First in-human evaluation of [1-13C]pyruvate in D2O for hyperpolarized MRI of the brain: A safety and feasibility study.

PURPOSE: To investigate the safety and value of hyperpolarized (HP) MRI of [1-13C]pyruvate in healthy volunteers using deuterium oxide (D2O) as a solvent. METHODS: Healthy volunteers (n = 5), were injected with HP [1-13C]pyruvate dissolved in D2O and imaged with a metabolite-specific 3D dual-echo dynamic EPI sequence at 3T at one site (Site 1). Volunteers were monitored following the procedure to assess safety. Image characteristics, including SNR, were compared to data acquired in a separate cohort using water as a solvent (n = 5) at another site (Site 2). The apparent spin-lattice relaxation time (T1) of [1-13C]pyruvate was determined both in vitro and in vivo from a mono-exponential fit to the image intensity at each time point of our dynamic data. RESULTS: All volunteers completed the study safely and reported no adverse effects. The use of D2O increased the T1 of [1-13C]pyruvate from 66.5 ± 1.6 s to 92.1 ± 5.1 s in vitro, which resulted in an increase in signal by a factor of 1.46 ± 0.03 at the time of injection (90 s after dissolution). The use of D2O also increased the apparent relaxation time of [1-13C]pyruvate by a factor of 1.4 ± 0.2 in vivo. After adjusting for inter-site SNR differences, the use of D2O was shown to increase image SNR by a factor of 2.6 ± 0.2 in humans. CONCLUSIONS: HP [1-13C]pyruvate in D2O is safe for human imaging and provides an increase in T1 and SNR that may improve image quality.

[6,6'-2 H2 ] fructose as a deuterium metabolic imaging probe in liver cancer.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. Imaging plays a crucial role in the early detection of HCC, although current methods are limited in their ability to characterize liver lesions. Most recently, deuterium metabolic imaging (DMI) has been demonstrated as a powerful technique for the imaging of metabolism in vivo. Here, we assess the metabolic flux of [6,6'-2 H2 ] fructose in cell cultures and in subcutaneous mouse models at 9.4 T. We compare these rates with the most widely used DMI probe, [6,6'-2 H2 ] glucose, exploring the possibility of developing 2 H fructose to overcome the limitations of glucose as a novel DMI probe for detecting liver tumors. Comparison of the in vitro metabolic rates implies their similar glycolytic metabolism in the TCA cycle due to comparable production rates of 2 H glutamate/glutamine (glx) for the two precursors, but overall higher glycolytic metabolism from 2 H glucose because of a higher production rate of 2 H lactate. In vivo kinetic studies suggest that HDO can serve as a robust reporter for the consumption of the precursors in liver tumors. As fructose is predominantly metabolized in the liver, deuterated water (HDO) produced from 2 H fructose is probably less contaminated from whole-body metabolism in comparison with glucose. Moreover, in studies of the normal liver, 2 H fructose is readily converted to 2 H glx, enabling the characterization of 2 H fructose kinetics. This overcomes a major limitation of previous 2 H glucose studies in the liver, which were unable to confidently discern metabolic flux due to overlapped signals of 2 H glucose and its metabolic product, 2 H glycogen. This suggests a unique role for 2 H fructose metabolism in HCC and the normal liver, making it a useful approach for assessing liver-related diseases and the progression to oncogenesis.

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.

Multicenter reproducibility of quantitative susceptibility mapping in a gadolinium phantom using MEDI+0 automatic zero referencing.

PURPOSE: To determine the reproducibility of quantitative susceptibility mapping at multiple sites on clinical and preclinical scanners (1.5 T, 3 T, 7 T, and 9.4 T) from different vendors (Siemens, GE, Philips, and Bruker) for standardization of multicenter studies. METHODS: Seven phantoms distributed from the core site, each containing 5 compartments with gadolinium solutions with fixed concentrations between 0.625 mM and 10 mM. Multi-echo gradient echo scans were performed at 1.5 T, 3 T, 7 T, and 9.4 T on 12 clinical and 3 preclinical scanners. DICOM images from the scans were processed into quantitative susceptibility maps using the Laplacian boundary value (LBV) and MEDI+0 automatic uniform reference algorithm. Region of interest (ROI) analyses were performed by a physicist to determine agreement between results from all sites. Measurement reproducibility was assessed using regression, Bland-Altman plots, and the intra-class correlation coefficient (ICC). RESULTS: Quantitative susceptibility mapping (QSM) from all scanners had similar, artifact-free visual appearance. Regression analysis showed a linear relationship between gadolinium concentrations and average QSM measurements for all phantoms (y = 350x - 0.0346, r2 >0.99). The SD of measurements increased almost linearly from 32 ppb to 230 ppb as the measured susceptibility increased from 0.26 ppm to 3.56 ppm. A Bland-Altman plot showed the bias, upper, and lower limits of agreement for all comparisons were -10, -210, and 200 ppb, respectively. The ICC was 0.991 with a 95% CI (0.973, 0.99). CONCLUSIONS: QSM shows excellent multicenter reproducibility for a large range of susceptibility values encountered in cranial and extra-cranial applications on a diverse set of scanner platforms.

Rapid automated liver quantitative susceptibility mapping.

BACKGROUND: Accurate measurement of the liver iron concentration (LIC) is needed to guide iron-chelating therapy for patients with transfusional iron overload. In this work, we investigate the feasibility of automated quantitative susceptibility mapping (QSM) to measure the LIC. PURPOSE: To develop a rapid, robust, and automated liver QSM for clinical practice. STUDY TYPE: Prospective. POPULATION: 13 healthy subjects and 22 patients. FIELD STRENGTH/SEQUENCES: 1.5 T and 3 T/3D multiecho gradient-recalled echo (GRE) sequence. ASSESSMENT: Data were acquired using a 3D GRE sequence with an out-of-phase echo spacing with respect to each other. All odd echoes that were in-phase (IP) were used to initialize the fat-water separation and field estimation (T2 *-IDEAL) before performing QSM. Liver QSM was generated through an automated pipeline without manual intervention. This IP echo-based initialization method was compared with an existing graph cuts initialization method (simultaneous phase unwrapping and removal of chemical shift, SPURS) in healthy subjects (n = 5). Reproducibility was assessed over four scanners at two field strengths from two manufacturers using healthy subjects (n = 8). Clinical feasibility was evaluated in patients (n = 22). STATISTICAL TESTS: IP and SPURS initialization methods in both healthy subjects and patients were compared using paired t-test and linear regression analysis to assess processing time and region of interest (ROI) measurements. Reproducibility of QSM, R2 *, and proton density fat fraction (PDFF) among the four different scanners was assessed using linear regression, Bland-Altman analysis, and the intraclass correlation coefficient (ICC). RESULTS: Liver QSM using the IP method was found to be ~5.5 times faster than SPURS (P < 0.05) in initializing T2 *-IDEAL with similar outputs. Liver QSM using the IP method were reproducibly generated in all four scanners (average coefficient of determination 0.95, average slope 0.90, average bias 0.002 ppm, 95% limits of agreement between -0.06 to 0.07 ppm, ICC 0.97). DATA CONCLUSION: Use of IP echo-based initialization enables robust water/fat separation and field estimation for automated, rapid, and reproducible liver QSM for clinical applications. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:725-732.

Free breathing three-dimensional cardiac quantitative susceptibility mapping for differential cardiac chamber blood oxygenation - initial validation in patients with cardiovascular disease inclusive of direct comparison to invasive catheterization.

BACKGROUND: Differential blood oxygenation between left (LV) and right ventricles (RV; ΔSaO2) is a key index of cardiac performance; LV dysfunction yields increased RV blood pool deoxygenation. Deoxyhemoglobin increases blood magnetic susceptibility, which can be measured using an emerging cardiovascular magnetic resonance (CMR) technique, Quantitative Susceptibility Mapping (QSM) - a concept previously demonstrated in healthy subjects using a breath-hold 2D imaging approach (2DBHQSM). This study tested utility of a novel 3D free-breathing QSM approach (3DNAVQSM) in normative controls, and validated 3DNAVQSM for non-invasive ΔSaO2 quantification in patients undergoing invasive cardiac catheterization (cath). METHODS: Initial control (n = 10) testing compared 2DBHQSM (ECG-triggered 2D gradient echo acquired at end-expiration) and 3DNAVQSM (ECG-triggered navigator gated gradient echo acquired in free breathing using a phase-ordered automatic window selection algorithm to partition data based on diaphragm position). Clinical testing was subsequently performed in patients being considered for cath, including 3DNAVQSM comparison to cine-CMR quantified LV function (n = 39), and invasive-cath quantified ΔSaO2 (n = 15). QSM was acquired using 3 T scanners; analysis was blinded to comparator tests (cine-CMR, cath). RESULTS: 3DNAVQSM generated interpretable QSM in all controls; 2DBHQSM was successful in 6/10. Among controls in whom both pulse sequences were successful, RV/LV susceptibility difference (and ΔSaO2) were not significantly different between 3DNAVQSM and 2DBHQSM (252 ± 39 ppb [17.5 ± 3.1%] vs. 211 ± 29 ppb [14.7 ± 2.0%]; p = 0.39). Acquisition times were 30% lower with 3DNAVQSM (4.7 ± 0.9 vs. 6.7 ± 0.5 min, p = 0.002), paralleling a trend towards lower LV mis-registration on 3DNAVQSM (p = 0.14). Among cardiac patients (63 ± 10y, 56% CAD) 3DNAVQSM was successful in 87% (34/39) and yielded higher ΔSaO2 (24.9 ± 6.1%) than in controls (p < 0.001). QSM-calculated ΔSaO2 was higher among patients with LV dysfunction as measured on cine-CMR based on left ventricular ejection fraction (29.4 ± 5.9% vs. 20.9 ± 5.7%, p < 0.001) or stroke volume (27.9 ± 7.5% vs. 22.4 ± 5.5%, p = 0.013). Cath measurements (n = 15) obtained within a mean interval of 4 ± 3 days from CMR demonstrated 3DNAVQSM to yield high correlation (r = 0.87, p < 0.001), small bias (- 0.1%), and good limits of agreement (±8.6%) with invasively measured ΔSaO2. CONCLUSION: 3DNAVQSM provides a novel means of assessing cardiac performance. Differential susceptibility between the LV and RV is increased in patients with cine-CMR evidence of LV systolic dysfunction; QSM-quantified ΔSaO2 yields high correlation and good agreement with the reference of invasively-quantified ΔSaO2.

Coherence enhancement in quantitative susceptibility mapping by means of anisotropic weighting in morphology enabled dipole inversion.

PURPOSE: To investigate an anisotropic structural prior in morphology enabled dipole inversion (MEDI) for improving accuracy in quantitative susceptibility mapping (QSM). THEORY AND METHODS: Anisotropic weighting (AW) was devised and implemented to incorporate orientation information into the edge agreement in the MEDI method. AW performance was compared with isotropic weighting by testing and validating on in vivo brain multiple orientation MRI data using COSMOS and the (33) component of the susceptibility tensor as reference. RESULTS: Suppressing streaking artifacts, AW improved not only QSM image quality but also accuracy in terms of RMSE (root mean square error), HFEN (high frequency error norm), SSIM (structural similarity index), and GDA (gradient direction agreement). In addition, it outperformed isotropic weighting in region of interest-based analysis. From a computational perspective, AW was as fast as isotropic weighting, taking approximately the same central processing unit times. CONCLUSION: Using AW in MEDI improves QSM accuracy compared with isotropic weighting. Magn Reson Med 79:1172-1180, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Cardiac quantitative susceptibility mapping (QSM) for heart chamber oxygenation.

PURPOSE: To demonstrate the feasibility of in vivo quantitative susceptibility mapping (QSM) in cardiac MRI and to show that mixed-venous oxygen saturation (SvO2 ) can be measured non-invasively using QSM. METHODS: Electrocardiographic-gated multi-echo 2D gradient echo data were collected at 1.5 T from 14 healthy volunteers during successive breath-holds. Phase wraps and fat chemical shift were removed using a graph-cut-based phase analysis and IDEAL in an iterative approach. The large susceptibility range from air in the lungs to blood in the heart was addressed by using the preconditioning approach in the dipole field inversion. SvO2 was calculated based on the difference in blood susceptibility between the right ventricle (RV) and left ventricle (LV). Cardiac QSM quality was assessed by two independent readers. RESULTS: Nine out of fourteen volunteers (64%) yielded interpretable cardiac QSM. QSM maps showed strong differential contrast between RV and LV blood with RV blood having higher susceptibility values (291.5 ± 32.4 ppb), which correspond to 78.3 ± 2.3% SvO2 . CONCLUSION: In vivo cardiac QSM is feasible and can be used to measure SvO2 , but improvements in data acquisition are needed. Magn Reson Med 79:1545-1552, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Magnetic susceptibility increases as diamagnetic molecules breakdown: Myelin digestion during multiple sclerosis lesion formation contributes to increase on QSM.

BACKGROUND: The pathological processes in the first weeks of multiple sclerosis (MS) lesion formation include myelin digestion that breaks chemical bonds in myelin lipid layers. This can increase lesion magnetic susceptibility, which is a potentially useful biomarker in MS patient management, but not yet investigated. PURPOSE: To understand and quantify the effects of myelin digestion on quantitative susceptibility mapping (QSM) of MS lesions. STUDY TYPE: Histological and QSM analyses on in vitro models of myelin breakdown and MS lesion formation in vivo. POPULATION/SPECIMENS: Acutely demyelinating white matter lesions from MS autopsy tissue were stained with the lipid dye oil red O. Myelin basic protein (MBP), a major membrane protein of myelin, was digested with trypsin. Purified human myelin was denatured with sodium dodecyl sulfate (SDS). QSM was performed on phantoms containing digestion products and untreated controls. In vivo QSM was performed on five MS patients with newly enhancing lesions, and then repeated within 2 weeks. FIELD STRENGTH/SEQUENCE: 3D T 2 * -weighted spoiled multiecho gradient echo scans performed at 3T. ASSESSMENT: Region of interest analyses were performed by a biochemist and a neuroradiologist to determine susceptibility changes on in vitro and in vivo QSM images. STATISTICAL TESTS: Not applicable. RESULTS: MBP degradation by trypsin increased the QSM measurement by an average of 112 ± 37 ppb, in excellent agreement with a theoretical estimate of 111 ppb. Degradation of human myelin by SDS increased the QSM measurement by 23 ppb. As MS lesions changed from gadolinium enhancing to nonenhancing over an average of 15.8 ± 3.7 days, their susceptibility increased by an average of 7.5 ± 6.3 ppb. DATA CONCLUSION: Myelin digestion in the early stages of MS lesion formation contributes to an increase in tissue susceptibility, detectable by QSM, as a lesion evolves from gadolinium enhancing to nonenhancing. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1281-1287.

Primal-dual and forward gradient implementation for quantitative susceptibility mapping.

PURPOSE: To investigate the computational aspects of the prior term in quantitative susceptibility mapping (QSM) by (i) comparing the Gauss-Newton conjugate gradient (GNCG) algorithm that uses numerical conditioning (ie, modifies the prior term) with a primal-dual (PD) formulation that avoids this, and (ii) carrying out a comparison between a central and forward difference scheme for the discretization of the prior term. THEORY AND METHODS: A spatially continuous formulation of the regularized QSM inversion problem and its PD formulation were derived. The Chambolle-Pock algorithm for PD was implemented and its convergence behavior was compared with that of GNCG for the original QSM. Forward and central difference schemes were compared in terms of the presence of checkerboard artifacts. All methods were tested and validated on a gadolinium phantom, ex vivo brain blocks, and in vivo brain MRI data with respect to COSMOS. RESULTS: The PD approach provided a faster convergence rate than GNCG. The GNCG convergence rate slowed considerably with smaller (more accurate) values of the conditioning parameter. Using a forward difference suppressed the checkerboard artifacts in QSM, as compared with the central difference. The accuracy of PD and GNCG were validated based on excellent correlation with COSMOS. CONCLUSIONS: The PD approach with forward difference for the gradient showed improved convergence and accuracy over the GNCG method using central difference. Magn Reson Med 78:2416-2427, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Clinical quantitative susceptibility mapping (QSM): Biometal imaging and its emerging roles in patient care.

Quantitative susceptibility mapping (QSM) has enabled magnetic resonance imaging (MRI) of tissue magnetic susceptibility to advance from simple qualitative detection of hypointense blooming artifacts to precise quantitative measurement of spatial biodistributions. QSM technology may be regarded to be sufficiently developed and validated to warrant wide dissemination for clinical applications of imaging isotropic susceptibility, which is dominated by metals in tissue, including iron and calcium. These biometals are highly regulated as vital participants in normal cellular biochemistry, and their dysregulations are manifested in a variety of pathologic processes. Therefore, QSM can be used to assess important tissue functions and disease. To facilitate QSM clinical translation, this review aims to organize pertinent information for implementing a robust automated QSM technique in routine MRI practice and to summarize available knowledge on diseases for which QSM can be used to improve patient care. In brief, QSM can be generated with postprocessing whenever gradient echo MRI is performed. QSM can be useful for diseases that involve neurodegeneration, inflammation, hemorrhage, abnormal oxygen consumption, substantial alterations in highly paramagnetic cellular iron, bone mineralization, or pathologic calcification; and for all disorders in which MRI diagnosis or surveillance requires contrast agent injection. Clinicians may consider integrating QSM into their routine imaging practices by including gradient echo sequences in all relevant MRI protocols. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2017;46:951-971.

Feasibility and reproducibility of whole brain myelin water mapping in 4 minutes using fast acquisition with spiral trajectory and adiabatic T2prep (FAST-T2) at 3T.

PURPOSE: To develop and measure the reproducibility of 4-min whole brain myelin water fraction (MWF) mapping using fast acquisition with spiral trajectory and T2prep (FAST-T2) sequence at 3T. METHODS: Experiments were performed on phantoms, 13 volunteers, and 16 patients with multiple sclerosis. MWF maps were extracted using a spatially constrained non-linear algorithm. The proposed adiabatic modified BIR-4 (mBIR-4) T2prep was compared with the conventional composite T2prep (COMP). The effect of reducing the number of echo times (TEs) from 15 to 6 (reducing scan time from 10 to 4 min) was evaluated. Reproducibility was assessed using correlation analysis, coefficient of variation (COV), and Bland-Altman plots. RESULTS: Compared with COMP, mBIR-4 provided more accurate T2 in phantoms and better MWF maps in human brains. Reducing the number of TEs had a negligible effect on MWF map quality, with a regional MWF difference of <0.8%. Regional MWFs obtained by repeated scans showed excellent correlation (R = 0.99), low COV (1.3%-2.4%), and negligible bias within ±1% limits of agreement. On a voxel-wise basis, the agreement remained strong (correlation R = 0.89 ± 0.03, bias = 0.01% ± 0.29%, limits of agreement = [-3.35% ± 0.73%, 3.33% ± 0.61%]). CONCLUSION: Whole brain MWF mapping with adiabatic FAST-T2 is feasible in 4 min and provides good intrasite reproducibility. Magn Reson Med 76:456-465, 2016. © 2015 Wiley Periodicals, Inc.

Multiple sclerosis lesion geometry in quantitative susceptibility mapping (QSM) and phase imaging.

PURPOSE: To demonstrate the phase and quantitative susceptibility mapping (QSM) patterns created by solid and shell spatial distributions of magnetic susceptibility in multiple sclerosis (MS) lesions. MATERIALS AND METHODS: Numerical simulations and experimental phantoms of solid- and shell-shaped magnetic susceptibility sources were used to generate magnitude, phase, and QSM images. Imaging of 20 consecutive MS patients was also reviewed for this Institutional Review Board (IRB)-approved MRI study to identify the appearance of solid and shell lesions on phase and QSM images. RESULTS: Solid and shell susceptibility sources were correctly reconstructed in QSM images, while the corresponding phase images depicted both geometries with shell-like patterns, making the underlying susceptibility distribution difficult to determine using phase alone. In MS patients, of the 60 largest lesions identified on T2 , 30 lesions were detected on both QSM and phase, of which 83% were solid and 17% were shells on QSM, and of which 30% were solid and 70% were shell on phase. Of the 21 shell-like lesions on phase, 76% appeared solid on QSM, 24% appeared shell on QSM. Of the five shell-like lesions on QSM, all were shell-like on phase. CONCLUSION: QSM accurately depicts both solid and shell patterns of magnetic susceptibility, while phase imaging fails to distinguish them.

Reproducibility of quantitative susceptibility mapping in the brain at two field strengths from two vendors.

PURPOSE: To assess the reproducibility of brain quantitative susceptibility mapping (QSM) in healthy subjects and in patients with multiple sclerosis (MS) on 1.5 and 3T scanners from two vendors. MATERIALS AND METHODS: Ten healthy volunteers and 10 patients were scanned twice on a 3T scanner from one vendor. The healthy volunteers were also scanned on a 1.5T scanner from the same vendor and on a 3T scanner from a second vendor. Similar imaging parameters were used for all scans. QSM images were reconstructed using a recently developed nonlinear morphology-enabled dipole inversion (MEDI) algorithm with L1 regularization. Region-of-interest (ROI) measurements were obtained for 20 major brain structures. Reproducibility was evaluated with voxel-wise and ROI-based Bland-Altman plots and linear correlation analysis. RESULTS: ROI-based QSM measurements showed excellent correlation between all repeated scans (correlation coefficient R ≥ 0.97), with a mean difference of less than 1.24 ppb (healthy subjects) and 4.15 ppb (patients), and 95% limits of agreements of within -25.5 to 25.0 ppb (healthy subjects) and -35.8 to 27.6 ppb (patients). Voxel-based QSM measurements had a good correlation (0.64 ≤ R ≤ 0.88) and limits of agreements of -60 to 60 ppb or less. CONCLUSION: Brain QSM measurements have good interscanner and same-scanner reproducibility for healthy and MS subjects, respectively, on the systems evaluated in this study.

Imaging brain glucose metabolism in vivo reveals propionate as a major anaplerotic substrate in pyruvate dehydrogenase deficiency.

A vexing problem in mitochondrial medicine is our limited capacity to evaluate the extent of brain disease in vivo. This limitation has hindered our understanding of the mechanisms that underlie the imaging phenotype in the brain of patients with mitochondrial diseases and our capacity to identify new biomarkers and therapeutic targets. Using comprehensive imaging, we analyzed the metabolic network that drives the brain structural and metabolic features of a mouse model of pyruvate dehydrogenase deficiency (PDHD). As the disease progressed in this animal, in vivo brain glucose uptake and glycolysis increased. Propionate served as a major anaplerotic substrate, predominantly metabolized by glial cells. A combination of propionate and a ketogenic diet extended lifespan, improved neuropathology, and ameliorated motor deficits in these animals. Together, intermediary metabolism is quite distinct in the PDHD brain-it plays a key role in the imaging phenotype, and it may uncover new treatments for this condition.

Series of first-order phase shifts correct lattice reduction of fractional K-space indices.

Lattice reduction of K-space acquisition at fractional indices refers to reducing the indices to the smallest nearby integer, thereby generating a Cartesian grid, allowing subsequent inverse Fourier Transformation. For band-limited signals, we show that the error in lattice reduction is equivalent to first order phase shifts, which in the infinite limit approaches W∞=φ(cotφ-i), where φ is a first-order phase shift vector. In general, the inverse corrections can be specified from the binary representation of the fractional part of the K-space indices. For non-uniform sparsity, we show how to incorporate the inverse corrections into compressed sensing reconstructions.

"Free super-resolution MRI by BRICKD slices".

BRICKD slices refers to shifting the field-of-view by fractional pixel increments between slices; half pixel shifts are analogous to the common brick wall layout. We demonstrate that compressed sensing reconstructions can harness the added information content of this approach and lead to improved performance over a simple stacked slices approach. The method is simple and could be easily implemented on a clinical imaging system.

Micro-Slab Coil Design for Hyperpolarized Metabolic Flux Analysis in Multiple Samples.

Abnormal metabolism is a hallmark of cancer cells. Accumulating evidence suggests that metabolic changes are likely to occur before other cellular responses in cancer cells upon drug treatment. Therefore, the metabolic activity or flux in cancer cells could be a potent biomarker for cancer detection and treatment monitoring. Magnetic resonance (MR)-based sensing technologies have been developed with hyperpolarized molecules for real-time flux analysis, but they still suffer from low sensitivity and throughput. To address this limitation, we have developed an innovative miniaturized MR coil, termed micro-slab MR coil, for simultaneous analysis of metabolic flux in multiple samples. Combining this approach with hyperpolarized probes, we were able to quantify the pyruvate-to-lactate flux in two different leukemic cell lines in a non-destructive manner, simultaneously. Further, we were able to rapidly assess flux changes with drug treatment in a single hyperpolarization experiment. This new multi-sample system has the potential to transform our ability to assess metabolic dynamics at scale.

Validation of MRI quantitative susceptibility mapping of superparamagnetic iron oxide nanoparticles for hyperthermia applications in live subjects.

The use of magnetic fluid hyperthermia (MFH) for cancer therapy has shown promise but lacks suitable methods for quantifying exogenous irons such as superparamagnetic iron oxide (SPIO) nanoparticles as a source of heat generation under an alternating magnetic field (AMF). Application of quantitative susceptibility mapping (QSM) technique to prediction of SPIO in preclinical models has been challenging due to a large variation of susceptibility values, chemical shift from tissue fat, and noisier data arising from the higher resolution required to visualize the anatomy of small animals. In this study, we developed a robust QSM for the SPIO ferumoxytol in live mice to examine its potential application in MFH for cancer therapy. We demonstrated that QSM was able to simultaneously detect high level ferumoxytol accumulation in the liver and low level localization near the periphery of tumors. Detection of ferumoxytol distribution in the body by QSM, however, required imaging prior to and post ferumoxytol injection to discriminate exogenous iron susceptibility from other endogenous sources. Intratumoral injection of ferumoxytol combined with AMF produced a ferumoxytol-dose dependent tumor killing. Histology of tumor sections corroborated QSM visualization of ferumoxytol distribution near the tumor periphery, and confirmed the spatial correlation of cell death with ferumoxytol distribution. Due to the dissipation of SPIOs from the injection site, quantitative mapping of SPIO distribution will aid in estimating a change in temperature in tissues, thereby maximizing MFH effects on tumors and minimizing side-effects by avoiding unwanted tissue heating.