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Showing papers in "NMR in Biomedicine in 2013"


Journal ArticleDOI
TL;DR: This study estimates the minimum number of DW directions and optimal b values required for HARDI by focusing on the angular frequency content of the DW signal itself, and estimates that SH terms above l = 8 are negligible in practice for b values up to 5000 s/mm2, implying that a minimum of 45 DW directions is sufficient to fully characterise theDW signal.
Abstract: High-angular-resolution diffusion-weighted imaging (HARDI) is one of the most common MRI acquisition schemes for use with higher order models of diffusion. However, the optimal b value and number of diffusion-weighted (DW) directions for HARDI are still undetermined, primarily as a result of the large number of available reconstruction methods and corresponding parameters, making it impossible to identify a single criterion by which to assess performance. In this study, we estimate the minimum number of DW directions and optimal b values required for HARDI by focusing on the angular frequency content of the DW signal itself. The spherical harmonic (SH) series provides the spherical analogue of the Fourier series, and can hence be used to examine the angular frequency content of the DW signal. Using high-quality data acquired along 500 directions over a range of b values, we estimate that SH terms above l = 8 are negligible in practice for b values up to 5000 s/mm(2), implying that a minimum of 45 DW directions is sufficient to fully characterise the DW signal. l > 0 SH terms were found to increase as a function of b value, levelling off at b = 3000 s/mm(2), suggesting that this value already provides the highest achievable angular resolution. In practice, it is recommended to acquire more than the minimum of 45 DW directions to avoid issues with imperfections in the uniformity of the DW gradient directions and to meet signal-to-noise requirements of the intended reconstruction method.

355 citations


Journal ArticleDOI
TL;DR: Dynamic contrast‐enhanced MRI (DCE‐MRI) is a functional MRI method where T1 ‐weighted MR images are acquired dynamically after bolus injection of a contrast agent.
Abstract: Dynamic contrast-enhanced MRI (DCE-MRI) is a functional MRI method where T1 -weighted MR images are acquired dynamically after bolus injection of a contrast agent. The data can be interpreted in terms of physiological tissue characteristics by applying the principles of tracer-kinetic modelling. In the brain, DCE-MRI enables measurement of cerebral blood flow (CBF), cerebral blood volume (CBV), blood–brain barrier (BBB) permeability–surface area product (PS) and the volume of the interstitium (ve). These parameters can be combined to form others such as the volume-transfer constant Ktrans, the extraction fraction E and the contrast-agent mean transit times through the intra- and extravascular spaces. A first generation of tracer-kinetic models for DCE-MRI was developed in the early 1990s and has become a standard in many applications. Subsequent improvements in DCE-MRI data quality have driven the development of a second generation of more complex models. They are increasingly used, but it is not always clear how they relate to the models of the first generation or to the model-free deconvolution methods for tissues with intact BBB. This lack of understanding is leading to increasing confusion on when to use which model and how to interpret the parameters. The purpose of this review is to clarify the relation between models of the first and second generations and between model-based and model-free methods. All quantities are defined using a generic terminology to ensure the widest possible scope and to reveal the link between applications in the brain and in other organs. Copyright © 2013 John Wiley & Sons, Ltd.

341 citations


Journal ArticleDOI
TL;DR: The techniques developed over the last decade are summarized with the different imaging strategies and post‐processing methods discussed from a practical point of view, including the description of their relative merits for the detection of CEST agents.
Abstract: Chemical exchange saturation transfer (CEST) has emerged as a novel MRI contrast mechanism that is well suited for molecular imaging studies This new mechanism can be used to detect small amounts of contrast agent through the saturation of rapidly exchanging protons on these agents, allowing a wide range of applications CEST technology has a number of indispensable features, such as the possibility of simultaneous detection of multiple 'colors' of agents and of changes in their environment (eg pH, metabolites, etc) through MR contrast Currently, a large number of new imaging schemes and techniques are being developed to improve the temporal resolution and specificity and to correct for the influence of B0 and B1 inhomogeneities In this review, the techniques developed over the last decade are summarized with the different imaging strategies and post-processing methods discussed from a practical point of view, including the description of their relative merits for the detection of CEST agents The goal of the present work is to provide the reader with a fundamental understanding of the techniques developed, and to provide guidance to help refine future applications of this technology This review is organized into three main sections ('Basics of CEST contrast', 'Implementation' and 'Post-processing'), and also includes a brief Introduction and Summary The 'Basics of CEST contrast' section contains a description of the relevant background theory for saturation transfer and frequency-labeled transfer, and a brief discussion of methods to determine exchange rates The 'Implementation' section contains a description of the practical considerations in conducting CEST MRI studies, including the choice of magnetic field, pulse sequence, saturation pulse, imaging scheme, and strategies to separate magnetization transfer and CEST The 'Post-processing' section contains a description of the typical image processing employed for B0 /B1 correction, Z-spectral interpolation, frequency-selective detection and improvement of CEST contrast maps

263 citations


Journal ArticleDOI
TL;DR: A new framework to enable rotationally invariant estimation of double wave vector diffusion metrics (d‐PFG), and demonstrates rotational invariance when estimating compartment eccentricity, which is complementary to that of fractional anisotropy from diffusion tensor imaging (DTI).
Abstract: Pulsed field gradient diffusion sequences (PFG) with multiple diffusion encoding blocks have been indicated to offer new microstructural tissue information, such as the ability to detect nonspherical compartment shapes in macroscopically isotropic samples, i.e. samples with negligible directional signal dependence on diffusion gradients in standard diffusion experiments. However, current acquisition schemes are not rotationally invariant in the sense that the derived metrics depend on the orientation of the sample, and are affected by the interplay of sampling directions and compartment orientation dispersion when applied to macroscopically anisotropic systems. Here we propose a new framework, the d-PFG 5-design, to enable rotationally invariant estimation of double wave vector diffusion metrics (d-PFG). The method is based on the idea that an appropriate orientational average of the signal emulates the signal from a powder preparation of the same sample, where macroscopic anisotropy is absent by construction. Our approach exploits the theory of exact numerical integration (quadrature) of polynomials on the rotation group, and we exemplify the general procedure with a set consisting of 60 pairs of diffusion wave vectors (the d-PFG 5-design) facilitating a theoretically exact determination of the fourth order Taylor or cumulant expansion of the orientationally averaged signal. The d-PFG 5-design is evaluated with numerical simulations and ex vivo high field diffusion MRI experiments in a nonhuman primate brain. Specifically, we demonstrate rotational invariance when estimating compartment eccentricity, which we show offers new microstructural information, complementary to that of fractional anisotropy (FA) from diffusion tensor imaging (DTI). The imaging observations are supported by a new theoretical result, directly relating compartment eccentricity to FA of individual pores. Copyright © 2013 John Wiley & Sons, Ltd.

203 citations


Journal ArticleDOI
TL;DR: This work has shown that Glu/Gln quantitation in the human brain in an array of conditions (e.g. mental illness, tumor, neuro‐degeneration) as well as in normal brain function is stable.
Abstract: Our understanding of the roles that the amino acids glutamate (Glu) and glutamine (Gln) play in the mammalian central nervous system has increased rapidly in recent times Many conditions are known to exhibit a disturbance in Glu-Gln equilibrium, and the exact relationships between these changed conditions and these amino acids are not fully understood This has led to increased interest in Glu/Gln quantitation in the human brain in an array of conditions (eg mental illness, tumor, neuro-degeneration) as well as in normal brain function Accordingly, this review has been undertaken to describe the increasing number of in vivo techniques available to study Glu and Gln separately, or pooled as 'Glx' The present MRS methods used to assess Glu and Gln vary in approach, complexity, and outcome, thus the focus of this review is on a description of MRS acquisition approaches, and an indication of relative utility of each technique rather than brain pathologies associated with Glu and/or Gln perturbation Consequently, this review focuses particularly on (1) one-dimensional (1)H MRS, (2) two-dimensional (1)H MRS, and (3) one-dimensional (13)C MRS techniques

199 citations


Journal ArticleDOI
TL;DR: An analytical solution of the Bloch–McConnell equations that describes the magnetization of coupled spin populations under radiofrequency irradiation is derived and it is shown that existing theoretical treatments for CEST are special cases of this approach.
Abstract: Chemical exchange observed by NMR saturation transfer (CEST) and spin-lock (SL) experiments provide an MRI contrast by indirect detection of exchanging protons. The determination of the relative concentrations and exchange rates is commonly achieved by numerical integration of the Bloch-McConnell equations. We derive an analytical solution of the Bloch-McConnell equations that describes the magnetization of coupled spin populations under radiofrequency irradiation. As CEST and off-resonant SL are equivalent, their steady-state magnetization and dynamics can be predicted by the same single eigenvalue: the longitudinal relaxation rate in the rotating frame R1ρ . For the case of slowly exchanging systems, e.g. amide protons, the saturation of the small proton pool is affected by transverse relaxation (R2b ). It turns out, that R2b is also significant for intermediate exchange, such as amine- or hydroxyl-exchange or paramagnetic CEST agents, if pools are only partially saturated. We propose a solution for R1ρ that includes R2 of the exchanging pool by extending existing approaches, and verify it by numerical simulations. With the appropriate projection factors, we obtain an analytical solution for CEST and SL for nonzero R2 of the exchanging pool, exchange rates in the range 1-10(4) Hz, B1 from 0.1 to 20 μT and arbitrary chemical shift differences between the exchanging pools, whilst considering the dilution by direct water saturation across the entire Z-spectra. This allows the optimization of irradiation parameters and the quantification of pH-dependent exchange rates and metabolite concentrations. In addition, we propose evaluation methods that correct for concomitant direct saturation effects. It is shown that existing theoretical treatments for CEST are special cases of this approach.

171 citations


Journal ArticleDOI
TL;DR: It is suggested that frequent nociceptive input has modified the structural and functional patterns of the frontal cortex, and these changes may explain the functional impairments in migraine patients.
Abstract: Migraine is a primary headache disorder characterized by recurrent attacks of throbbing pain associated with neurological, gastrointestinal and autonomic symptoms. Previous studies have detected structural deficits and functional impairments in migraine patients. However, researchers have failed to investigate the functional connectivity alterations of regions with structural deficits during the resting state. Twenty-one migraine patients without aura and 21 age-and gender-matched healthy controls participated in our study. Voxel-based morphometric (VBM) analysis and functional connectivity were employed to investigate the abnormal structural and resting-state properties, respectively, in migraine patients without aura. Relative to healthy comparison subjects, migraine patients showed significantly decreased gray matter volume in five brain regions: the left medial prefrontal cortex (MPFC), dorsal anterior cingulate cortex (dACC), right occipital lobe, cerebellum and brainstem. The gray matter volume of the dACC was correlated with the duration of disease in migraine patients, and thus we chose this region as the seeding area for resting-state analysis. We found that migraine patients showed increased functional connectivity between several regions and the left dACC, i.e. the bilateral middle temporal lobe, orbitofrontal cortex (OFC) and left dorsolateral prefrontal cortex (DLPFC). Furthermore, the functional connectivity between the dACC and two regions (i.e. DLPFC and OFC) was correlated with the duration of disease in migraine patients. We suggest that frequent nociceptive input has modified the structural and functional patterns of the frontal cortex, and these changes may explain the functional impairments in migraine patients. Copyright (C) 2012 John Wiley & Sons, Ltd.

157 citations


Journal ArticleDOI
TL;DR: This article presents a brief review of preclinical in vivo cell‐tracking methods and applications using perfluorocarbon (PFC) probes and fluorine‐19 (19F) MRI detection and addresses the potential applicability of 19F cell tracking to clinical trials.
Abstract: This article presents a brief review of preclinical in vivo cell-tracking methods and applications using perfluorocarbon (PFC) probes and fluorine-19 ((19) F) MRI detection. Detection of the (19) F signal offers high cell specificity and quantification ability in spin density-weighted MR images. We discuss the compositions of matter, methods and applications of PFC-based cell tracking using ex vivo and in situ PFC labeling in preclinical studies of inflammation and cellular therapeutics. We also address the potential applicability of (19) F cell tracking to clinical trials.

148 citations


Journal ArticleDOI
TL;DR: In this review, the theoretical underpinnings of calibrated BOLD, and issues regarding this theory that are still to be resolved, are discussed and important aspects of practical implementation are reviewed.
Abstract: The dynamics of the blood oxygenation level-dependent (BOLD) response are dependent on changes in cerebral blood flow, cerebral blood volume and the cerebral metabolic rate of oxygen consumption. Furthermore, the amplitude of the response is dependent on the baseline physiological state, defined by the haematocrit, oxygen extraction fraction and cerebral blood volume. As a result of this complex dependence, the accurate interpretation of BOLD data and robust intersubject comparisons when the baseline physiology is varied are difficult. The calibrated BOLD technique was developed to address these issues. However, the methodology is complex and its full promise has not yet been realised. In this review, the theoretical underpinnings of calibrated BOLD, and issues regarding this theory that are still to be resolved, are discussed. Important aspects of practical implementation are reviewed and reported applications of this methodology are presented.

143 citations


Journal ArticleDOI
TL;DR: Of the calculated MRI metrics, ƒ was the strongest indicator of myelin content, while longitudinal relaxation rates and diffusivity measurements were the strongest indicators of changes in tissue structure, like previous studies of multiple sclerosis in humans and animal models of demyelination.
Abstract: The cuprizone mouse model of demyelination was used to investigate the influence that white matter changes have on different magnetic resonance imaging results. In vivo T2-weighted and magnetization transfer images (MTIs) were acquired weekly in control (n = 5) and cuprizone-fed (n = 5) mice, with significant increases in signal intensity in T2-weighted images (p < 0.001) and lower magnetization transfer ratio (p < 0.001) in the corpus callosum of the cuprizone-fed mice starting at 3 weeks and peaking at 4 and 5 weeks, respectively. Diffusion tensor imaging (DTI), quantitative MTI (qMTI), and T1/T2 measurements were used to analyze freshly excised tissue after 6 weeks of cuprizone administration. In multicomponent T2 analysis with 10 ms echo spacing, there was no visible myelin water component associated with the short T2 value. Quantitative MTI metrics showed significant differences in the corpus callosum and external capsule of the cuprizone-fed mice, similar to previous studies of multiple sclerosis in humans and animal models of demyelination. Fractional anisotropy was significantly lower and mean, axial, and radial diffusivity were significantly higher in the cuprizone-fed mice. Cellular distributions measured in electron micrographs of the corpus callosum correlated strongly to several different quantitative MRI metrics. The largest Spearman correlation coefficient varied depending on cellular type: T1 versus the myelinated axon fraction (ρ = −0.90), the bound pool fraction (ƒ) versus the myelin sheath fraction (ρ = 0.93), and axial diffusivity versus the non-myelinated cell fraction (ρ = 0.92). Using Pearson's correlation coefficient, ƒ was strongly correlated to the myelin sheath fraction (r = 0.98) with a linear equation predicting myelin content (5.37ƒ − 0.25). Of the calculated MRI metrics, ƒ was the strongest indicator of myelin content, while longitudinal relaxation rates and diffusivity measurements were the strongest indicators of changes in tissue structure. Copyright © 2013 John Wiley & Sons, Ltd.

131 citations


Journal ArticleDOI
TL;DR: This review summarizes the recent developments in qualitative UTE Imaging and quantitative UTE imaging (techniques to quantify the MR properties, including T1, T2* and the magnetization transfer ratio, and tissue properties, as well as total, bound and free water content) of cortical bone in vitro and in vivo.
Abstract: Osteoporosis causes over 1.5 million fractures per year, costing about $15 billion annually in the USA. Current guidelines utilize bone mineral density (BMD) to assess fracture risk; however, BMD alone only accounts for 30-50% of fractures. The other two major components of bone, organic matrix and water, contribute significantly to bone mechanical properties, but cannot be assessed with conventional imaging techniques in spite of the fact that they make up about 57% of cortical bone by volume. Conventional clinical MRI usually detects signals from water in tissues without difficulty, but cannot detect the water bound to the organic matrix, or the free water in the microscopic pores of the Haversian and the lacunar-canalicular system of cortical bone, because of their very short apparent transverse relaxation times (T2 *). In recent years, a new class of sequences, ultrashort-TE (UTE) sequences, with nominal TEs of less than 100 µs, which are much shorter than the TEs available with conventional sequences, have received increasing interest. These sequences can detect water signals from within cortical bone and provide an opportunity to study disease of this tissue in a new way. This review summarizes the recent developments in qualitative UTE imaging (techniques and contrast mechanisms to produce bone images with high contrast) and quantitative UTE imaging (techniques to quantify the MR properties, including T1 , T2 * and the magnetization transfer ratio, and tissue properties, including bone perfusion, as well as total, bound and free water content) of cortical bone in vitro and in vivo. The limitations of the current techniques for clinical applications and future directions are also discussed.

Journal ArticleDOI
TL;DR: The elevated T2 measures with and without fat saturation at all ages of DMD examined, compared with unaffected controls indicate that the dystrophic muscles have increased regions of damage, edema and fat infiltration.
Abstract: Purpose Skeletal muscles of children with Duchenne muscular dystrophy (DMD) have enhanced susceptibility to damage and progressive lipid infiltration, which contribute to an increase in magnetic resonance proton transverse relaxation time (T2). Therefore, examining T2 changes in individual muscles may be useful for monitoring disease progression in DMD. In this study we utilized mean T2, percent elevated pixels, and T2 heterogeneity to assess changes in composition of dystrophic muscles. In addition, we used fat saturation (fatsat) to distinguish T2 changes due to edema and inflammation from fat infiltration in muscles.

Journal ArticleDOI
TL;DR: A positive correlation was observed between GluCEST contrast and 1H MRS‐measured Glu/total creatine ratio and this method potentially provides a novel noninvasive biomarker for the diagnosis of the disease in preclinical stages and enables the development of disease‐modifying therapies for AD.
Abstract: Glutamate (Glu) is a major excitatory neurotransmitter in the brain and has been shown to decrease in the early stages of Alzheimer’s disease (AD). Using a glutamate chemical (amine) exchange saturation transfer (GluCEST) method, we imaged the change in [Glu] in the APP-PS1 transgenic mouse model of AD at high spatial resolution. Compared with wild-type controls, AD mice exhibited a notable reduction in GluCEST contrast (~30%) in all areas of the brain. The change in [Glu] was further validated through 1 H MRS. A positive correlation was observed between GluCEST contrast and 1 H MRS-measured Glu/total creatine ratio. This method potentially provides a novel noninvasive biomarker for the diagnosis of the disease in preclinical stages and enables the development of disease-modifying therapies for AD. Copyright © 2012 John Wiley & Sons, Ltd.

Journal ArticleDOI
TL;DR: Overall, the use of USPIO nanoparticles can determine baseline CBV and its changes induced by functional activity and pharmacological interventions and measures a single physiological parameter that is easily interpretable.
Abstract: The cerebral blood volume (CBV) is a crucial physiological indicator of tissue viability and vascular reactivity. Thus, noninvasive CBV mapping has been of great interest. For this, ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, including monocrystalline iron oxide nanoparticles, can be used as long-half-life, intravascular susceptibility agents of CBV MRI measurements. Moreover, CBV-weighted functional MRI (fMRI) with USPIO nanoparticles provides enhanced sensitivity, reduced large vessel contribution and improved spatial specificity relative to conventional blood oxygenation level-dependent fMRI, and measures a single physiological parameter that is easily interpretable. We review the physiochemical and magnetic properties, and pharmacokinetics, of USPIO nanoparticles in brief. We then extensively discuss quantifications of baseline CBV, vessel size index and functional CBV change. We also provide reviews of dose-dependent sensitivity, vascular filter function, specificity, characteristics and impulse response function of CBV fMRI. Examples of CBV fMRI specificity at the laminar and columnar resolution are provided. Finally, we briefly review the application of CBV measurements to functional and pharmacological studies in animals. Overall, the use of USPIO nanoparticles can determine baseline CBV and its changes induced by functional activity and pharmacological interventions.

Journal ArticleDOI
TL;DR: The article succinctly describes the principles that differentiate water and fat proton signals, summarizes the advantages and limitations of various techniques and offers a few illustrative examples, and concludes by briefly discussing some future research directions.
Abstract: Accurate, precise and reliable techniques for the quantification of body and organ fat distributions are important tools in physiology research. They are critically needed in studies of obesity and diseases involving excess fat accumulation. Proton MR methods address this need by providing an array of relaxometry-based (T1, T2) and chemical shift-based approaches. These techniques can generate informative visualizations of regional and whole-body fat distributions, yield measurements of fat volumes within specific body depots and quantify fat accumulation in abdominal organs and muscles. MR methods are commonly used to investigate the role of fat in nutrition and metabolism, to measure the efficacy of short- and long-term dietary and exercise interventions, to study the implications of fat in organ steatosis and muscular dystrophies and to elucidate pathophysiological mechanisms in the context of obesity and its comorbidities. The purpose of this review is to provide a summary of mainstream MR strategies for fat quantification. The article succinctly describes the principles that differentiate water and fat proton signals, summarizes the advantages and limitations of various techniques and offers a few illustrative examples. The article also highlights recent efforts in the MR of brown adipose tissue and concludes by briefly discussing some future research directions.

Journal ArticleDOI
TL;DR: It is concluded that accurate DTI of skeletal muscle requires an SNR of at least 25, a b value of between 400 and 500 s/mm2, and data acquired with at least 12 diffusion gradient directions homogeneously distributed on half a sphere.
Abstract: In this study, we have performed simulations to address the effects of diffusion encoding parameters, signal-to-noise ratio (SNR) and T-2 on skeletal muscle diffusion tensor indices and fiber tracts. Where appropriate, simulations were corroborated and validated by in vivo diffusion tensor imaging (DTI) of human skeletal muscle. Specifically, we have addressed: (i) the accuracy and precision of the diffusion parameters and eigenvectors at different SNR levels; (ii) the effects of the diffusion gradient direction encoding scheme; (iii) the optimal b value for diffusion tensor estimation; (iv) the effects of changes in skeletal muscle T-2; and, finally, the influence of SNR on fiber tractography and derived (v) fiber lengths, (vi) pennation angles and (vii) fiber curvatures. We conclude that accurate DTI of skeletal muscle requires an SNR of at least 25, a b value of between 400 and 500 s/mm(2), and data acquired with at least 12 diffusion gradient directions homogeneously distributed on half a sphere. Furthermore, for DTI studies focusing on skeletal muscle injury or pathology, apparent changes in the diffusion parameters need to be interpreted with great care in view of the confounding effects of T-2, particularly for moderate to low SNR values. Copyright (c) 2013 John Wiley & Sons, Ltd.

Journal ArticleDOI
TL;DR: Both scientists just entering the MR field and more experienced MR researchers interested in the application of advanced BOLD‐based techniques to the study of the brain in health and disease are targeted.
Abstract: The quantitative evaluation of brain hemodynamics and metabolism, particularly the relationship between brain function and oxygen utilization, is important for the understanding of normal human brain operation, as well as the pathophysiology of neurological disorders. It can also be of great importance for the evaluation of hypoxia within tumors of the brain and other organs. A fundamental discovery by Ogawa and coworkers of the blood oxygenation level-dependent (BOLD) contrast opened up the possibility to use this effect to study brain hemodynamic and metabolic properties by means of MRI measurements. Such measurements require the development of theoretical models connecting the MRI signal to brain structure and function, and the design of experimental techniques allowing MR measurements to be made of the salient features of theoretical models. In this review, we discuss several such theoretical models and experimental methods for the quantification of brain hemodynamic and metabolic properties. The review's main focus is on methods for the evaluation of the oxygen extraction fraction (OEF) based on the measurement of the blood oxygenation level. A combination of the measurement of OEF and the cerebral blood flow (CBF) allows an evaluation to be made of the cerebral metabolic rate of oxygen consumption (CMRO2 ). We first consider in detail the magnetic properties of blood - magnetic susceptibility, MR relaxation and theoretical models of the intravascular contribution to the MR signal under different experimental conditions. We then describe a 'through-space' effect - the influence of inhomogeneous magnetic fields, created in the extravascular space by intravascular deoxygenated blood, on the formation of the MR signal. Further, we describe several experimental techniques taking advantage of these theoretical models. Some of these techniques - MR susceptometry and T2 -based quantification of OEF - utilize the intravascular MR signal. Another technique - quantitative BOLD - evaluates OEF by making use of through-space effects. In this review, we target both scientists just entering the MR field and more experienced MR researchers interested in the application of advanced BOLD-based techniques to the study of the brain in health and disease.

Journal ArticleDOI
TL;DR: 39 steps are presented which guide the reader through the theoretical principles, practical decisions, potential problems, current limitations and latest advances in DSC‐MRI.
Abstract: Dynamic susceptibility contrast (DSC) MRI is the most commonly used MRI method to assess cerebral perfusion and other related haemodynamic parameters Although the technique is well established and used routinely in clinical centres, there are still many problems that impede accurate perfusion quantification In this review article, we present 39 steps which guide the reader through the theoretical principles, practical decisions, potential problems, current limitations and latest advances in DSC-MRI The 39 steps span the collection, analysis and interpretation of DSC-MRI data, expounding issues and possibilities relating to the contrast agent, the acquisition of DSC-MRI data, data pre-processing, the contrast concentration-time course, the arterial input function, deconvolution, common perfusion parameters, post-processing possibilities, patient studies, absolute versus relative quantification and automated analysis methods

Journal ArticleDOI
TL;DR: This method shows great promise for the elucidation of the distinctive metabolism and metabolic control of cancer cells, suggesting multiple ways whereby hyperpolarized U‐13C,2H7‐glucose NMR could aid in the diagnosis and characterization of cancer in vivo.
Abstract: The recent development of dissolution dynamic nuclear polarization (DNP) gives NMR the sensitivity to follow metabolic processes in living systems with high temporal resolution. In this article, we apply dissolution DNP to study the metabolism of hyperpolarized U-13C,2H7-glucose in living, perfused human breast cancer cells. Spectrally selective pulses were used to maximize the signal of the main product, lactate, whilst preserving the glucose polarization; in this way, both C1-lactate and C3-lactate could be observed with high temporal resolution. The production of lactate by T47D breast cancer cells can be characterized by Michaelis–Menten-like kinetics, with Km = 3.5 ± 1.5 mm and Vmax = 34 ± 4 fmol/cell/min. The high sensitivity of this method also allowed us to observe and quantify the glycolytic intermediates dihydroxyacetone phosphate and 3-phosphoglycerate. Even with the enhanced DNP signal, many other glycolytic intermediates could not be detected directly. Nevertheless, by applying saturation transfer methods, the glycolytic intermediates glucose-6-phosphate, fructose-6-phosphate, fructose-1,6-bisphosphate, glyceraldehyde-3-phosphate, phosphoenolpyruvate and pyruvate could be observed indirectly. This method shows great promise for the elucidation of the distinctive metabolism and metabolic control of cancer cells, suggesting multiple ways whereby hyperpolarized U-13C,2H7-glucose NMR could aid in the diagnosis and characterization of cancer in vivo. Copyright © 2013 John Wiley & Sons, Ltd.

Journal ArticleDOI
TL;DR: Baseline cerebral alterations were investigated using amplitude of low‐frequency fluctuation and region of interest (ROI)‐based functional connectivity (FC) analyses, which could lead to a better understanding of intrinsic functional architecture of baseline brain activity in MwoA.
Abstract: Although previous resting-state studies have reported abnormal functional cerebral changes in patients with migraine without aura (MwoA), few have focused on alterations in both regional spontaneous neuronal activity and corresponding brain circuits in MwoA patients during rest. Eighteen MwoA patients and 18 age- and gender-matched healthy controls (HC) were recruited in the current study. Baseline cerebral alterations were investigated using amplitude of low-frequency fluctuation (ALFF) and region of interest (ROI)-based functional connectivity (FC) analyses. Compared with HC, MwoA patients showed decreased ALFF values in the left rostral anterior cingulate cortex (rACC) and bilateral prefrontal cortex (PFC) as well as increased ALFF values in the right thalamus. FC analysis also revealed abnormal FCs associated with these ROIs. In addition, ALFF values of the left rACC correlated with duration of disease in MwoA. Our findings could lead to a better understanding of intrinsic functional architecture of baseline brain activity in MwoA, providing both regional and brain circuit spontaneous neuronal activity properties. Copyright (c) 2013 John Wiley & Sons, Ltd.

Journal ArticleDOI
TL;DR: The in vivo use of targeted paramagnetic liposomes has facilitated the specific imaging of pathophysiological processes, such as angiogenesis and inflammation, and MR image‐guided drug delivery using such liposome allows the visualization and quantification of local drug delivery.
Abstract: Liposomes are a versatile class of nanoparticles with tunable properties, and multiple liposomal drug formulations have been clinically approved for cancer treatment. In recent years, an extensive library of gadolinium (Gd)containing liposomal MRI contrast agents has been developed for molecular and cellular imaging of disease-specific markers and for image-guided drug delivery. This review discusses the advances in the development and novel applications of paramagnetic liposomes in molecular and cellular imaging, and in image-guided drug delivery. A high targeting specificity has been achieved in vitro using ligand-conjugated paramagnetic liposomes. On targeting of internalizing cell receptors, the effective longitudinal relaxivity r1 of paramagnetic liposomes is modulated by compartmentalization effects. This provides unique opportunities to monitor the biological fate of liposomes. In vivo contrast-enhanced MRI studies with nontargeted liposomes have shown the extravasation of liposomes in diseases associated with endothelial dysfunction, such as tumors and myocardial infarction. The in vivo use of targeted paramagnetic liposomes has facilitated the specific imaging of pathophysiological processes, such as angiogenesis and inflammation. Paramagnetic liposomes loaded with drugs have been utilized for therapeutic interventions. MR image-guided drug delivery using such liposomes allows the visualization and quantification of local drug delivery. Copyright © 2013 John Wiley & Sons, Ltd.

Journal ArticleDOI
TL;DR: The purpose of this study was to evaluate whether texture‐based analysis of standard MRI sequences and diffusion‐weighted imaging can help in the discrimination of parotid gland masses.
Abstract: The purpose of this study was to evaluate whether texture-based analysis of standard MRI sequences and diffusion-weighted imaging can help in the discrimination of parotid gland masses. The MR images of 38 patients with a biopsy- or surgery-proven parotid gland mass were retrospectively analyzed. All patients were examined on the same 3.0 Tesla MR unit, with one standard protocol. The ADC (apparent diffusion coefficient) values of the tumors were measured with three regions of interest (ROIs) covering the entire tumor. Texture-based analysis was performed with the texture analysis software MaZda (version 4.7), with ROI measurements covering the entire tumor in three slices. COC (co-occurrence matrix), RUN (run-length matrix), GRA (gradient), ARM (auto-regressive model), and WAV (wavelet transform) features were calculated for all ROIs. Three subsets of 10 texture features each were used for a linear discriminant analysis (LDA) in combination with k nearest neighbor classification (k-NN). Using histology as a standard of reference, benign tumors, including subtypes, and malignant tumors were compared with regard to ADC and texture-based values, with a one-way analysis of variance with post-hoc t-tests. Significant differences were found in the mean ADC values between Warthin tumors and pleomorphic adenomas, as well as between Warthin tumors and benign lesions. Contrast-enhanced T1-weighted images contained the most relevant textural information for the discrimination between benign and malignant parotid masses, and also for the discrimination between pleomorphic adenomas and Warthin tumors. STIR images contained the least relevant texture features, particularly for the discrimination between pleomorphic adenomas and Warthin tumors. Texture analysis proved to differentiate benign from malignant lesions, as well as pleomorphic adenomas from Warthin tumors, based on standard T(1w) sequences (without and with contrast). Of all benign parotid masses, Warthin tumors had significantly lower ADC values than the other entities.

Journal ArticleDOI
TL;DR: A rapid multislice pulse sequence capable of three‐dimensional motion encoding that is also suitable for simultaneously encoding motion with multiple frequency components is introduced based on a gradient‐recalled echo (GRE) sequence and exploits the principles of fractional encoding.
Abstract: In MR elastography (MRE), periodic tissue motion is phase encoded using motion-encoding gradients synchronized to an externally applied periodic mechanical excitation. Conventional methods result in extended scan time for quality phase images, thus limiting the broad application of MRE in the clinic. For practical scan times, researchers have been relying on one-dimensional or two-dimensional motion-encoding, low-phase sampling and a limited number of slices, and artifact-prone, single-shot, echo planar imaging (EPI) readout. Here, we introduce a rapid multislice pulse sequence capable of three-dimensional motion encoding that is also suitable for simultaneously encoding motion with multiple frequency components. This sequence is based on a gradient-recalled echo (GRE) sequence and exploits the principles of fractional encoding. This GRE MRE pulse sequence was validated as capable of acquiring full three-dimensional motion encoding of isotropic voxels in a large volume within less than a minute. This sequence is suitable for monofrequency and multifrequency MRE experiments. In homogeneous paraffin phantoms, the eXpresso sequence yielded similar storage modulus values as those obtained with conventional methods, although with markedly reduced variances (7.11 ± 0.26 kPa for GRE MRE versus 7.16 ± 1.33 kPa for the conventional spin-echo EPI sequence). The GRE MRE sequence obtained better phase-to-noise ratios than the equivalent spin-echo EPI sequence (matched for identical acquisition time) in both paraffin phantoms and in vivo data in the liver (59.62 ± 11.89 versus 27.86 ± 3.81, 61.49 ± 14.16 versus 24.78 ± 2.48 and 58.23 ± 10.39 versus 23.48 ± 2.91 in the X, Y and Z components, respectively, in the case of liver experiments). Phase-to-noise ratios were similar between GRE MRE used in monofrequency or multifrequency experiments (75.39 ± 14.93 versus 86.13 ± 18.25 at 28 Hz, 71.52 ± 24.74 versus 86.96 ± 30.53 at 56 Hz and 95.60 ± 36.96 versus 61.35 ± 26.25 at 84Hz, respectively). Copyright © 2013 John Wiley & Sons, Ltd.

Journal ArticleDOI
TL;DR: A review of the selection of models in dynamic contrast‐enhanced MRI (DCE‐MRI) is conducted, with emphasis on the balance between the bias and variance required to produce stable and accurate estimates of vascular parameters.
Abstract: A review of the selection of models in dynamic contrast-enhanced MRI (DCE-MRI) is conducted, with emphasis on the balance between the bias and variance required to produce stable and accurate estimates of vascular parameters. The vascular parameters considered as a first-order model are the forward volume transfer constant K(trans) , the plasma volume fraction vp and the interstitial volume fraction ve . To illustrate the critical issues in model selection, a data-driven selection of models in an animal model of cerebral glioma is followed. Systematic errors and extended models are considered. Studies with nested and non-nested pharmacokinetic models are reviewed; models considering water exchange are considered.

Journal ArticleDOI
TL;DR: The purpose of this article is to discuss the clinical applications of available imaging techniques, and in particular dynamic contrast‐enhanced T1‐weighted MR imaging (DCE‐MRI), to evaluate tumor vascular leakiness.
Abstract: Various imaging techniques have been employed to evaluate blood–brain-barrier leakiness in brain tumors, as higher tumor vascular leakiness is known to be associated with higher grade and malignant potential of the tumor, and hence can help provide additional diagnostic and prognostic information. These imaging techniques range from routine post-contrast T1-weighted images that highlight degree of contrast enhancement to absolute measurement of quantitative metrics of vascular leakiness employing complex pharmacokinetic modeling. The purpose of this article is to discuss the clinical applications of available imaging techniques, and in particular dynamic contrast-enhanced T1-weighted MR imaging (DCE-MRI), to evaluate tumor vascular leakiness. Copyright © 2013 John Wiley & Sons, Ltd.

Journal ArticleDOI
TL;DR: It is demonstrated that, under some experimental conditions, short‐TE MRS can be employed for the reproducible detection of GABA at 3 T, but that the technique should be used with caution, as the results are dependent on the experimental conditions.
Abstract: Short-TE MRS has been proposed recently as a method for the in vivo detection and quantification of gamma-aminobutyric acid (GABA) in the human brain at 3 T. In this study, we investigated the accuracy and reproducibility of short-TE MRS measurements of GABA at 3 T using both simulations and experiments. LCModel analysis was performed on a large number of simulated spectra with known metabolite input concentrations. Simulated spectra were generated using a range of spectral linewidths and signal-to-noise ratios to investigate the effect of varying experimental conditions, and analyses were performed using two different baseline models to investigate the effect of an inaccurate baseline model on GABA quantification. The results of these analyses indicated that, under experimental conditions corresponding to those typically observed in the occipital cortex, GABA concentration estimates are reproducible (mean reproducibility error, <20%), even when an incorrect baseline model is used. However, simulations indicate that the accuracy of GABA concentration estimates depends strongly on the experimental conditions (linewidth and signal-to-noise ratio). In addition to simulations, in vivo GABA measurements were performed using both spectral editing and short-TE MRS in the occipital cortex of 14 healthy volunteers. Short-TE MRS measurements of GABA exhibited a significant positive correlation with edited GABA measurements (R = 0.58, p < 0.05), suggesting that short-TE measurements of GABA correspond well with measurements made using spectral editing techniques. Finally, within-session reproducibility was assessed in the same 14 subjects using four consecutive short-TE GABA measurements in the occipital cortex. Across all subjects, the average coefficient of variation of these four GABA measurements was 8.7 +/- 4.9%. This study demonstrates that, under some experimental conditions, short-TE MRS can be employed for the reproducible detection of GABA at 3 T, but that the technique should be used with caution, as the results are dependent on the experimental conditions. Copyright (c) 2013 John Wiley & Sons, Ltd.

Journal ArticleDOI
TL;DR: V ventilation histograms and their associated CVs distinguished between subjects with COPD with similar ventilation defect scores, but visibly different ventilation patterns, and heterogeneity was analyzed using the coefficient of variation (CV).
Abstract: In this study, hyperpolarized 129Xe MR ventilation and 1H anatomical images were obtained from three subject groups: young healthy volunteers (HVs), subjects with chronic obstructive pulmonary disease (COPD) and age-matched controls (AMCs). Ventilation images were quantified by two methods: an expert reader-based ventilation defect score percentage (VDS%) and a semi-automated segmentation-based ventilation defect percentage (VDP). Reader-based values were assigned by two experienced radiologists and resolved by consensus. In the semi-automated analysis, 1H anatomical images and 129Xe ventilation images were both segmented following registration to obtain the thoracic cavity volume and ventilated volume, respectively, which were then expressed as a ratio to obtain the VDP. Ventilation images were also characterized by generating signal intensity histograms from voxels within the thoracic cavity volume, and heterogeneity was analyzed using the coefficient of variation (CV). The reader-based VDS% correlated strongly with the semi-automatically generated VDP (r = 0.97, p < 0.0001) and with CV (r = 0.82, p < 0.0001). Both 129Xe ventilation defect scoring metrics readily separated the three groups from one another and correlated significantly with the forced expiratory volume in 1 s (FEV1) (VDS%: r = –0.78, p = 0.0002; VDP: r = –0.79, p = 0.0003; CV: r = –0.66, p = 0.0059) and other pulmonary function tests. In the healthy subject groups (HVs and AMCs), the prevalence of ventilation defects also increased with age (VDS%: r = 0.61, p = 0.0002; VDP: r = 0.63, p = 0.0002). Moreover, ventilation histograms and their associated CVs distinguished between subjects with COPD with similar ventilation defect scores, but visibly different ventilation patterns. Copyright © 2012 John Wiley & Sons, Ltd.

Journal ArticleDOI
TL;DR: This article presents the safety concept, design and installation of a pH2 converter, operated in a clinical setting, and a dependence of line width on pH2 enrichment is observed.
Abstract: Pure parahydrogen (pH2) is the prerequisite for optimal pH2-based hyperpolarization experiments, promising approaches to access the hidden orders of magnitude of MR signals. pH2 production on-site in medical research centers is vital for the proliferation of these technologies in the life sciences. However, previously suggested designs do not meet our requirements for safety or production performance (flow rate, pressure or enrichment). In this article, we present the safety concept, design and installation of a pH2 converter, operated in a clinical setting. The apparatus produces a continuous flow of four standard liters per minute of ≈98% enriched pH2 at a pressure maximum of 50 bar. The entire production cycle, including cleaning and cooling to 25 K, takes less than 5 h, only ≈45 min of which are required for actual pH2 conversion. A fast and simple quantification procedure is described. The lifetimes of pH2 in a glass vial and aluminum storage cylinder are measured to be T1C(glass vial) = 822 ± 29 min and T1C(Al cylinder) = 129 ± 36 days, thus providing sufficiently long storage intervals and allowing the application of pH2 on demand. A dependence of line width on pH2 enrichment is observed. As examples, 1H hyperpolarization of pyridine and 13C hyperpolarization of hydroxyethylpropionate are presented. Copyright © 2012 John Wiley & Sons, Ltd.

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TL;DR: Results indicate that TE provides higher detectability of 2HG than TE = 97 ms, and that this improved capability is gained when data are analyzed with basis spectra that include the effects of the volume localizing radiofrequency and gradient pulses.
Abstract: 2-Hydroxyglutarate (2HG) is produced in gliomas with mutations of isocitrate dehydrogenase (IDH) 1 and 2. The 1H resonances of the J-coupled spins of 2HG are extensively overlapped with signals from other metabolites. Here, we report a comparative study at 3 T of the utility of the point-resolved spectroscopy sequence with a standard short TE (35 ms) and a long TE (97 ms), which had been theoretically designed for the detection of the 2HG 2.25-ppm resonance. The performance of the methods is evaluated using data from phantoms, seven healthy volunteers and 22 subjects with IDH-mutated gliomas. The results indicate that TE = 97 ms provides higher detectability of 2HG than TE = 35 ms, and that this improved capability is gained when data are analyzed with basis spectra that include the effects of the volume localizing radiofrequency and gradient pulses. Copyright © 2013 John Wiley & Sons, Ltd.

Journal ArticleDOI
TL;DR: A correlation of NOE‐mediated saturation transfer with the structural state of bovine serum albumin (BSA) is reported, which points to a possible contrast mechanism for MRI sensitive to the structural integrity of proteins in cells.
Abstract: MR Z-spectroscopy allows enhanced imaging contrast on the basis of saturation transfer between the proton pools of cellular compounds and water, occurring via chemical exchange (chemical exchange saturation transfer, CEST) or dipole-dipole coupling (nuclear Overhauser effect, NOE). In previous studies, signals observed in the aliphatic proton region of Z-spectra have been assigned to NOEs between protons in water molecules and protons at the surface of proteins. We investigated a possible relationship between the signal strength of NOE peaks in Z-spectra obtained at B0 = 7 T and protein structure. Here, we report a correlation of NOE-mediated saturation transfer with the structural state of bovine serum albumin (BSA), which was monitored by fluorescence spectroscopy. Encouraged by CEST signal changes observed in tumor tissue, our observation also points to a possible contrast mechanism for MRI sensitive to the structural integrity of proteins in cells. Therefore, protein folding should be considered as an additional property affecting saturation transfer between water and proteins, in combination with the microenvironment and physiological quantities, such as metabolite concentration, temperature and pH.