 mT that is being carried out in our laboratory for tumor imaging and the evaluation of tumor hypoxia based on quantitative evaluation of Overhauser enhancement is also described. Alternate approaches to spectral–spatial imaging using the transverse decay constants to infer in situ line widths and hence in vivo pO2 using CW and time-domain EPR imaging are also discussed. The nature of the spin probes used, the quality of the images obtained in all the three methods, the achievable resolution, limitations and possible future directions in small animal functional imaging with these modalities are summarized. Copyright © 2004 John Wiley & Sons, Ltd.
TL;DR: The utility of this Mn‐enhanced MRI (MEMRI) method for analyzing early postnatal patterning of the mouse cerebellum is demonstrated and it is shown that MEMRI enhancement correlates qualitatively with granule cell density in the developing cerebellity.
Abstract: Given the importance of genetically modified mice in studies of mammalian brain development and human congenital brain diseases, MRI has the potential to provide an efficient in vivo approach for analyzing mutant phenotypes in the early postnatal mouse brain. The combination of reduced tissue contrast at the high magnetic fields required for mice, and the changing cellular composition of the developing mouse brain make it difficult to optimize MRI contrast in neonatal mouse imaging. We have explored an easily implemented approach for contrast-enhanced imaging, using systemically administered manganese (Mn) to reveal fine anatomical detail in T1-weighted MR images of neonatal mouse brains. In particular, we demonstrate the utility of this Mn-enhanced MRI (MEMRI) method for analyzing early postnatal patterning of the mouse cerebellum. Through comparisons with matched histological sections, we further show that MEMRI enhancement correlates qualitatively with granule cell density in the developing cerebellum, suggesting that the cerebellar enhancement is due to uptake of Mn in the granule neurons. Finally, variable cerebellar defects in mice with a conditional mutation in the Gbx2 gene were analyzed with MEMRI to demonstrate the utility of this method for mutant mouse phenotyping. Taken together, our results indicate that MEMRI provides an efficient and powerful in vivo method for analyzing neonatal brain development in normal and genetically engineered mice. Copyright © 2004 John Wiley & Sons, Ltd.
TL;DR: It is suggested that pre‐treatment MRI and three‐dimensional 1H‐MRSI provide information that predicts outcome for patients with malignant gliomas and have drawn attention to variables that should be examined prospectively in future studies using these techniques.
Abstract: Although MR imaging (MRI) and MR spectroscopic imaging (MRSI) have been applied in the diagnosis and treatment planning for brain tumors, their prognostic significance has not yet been determined. The goal of this study was to identify pre-treatment MRI and MRSI parameters for patients with malignant glioma that may be useful in predicting survival. Two populations of patients with newly-diagnosed malignant glioma were examined with MRI and three-dimensional proton ((1)H) MRSI. Thirty-nine patients (22 grade 3 and 17 glioblastoma multiforme, GBM) were studied prior to surgery, and 33 GBM patients were studied after surgery but prior to treatment with radiation and chemotherapy. Signal intensities of choline (Cho), creatine (Cr), N-acetyl aspartate (NAA), and lactate/lipid (LL) were estimated from the spectra. Recursive partitioning methods were applied to parameters that included age, histological grade, MRI and MRSI variables to generate survival trees. Patients were grouped into high and low risk categories and the corresponding Kaplan-Meier curves were plotted for comparison between groups. The parameters that were selected by recursive partitioning as being predictive of poor outcome were older age, larger contrast enhancement, higher Cho-to-Cr, higher Cho-to-NAA, higher LL and lower Cr-to-NAA abnormalities. The survival functions were significantly different between the sub-groups of patients obtained from the survival tree for both pre-surgery and post-surgery data. The results of this study suggest that pre-treatment MRI and three-dimensional (1)H-MRSI provide information that predicts outcome for patients with malignant gliomas and have drawn attention to variables that should be examined prospectively in future studies using these techniques.
TL;DR: A key issue is whether sufficient accumulation of Mn2+ in heart cells for imaging can occur without cardiotoxicity, and findings to date indicate this is possible.
Abstract: The use of manganese-based MRI contrast materials, either manganese salts or chelates, has spanned the entire timeframe of cardiac MRI. However interest in Mn compounds for cardiac MRI has been sporadic because of concerns over cardiotoxicity associated with significant concentration of free Mn2+ and notable success of gadolinium chelates in cardiac application. Initial strategies to overcome cardiotoxicity included chelation of Mn2+ to reduce the concentration of the free ion in vivo, and addition of Ca2+ in combination with Mn2+ to competitively reduce binding of Mn2+ to Ca2+ channels in the heart. Both approaches met with mixed success, but were subsequently discontinued in favor of gadolinium-based approaches. However Mn2+-based media potentially offer unique advantages for characterizing heart pathology over conventional Gd-based contrast media because Mn2+ is taken up by heart cells and retained for hours. Cellular uptake occurs through calcium channels so contrast on delayed images may be interpreted according to regional or global functional status. Since Mn2+ is retained in the heart, Mn-based media can be administered outside the magnet and the contrast pattern measured hours later to provide assessment of uptake. A key issue is whether sufficient accumulation of Mn2+ in heart cells for imaging can occur without cardiotoxicity, and findings to date indicate this is possible. This review examines the current status of Mn2+-enhanced MRI of heart with particular focus on the hypothesis that Mn2+ uptake can be interpreted in terms of heart function.
TL;DR: This work aims to review the applications of ultrasmall superparamagnetic iron oxide contrast agents in MR animal studies, with an emphasis on the investigation of microvascular parameters.
Abstract: Ultrasmall superparamagnetic iron oxide nanoparticles have been widely used during the past decade as MR intravascular contrast agents in the study of animal models. Such agents enhance both T1 and T2/T2* relaxation, although for animal studies it is the later type of enhancement that is most commonly exploited. Their strong microscopic intravascular susceptibility effect enables the local blood volume distribution to be mapped in various organs. High spatial resolution and sensitivity can be achieved, because the long half-life of these agents in blood, combined with anesthetization, permits steady-state measurements over extended periods. This capability has been utilized to study the cerebrovascular blood volume distributions and their changes in normal, activated, pathologic and pharmacologically or genetically modified states, particularly in rodent animal models. It has also been applied to study blood volume changes in other tissues, such as the myocardium. The relaxation rate shifts Delta R2 and Delta R2* induced by iron oxide agents may differ depending on certain morphological characteristics of the microvascular network, and sensitive Delta R2 and Delta R2* mapping can potentially provide, in addition to blood volume, measurement of other important microvascular parameters such as blood vessel density and size. This work aims to review the applications of ultrasmall superparamagnetic iron oxide contrast agents in MR animal studies, with an emphasis on the investigation of microvascular parameters.
TL;DR: This study validates USPIO‐enhanced MRI as an important tool for the noninvasive visualization of brain inflammation in stroke and other CNS pathologies.
Abstract: Brain inflammation contributes to the tissue injury caused by ischemic stroke. Macrophages as the most abundant inflammatory cell population in stroke lesions can be visualized using ultrasmall superparamagnetic iron oxide (USPIO) as a cell-specific contrast agent for magnetic resonance imaging (MRI). The aim of our present study was to delineate the inflammatory response during experimental cerebral infarction by means of USPIO-enhanced MRI and to correlate the spatial distribution of USPIO-induced MR signal alterations with cellular infiltration and iron deposition. To this end USPIOs were administered to Wistar rats 5 days after photothrombotic cerebral infarction. MR imaging at 7 T performed 24 h later displayed a rim-like signal loss around the infarction in the USPIO treated animals. On histological brain sections obtained from the same animals after MRI the distribution of iron and ED1+ phagocytes was in full spatial agreement with the signal loss seen on T2*-weighted images. Our study validates USPIO-enhanced MRI as an important tool for the noninvasive visualization of brain inflammation in stroke and other CNS pathologies.
TL;DR: It was found that, in parallel to the growth arrest by this drug, the volume fraction of the slowly diffusing water increased, suggesting a TMI‐induced cell swelling, which can serve as a basis for extending diffusion breast MRI in the clinical setting.
Abstract: The parameters that characterize the intricate water diffusion in tumors may serve to reveal their distinct pathology. Specifically, the application of diffusion magnetic resonance imaging (MRI) can aid in characterizing breast cancer, as well as monitoring response to therapy. We present here a non-invasive, quantitative MRI investigation, at high spatial resolution, of water diffusion in hormonal dependent MCF7 breast tumors implanted orthotopically in immunodeficient mice. Distinctive MRI protocols were designed in this study, utilizing a broad range of diffusion times and diffusion gradient strengths. Application of these protocols allowed water diffusion in the tissue extracellular and intracellular compartments to be distinguished, and the effect of restricted diffusion and water exchange on the water diffusion in these compartments to be evaluated. Pixel-by-pixel analysis yielded parametric maps of the estimated volume fraction and apparent diffusion coefficient of each compartment. The diffusion of the water in the extracellular microenvironment was approximately two fold slower than that of free water, and in the intracellular compartment was about one order of magnitude slower than that of free water and demonstrated restriction of water diffusion at long diffusion times. Mapping of the water fraction in each compartment was further employed to monitor changes during tumor progression and to assess tumor response to hormonal manipulation with a new antiestrogenic drug, tamoxifen methiodide (TMI). It was found that, in parallel to the growth arrest by this drug, the volume fraction of the slowly diffusing water increased, suggesting a TMI-induced cell swelling. This study can serve as a basis for extending diffusion breast MRI in the clinical setting.
TL;DR: Simulations of intrav vascular and extravascular blood‐oxygenation level‐dependent (BOLD) effects in muscle suggested that intravascular BOLD makes a major contribution to the transient changes, although other factors such as increased vascular volume or increased muscle cell T2 may also contribute.
Abstract: Transient increases in signal intensity (DeltaSI, peak 2.6 +/- 0.6 %, mean +/- SE, n = 14) were observed in axial, gradient-echo, echo-planar magnetic resonance images acquired at 1.5 T from human anterior tibialis muscle following single, 1 s duration, isometric ankle dorsiflexion contractions. The magnitude of the MRI-measured DeltaSI was not significantly different using TR of 2000 vs 500 ms, or using spin-echo vs gradient-echo echo-planar pulse sequences. However, DeltaSI measured by gradient-echo sequences was significantly greater at 3 vs 1.5 T (3.8 +/- 0.8 vs 1.6 +/- 0.2 %, n = 5). The time course of the transient DeltaSI (peak at 7.9 +/- 0.4 s after each contraction, decay with half-time of 4.6 +/- 0.6 s) was comparable to the time course of the transient increase in relative heme saturation (13 +/- 2 %, n = 5) measured after single contractions in another group of subjects by near-infrared spectroscopy (peak at 9.3 +/- 0.5 s, decay with half-time 6.2 +/- 0.8 s, n = 8). Simulations of intravascular and extravascular blood-oxygenation level-dependent (BOLD) effects in muscle suggested that intravascular BOLD makes a major contribution to the transient changes, although other factors such as increased vascular volume or increased muscle cell T2 may also contribute. The transients can be exploited for muscle functional imaging analogous to BOLD-based brain functional imaging, and might provide an index of peripheral vascular function.
TL;DR: This special issue is aimed at providing the readers of this journal with an indication of the exciting and important areas in which in vivo electron paramagnetic resonance (EPR) is making contributions to experimental progress and to provide perspectives on future developments, including the potential for in vivo EPR to be an important new clinical tool.
Abstract: This special issue is aimed at providing the readers of this journal with an indication of the exciting and important areas in which in vivo electron paramagnetic resonance (EPR) [or equivalently electron spin resonance (ESR)] is making contributions to experimental progress and to provide perspectives on future developments, including the potential for in vivo EPR to be an important new clinical tool. There also are many situations where the combination of in vivo EPR with NMR may be very synergistic. EPR (ESR) is a magnetic resonance-based technique that detects species with unpaired electrons. The technique has become a major tool in diverse fields ranging from biology and chemistry to solid-state physics. In the last few years, many publications have demonstrated that EPR measurements in living animals (in vivo EPR) can provide very significant new insights to physiology, pathophysiology and pharmacology. The most successful applications of in vivo EPR have been non-invasive measurements of oxygen, nitric oxide, bioradicals, pH and redox state, with applications in oncology, cardiology, neuroscience and toxicology. EPR also appears to be the method of choice for measuring radiation dose retrospectively, including the potential to do this in vivo in human subjects. While far from comprehensive, the reviews, original contributions and viewpoints provided in this issue by several leaders in the field of in vivo EPR should provide the readers with confirmation that in vivo EPR is an exciting field that is likely to provide very valuable complementary information for many NMR-based studies in experimental animals and, probably, also for clinical studies.
TL;DR: Ex vivo analysis of in vivo 1H‐magnetic resonance (MR) spectroscopic appearances of cervical cancer using an endovaginal receiver coil and magic angle spinning (MAS) MR spectroscopy of tissue samples showed significant differences not only in triglyceride‐CH2, but also in CH3, a 2 ppm resonance, choline‐containing compounds and creatine between tissues from control women and cancer tissue.
Abstract: The objective of this study was to establish in vivo (1)H-magnetic resonance (MR) spectroscopic appearances of cervical cancer using an endovaginal receiver coil and corroborate findings with magic angle spinning (MAS) MR spectroscopy of tissue samples. Fifty-three women (14 controls and 39 with cervical cancer) underwent endovaginal coil MR imaging at 1.5 T with T(1)- and T(2)-weighted scans sagittal and transverse to the cervix. Localized (1)H MR spectra (PRESS technique, TR 1600 ms, TE 135 ms) were accumulated in all controls and 29 cancer patients whose tumour filled > 50% of a single 3.4 cm(3) voxel. Peaks from triglyceride-CH(2) and -CH(3) were defined as present and in-phase (with the choline resonance), present but out-of-phase, or not present. Peak areas of choline-containing compounds were standardized to the area of unsuppressed tissue water resonance. Comparisons in observed resonances between groups were made using Fisher's exact test (qualitative data) and a t-test (quantitative data). Biopsies from these women analysed using MAS-MR spectroscopy and normalized to the intensity of an external standard of silicone rubber were similarly compared. Adequate water suppression permitted spectral analysis in 11 controls and 27 cancer patients. In-phase triglyceride-CH(2) resonances (1.3 ppm) were observed in 74% of tumours but in no control women (p < 0.001). No differences were observed in the presence of a 2 ppm resonance, choline-containing compounds or creatine in cancer compared with control women. However, ex vivo analysis showed significant differences not only in -CH(2), but also in -CH(3), a 2 ppm resonance, choline-containing compounds and creatine between tissues from control women and cancer tissue (p < 0.001, = 0.001, = 0.036, < 0.001 and = 0.004 respectively). On in vivo (1)H-MR spectroscopy, the presence of positive triglyceride-CH(2) resonances can be used to detect and confirm the presence of cervical cancer. However, technical improvements are required before routine clinical use.
TL;DR: SH U 555 C proved to be a contrast agent with a high T1‐effect suitable for both first‐pass MRA comparable to gadolinium‐enhanced MRA and high resolution equilibrium MRA up to 42 min post‐injection.
Abstract: The purpose of this study was to study different doses for first-pass and equilibrium phase MRA of aortoiliac vessels with a superparamagnetic iron oxide (SPIO) intravascular MR contrast agent (SH U 555 C) after single i.v. bolus injection. Sixteen healthy volunteers were prospectively enrolled into this single-blind, placebo-controlled clinical trial. SHU 555 C was injected as an i.v. bolus at stepwise increased dose levels of 5, 10, 20 and 40 micromol Fe/kg bodyweight (b.w.) corresponding to injection volumes of 0.01, 0.02, 0.04 and 0.08 ml/kg b.w. Serial high-resolution three-dimensional MRA of the aortoiliac vessels was acquired during first-pass and equilibrium, at 6 min intervals up to 42 min after contrast application using a breath-hold three-dimensional FLASH sequence on a 1.5 T scanner. Intravascular enhancement was calculated within the abdominal aorta and the inferior vena cava and a statistical analysis for significant differences in vessel enhancement was performed during the bolus and equilibrium phases. The visibility of vessels was ranked and effects of potential artifacts on image quality were graded for each time point and dose group. SH U 555 C showed a dose-dependent intravascular enhancement during the observation period (42 min). The highest dose of 40 micromol Fe/kg b.w. revealed the highest image quality during first-pass and equilibrium phases. The intravascular enhancement in the aorta increased dose-dependently from 5 to 40 micromol kg b.w. during first-pass and equilibrium phases (p<0.05). Intravascular signal inhomogeneities were observed at lower doses and decreased with increasing doses. First-pass MRA was diagnostic at doses of 10, 20 and 40 micromol Fe/kg b.w. For equilibrium MRA, a dose of 40 micromol Fe/kg b.w. was considered to be diagnostic. SH U 555 C proved to be a contrast agent with a high T1-effect suitable for both first-pass MRA comparable to gadolinium-enhanced MRA and high resolution equilibrium MRA up to 42 min post-injection (p.i.).