Improved total sensitivity estimation for multiple receive coils in MRI using ratios of first-order statistics.

OBJECT: Spatial variation in the sensitivity profiles of receive coils in MRI leads to spatially dependent scaling of the signal amplitude across an image. In practice, total sensitivity of the coil array is either calibrated or corrected directly by comparison to a uniform sensitivity image, fitting of coil profiles, or indirectly by constraining the reconstructed image or coil profiles. In the absence of these corrections, popular coil summation strategies are often designed to maximize the signal-to-noise ratio or optimize under-sampled encoding but not necessarily estimate the value of the signal unscaled by the coil spatial sensitivity. MATERIALS AND METHODS: We use ratios of first-order statistics to approach the unscaled value of the signal at any position. Motivated by the assumption that the coil array is a sample from much larger number of possible coils, we present two approaches to scale the mean signal in all coils: (1) an argument for use of the mode of the normalized signals, and (2) using a one-dimensional analog derive an approximate expression for scaling with the ratio of the square-of-the-mean to the mean-of-the-squares. We test these approaches with simulation where idealized coil elements are arrayed around an object, and on directly acquired data with an 8-channel coil array on a uniform 13C phantom, and on Hyperpolarized 13C pyruvate brain MRI. RESULTS: We show improved image uniformity using the ratios of first order statistics compared to a simple homomorphic filter, noting that these approaches are more sensitive to noise. DISCUSSION: We present simple methods for correcting the spatial variation in sensitivity profiles in the context of a coil array. These methods can be used as an initial or adjunct step in data post-processing.

Hyperpolarized [5-13C,4,4-2H2,5-15N]-L-glutamine provides a means of annotating in vivo metabolic utilization of glutamine.

Glutamine is consumed by rapidly proliferating cells and can provide the carbon and nitrogen required for growth through various metabolic pathways. However, delineating the metabolic fate of glutamine is challenging to interrogate in vivo. Hyperpolarized magnetic resonance, by providing high transient nuclear magnetic resonance signals, provides an approach to measure fast biochemical processes in vivo. Aminohydrolysis of glutamine at carbon-5 plays an important role in providing nitrogen and carbon for multiple pathways. Here, we provide a synthetic strategy for isotope-enriched forms of glutamine that prolongs glutamine-C5 relaxation times and thereby reveals in vivo reactions involving carbon-5. We investigate multiple enrichment states, finding [5-13C,4,4-2H2,5-15N]-L-glutamine to be optimal for hyperpolarized measurement of glutamine conversion to glutamate in vivo. Leveraging this compound, we explore pancreatic cancer glutamine metabolism in vivo. Taken together, this work provides a means for studying glutamine metabolic flux in vivo and demonstrates on-target effects of metabolic enzyme inhibitors.

Multi-sample measurement of hyperpolarized pyruvate-to-lactate flux in melanoma cells.

Hyperpolarized [1-13 C] pyruvate can be used to examine the metabolic state of cancer cells, highlighting a key metabolic characteristic of cancer: the upregulated metabolic flux to lactate, even in the presence of oxygen (Warburg effect). Thus, the rate constant of 13 C exchange of pyruvate to lactate, kPL , can serve as a metabolic biomarker of cancer presence, aggressiveness and therapy response. Established in vitro hyperpolarized experiments dissolve the probe for each cell sample independently, an inefficient process that consumes excessive time and resources. Expanding on our previous development of a microcoil with greatly increased detection sensitivity (103 -fold) compared with traditional in vitro methods, we present a novel microcoil equipped with a 10-µL vertical reservoir and an experimental protocol utilizing deuterated dissolution buffer to measure metabolic flux in multiple mass-limited cell suspension samples using a single dissolution. This method increases efficiency and potentially reduces the methodological variability associated with hyperpolarized experiments. This technique was used to measure pyruvate-to-lactate flux in melanoma cells to assess BRAF-inhibition treatment response. There was a significant reduction of kPL in BRAFV600E cells following 24 and 48 hours of treatment with 2 µM vemurafenib (P ≤ .05). This agrees with significant changes observed in the pool sizes of extracellular lactate (P ≤ .05) and glucose (P ≤ .001) following 6 and 48 hours of treatment, respectively, and a significant reduction in cell proliferation following 72 hours of treatment (P ≤ .01). BRAF inhibition had no significant effect on the metabolic flux of BRAFWT cells. These data demonstrate a 6-8-fold increase in efficiency for the measurement of kPL in cell suspension samples compared with traditional hyperpolarized in vitro methods.

Dynamic volumetric hyperpolarized 13 C imaging with multi-echo EPI.

PURPOSE: To generate dynamic, volumetric maps of hyperpolarized [1-13 C]pyruvate and its metabolic products in vivo. METHODS: Maps of chemical species were generated with iterative least squares (IDEAL) reconstruction from multiecho echo-planar imaging (EPI) of phantoms of thermally polarized 13 C-labeled chemicals and mice injected with hyperpolarized [1-13 C]pyruvate on a preclinical 3T scanner. The quality of the IDEAL decomposition of single-shot and multishot phantom images was evaluated using quantitative results from a simple pulse-and-acquire sequence as the gold standard. Time course and area-under-the-curve plots were created to analyze the distribution of metabolites in vivo. RESULTS: Improved separation of chemical species by IDEAL, evaluated by the amount of residual signal measured for chemicals not present in the phantoms, was observed as the number of EPI shots was increased from one to four. Dynamic three-dimensional metabolite maps of [1-13 C]pyruvate,[1-13 C]pyruvatehydrate, [1-13 C]lactate, [1-13 C]bicarbonate, and [1-13 C]alanine generated by IDEAL from interleaved multishot multiecho EPI of live mice were used to construct time course and area-under-the-curve graphs for the heart, kidneys, and liver, which showed good agreement with previously published results. CONCLUSIONS: IDEAL decomposition of multishot multiecho 13C EPI images is a simple, yet robust method for generating high-quality dynamic volumetric maps of hyperpolarized [1-13 C]pyruvate and its products in vivo and has potential applications for the assessment of multiorgan metabolic phenomena.

Hyperpolarized MRI of Human Prostate Cancer Reveals Increased Lactate with Tumor Grade Driven by Monocarboxylate Transporter 1.

Metabolic imaging using hyperpolarized magnetic resonance can increase the sensitivity of MRI, though its ability to inform on relevant changes to biochemistry in humans remains unclear. In this work, we image pyruvate metabolism in patients, assessing the reproducibility of delivery and conversion in the setting of primary prostate cancer. We show that the time to max of pyruvate does not vary significantly within patients undergoing two separate injections or across patients. Furthermore, we show that lactate increases with Gleason grade. RNA sequencing data demonstrate a significant increase in the predominant pyruvate uptake transporter, monocarboxylate transporter 1. Increased protein expression was also observed in regions of high lactate signal, implicating it as the driver of lactate signal in vivo. Targeted DNA sequencing for actionable mutations revealed the highest lactate occurred in patients with PTEN loss. This work identifies a potential link between actionable genomic alterations and metabolic information derived from hyperpolarized pyruvate MRI.

Hyperpolarized [6-13C,15N3]-Arginine as a Probe for in Vivo Arginase Activity.

Alterations in arginase enzyme expression are linked with various diseases and have been shown to support disease progression, thus motivating the development of an imaging probe for this enzymatic target. 13C-enriched arginine can be used as a hyperpolarized (HP) magnetic resonance (MR) probe for arginase flux since the arginine carbon-6 resonance (157 ppm) is converted to urea (163 ppm) following arginase-catalyzed hydrolysis. However, scalar relaxation from adjacent 14N-nuclei shortens cabon-6 T 1 and T 2 times, yielding poor spectral properties. To address these limitations, we report the synthesis of [6-13C,15N3]-arginine and demonstrate that 15N-enrichment increases carbon-6 relaxation times, thereby improving signal-to-noise ratio and spectral resolution. By overcoming these limitations with this novel isotope-labeling scheme, we were able to perform in vitro and in vivo arginase activity measurements with HP MR. We present HP [6-13C,15N3]-arginine as a noninvasive arginase imaging agent for preclinical studies, with the potential for future clinical diagnostic use.

Hyperpolarized MRI Visualizes Warburg Effects and Predicts Treatment Response to mTOR Inhibitors in Patient-Derived ccRCC Xenograft Models.

The ever-changing tumor microenvironment constantly challenges individual cancer cells to balance supply and demand, presenting tumor vulnerabilities and therapeutic opportunities. Everolimus and temsirolimus are inhibitors of mTOR (mTORi) approved for treating metastatic renal cell carcinoma (mRCC). However, treatment outcome varies greatly among patients. Accordingly, administration of mTORi in mRCC is diminishing, which could potentially result in missing timely delivery of effective treatment for select patients. Here, we implemented a clinically applicable, integrated platform encompassing a single dose of [1-13C] pyruvate to visualize the in vivo effect of mTORi on the conversion of pyruvate to lactate using hyperpolarized MRI. A striking difference that predicts treatment benefit was demonstrated using two preclinical models derived from patients with clear cell RCC (ccRCC) who exhibited primary resistance to VEGFRi and quickly succumbed to their diseases within 6 months after the diagnosis of metastasis without receiving mTORi. Our findings suggest that hyperpolarized MRI could be further developed to personalize kidney cancer treatment. SIGNIFICANCE: These findings demonstrate hyperpolarized [1-13C]pyruvate MRI as a tool for accurately assessing the clinical success of mTOR inhibition in patients with ccRCC.

Metabolic Imaging of the Human Brain with Hyperpolarized 13C Pyruvate Demonstrates 13C Lactate Production in Brain Tumor Patients.

Hyperpolarized (HP) MRI using [1-13C] pyruvate is a novel method that can characterize energy metabolism in the human brain and brain tumors. Here, we present the first dynamically acquired human brain HP 13C metabolic spectra and spatial metabolite maps in cases of both untreated and recurrent tumors. In vivo production of HP lactate from HP pyruvate by tumors was indicative of altered cancer metabolism, whereas production of HP lactate in the entire brain was likely due to baseline metabolism. We correlated our results with standard clinical brain MRI, MRI DCE perfusion, and in one case FDG PET/CT. Our results suggest that HP 13C pyruvate-to-lactate conversion may be a viable metabolic biomarker for assessing tumor response.Significance: Hyperpolarized pyruvate MRI enables metabolic imaging in the brain and can be a quantitative biomarker for active tumors.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3755/F1.large.jpg Cancer Res; 78(14); 3755-60. ©2018 AACR.

In Vivo Imaging of Glutamine Metabolism to the Oncometabolite 2-Hydroxyglutarate in IDH1/2 Mutant Tumors.

The oncometabolite 2-hydroxyglutarate (2-HG) is a signature biomarker in various cancers, where it accumulates as a result of mutations in isocitrate dehydrogenase (IDH). The metabolic source of 2-HG, in a wide variety of cancers, dictates both its generation and also potential therapeutic strategies, but this remains difficult to access in vivo. Here, utilizing patient-derived chondrosarcoma cells harboring endogenous mutations in IDH1 and IDH2, we report that 2-HG can be rapidly generated from glutamine in vitro. Then, using hyperpolarized magnetic resonance imaging (HP-MRI), we demonstrate that in vivo HP [1-13C] glutamine can be used to non-invasively measure glutamine-derived HP 2-HG production. This can be readily modulated utilizing a selective IDH1 inhibitor, opening the door to targeting glutamine-derived 2-HG therapeutically. Rapid rates of HP 2-HG generation in vivo further demonstrate that, in a context-dependent manner, glutamine can be a primary carbon source for 2-HG production in mutant IDH tumors.

Hyperpolarized 13C pyruvate mouse brain metabolism with absorptive-mode EPSI at 1T.

The expected signal in echo-planar spectroscopic imaging experiments was explicitly modeled jointly in spatial and spectral dimensions. Using this as a basis, absorptive-mode type detection can be achieved by appropriate choice of spectral delays and post-processing techniques. We discuss the effects of gradient imperfections and demonstrate the implementation of this sequence at low field (1.05T), with application to hyperpolarized [1-13C] pyruvate imaging of the mouse brain. The sequence achieves sufficient signal-to-noise to monitor the conversion of hyperpolarized [1-13C] pyruvate to lactate in the mouse brain. Hyperpolarized pyruvate imaging of mouse brain metabolism using an absorptive-mode EPSI sequence can be applied to more sophisticated murine disease and treatment models. The simple modifications presented in this work, which permit absorptive-mode detection, are directly translatable to human clinical imaging and generate improved absorptive-mode spectra without the need for refocusing pulses.

Sampling Hyperpolarized Molecules Utilizing a 1 Tesla Permanent Magnetic Field.

Hyperpolarized magnetic resonance spectroscopy (HP MRS) using dynamic nuclear polarization (DNP) is a technique that has greatly enhanced the sensitivity of detecting (13)C nuclei. However, the HP MRS polarization decays in the liquid state according to the spin-lattice relaxation time (T1) of the nucleus. Sampling of the signal also destroys polarization, resulting in a limited temporal ability to observe biologically interesting reactions. In this study, we demonstrate that sampling hyperpolarized signals using a permanent magnet at 1 Tesla (1T) is a simple and cost-effective method to increase T1s without sacrificing signal-to-noise. Biologically-relevant information may be obtained with a permanent magnet using enzyme solutions and in whole cells. Of significance, our findings indicate that changes in pyruvate metabolism can also be quantified in a xenograft model at this field strength.

Closed-Bore Interventional MRI: Percutaneous Biopsies and Ablations.

OBJECTIVE: The purpose of this article is to review clinical applications and technologic development of MRI-guided percutaneous interventions performed in closed-bore MRI scanners. CONCLUSION: Interventional MRI has rapidly adapted to the closed-bore environment. New tools are being developed to facilitate the use of MRI-guided procedures, and cost-effectiveness studies are exploring the economics of interventional MRI.

High-resolution, three-dimensional diffusion-weighted breast imaging using DESS.

PURPOSE: To evaluate the use of the double-echo steady-state (DESS) sequence for acquiring high-resolution breast images with diffusion and T2 weighting. MATERIALS AND METHODS: Phantom scans were used to verify the T2 and diffusion weighting of the DESS sequence. Image distortion was evaluated in volunteers by comparing DESS images and conventional diffusion-weighted images (DWI) to spoiled gradient-echo images. The DESS sequence was added to a standard clinical protocol, and the resulting patient images were used to evaluate overall image quality and image contrast in lesions. RESULTS: The diffusion weighting of the DESS sequence can be easily modulated by changing the spoiler gradient area and flip angle. Radiologists rated DESS images as having higher resolution and less distortion than conventional DWI. Lesion-to-tissue contrast ratios are strongly correlated between DWI and DESS images (R=0.83) and between T2-weighted fast spin-echo and DESS images (R=0.80). CONCLUSION: The DESS sequence is able to acquire high-resolution 3D diffusion- and T2-weighted images in short scan times, with image quality that facilitates morphological assessment of lesions.

Simultaneous estimation of T(2) and apparent diffusion coefficient in human articular cartilage in vivo with a modified three-dimensional double echo steady state (DESS) sequence at 3 T.

T(2) mapping and diffusion-weighted imaging complement morphological imaging for assessing cartilage disease and injury. The double echo steady state sequence has been used for morphological imaging and generates two echoes with markedly different T(2) and diffusion weighting. Modifying the spoiler gradient area and flip angle of the double echo steady state sequence allows greater control of the diffusion weighting of both echoes. Data from two acquisitions with different spoiler gradient areas and flip angles are used to simultaneously estimate the T(2) and apparent diffusion coefficient of each voxel. This method is verified in phantoms and validated in vivo in the knee; estimates from different regions of interest in the phantoms and cartilage are compared to those obtained using standard spin-echo methods. The Pearson correlations were 0.984 for T(2) (∼2% relative difference between spin-echo and double echo steady state estimates) and 0.997 for apparent diffusion coefficient (˜1% relative difference between spin-echo and double echo steady state estimates) for the phantom study and 0.989 for T(2) and 0.987 for apparent diffusion coefficient in regions of interest in the human knee in vivo. High accuracy for simultaneous three-dimensional T(2) and apparent diffusion coefficient measurements are demonstrated, while also providing morphologic three-dimensional images without blurring or distortion in reasonable scan times.