Showing papers in "NMR in Biomedicine in 2011"

In vivo characterization of the liver fat 1H MR spectrum

Abstract: A theoretical triglyceride model was developed for in vivo human liver fat 1H MRS characterization, using the number of double bonds (–CH=CH–), number of methylene-interrupted double bonds (–CH=CH–CH2–CH=CH–) and average fatty acid chain length. Five 3 T, single-voxel, stimulated echo acquisition mode spectra (STEAM) were acquired consecutively at progressively longer TEs in a fat–water emulsion phantom and in 121 human subjects with known or suspected nonalcoholic fatty liver disease. T2-corrected peak areas were calculated. Phantom data were used to validate the model. Human data were used in the model to determine the complete liver fat spectrum. In the fat–water emulsion phantom, the spectrum predicted by the model (based on known fatty acid chain distribution) agreed closely with spectroscopic measurement. In human subjects, areas of CH2 peaks at 2.1 and 1.3 ppm were linearly correlated (slope, 0.172; r = 0.991), as were the 0.9 ppm CH3 and 1.3 ppm CH2 peaks (slope, 0.125; r = 0.989). The 2.75 ppm CH2 peak represented 0.6% of the total fat signal in high-liver-fat subjects. These values predict that 8.6% ofm the total fat signal overlies the water peak. The triglyceride model can characterize human liver fat spectra. This allows more accurate determination of liver fat fraction from MRI and MRS.

Fluorine (19F) MRS and MRI in biomedicine.

Abstract: Shortly after the introduction of (1)H MRI, fluorinated molecules were tested as MR-detectable tracers or contrast agents. Many fluorinated compounds, which are nontoxic and chemically inert, are now being used in a broad range of biomedical applications, including anesthetics, chemotherapeutic agents, and molecules with high oxygen solubility for respiration and blood substitution. These compounds can be monitored by fluorine ((19)F) MRI and/or MRS, providing a noninvasive means to interrogate associated functions in biological systems. As a result of the lack of endogenous fluorine in living organisms, (19)F MRI of 'hotspots' of targeted fluorinated contrast agents has recently opened up new research avenues in molecular and cellular imaging. This includes the specific targeting and imaging of cellular surface epitopes, as well as MRI cell tracking of endogenous macrophages, injected immune cells and stem cell transplants.

A novel background field removal method for MRI using projection onto dipole fields (PDF).

Abstract: For optimal image quality in susceptibility-weighted imaging and accurate quantification of susceptibility, it is necessary to isolate the local field generated by local magnetic sources (such as iron) from the background field that arises from imperfect shimming and variations in magnetic susceptibility of surrounding tissues (including air). Previous background removal techniques have limited effectiveness depending on the accuracy of model assumptions or information input. In this article, we report an observation that the magnetic field for a dipole outside a given region of interest (ROI) is approximately orthogonal to the magnetic field of a dipole inside the ROI. Accordingly, we propose a nonparametric background field removal technique based on projection onto dipole fields (PDF). In this PDF technique, the background field inside an ROI is decomposed into a field originating from dipoles outside the ROI using the projection theorem in Hilbert space. This novel PDF background removal technique was validated on a numerical simulation and a phantom experiment and was applied in human brain imaging, demonstrating substantial improvement in background field removal compared with the commonly used high-pass filtering method.

13C MRS studies of neuroenergetics and neurotransmitter cycling in humans.

Abstract: In the last 25 years, (13)C MRS has been established as the only noninvasive method for the measurement of glutamate neurotransmission and cell-specific neuroenergetics. Although technically and experimentally challenging, (13)C MRS has already provided important new information on the relationship between neuroenergetics and neuronal function, the energy cost of brain function, the high neuronal activity in the resting brain state and how neuroenergetics and neurotransmitter cycling are altered in neurological and psychiatric disease. In this article, the current state of (13)C MRS as it is applied to the study of neuroenergetics and neurotransmitter cycling in humans is reviewed. The focus is predominantly on recent findings in humans regarding metabolic pathways, applications to clinical research and the technical status of the method. Results from in vivo (13)C MRS studies in animals are discussed from the standpoint of the validation of MRS measurements of neuroenergetics and neurotransmitter cycling, and where they have helped to identify key questions to address in human research. Controversies concerning the relationship between neuroenergetics and neurotransmitter cycling and factors having an impact on the accurate determination of fluxes through mathematical modeling are addressed. We further touch upon different (13)C-labeled substrates used to study brain metabolism, before reviewing a number of human brain diseases investigated using (13)C MRS. Future technological developments are discussed that will help to overcome the limitations of (13)C MRS, with special attention given to recent developments in hyperpolarized (13)C MRS.

Imaging pH and metastasis.

Abstract: Metastasis is a multistep process that culminates in the spread of cells from a primary tumor to a distant site or organs. For tumor cells to be able to metastasize, they have to locally invade through basement membrane into the lymphatic and the blood vasculatures. Eventually they extravasate from the blood and colonize in the secondary organ. This process involves multiple interactions between the tumor cells and their microenvironments. The microenvironment surrounding tumors has a significant impact on tumor development and progression. A key factor in the microenvironment is an acidic pH. The extracellular pH of solid tumors is more acidic in comparison to normal tissue as a consequence of high glycolysis and poor perfusion. It plays an important role in almost all steps of metastasis. The past decades have seen development of technologies to non-invasively measure intra- and/or extracellular pH. Most successful measurements are MR-based, and sensitivity and accuracy have dramatically improved. Quantitatively imaging the distribution of acidity helps us understand the role of the tumor microenvironment in cancer progression. The present review discusses different MR methods in measuring tumor pH along with emphasizing the importance of extracelluar tumor low pH on different steps of metastasis; more specifically focusing on epithelial-to-mesenchymal transition (EMT), and anti cancer immunity.

Dynamic nuclear polarization polarizer for sterile use intent

Abstract: A novel polarizer based on the dissolution-dynamic nuclear polarization (DNP) method has been designed, built and tested. The polarizer differs from those previously described by being designed with sterile use intent and being compatible with clinical use. The main features are: (1) an integral, disposable fluid path containing all pharmaceuticals constituting a sterile barrier, (2) a closed-cycle cryogenic system designed to eliminate consumption of liquid cryogens and (3) multi-sample polarization to increase throughput. The fluid path consists of a vial with the agent to be polarized, a pair of concentric inlet and outlet tubes connected to a syringe with dissolution medium and a receiver, respectively. The fluid path can operate at up to 400 K and 2.0 MPa and generates volumes as high as 100 mL. An inline filter removes the amount of electron paramagnetic agent in the final product by more than 100-fold in the case of [1-13C]pyruvate. The system uses a sorption pump in conjunction with a conventional cryocooler. The system operates through cycles of pumping to low temperature and regeneration of the sorption pump. The magnet accommodates four samples at the same time. A temperature of less than 1 K was achieved for 68 h (no sample heat loads) with a liquid helium volume of 2.4 L. The regeneration of the liquid helium could be achieved in less than 10 h, and the transition to cold (< 1.2 K) was achieved in less than 90 min. A solid state polarization of 36 ± 4% for [1-13C]pyruvic acid was obtained with only 10 mW of microwave power. The loading of a sample adds less than 50 J of heat to the helium bath by introducing the sample over 15 min. The heat load imposed on the helium bath during dissolution was less than 70 J. The measured liquid state polarization was 18 ± 2%. Copyright © 2011 John Wiley & Sons, Ltd.

Preliminary observations of increased diffusional kurtosis in human brain following recent cerebral infarction

Abstract: By application of the MRI method of diffusional kurtosis imaging, a substantially increased diffusional kurtosis was observed within the cerebral ischemic lesions of three stroke subjects, 13–26 h following the onset of symptoms. This increase is interpreted as probably reflecting a higher degree of diffusional heterogeneity in the lesions when compared with normal-appearing contralateral tissue. In addition, for two of the subjects with white matter infarcts, the increase had a strong fiber tract orientational dependence. It is proposed that this effect is consistent with a large drop in the intra-axonal diffusivity, possibly related to either axonal varicosities or alterations associated with the endoplasmic reticulum.

MR‐visible lipids and the tumor microenvironment

Abstract: MR-visible lipids or mobile lipids are defined as lipids that are observable using proton MRS in cells and tissues These MR-visible lipids are composed of triglycerides and cholesterol esters that accumulate in neutral lipid droplets, where their MR visibility is conferred as a result of the increased molecular motion available in this unique physical environment This review discusses the factors that lead to the biogenesis of MR-visible lipids in cancer cells and in other cell types, such as immune cells and fibroblasts We focus on the accumulations of mobile lipids that are inducible in cultured cells by a number of stresses, including culture conditions, and in response to activating stimuli or apoptotic cell death induced by anticancer drugs This is compared with animal tumor models, where increases in mobile lipids are observed in response to chemo- and radiotherapy, and to human tumors, where mobile lipids are observed predominantly in high-grade brain tumors and in regions of necrosis Conducive conditions for mobile lipid formation in the tumor microenvironment are discussed, including low pH, oxygen availability and the presence of inflammatory cells It is concluded that MR-visible lipids appear in cancer cells and human tumors as a stress response Mobile lipids stored as neutral lipid droplets may play a role in the detoxification of the cell or act as an alternative energy source, especially in cancer cells, which often grow in ischemic/hypoxic environments The role of MR-visible lipids in cancer diagnosis and the assessment of the treatment response in both animal models of cancer and human brain tumors is also discussed Although technical limitations exist in the accurate detection of intratumoral mobile lipids, early increases in mobile lipids after therapeutic interventions may be useful as a potential biomarker for the assessment of treatment response in cancer

31P MRSI and 1H MRS at 7 T: initial results in human breast cancer.

Abstract: This study demonstrates the feasibility of the noninvasive determination of important biomarkers of human (breast) tumor metabolism using high-field (7-T) MRI and MRS. (31) P MRSI at this field strength was used to provide a direct method for the in vivo detection and quantification of endogenous biomarkers. These encompass phospholipid metabolism, phosphate energy metabolism and intracellular pH. A double-tuned, dual-element transceiver was designed with focused radiofrequency fields for unilateral breast imaging and spectroscopy tuned for optimized sensitivity at 7 T. T(1) -weighted three-dimensional MRI and (1) H MRS were applied for the localization and quantification of total choline compounds. (31) P MRSI was obtained within 20 min per subject and mapped in three dimensions over the breast with pixel volumes of 10 mL. The feasibility of monitoring in vivo metabolism was demonstrated in two patients with breast cancer during neoadjuvant chemotherapy, validated by ex vivo high-resolution magic angle spinning NMR and compared with data from an age-matched healthy volunteer. Concentrations of total choline down to 0.4 mM could be detected in the human breast in vivo. Levels of adenosine and other nucleoside triphosphates, inorganic phosphate, phosphocholine, phosphoethanolamine and their glycerol diesters detected in glandular tissue, as well as in tumor, were mapped over the entire breast. Altered levels of these compounds were observed in patients compared with an age-matched healthy volunteer; modulation of these levels occurred in breast tumors during neoadjuvant chemotherapy. To our knowledge, this is the first comprehensive MRI and MRS study in patients with breast cancer, which reveals detailed information on the morphology and phospholipid metabolism from volumes as small as 10 mL. This endogenous metabolic information may provide a new method for the noninvasive assessment of prognostic and predictive biomarkers in breast cancer treatment.

The influence of white matter fibre orientation on MR signal phase and decay.

Abstract: MRI phase images of the brain exhibit excellent contrast and high signal-to-noise ratio. It has been shown recently that the phase contrast not only depends on a tissue's magnetic susceptibility but also on its architecture, which offers new ways of studying biological tissues in vivo. We combined diffusion tensor imaging and multi-echo susceptibility-weighted imaging to investigate the relationship between white matter fibre orientation and gradient-echo phase and magnitude. The local angle between white matter fibres and the main magnetic field was computed from the principal diffusion direction. The phase and signal decay of the gradient-echo images revealed a characteristic relationship with fibre orientation. The phase is in agreement with a recently reported model of cerebral white matter phase contrast in MRI. Copyright © 2010 John Wiley & Sons, Ltd.

Parahydrogen-induced polarization (PHIP) hyperpolarized MR receptor imaging in vivo: A pilot study of 13C imaging of atheroma in mice

Abstract: MR techniques using hyperpolarized (13)C have successfully produced examples of angiography and intermediary metabolic imaging, but, to date, no receptor imaging has been attempted. The goal of this study was to synthesize and evaluate a novel hyperpolarizable molecule, 2,2,3,3-tetrafluoropropyl 1-(13)C-propionate-d(2,3,3) (TFPP), for the detection of atheromatous plaques in vivo. TFPP binds to lipid bilayers and its use in hyperpolarized MR could prove to be a major step towards receptor imaging. The precursor, 2,2,3,3-tetrafluoropropyl 1-(13)C-acrylate-d(2,3,3) (TFPA), binds to 1,2-dimyristoylphosphatidylcholine lipid bilayers with a 1.6-ppm chemical shift in the (19)F MR spectrum. This molecule was designed to be hyperpolarized through the addition of parahydrogen to the (13)C-acrylate moiety by parahydrogen-induced polarization. TFPA was hyperpolarized to TFPP to an extent similar to that of the hydroxyethylacrylate to hydroxyethylpropionate transition: 17 ± 4% for TFPP versus 20% for hydroxyethylpropionate; T(1) relaxation times (45 ± 2 s versus 55 ± 2 s) were comparable and the hyperpolarized properties of TFPP were characterized. Hydroxyethylacrylate, like TFPA, has a chemical structure with an acrylate moiety, but does not contain the lipid-binding tetrafluoropropyl functional group. Hyperpolarized TFPP binds to the lipid bilayer, appearing as a second, chemically shifted (13)C hyperpolarized MR signal with a further reduction in the longitudinal relaxation time (T(1) = 21 ± 1 s). In aortas harvested from low-density lipoprotein receptor knock-out mice fed with a high-fat diet for 9 months, and in which atheroma is deposited in the aorta and heart, TFPP showed greater binding to lipid on the intimal surface than in control mice fed a normal diet. When TFPP was hyperpolarized and administered in vivo to atheromatous mice in a pilot study, increased binding was observed on the endocardial surface of the intact heart compared with normally fed controls. Hyperpolarized TFPP has bio-sensing specificity for lipid, coupled with a 42,000-fold sensitivity gain in the MR signal at 4.7 T. Binding of TFPP with lipids results in the formation of a characteristic second peak in MRS. TFPP therefore has the potential to act as an in vivo molecular probe for atheromatous plaque imaging and may serve as a model of receptor-targeted bio-imaging with enhanced MR sensitivity.

State of the art direct 13C and indirect 1H-[13C] NMR spectroscopy in vivo. A practical guide

Abstract: Carbon-13 NMR spectroscopy in combination with (13)C-labeled substrate infusion is a powerful technique for measuring a large number of metabolic fluxes noninvasively in vivo. It has been used to quantify glycogen synthesis rates, establish quantitative relationships between energy metabolism and neurotransmission, and evaluate the importance of different substrates. Measurements can, in principle, be performed through direct (13)C NMR detection or via indirect (1)H-[(13)C] NMR detection of the protons attached to (13)C nuclei. The choice of detection scheme and pulse sequence depends on the magnetic field strength, whereas substrate selection depends on metabolic pathways. (13)C NMR spectroscopy remains a challenging technique that requires several nonstandard hardware modifications, infusion of (13)C-labeled substrates, and sophisticated processing and metabolic modeling. In this study, the various aspects of direct (13)C and indirect (1)H-[(13)C] NMR are reviewed with the aim of providing a practical guide.

A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis.

Abstract: To explore brain involvement in chronic fatigue syndrome (CFS), the statistical parametric mapping of brain MR images has been extended to voxel-based regressions against clinical scores. Using SPM5 we performed voxel-based morphometry (VBM) and analysed T1- and T2-weighted spin-echo MR signal levels in 25 CFS subjects and 25 normal controls (NC). Clinical scores included CFS fatigue duration, a score based on the 10 most common CFS symptoms, the Bell score, the hospital anxiety and depression scale (HADS) anxiety and depression, and hemodynamic parameters from 24-h blood pressure monitoring. We also performed group × hemodynamic score interaction regressions to detect locations where MR regressions were opposite for CFS and NC, thereby indicating abnormality in the CFS group. In the midbrain, white matter volume was observed to decrease with increasing fatigue duration. For T1-weighted MR and white matter volume, group × hemodynamic score interactions were detected in the brainstem [strongest in midbrain grey matter (GM)], deep prefrontal white matter (WM), the caudal basal pons and hypothalamus. A strong correlation in CFS between brainstem GM volume and pulse pressure suggested impaired cerebrovascular autoregulation. It can be argued that at least some of these changes could arise from astrocyte dysfunction. These results are consistent with an insult to the midbrain at fatigue onset that affects multiple feedback control loops to suppress cerebral motor and cognitive activity and disrupt local CNS homeostasis, including resetting of some elements of the autonomic nervous system (ANS). © 2011 The Authors. NMR in Biomedicine published by John Wiley & Sons, Ltd.

Imaging tumor hypoxia by magnetic resonance methods

Abstract: Tumor hypoxia results from the negative balance between the oxygen demands of the tissue and the capacity of the neovasculature to deliver sufficient oxygen. The resulting oxygen deficit has important consequences with regard to the aggressiveness and malignancy of tumors, as well as their resistance to therapy, endowing the imaging of hypoxia with vital repercussions in tumor prognosis and therapy design. The molecular and cellular events underlying hypoxia are mediated mainly through hypoxia-inducible factor, a transcription factor with pleiotropic effects over a variety of cellular processes, including oncologic transformation, invasion and metastasis. However, few methodologies have been able to monitor noninvasively the oxygen tensions in vivo. MRI and MRS are often used for this purpose. Most MRI approaches are based on the effects of the local oxygen tension on: (i) the relaxation times of (19)F or (1)H indicators, such as perfluorocarbons or their (1)H analogs; (ii) the hemodynamics and magnetic susceptibility effects of oxy- and deoxyhemoglobin; and (iii) the effects of paramagnetic oxygen on the relaxation times of tissue water. (19)F MRS approaches monitor tumor hypoxia through the selective accumulation of reduced nitroimidazole derivatives in hypoxic zones, whereas electron spin resonance methods determine the oxygen level through its influence on the linewidths of appropriate paramagnetic probes in vivo. Finally, Overhauser-enhanced MRI combines the sensitivity of EPR methodology with the resolution of MRI, providing a window into the future use of hyperpolarized oxygen probes.

Imaging pH with hyperpolarized 13C.

Abstract: pH is a fundamental physiological parameter that is tightly controlled by endogenous buffers. The acid-base balance is altered in many disease states, such as inflammation, ischemia and cancer. Despite the importance of pH, there are currently no routine methods for imaging the spatial distribution of pH in humans. The enormous gain in sensitivity afforded by dynamic nuclear polarization (DNP) has provided a novel way in which to image tissue pH using MR, which has the potential to be translated into the clinic. This review explores the advantages and disadvantages of current pH imaging techniques and how they compare with DNP-based approaches for the measurement and imaging of pH with hyperpolarized (13)C. Intravenous injection of hyperpolarized (13)C-labeled bicarbonate results in the rapid production of hyperpolarized (13)CO(2) in the reaction catalyzed by carbonic anhydrase. As this reaction is close to equilibrium in the body and is pH dependent, the ratio of the (13)C signal intensities from H(13)CO(3)(-) and (13)CO(2), measured using MRS, can be used to calculate pH in vivo. The application of this technique to a murine tumor model demonstrated that it measured predominantly extracellular pH and could be mapped in the animal using spectroscopic imaging techniques. A second approach has been to use the production of hyperpolarized (13)CO(2) from hyperpolarized [1-(13)C]pyruvate to measure predominantly intracellular pH. In tissues with a high aerobic capacity, such as the heart, the hyperpolarized [1-(13)C]pyruvate undergoes rapid oxidative decarboxylation, catalyzed by intramitochondrial pyruvate dehydrogenase. Provided that there is sufficient carbonic anhydrase present to catalyze the rapid equilibration of the hyperpolarized (13)C label between CO(2) and bicarbonate, the ratio of their resonance intensities may again be used to estimate pH, which, in this case, is predominantly intracellular. As both pyruvate and bicarbonate are endogenous molecules they have the potential to image tissue pH in the clinic.

Real-time volumetric MRI thermometry of focused ultrasound ablation in vivo: a feasibility study in pig liver and kidney.

Abstract: MR thermometry offers the possibility to precisely guide high-intensity focused ultrasound (HIFU) for the noninvasive treatment of kidney and liver tumours. The objectives of this study were to demonstrate therapy guidance by motion-compensated, rapid and volumetric MR temperature monitoring and to evaluate the feasibility of MR-guided HIFU ablation in these organs. Fourteen HIFU sonications were performed in the kidney and liver of five pigs under general anaesthesia using an MR-compatible Philips HIFU platform prototype. HIFU sonication power and duration were varied. Volumetric MR thermometry was performed continuously at 1.5 T using the proton resonance frequency shift method employing a multi-slice, single-shot, echo-planar imaging sequence with an update frequency of 2.5 Hz. Motion-related suceptibility artefacts were compensated for using multi-baseline reference images acquired prior to sonication. At the end of the experiment, the animals were sacrificed for macroscopic and microscopic examinations of the kidney, liver and skin. The standard deviation of the temperature measured prior to heating in the sonicated area was approximately 1 °C in kidney and liver, and 2.5 °C near the skin. The maximum temperature rise was 30 °C for a sonication of 1.2 MHz in the liver over 15 s at 300 W. The thermal dose reached the lethal threshold (240 CEM(43) ) in two of six cases in the kidney and four of eight cases in the liver, but remained below this value in skin regions in the beam path. These findings were in agreement with histological analysis. Volumetric thermometry allows real-time monitoring of the temperature at the target location in liver and kidney, as well as in surrounding tissues. Thermal ablation was more difficult to achieve in renal than in hepatic tissue even using higher acoustic energy, probably because of a more efficient heat evacuation in the kidney by perfusion.

Diffusion tensor imaging discriminates between glioblastoma and cerebral metastases in vivo.

Abstract: In a prospective study, patients with a radiologically proven brain tumour underwent diffusion tensor imaging (DTI) prior to definitive diagnosis and treatment. Twenty-eight patients with a histologically proven glioblastoma or metastasis were included in the study. Following the definition of regions of interest, DTI metrics [mean diffusivity (MD) and fractional anisotropy (FA)] were calculated for the tumour volume and the surrounding region of peritumoral oedema. These metrics were then subjected to logistic regression to investigate their ability to discriminate between glioblastomas and cerebral metastases. A cross-validation was performed to investigate the ability of the model to predict tumour. The logistic regression analysis correctly distinguished glioblastoma in 15 of 16 cases (93.8%) and metastasis in 11 of 12 cases (91.7%). Cross-validation resulted in the model correctly predicting 14 of 16 (87.5%) glioblastomas and 10 of 12 (83.3%) metastases studied. MD was significantly higher (p = 0.02) and FA was significantly lower (p = 0.04) within the oedema surrounding metastases than within the oedema around glioblastomas. MD was significantly higher (p = 0.02) within the tumour volume of the glioblastomas. Our results demonstrate that, when DTI metrics from the tumour volume and surrounding peritumoral oedema are studied in combination, glioblastoma can be reliably discriminated from cerebral metastases. Copyright © 2010 John Wiley & Sons, Ltd.

Validation of the in vivo assessment of pyruvate dehydrogenase activity using hyperpolarised 13C MRS

Abstract: Many diseases of the heart are characterised by changes in substrate utilisation, which is regulated in part by the activity of the enzyme pyruvate dehydrogenase (PDH). Consequently, there is much interest in the in vivo evaluation of PDH activity in a range of physiological and pathological states to obtain information on the metabolic mechanisms of cardiac diseases. Hyperpolarised [1-(13)C]pyruvate, detected using MRS, is a novel technique for the noninvasive evaluation of PDH flux. PDH flux has been assumed to directly reflect in vivo PDH activity, although to date this assumption remains unproven. Control animals and animals undergoing interventions known to modulate PDH activity, namely high fat feeding and dichloroacetate infusion, were used to investigate the relationship between in vivo hyperpolarised MRS measurements of PDH flux and ex vivo measurements of PDH enzyme activity (PDH(a)). Further, the plasma concentrations of pyruvate and other important metabolites were evaluated following pyruvate infusion to assess the metabolic consequences of pyruvate infusion during hyperpolarised MRS experiments. Hyperpolarised MRS measurements of PDH flux correlated significantly with ex vivo measurements of PDH(a), confirming that PDH activity influences directly the in vivo flux of hyperpolarised pyruvate through cardiac PDH. The maximum plasma concentration of pyruvate reached during hyperpolarised MRS experiments was approximately 250 µM, equivalent to physiological pyruvate concentrations reached during exercise or with dietary interventions. The concentrations of other metabolites, including lactate, glucose and β-hydroxybutyrate, did not vary during the 60 s following pyruvate infusion. Hence, during the 60-s data acquisition period, metabolism was minimally affected by pyruvate infusion.

Noninvasive quantification of ascorbate and glutathione concentration in the elderly human brain

Abstract: In this study, ascorbate (Asc) and glutathione (GSH) concentrations were quantified noninvasively using double-edited (1)H MRS at 4 T in the occipital cortex of healthy young [age (mean ± standard deviation) = 20.4 ± 1.4 years] and elderly (age = 76.6 ± 6.1 years) human subjects. Elderly subjects had a lower GSH concentration than younger subjects (p < 0.05). The Asc concentration was not significantly associated with age. Furthermore, the lactate (Lac) concentration was higher in elderly than young subjects. Lower GSH and higher Lac concentrations are indications of defective protection against oxidative damage and impaired mitochondrial respiration. The extent to which the observed concentration differences could be associated with physiological differences and methodological artifacts is discussed. In conclusion, GSH and Asc concentrations were compared noninvasively for the first time in young vs elderly subjects.

MRS and MRSI guidance in molecular medicine: targeting and monitoring of choline and glucose metabolism in cancer

Abstract: Magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) are valuable tools to detect metabolic changes in tumors. The currently emerging era of molecular medicine, which is shaped by molecularly targeted anticancer therapies combined with molecular imaging of the effects of such therapies, requires powerful imaging technologies that are able to detect molecular information. MRS and MRSI (MRS/I) are such technologies that are able to detect metabolites arising from glucose and choline metabolism in noninvasive in vivo settings and at higher resolution in tissue samples. The roles that MRS/I plays in diagnosing different types of cancer as well as in early monitoring of tumor response to traditional chemotherapies are reviewed. Emerging roles of MRS/I in the development and detection of novel targeted anticancer therapies that target oncogenic signaling pathways or targets in choline or glucose metabolism are discussed.

Assessment of therapeutic response and treatment planning for brain tumors using metabolic and physiological MRI

Abstract: MRI is routinely used for diagnosis, treatment planning and assessment of response to therapy for patients with glioma. Gliomas are spatially heterogeneous and infiltrative lesions that are quite variable in terms of their response to therapy. Patients classified as having low-grade histology have a median overall survival of 7 years or more, but need to be monitored carefully to make sure that their tumor does not upgrade to a more malignant phenotype. Patients with the most aggressive grade IV histology have a median overall survival of 12-15 months and often undergo multiple surgeries and adjuvant therapies in an attempt to control their disease. Despite improvements in the spatial resolution and sensitivity of anatomic images, there remain considerable ambiguities in the interpretation of changes in the size of the gadolinium-enhancing lesion on T(1) -weighted images as a measure of treatment response, and in differentiating between treatment effects and infiltrating tumor within the larger T(2) lesion. The planning of focal therapies, such as surgery, radiation and targeted drug delivery, as well as a more reliable assessment of the response to therapy, would benefit considerably from the integration of metabolic and physiological imaging techniques into routine clinical MR examinations. Advanced methods that have been shown to provide valuable data for patients with glioma are diffusion, perfusion and spectroscopic imaging. Multiparametric examinations that include the acquisition of such data are able to assess tumor cellularity, hypoxia, disruption of normal tissue architecture, changes in vascular density and vessel permeability, in addition to the standard measures of changes in the volume of enhancing and nonenhancing anatomic lesions. This is particularly critical for the interpretation of the results of Phase I and Phase II clinical trials of novel therapies, which are increasingly including agents that are designed to have anti-angiogenic and anti-proliferative properties as opposed to having a direct effect on tumor cell viability.

A method for rapid in vivo measurement of blood T1

Abstract: We present a technique to measure the longitudinal relaxation time constant of venous blood (T(1b) ) in vivo in a few seconds. The MRI sequence consists of a thick-slab adiabatic inversion, followed by a series of slice-selective excitations and single-shot echo planar imaging readouts. The time intervals between excitations were chosen so that blood in macroscopic vessels is fully refreshed between excitations, making the blood signal follow an unperturbed inversion recovery curve. Static tissue, which experiences the inversion and all excitation pulses, quickly reaches a steady state at a low signal as a result of partial saturation. This allows blood-filled voxels to be discriminated from those containing static tissue, and to be fitted voxel-by-voxel to a simple inversion recovery model. The sequence was tested on a flow phantom with the proposed method, yielding T(1) values consistent to within 3% of those obtained using a conventional inversion recovery sequence with a spin-echo readout. The method was applied to seven adult volunteers and 18 neonates. The blood T(1) of the neonates (1799 ± 206 ms; range, 1393-2035 ms) was found to be more variable than that of adults (1717 ± 39 ms; range, 1662-1779 ms). A linear correlation between the inverse of T(1b) and the haematocrit was established in 12 neonates (R(2) = 0.90).

Diffusion-weighted MRI in early chemotherapy response evaluation of patients with diffuse large B-cell lymphoma – a pilot study: comparison with 2-deoxy-2-fluoro- D-glucose-positron emission tomography/computed tomography

Abstract: To determine the feasibility of diffusion-weighted MRI (DWI) in the evaluation of the early chemotherapeutic response in patients with aggressive non-Hodgkin's lymphoma (NHL), eight patients with histologically proven diffuse large B-cell lymphoma were imaged by MRI, including DWI, and positron emission tomography/computed tomography (PET/CT) before treatment (E1), and after 1 week (E2) and two cycles (E3) of chemotherapy In all patients, whole-body screening using T1- and T2-weighted images in the coronal plane was performed To quantitatively evaluate the chemotherapeutic response, axial images including DWI were acquired Apparent diffusion coefficient (ADC) maps were reconstructed, and the ADC value of the tumor was measured In addition, the tumor volume was estimated on axial T2-weighted images The maximum standardized uptake value (SUVmax) and active tumor volume were measured on fused PET/CT images Lymphomas showed high signal intensity on DW images and low signal intensity on ADC maps, except for necrotic foci The mean pre-therapy ADC was 071 × 10−3 mm2/s; it increased by 77% at E2 (p < 005) and 24% more at E3 (insignificant); the total increase was 106% (p < 005) The mean tumor volume by MRI was 276 mL at baseline; it decreased by 58% at E2 (p < 005) and 65% more at E3 (p < 005), giving a total decrease of 84% (p < 005) All the imaged pre-therapy tumors were strongly positive on PET/CT, with a mean SUVmax of 20 The SUVmax decreased by 60% at E2 (p < 005) and 59% more at E3 (p < 005), giving a total decrease of 83% (p < 005) The active tumor burden decreased by 66% at E2 (p < 005) At baseline, both central and peripheral tumor ADC values correlated inversely with SUVmax (p < 005), and also correlated inversely with active tumor burden on PET/CT and with tumor volume on MRI at E2 (p < 005) In conclusion, the results of DWI in combination with whole-body MRI were comparable with those of integrated PET/CT Copyright © 2011 John Wiley & Sons, Ltd

Spectral-spatial excitation for rapid imaging of DNP compounds.

Abstract: Dynamic nuclear polarization and dissolution offer the exciting possibility of imaging biochemical reactions in vivo, including some of the key enzymatic reactions involved in cellular metabolism. The development of new pulse sequence strategies has been motivated by demanding applications, such as the imaging of hyperpolarized metabolite distributions in the heart. In this article, the key considerations surrounding the application of spectral–spatial imaging pulse sequences for hyperpolarized 13C metabolic imaging in cardiac and cancer applications are explored. Spiral pulse sequences for multislice imaging of [1-13C]pyruvate in the heart were developed, as well as time-resolved, three-dimensional, echo-planar imaging sequences for the imaging of [1-13C]pyruvate–lactate exchange in cancer. The advantages and challenges associated with these sequences were determined by testing in pig and rat models. Copyright © 2011 John Wiley & Sons, Ltd.

Efficient γ-aminobutyric acid editing at 3T without macromolecule contamination: MEGA-SPECIAL.

Abstract: One of the most commonly used methods for in vivo MRS detection of γ-aminobutyric acid (GABA) is the MEGA-point-resolved spectroscopy (MEGA-PRESS) technique. However, accurate quantification of GABA using MEGA-PRESS is complicated by spectral co-editing of macromolecular resonances. In this article, a new pulse sequence is presented which enables GABA editing at 3T with the removal of macromolecule contamination. This sequence combines the conventional MEGA editing scheme with the SPECIAL localisation technique, and is therefore named MEGA-SPECIAL. Simulations and phantom experiments indicate that this new approach provides improved GABA editing efficiency relative to MEGA-PRESS, and in vivo results demonstrate effective removal of macromolecule contamination. In a study of the occipital lobe of five healthy volunteers, the macromolecule-corrected GABA/creatine ratio was found to be 0.093 ± 0.007 (mean ± standard deviation), whereas prior to macromolecule correction, the ratio was found to be 0.173 ± 0.013. Copyright © 2011 John Wiley & Sons, Ltd.

Blood oxygenation level‐dependent (BOLD) total and extravascular signal changes and ΔR2* in human visual cortex at 1.5, 3.0 and 7.0 T

Abstract: The characterisation of the extravascular (EV) contribution to the blood oxygenation level-dependent (BOLD) effect is important for understanding the spatial specificity of BOLD contrast and for modelling approaches that aim to extract quantitative metabolic parameters from the BOLD signal. Using bipolar crusher gradients, total (b = 0 s/mm2) and predominantly EV (b = 100 s/mm2) gradient echo BOLD ΔR2* and signal changes (ΔS/S) in response to visual stimulation (flashing checkerboard; f = 8 Hz) were investigated sequentially (within < 3 h) at 1.5, 3.0 and 7.0 T in the same subgroup of healthy volunteers (n = 7) and at identical spatial resolutions (3.5 × 3.5 × 3.5 mm3). Total ΔR2* (z-score analysis) values were −0.61 ± 0.10 s−1 (1.5 T), −0.74 ± 0.05 s−1 (3.0 T) and −1.37 ± 0.12 s−1 (7.0 T), whereas EV ΔR2* values were −0.28 ± 0.07 s−1 (1.5 T), −0.52 ± 0.07 s−1 (3.0 T) and −1.25 ± 0.11 s−1 (7.0 T). Although EV ΔR2* increased linearly with field, as expected, it was found that EV ΔS/S increased less than linearly with field in a manner that varied with TE choice. Furthermore, unlike ΔR2*, total and EV ΔS/S did not converge at 7.0 T. These trends were similar whether a z-score analysis or occipital lobe-based region-of-interest approach was used for voxel selection. These findings suggest that calibrated BOLD approaches may benefit from an EV ΔR2* measurement as opposed to a ΔS/S measurement at a single TE. Copyright © 2010 John Wiley & Sons, Ltd.

Quantifying cortical bone water in vivo by three-dimensional ultra-short echo-time MRI

Abstract: Bone contains a significant fraction of water that is not detectable with ordinary Cartesian imaging sequences. The advent of ultra-short echo-time (UTE) methods has allowed the recovery of this submillisecond T2* water. In this work, we have developed a new three-dimensional hybrid-radial ultra-short echo-time (3D HRUTE) imaging technique based on slab selection by means of half-sinc pulses, variable-TE slice encoding and algorithms for quantification. The protocol consists of collecting two datasets differing in TR, from which T1 is extracted, which is needed for quantification. Unlike T2*, which has been found to vary within a narrow range and does not require individual correction, T1 is critically subject dependent (range, 100–350 ms). No soft-tissue suppression was used to preserve the signal-to-noise ratio of the short-T2 bone water protons or to minimize the loss of relatively mobile water in large pores. Critical for quantification is correction for spatial variations in reception field and selection of the endosteal boundary for inclusion of pixels in the bone water calculation, because of the ruffled boundary stemming from trabecularization of the endosteal surface. The reproducibility, evaluated in 10 subjects covering the age range 30–80 years, yielded an average coefficient of variation of 4.2% and an intraclass correlation coefficient of 0.95, suggesting that a treatment effect on the order of 5% could be detected in as few as 10 subjects. Lastly, experiments in specimens by means of graded deuterium exchange showed that approximately 90% of the detected signal arises from water protons, whose relaxation rates (1/T1 and 1/T2*) scale linearly with the isotopic volume fraction of light water after stepwise exchange with heavy water. The data thus show conclusively that the method quantifies water even though, in vivo, no distinction can be made between various fractions, such as collagen-bound vs pore-resident water. Copyright © 2011 John Wiley & Sons, Ltd.

Reproducibility of prefrontal γ-aminobutyric acid measurements with J-edited spectroscopy

Abstract: γ-Aminobutyric acid (GABA) is the chief inhibitory neurotransmitter of the human brain, and GABA-ergic dysfunction has been implicated in a variety of neuropsychiatric disorders. Recent MRS techniques have allowed the quantification of GABA concentrations in vivo, and could therefore provide biologically relevant information. Few reports have formally characterized the reproducibility of these techniques, and differences in field strength, acquisition and processing parameters may result in large differences in measured GABA values. Here, we used a J-edited, single-voxel spectroscopy method of measurement of GABA + macromolecules (GABA + ) in the anterior cingulate cortex (ACC) and right frontal white matter (rFWM) at 3 T. We measured the coefficient of variation within subjects (CVw) and intra-class correlation coefficients on two repeated scans obtained from 10 healthy volunteers with processing procedures developed in-house for the quantification of GABA + and other major metabolites. In addition, by segmenting the spectroscopic voxel into cerebrospinal fluid, gray matter and white matter, and employing a linear regression technique to extrapolate metabolite values to pure gray and white matter, we determined metabolite differences between gray and white matter in ACC and rFWM. CVw values for GABA + /creatine, GABA + /H2O, GABA + , creatine, partially co-edited glutamate + glutamine (Glx)/creatine, partially co-edited Glx and N-acetylaspartic acid (NAA)/creatine were all below 12% in both ACC and rFWM. After extrapolation to pure gray and pure white matter, CVw values for all metabolites were below 16%. We found metabolite ratios between gray and white matter for GABA + /creatine, GABA + , creatine, partially co-edited Glx and NAA/creatine to be 0.88 ± 0.21 (standard deviation), 1.52 ± 0.32, 1.77 ± 0.4, 2.69 ± 0.74 and 0.70 ± 0.05, respectively. This study validates a reproducible method for the quantification of brain metabolites, and provides information on gray/white matter differences that may be important in the interpretation of results in clinical populations. Published in 2011 by John Wiley & Sons, Ltd.

Imaging the Extracellular pH of Tumors by MRI after Injection of a Single Cocktail of T1 and T2 Contrast Agents

Abstract: The extracellular pH (pHe) of solid tumors is acidic, and there is evidence that an acidic pHe is related to invasiveness. Herein,wedescribeanMRIsingle-infusion methodtomeasurepHeingliomas usingacocktailofcontrastagents(CAs). The cocktail contained gadolinium‐1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaminophosphonate (GdDOTA-4AmP) and dysprosium‐1,4,7,10-tetraazacyclododecane-N,N(,N((,N(((-tetrakis(methylenephosphonic acid) (DyDOTP), whose effects on relaxation are sensitive and insensitive to pH, respectively. The Gd-CA dominated the spin‐lattice relaxivity DR1, whereas the Dy-CA dominated the spin‐spin relaxivity DR2 � . The DR2 � effects were used to determinethepixel-wiseconcentrationof[Dy]which,in turn,wasusedtocalculate avaluefor[Gd]concentration.This value was used to convert DR1 values to the molar relaxivity Dr1 and, hence, pHe maps. The development of the method involvedin vivocalibration and measurements in a rat brain glioma model. Thecalibration phase consisted of determining a quantitative relationship between DR1 and DR2 � induced by the two pH-independent CAs, gadolinium‐diethylenetriaminepentaacetic acid (GdDTPA) and DyDOTP, using echo planar spectroscopic imaging (EPSI) and T1-weighted images. The intensities and linewidths of the water peaks in EPSI images were affected by CA and were used to follow the pharmacokinetics. These data showed a linear relationship between inner- and outer-sphere relaxation rate constants that were used for CA concentration determination. Nonlinearity in the slope of the relationship was observed and ascribed to variations in vascular permeability. In the pHe measurement phase, GdDOTA-4AmP was infused instead of GdDTPA, and relaxivities were obtained through the combination of interleaved T1-weighted images (R1) and EPSI for DR2 � . The resulting r1 values yielded pHe maps with high spatial

7-T (1) H MRS with adiabatic refocusing at short TE using radiofrequency focusing with a dual-channel volume transmit coil.

Abstract: In vivo MRS of the human brain at ultrahigh field allows for the identification of a large number of metabolites at higher spatial resolutions than currently possible in clinical practice. However, the in vivo localization of single-voxel spectroscopy has been shown to be challenging at ultrahigh field because of the low bandwidth of refocusing radiofrequency (RF) pulses. Thus far, the proposed methods for localized MRS at 7 T suffer from long TE, inherent signal loss and/or a large chemical shift displacement artifact that causes a spatial displacement between resonances, and results in a decreased efficiency in editing sequences. In this work, we show that, by driving a standard volume coil with two RF amplifiers, focusing the B 1+ field in a certain location and using high-bandwidth adiabatic refocusing pulses, a semi-LASER (semi-localized by adiabatic selective refocusing) localization is feasible at short TE in the human brain with full signal acquisition and a low chemical shift displacement artifact at 7 T.