Showing papers in "NMR in Biomedicine in 2006"

Lipid-based nanoparticles for contrast-enhanced MRI and molecular imaging.

Abstract: In the field of MR imaging and especially in the emerging field of cellular and molecular MR imaging, flexible strategies to synthesize contrast agents that can be manipulated in terms of size and composition and that can be easily conjugated with targeting ligands are required. Furthermore, the relaxivity of the contrast agents, especially for molecular imaging applications, should be very high to deal with the low sensitivity of MRI. Lipid-based nanoparticles, such as liposomes or micelles, have been used extensively in recent decades as drug carrier vehicles. A relatively new and promising application of lipidic nanoparticles is their use as multimodal MR contrast agents. Lipids are amphiphilic molecules with both a hydrophobic and a hydrophilic part, which spontaneously assemble into aggregates in an aqueous environment. In these aggregates, the amphiphiles are arranged such that the hydrophobic parts cluster together and the hydrophilic parts face the water. In the low concentration regime, a wide variety of structures can be formed, ranging from spherical micelles to disks or liposomes. Furthermore, a monolayer of lipids can serve as a shell to enclose a hydrophobic core. Hydrophobic iron oxide particles, quantum dots or perfluorocarbon emulsions can be solubilized using this approach. MR-detectable and fluorescent amphiphilic molecules can easily be incorporated in lipidic nanoparticles. Furthermore, targeting ligands can be conjugated to lipidic particles by incorporating lipids with a functional moiety to allow a specific interaction with molecular markers and to achieve accumulation of the particles at disease sites. In this review, an overview of different lipidic nanoparticles for use in MRI is given, with the main emphasis on Gd-based contrast agents. The mechanisms of particle formation, conjugation strategies and applications in the field of contrast-enhanced, cellular and molecular MRI are discussed.

Liver fibrosis: non‐invasive assessment with MR elastography

Abstract: The aim of this study was to assess the feasibility of using non-invasive MR elastography for determining the stage of liver fibrosis. Twenty-five consecutive patients who had liver biopsy for suspicion of chronic liver disease were included in the study. The stage of fibrosis on the biopsies was assessed according to the METAVIR scoring system from F0, no fibrosis, to F4, cirrhosis. MR elastography was performed by transmitting low-frequency (65 Hz) mechanical waves into the liver with a transducer placed at the back of the patients. The MR pulse sequence was a motion-sensitized spin-echo sequence, phase-locked to the mechanical excitation. The phase maps were processed to obtain shear elasticity and shear viscosity maps. The mean hepatic shear elasticity increased with increasing stage of fibrosis. The mean elasticity was 2.24 +/- 0.23 kPa in the 11 patients without substantial fibrosis (F0-F1 grades), 2.56 +/- 0.24 kPa in the four patients with substantial fibrosis (F2-F3) and 4.68 +/- 1.61 kPa in the 10 patients with cirrhosis (F4). The differences between groups were statistically significant (p

Three-dimensional characterization of non-gaussian water diffusion in humans using diffusion kurtosis imaging

Abstract: Conventional diffusion tensor imaging (DTI) measures water diffusion parameters based on the assumption that the spin displacement distribution is a Gaussian function. However, water movement in biological tissue is often non-Gaussian and this non-Gaussian behavior may contain useful information related to tissue structure and pathophysiology. Here we propose an approach to directly measure the non-Gaussian property of water diffusion, characterized by a four-dimensional matrix referred to as the diffusion kurtosis tensor. This approach does not require the complete measurement of the displacement distribution function and, therefore, is more time efficient compared with the q-space imaging technique. A theoretical framework of the DK calculation is established, and experimental results are presented for humans obtained within a clinically feasible time of about 10 min. The resulting kurtosis maps are shown to be robust and reproducible. Directionally-averaged apparent kurtosis coefficients (AKC, a unitless parameter) are 0.74 +/- 0.03, 1.09 +/- 0.01 and 0.84 +/- 0.02 for gray matter, white matter and thalamus, respectively. The three-dimensional kurtosis angular plots show tissue-specific geometry for different brain regions and demonstrate the potential of identifying multiple fiber structures in a single voxel. Diffusion kurtosis imaging is a useful method to study non-Gaussian diffusion behavior and can provide complementary information to that of DTI.

Quantitative MRI of cartilage and bone: degenerative changes in osteoarthritis

Abstract: Magnetic resonance imaging (MRI) and quantitative image analysis technology has recently started to generate a great wealth of quantitative information on articular cartilage and bone physiology, pathophysiology and degenerative changes in osteoarthritis. This paper reviews semiquantitative scoring of changes of articular tissues (e.g. WORMS = whole-organ MRI scoring or KOSS = knee osteoarthritis scoring system), quantification of cartilage morphology (e.g. volume and thickness), quantitative measurements of cartilage composition (e.g. T2, T1rho, T1Gd = dGEMRIC index) and quantitative measurement of bone structure (e.g. app. BV/TV, app. TbTh, app. Tb.N, app. Tb.Sp) in osteoarthritis. For each of these fields we describe the hardware and MRI sequences available, the image analysis systems and techniques used to derive semiquantitative and quantitative parameters, the technical accuracy and precision of the measurements reported to date and current results from cross-sectional and longitudinal studies in osteoarthritis. Moreover, the paper summarizes studies that have compared MRI-based measurements with radiography and discusses future perspectives of quantitative MRI in osteoarthritis. In summary, the above methodologies show great promise for elucidating the pathophysiology of various tissues and identifying risk factors of osteoarthritis, for developing structure modifying drugs (DMOADs) and for combating osteoarthritis with new and better therapy.

Sodium and T1ρ MRI for molecular and diagnostic imaging of articular cartilage

Abstract: In this article, both sodium magnetic resonance (MR) and T1ρ relaxation mapping aimed at measuring molecular changes in cartilage for the diagnostic imaging of osteoarthritis are reviewed. First, an introduction to structure of cartilage, its degeneration in osteoarthritis (OA) and an outline of diagnostic imaging methods in quantifying molecular changes and early diagnostic aspects of cartilage degeneration are described. The sodium MRI section begins with a brief overview of the theory of sodium NMR of biological tissues and is followed by a section on multiple quantum filters that can be used to quantify both bi-exponential relaxation and residual quadrupolar interaction. Specifically, (i) the rationale behind the use of sodium MRI in quantifying proteoglycan (PG) changes, (ii) validation studies using biochemical assays, (iii) studies on human OA specimens, (iv) results on animal models and (v) clinical imaging protocols are reviewed. Results demonstrating the feasibility of quantifying PG in OA patients and comparison with that in healthy subjects are also presented. The section concludes with the discussion of advantages and potential issues with sodium MRI and the impact of new technological advancements (e.g. ultra-high field scanners and parallel imaging methods). In the theory section on T1ρ, a brief description of (i) principles of measuring T1ρ relaxation, (ii) pulse sequences for computing T1ρ relaxation maps, (iii) issues regarding radio frequency power deposition, (iv) mechanisms that contribute to T1ρ in biological tissues and (v) effects of exchange and dipolar interaction on T1ρ dispersion are discussed. Correlation of T1ρ relaxation rate with macromolecular content and biomechanical properties in cartilage specimens subjected to trypsin and cytokine-induced glycosaminoglycan depletion and validation against biochemical assay and histopathology are presented. Experimental T1ρ data from osteoarthritic specimens, animal models, healthy human subjects and as well from osteoarthritic patients are provided. The current status of T1ρ relaxation mapping of cartilage and future directions is also discussed. Copyright © 2006 John Wiley & Sons, Ltd.

An introduction to coil array design for parallel MRI.

Abstract: The basic principles of radiofrequency coil array design for parallel MRI are described from both theoretical and practical perspectives. Because parallel MRI techniques rely on coil array sensitivities to provide spatial information about the sample, a careful choice of array design is essential. The concepts of coil array spatial encoding are first discussed from four qualitative perspectives. These qualitative descriptions include using coil arrays to emulate spatial harmonics, choosing coils with selective sensitivities to aliased pixels, using coil sensitivities with broad k-space reception profiles, and relying on detector coils to provide a set of generalized projections of the sample. This qualitative discussion is followed by a quantitative analysis of coil arrays, which is discussed in terms of the baseline SNR of the received images as well as the noise amplifications (g-factor) in the reconstructed data. The complications encountered during the experimental evaluation of coil array SNR are discussed, and solutions are proposed. A series of specific array designs are reviewed, with an emphasis on the general design considerations that motivate each approach. Finally, a set of special topics is discussed, which reflect issues that have become important, especially as arrays are being designed for more high-performance applications of parallel MRI. These topics include concerns about the depth penetration of arrays composed of small elements, the use of adaptive arrays for systems with limited receiver channels, the management of inductive coupling between array elements, and special considerations required at high field strengths. The fundamental limits of spatial encoding using coil arrays are discussed, with a primary emphasis on how the determination of these limits impacts the design of optimized arrays. This review is intended to provide insight into how arrays are currently used for parallel MRI and to place into context the new innovations that are to come.

Development of a decision support system for diagnosis and grading of brain tumours using in vivo magnetic resonance single voxel spectra.

Abstract: A computer-based decision support system to assist radiologists in diagnosing and grading brain tumours has been developed by the multi-centre INTERPRET project. Spectra from a database of 1H single-voxel spectra of different types of brain tumours, acquired in vivo from 334 patients at four different centres, are clustered according to their pathology, using automated pattern recognition techniques and the results are presented as a two-dimensional scatterplot using an intuitive graphical user interface (GUI). Formal quality control procedures were performed to standardize the performance of the instruments and check each spectrum, and teams of expert neuroradiologists, neurosurgeons, neurologists and neuropathologists clinically validated each case. The prototype decision support system (DSS) successfully classified 89% of the cases in an independent test set of 91 cases of the most frequent tumour types (meningiomas, low-grade gliomas and high-grade malignant tumours--glioblastomas and metastases). It also helps to resolve diagnostic difficulty in borderline cases. When the prototype was tested by radiologists and other clinicians it was favourably received. Results of the preliminary clinical analysis of the added value of using the DSS for brain tumour diagnosis with MRS showed a small but significant improvement over MRI used alone. In the comparison of individual pathologies, PNETs were significantly better diagnosed with the DSS than with MRI alone.

Parallel RF transmission in MRI

Abstract: Following the development of parallel imaging, parallel transmission describes the use of multiple RF transmit coils. Parallel transmission can be applied to improve RF excitation, in particular, multidimensional, spatially selective RF excitation. For instance, parallel transmission is able to shorten spatially selective RF pulses in two or three dimensions, or to minimize the occurring SAR. One potential major application might be the compensation of patient-induced B(1) inhomogeneities, particularly at high main fields. This paper provides an overview of selected aspects of this new transmission approach. The basic principles of parallel transmission are discussed, initial experimental proofs are described, and the impact of error propagation on coil design for parallel transmission is outlined.

Comparison of HR MAS MR spectroscopic profiles of breast cancer tissue with clinical parameters.

Abstract: Breast cancer is the most frequent form of cancer in women and improved diagnostic methods are desirable. Malignant cells have altered metabolism and metabolic mapping might become a tool in cancer diagnostics. High-resolution magic angle spinning (HR MAS) MR spectroscopy of tissue biopsies provides detailed information on metabolic composition. The 600 MHz 1H HR MAS spectra were acquired of breast cancer tissue from 85 patients and adjacent non-involved tissue from 18 of these patients. Tissue specimens were investigated by microscopy after MR analysis. The resulting spectra were examined by three different approaches. Relative intensities of glycerophosphocholine (GPC), phosphocholine (PC) and choline were compared for cancerous and non-involved specimens. Eight metabolites, choline, creatine, beta-glucose, GPC, glycine, myo-inositol, PC and taurine, were quantified from the recorded spectra and compared with tumor histological type and size, patient's lymph node status and tissue composition of sample. The spectra were also compared with tumor histological type and size, lymph node status and tissue composition of samples using principal component analysis (PCA). Tumor samples could be distinguished from non-involved samples (82% sensitivity, 100% specificity) based on relative intensities of signals from GPC, PC and choline in 1H HR MAS spectra. Tissue concentrations of metabolites showed few differences between groups of samples, which can be caused by limitations in the quantification procedure. Choline and glycine concentrations were found to be significantly higher in tumors larger than 2 cm compared with smaller tumors. PCA of MAS spectra from patients with invasive ductal carcinomas indicated a possible prediction of spread to axillary lymph nodes. Metabolite estimates and PCA of MAS spectra were influenced by the percentage of tumor cells in the investigated specimens.

Clinical ultrashort echo time imaging of bone and other connective tissues

Abstract: The background underpinning the clinical use of ultrashort echo time, SPRITE and other pulse sequences for imaging bone and other connective tissues with short T2 is reviewed. Features of the basic physics relevant to UTE imaging are described, including the consequences when the radiofrequency pulse duration is of the order of T2 so that rotation of tissue magnetization into the transverse plane is incomplete. Consequences of the broad linewidth of short T2 components are also discussed, including partial saturation by off-resonance fat suppression pulses as well as those used in multislice and multiecho imaging. The need for rapid data acquisition of the order of T2 is explained. The basic two-dimensional UTE pulse sequence with its half excitation pulse and radial imaging from the centre of k-space is described, together with options that suppress fat and/or reduce the signal from long T2 components. The basic features of SPRITE and other sequences with very short TE are described. Image interpretation is discussed. Clinical features of the imaging of cortical bone, tendons, ligaments, menisci, periosteum and the spine are illustrated. The source of the short T2 signal in these tissues is predominantly collagen and water tightly bound to collagen. Short T2 components in all of these tissues are detectible and may show high signals. Possible future developments are outlined, as are technical limitations of clinical magnetic resonance systems.

Role of proton MR for the study of muscle lipid metabolism.

Abstract: 1H-MR spectroscopy (MRS) of intramyocellular lipids (IMCL) became particularly important when it was recognized that IMCL levels are related to insulin sensitivity. While this relation is rather complex and depends on the training status of the subjects, various other influences such as exercise and diet also influence IMCL concentrations. This may open insight into many metabolic interactions; however, it also requires careful planning of studies in order to control all these confounding influences. This review summarizes various historical, methodological, and practical aspects of 1H-MR spectroscopy (MRS) of muscular lipids. That includes a differentiation of bulk magnetic susceptibility effects and residual dipolar coupling that can both be observed in MRS of skeletal muscle, yet affecting different metabolites in a specific way. Fitting of the intra- (IMCL) and extramyocellular (EMCL) signals with complex line shapes and the transformation into absolute concentrations is discussed. Since the determination of IMCL in muscle groups with oblique fiber orientation or in obese subjects is still difficult, potential improvement with high-resolution spectroscopic imaging or at higher field strength is considered. Fat selective imaging is presented as a possible alternative to MRS and the potential of multinuclear MRS is discussed. 1H-MRS of muscle lipids allows non-invasive and repeated studies of muscle metabolism that lead to highly relevant findings in clinics and patho-physiology.

Comprehensive processing, display and analysis for in vivo MR spectroscopic imaging.

Abstract: Image reconstruction for magnetic resonance spectroscopic imaging (MRSI) requires specialized spatial and spectral data processing methods and benefits from the use of several sources of prior information that are not commonly available, including MRI-derived tissue segmentation, morphological analysis and spectral characteristics of the observed metabolites. In addition, incorporating information obtained from MRI data can enhance the display of low-resolution metabolite images and multiparametric and regional statistical analysis methods can improve detection of altered metabolite distributions. As a result, full MRSI processing and analysis can involve multiple processing steps and several different data types. In this paper, a processing environment is described that integrates and automates these data processing and analysis functions for imaging of proton metabolite distributions in the normal human brain. The capabilities include normalization of metabolite signal intensities and transformation into a common spatial reference frame, thereby allowing the formation of a database of MR-measured human metabolite values as a function of acquisition, spatial and subject parameters. This development is carried out under the MIDAS project (Metabolite Imaging and Data Analysis System), which provides an integrated set of MRI and MRSI processing functions. It is anticipated that further development and distribution of these capabilities will facilitate more widespread use of MRSI for diagnostic imaging, encourage the development of standardized MRSI acquisition, processing and analysis methods and enable improved mapping of metabolite distributions in the human brain.

Quantitative MRI for the assessment of bone structure and function.

Abstract: Osteoporosis is the most common degenerative disease in the elderly. It is characterized by low bone mass and structural deterioration of bone tissue, leading to morbidity and increased fracture risk in the hip, spine and wrist-all sites of predominantly trabecular bone. Bone densitometry, currently the standard methodology for diagnosis and treatment monitoring, has significant limitations in that it cannot provide information on the structural manifestations of the disease. Recent advances in imaging, in particular MRI, can now provide detailed insight into the architectural consequences of disease progression and regression in response to treatment. The focus of this review is on the emerging methodology of quantitative MRI for the assessment of structure and function of trabecular bone. During the past 10 years, various approaches have been explored for obtaining image-based quantitative information on trabecular architecture. Indirect methods that do not require resolution on the scale of individual trabeculae and therefore can be practiced at any skeletal location, make use of the induced magnetic fields in the intertrabecular space. These fields, which have their origin in the greater diamagnetism of bone relative to surrounding marrow, can be measured in various ways, most typically in the form of R2', the recoverable component of the total transverse relaxation rate. Alternatively, the trabecular network can be quantified by high-resolution MRI (micro-MRI), which requires resolution adequate to at least partially resolve individual trabeculae. Micro-MRI-based structure analysis is therefore technically demanding in terms of image acquisition and algorithms needed to extract the structural information under conditions of limited signal-to-noise ratio and resolution. Other requirements that must be met include motion correction and image registration, both critical for achieving the reproducibility needed in repeat studies. Key clinical applications targeted involve fracture risk prediction and evaluation of the effect of therapeutic intervention.

Encoding and reconstruction in parallel MRI.

Abstract: The advent of parallel MRI over recent years has prompted a variety of concepts and techniques for performing parallel imaging. A main distinguishing feature among these is the specific way of posing and solving the problem of image reconstruction from undersampled multiple-coil data. The clearest distinction in this respect is that between k-space and image-domain methods. The present paper reviews the basic reconstruction approaches, aiming to emphasize common principles along with actual differences. To this end the treatment starts with an elaboration of the encoding mechanisms and sampling strategies that define the reconstruction task. Based on these considerations a formal framework is developed that permits the various methods to be viewed as different solutions of one common problem. Besides the distinction between k-space and image-domain approaches, special attention is given to the implications of general vs lattice sampling patterns. The paper closes with remarks concerning noise propagation and control in parallel imaging and an outlook upon key issues to be addressed in the future. Copyright © 2006 John Wiley & Sons, Ltd.

ProFit: two-dimensional prior-knowledge fitting of J-resolved spectra.

Abstract: A two-dimensional fitting procedure is introduced, capable of extracting the full amount of information from 2D J-resolved magnetic resonance spectroscopic data. The fitting procedure uses a linear combination of 2D model spectra. For reducing the degrees of freedom and increasing robustness, it is divided into a non-linear outer loop and an inner linear least-squares fit for the concentrations. In vitro and in vivo experiments on a whole-body 3 T MR scanner show the detectability of a wide range of metabolites in the human brain, namely total creatine, N-acetylaspartate, N-acetylaspartylglutamate, choline-containing compounds, glutamate, myo-inositol, glutathione, scyllo-inositol, gamma-aminobutyric acid, alanine and ascorbic acid.

MRI of atherosclerosis in clinical trials.

Abstract: Magnetic resonance imaging (MRI) of the arterial wall has emerged as a viable technology for characterizing atherosclerotic lesions in vivo, especially within carotid arteries and other large vessels. This capability has facilitated the use of carotid MRI in clinical trials to evaluate therapeutic effects on atherosclerotic lesions themselves. MRI is specifically able to characterize three important aspects of the lesion: size, composition and biological activity. Lesion size, expressed as a total wall volume, may be more sensitive than maximal vessel narrowing (stenosis) as a measure of therapeutic effects, as it reflects changes along the entire length of the lesion and accounts for vessel remodeling. Lesion composition (e.g. lipid, fibrous and calcified content) may reflect therapeutic effects that do not alter lesion size or stenosis, but cause a transition from a vulnerable plaque composition to a more stable one. Biological activity, most notably inflammation, is an emerging target for imaging that is thought to destabilize plaque and which may be a systemic marker of vulnerability. The ability of MRI to characterize each of these features in carotid atherosclerotic lesions gives it the potential, under certain circumstances, to replace traditional trials involving large numbers of subjects and hard end-points--heart attacks and strokes--with smaller, shorter trials involving imaging end-points. In this review, the state of the art in MRI of atherosclerosis is presented in terms of hardware, image acquisition protocols and post-processing. Also, the results of validation studies for measuring lesion size, composition and inflammation will be summarized. Finally, the status of several clinical trials involving MRI of atherosclerosis will be reviewed.

Dynamic MRS and MRI of skeletal muscle function and biomechanics.

Abstract: MR is a powerful technique for studying the biomechanical and functional properties of skeletal muscle in vivo in health and disease. This review focuses on 31P, 1H and 13C MR spectroscopy for assessment of the dynamics of muscle metabolism and on dynamic 1H MRI methods for non-invasive measurement of the biomechanical and functional properties of skeletal muscle. The information thus obtained ranges from the microscopic level of the metabolism of the myocyte to the macroscopic level of the contractile function of muscle complexes. The MR technology presented plays a vital role in achieving a better understanding of many basic aspects of muscle function, including the regulation of mitochondrial activity and the intricate interplay between muscle fiber organization and contractile function. In addition, these tools are increasingly being employed to establish novel diagnostic procedures as well as to monitor the effects of therapeutic and lifestyle interventions for muscle disorders that have an increasing impact in modern society.

Expression of transferrin receptor and ferritin following ferumoxides-protamine sulfate labeling of cells: implications for cellular magnetic resonance imaging.

Abstract: Ferumoxides-protamine sulfate (FE-Pro) complexes are used for intracellular magnetic labeling of cells to non-invasively monitor cell trafficking by in vivo MRI. FE-Pro labeling is non-toxic to cells; however, the effects of FE-Pro labeling on cellular expression of transferrin receptor (TfR-1) and ferritin, proteins involved in iron transport and storage, has not been reported. FE-Pro-labeled human mesenchymal stem cells (MSCs), HeLa cells and primary macrophages were cultured from 1 week to 2 months and evaluated for TfR-1 and ferritin gene expression by RT-PCR and protein levels were determined using Western blots. MTT (proliferation assay) and reactive oxygen species (ROS) analysis were performed. FE-Pro labeling of HeLa and MSCs resulted in a transient decrease in TfR-1 mRNA and protein levels. In contrast, Fe-Pro labeling of primary macrophages resulted in an increase in TfR-1 mRNA but not in TfR-1 protein levels. Ferritin mRNA and protein levels increased transiently in labeled HeLa and macrophages but were sustained in MSCs. No changes in MTT and ROS analysis were noted. In conclusion, FE-Pro labeling elicited physiological changes of iron metabolism or storage, validating the safety of this procedure for cellular tracking by MRI.

Perfusion, diffusion and spectroscopy values in newly diagnosed cerebral gliomas.

Abstract: Purpose To evaluate perfusion, diffusion, and spectroscopy values in enhancing and non-enhancing lesions for patients with newly diagnosed gliomas of different grades. Materials and Methods Sixty-seven patients with newly diagnosed glioma were entered into the study 20 grade II, 26 grade III and 21 grade IV. MR data were acquired at 1.5T and included diffusion weighted images (59/67 patients), dynamic perfusion weighted images (30/67 patients) and 3D H-1 MR spectroscopy (64/67 patients). Enhancing and non-enhancing lesions were delineated by a neuroradiologist and applied to maps of relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC), relative anisotropy (RA) and metabolite intensities. Results The median rCBV within enhancing regions of grade IV gliomas was significantly elevated relative to enhancing regions in grade III gliomas and normal brain. ADC was elevated relative to normal brain, but was not significantly different between grades or between enhancing and non-enhancing regions. The RA was higher in the non-enhancing region of grade IV gliomas relative to grade II and grade III. Levels of lactate plus lipid were significantly elevated in grade IV relative to grade II and grade III gliomas. Both enhancing and non-enhancing regions in grade IV gliomas showed significant correlations between CBV, ADC and choline levels. Conclusion The data were consistent with grade IV gliomas having higher membrane turnover, increased cell density and increased vascularity within enhancing lesions. Analysis of the correlations among parameters within grade IV gliomas suggested that high vascularity (high rCBV) was correlated with increased cellularity (low ADC) and increased membrane turnover (high choline) in these lesions. The non-enhancing region of grades II and III gliomas had MR parameters consistent with increased cellularity and/or membrane turnover. Copyright © 2006 John Wiley & Sons, Ltd.

Evaluation of Gd(III)DTPA-terminated poly(propylene imine) dendrimers as contrast agents for MR imaging.

Abstract: Different generations of Gd(III)DTPA-terminated poly(propylene imine) dendrimers {G1 (n ¼ 4 Gd(III) ions per molecule), G3 (n ¼ 16) and G5 (n ¼ 64)} and reference Gd(III)DTPA complex (G0 (n ¼ 1)) were characterized in terms of (i) longitudinal (r1) and transverse (r2) relaxivities in mouse blood plasma, (ii) concentration detection limits in vitro and (iii) in vivo contrast-enhanced MR imaging (CE-MRI) in mice at 1.5 T. Serial and dynamic CE-MRI were performed to monitor the distribution of MRI contrast agent in the heart, arteries, renal system, liver, spleen, bladder and tumor periphery. The relaxivities increased non-linearly with molecular weight (for G0 ionic r1 ¼ 8.1 mM � 1 s � 1 and ionic r2 ¼ 8.6 mM � 1 s � 1 to G5 19.3 and 25.0, respectively). The minimal detectable dendrimer concentration was more than two orders of magnitude lower for G5 (8.1 � 10 � 8 M) than for G0 (3.1 � 10 � 5 M). Sub-millimeter-sized blood vessels were well visualized with serial CE-MRI with each contrast agent. Dynamic CE-MRI showed timely renal clearance for all contrast agents, but a stronger and a prolonged blood signal enhancement for the higher generations of the dendritic contrast agent. Moreover, G0 and G1 showed a rapid tumor wash-in and wash-out, whereas G3 and G5 displayed a more gradual and prolonged tumor wash-in. In conclusion, both G0 and dendritic contrast agents G1, G3 and G5 are well suited for non-tissue-specific MRI of sub- millimeter-sized blood vessels and evaluating tumor microcirculatory characteristics in mice. Higher generations of dendritic contrast agents display lower concentration detection limits, which suggests their future use for molecular imaging. Copyright # 2006 John Wiley & Sons, Ltd.

Potential and feasibility of parallel MRI at high field.

Abstract: This survey focuses on the fusion of two major lines of recent progress in MRI methodology: parallel imaging with receiver coil arrays and the transition to high and ultra-high field strength for human applications. As discussed in this paper, combining the two developments has vast potential due to multiple specific synergies. First, parallel acquisition and high field are highly complementary in terms of their individual advantages and downsides. As a consequence, the joint approach generally offers enhanced flexibility in the design of scanning strategies. Second, increasing resonance frequency changes the electrodynamics of the MR signal in such a way that parallel imaging becomes more effective in large objects. The underlying conceptual and theoretical considerations are reviewed in detail. In further sections, technical challenges and practical aspects are discussed. The feasibility of parallel MRI at ultra-high field is illustrated by current results of parallel human MRI at 7 T.

An account of the discrepancy between MRI and PET cerebral blood flow measures. A high-field MRI investigation

Abstract: There is controversy concerning the discrepancy between absolute cerebral blood flow (CBF) values measured using positron emission tomography (PET) and magnetic resonance imaging (MRI). To gain insight into this problem, the increased signal-to-noise ratio (SNR) and extended T1 relaxation times of blood and tissue at 3.0 T were exploited to perform pulsed arterial spin labeling (PASL) MRI measurements as a function of spatial resolution and post-labeling delay. The results indicate that, when using post-labeling delays shorter than 1500 ms, MRI gray matter flow values may become as high as several times the correct CBF values owing to tissue signal contamination by remaining arterial blood water label. For delays above 1500 ms, regional PASL-based CBF values (n = 5; frontal gray matter: 48.8 ± 3.3(SD) ml/100 g/min; occipital gray matter: 49.3 ± 4.5 ml/100 g/min) comparable with PET-based measurements can be obtained by using spatial resolutions comparable with PET (5–7.5 mm in-plane). At very high resolution (2.5 × 2.5 × 3 mm3), gray matter CBF values were found to increase by 10–20%, a consequence attributed to reduction in partial volume effects with cerebrospinal fluid and white matter. The recent availability of MRI field strengths of 3.0 T and higher will facilitate the use of MRI-based CBF measurements in the clinic. Copyright © 2006 John Wiley & Sons, Ltd.

Skeletal muscle energetics with PNMR: personal views and historic perspectives.

Abstract: This article reviews historical and current NMR approaches to describing in vivo bioenergetics of skeletal muscles in normal and diseased populations. It draws upon the first author's more than 70 years of personal experience in enzyme kinetics and the last author's physiological approaches. The development of in vivo PNMR jointly with researchers around the world is described. It is explained how non-invasive PNMR has advanced human exercise biochemistry, physiology and pathology. Further, after a brief explanation of bioenergetics with PNMR on creatine kinase, anerobic glycolysis and mitochondrial oxidative phosphorylation, some basic and controversial subjects are focused upon, and the authors' view of the subjects are offered, with questions and answers. Some of the research has been introduced in exercise physiology. Future directions of NMR on bioenergetics, as a part of system biological approaches, are indicated.

Improved two-dimensional J-resolved spectroscopy.

Abstract: Localised two-dimensional J-resolved spectroscopy (JPRESS) is optimised for the in vivo detection of J-coupled metabolites using magnetic resonance spectroscopy at 3 T. The acquisition of echo signals starts as early as possible (i.e. maximum-echo sampling). This sampling scheme increases sensitivity and decreases overlap of peak tails, hence alleviating baseline problems. Reconstruction issues are discussed and the sensitivity is compared analytically with that of 1D PRESS. The qualitative behaviour of eddy currents in JPRESS is outlined and a 2D eddy current correction procedure based on the 1D phase deconvolution method is proposed.

Autocalibrated coil sensitivity estimation for parallel imaging.

Abstract: Parallel imaging has proven to be a robust solution to the problem of acquisition speed in MRI. These methods are based on extracting spatial information from an array of multiple surface coils in order to speed up image acquisition. One of the most essential elements of any parallel imaging method is the information describing the coil sensitivity distribution throughout the sample. This paper covers some of the advanced methods to obtain coil sensitivity-related information, focusing particularly on the class of methods referred to as autocalibrating. These methods all acquire the data for coil sensitivity estimation directly before, during or directly after the reduced data acquisition. After a review of standard methods for coil sensitivity estimation, some of the basic and advanced autocalibrating methods are reviewed, and some example applications shown.

Cell labeling for magnetic resonance imaging with the T1 agent manganese chloride

Abstract: There is growing interest in using MRI to track cellular migration. To date, most work in this area has been performed using ultra-small particles of iron oxide. Immune cells are difficult to label with iron oxide particles. The ability of adoptively infused tumor specific T cells and N cells to traffic to the tumor microenvironment may be a critical determinant of their therapeutic efficacy. We tested the hypothesis that lymphocytes and B cells would label with MnCl2 to a level that would allow their detection by T1-weighted MRI. Significant signal enhancement was observed in human lymphocytes after a 1 h incubation with 0.05-1.0 mM MnCl2. A flow cytometry-based evaluation using propidium iodide and Annexin V staining showed that lymphocytes did not undergo apoptosis or necrosis immediately after and 24 h following a 1 h incubation with up to 1.0 mM MnCl2. Importantly, NK cells and cytotoxic T cells maintained their in vitro killing capacity after being incubated with up to 0.5 mM MnCl2. This is the first report to describe the use of MnCl2 to label lymphocytes. Our data suggests MnCl2 might be an alternative to iron oxide cell labeling for MRI-based cell migration studies. Copyright # 2006 John Wiley & Sons, Ltd.

Metabolite identification in human liver needle biopsies by high-resolution magic angle spinning 1H NMR spectroscopy

Abstract: High-resolution magic angle spinning (HR-MAS) 1 H NMR spectroscopy of intact human liver needle biopsies has not been previously reported. HR-MAS NMR spectra collected on 17 specimens with tissue amounts between � 0.5 and 12 mg showed very good spectral resolution and signal-to-noise ratios. One-dimensional 1 H spectra revealed many intense signals corresponding to cellular metabolites. In addition, some high molecular weight metabolites, such as glycogen and mobile fatty acids, could be observed in some spectra. Resonance assignments for 22 metabolites were obtained by combining the analysis of three different types of 1D 1 H spectral editing, such as T2 filtering or the nuclear Overhauser effect and 2D TOCSY and 13 C-HSQC spectra. Biochemical stability of the liver tissue during up to 16 h of magic angle spinning at 277 K was studied. Biochemical trends corresponding to the different pathologies were observed, involving free fragments of lipids among other metabolites. NMR signal intensity ratios can be useful for discrimination among non-pathological, hepatitis C affected and cirrhotic liver tissues. Overall, this work demonstrates the applicability of HR-MAS NMR spectroscopy to the biochemical characterization of needle biopsies of the human liver. Copyright # 2006 John Wiley & Sons, Ltd.

MRI assessment of cartilage ultrastructure

Abstract: In T2-weighted MRI images joint cartilage can appear laminated. The multilaminar appearance is visualized as zones of different intensity. This appearance is based on the dipolar interaction of water molecules within cartilage zones of different collageneous network structures. Therefore, the MR visualization of zones of anisotropic arrangement of the collagen fibers depends upon their orientation to the static magnetic field (magic-angle effect). The aim of this article is to demonstrate the potential of high-resolution MRI for characterizing cartilage network structuring and biomechanical properties. Information equivalent to that from polarization light microscopy can be derived noninvasively. Based on NMR microscopic (microMRI) data, potential new possibilities of MRI for quantitative assessment of collagen structuring and intracartilagenous load distribution are presented. These methods use MR intensity angle dependence and load influence on cartilage visualization. Alternatively to the determination of mechanical parameters from cartilage deformation, it is demonstrated that stress distribution and biomechanical properties can be derived in principle from the local intensity variation of anisotropic fiber orientation zones. The limitations with respect to a clinical application of the proposed methods are discussed.

The role of vessel maturation and vessel functionality in spontaneous fluctuations of T2*‐weighted GRE signal within tumors

Abstract: Acute hypoxia (transient cycles of hypoxia-reoxygenation) is known to occur in solid tumors and is generally believed to be caused by tumor blood flow instabilities. It was recently demonstrated that T2*-weighted (T2*w) gradient echo (GRE) MRI is a powerful non-invasive method for investigating periodic changes in tumor pO2 and blood flow associated with acute hypoxia. Here, the possible correlation between tumor vessel immaturity, vessel functionality and T2*w GRE signal fluctuations was investigated. Intramuscularly implanted FSa II fibrosarcoma-bearing mice were imaged at 4.7 T. Maps of spontaneous fluctuations of MR signal intensity in tumor tissue during air breathing were obtained using a T2*w GRE sequence. This same sequence was also employed during air-5% CO2 breathing (hypercapnia) and carbogen breathing (hypercapnic hyperoxia) to obtain parametric maps representing vessel maturation and vessel function, respectively. Vascular density, vessel maturation and vessel perfusion were also assessed histologically by using CD31 labeling, alpha-smooth muscle actin immunoreactivity and Hoechst 33242 labeling, respectively. About 50% of the tumor fluctuations occurred in functional tumor regions (responsive to carbogen) and 80% occurred in tumor regions with immature vessels (lack of response to hypercapnia). The proportion of hypercapnia-responsive voxels were found to be twice as great in fluctuating than in non-fluctuating tumor areas (P: 0.22 vs 0.13). Similarly, the proportion of functional voxels was somewhat greater in fluctuating tumor areas (P: 0.54 vs 0.43). The mean values of MR signal changes during hypercapnia (VD) and during carbogen breathing (VF) (significant voxels only) were also larger in fluctuating than in non-fluctuating tumor areas (P < 0.05). This study demonstrated that adequate vessel functionality and advanced vessel maturation could explain at least in part the occurrence of spontaneous T2*w GRE signal fluctuations. Functionality and maturation are not required for signal fluctuations, however, because a large fraction of fluctuations could still occur in non-perfused and/or immature vessels.

Muscle blood flow and oxygenation measured by NMR imaging and spectroscopy.

Abstract: Tissue perfusion and oxygenation in many organs can be evaluated by various NMR techniques. This review focuses on the specificities, limitations and adaptations of the NMR tools available to investigate perfusion and oxygenation in the skeletal muscle of humans and animal models. A description of how they may be used simultaneously is provided as well. 1H NMR spectroscopy of myoglobin (Mb) monitors intramyocytic oxygenation. It measures the level of deoxy-Mb, from which Mb concentration, Mb desaturation/resaturation rates, muscle oxygenation changes and intracellular partial oxygen pressure (pO2) can be calculated. Positive and negative blood oxygen level-dependent (BOLD) contrasts exist in skeletal muscle. BOLD contrasts primarily reflect changes in capillary-venous oxygenation, but are also directly or indirectly dependent on muscle blood volume, perfusion, vascular network architecture and angulation, relative to the main magnetic field. Arterial spin labelling (ASL) techniques, having high spatial and temporal resolution, are the methods of choice to quantify and map skeletal muscle perfusion non-invasively. Limitations of ASL are poor contrast-to-noise ratio and sensitivity to movement; however, with the introduction of specific adaptations, it has been proven possible to measure skeletal muscle perfusion at both rest and during exercise. The possibility of combining these NMR measurements with others into a single dynamic protocol is most interesting. The 'multiparametric functional (mpf) NMR' concept can be extended to include the evaluation of muscle energy metabolism simultaneously with 31P NMR or with lactate double quantum filtered 1H NMR spectroscopy, an approach which would make NMR an exceptional tool for non-invasive investigations of integrative physiology and biochemistry in skeletal muscle in vivo.