Quantification of the in vivo brain ultrashort-T2* component in healthy volunteers.

PURPOSE: Recent work has shown MRI is able to measure and quantify signals of phospholipid membrane-bound protons associated with myelin in the human brain. This work seeks to develop an improved technique for characterizing this brain ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ component in vivo accounting for T 1 $$ {\mathrm{T}}_1 $$ weighting. METHODS: Data from ultrashort echo time scans from 16 healthy volunteers with variable flip angles (VFA) were collected and fitted into an advanced regression model to quantify signal fraction, relaxation time, and frequency shift of the ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ component. RESULTS: The fitted components show intra-subject differences of different white matter structures and significantly elevated ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ signal fraction in the corticospinal tracts measured at 0.09 versus 0.06 in other white matter structures and significantly elevated ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ frequency shift in the body of the corpus callosum at - $$ - $$ 1.5 versus - $$ - $$ 2.0 ppm in other white matter structures. CONCLUSION: The significantly different measured components and measured T 1 $$ {\mathrm{T}}_1 $$ relaxation time of the ultrashort- T 2 ∗ $$ {\mathrm{T}}_2\ast $$ component suggest that this method is picking up novel signals from phospholipid membrane-bound protons.

Probing human heart TCA cycle metabolism and response to glucose load using hyperpolarized [2-13 C]pyruvate MRS.

INTRODUCTION: The healthy heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2-13 C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes. This study aimed to develop methods, demonstrate feasibility for [2-13 C]pyruvate MRI in the human heart for the first time, and assess cardiac metabolic flexibility. METHODS: Good manufacturing practice [2-13 C]pyruvic acid was polarized in a 5 T polarizer for 2.5-3 h. Following dissolution, quality control parameters of HP pyruvate met all safety and sterility criteria for pharmacy release, prior to administration to study subjects. Three healthy subjects each received two HP injections and MR scans, first under fasting conditions, followed by oral glucose load. A 5 cm axial slab-selective spectroscopy approach was prescribed over the left ventricle and acquired at 3 s intervals on a 3 T clinical MRI scanner. RESULTS: The study protocol, which included HP substrate injection, MR scanning, and oral glucose load, was performed safely without adverse events. Key downstream metabolites of [2-13 C]pyruvate metabolism in cardiac myocytes include the glycolytic derivative [2-13 C]lactate, TCA-associated metabolite [5-13 C]glutamate, and [1-13 C]acetylcarnitine, catalyzed by carnitine acetyltransferase (CAT). After glucose load, 13 C-labeling of lactate, glutamate, and acetylcarnitine from 13 C-pyruvate increased by an average of 39.3%, 29.5%, and 114% respectively in the three subjects, which could result from increases in lactate dehydrogenase, pyruvate dehydrogenase, and CAT enzyme activity as well as TCA cycle flux (glucose oxidation). CONCLUSIONS: HP [2-13 C]pyruvate imaging is safe and permits noninvasive assessment of TCA cycle intermediates and the acetyl buffer, acetylcarnitine, which is not possible using HP [1-13 C]pyruvate. Cardiac metabolite measurement in the fasting/fed states provides information on cardiac metabolic flexibility and the acetylcarnitine pool.

Regional quantification of cardiac metabolism with hyperpolarized [1-13C]-pyruvate CMR evaluated in an oral glucose challenge.

BACKGROUND: The heart has metabolic flexibility, which is influenced by fed/fasting states, and pathologies such as myocardial ischemia and hypertrophic cardiomyopathy (HCM). Hyperpolarized (HP) 13C-pyruvate MRI is a promising new tool for non-invasive quantification of myocardial glycolytic and Krebs cycle flux. However, human studies of HP 13C-MRI have yet to demonstrate regional quantification of metabolism, which is important in regional ischemia and HCM patients with asymmetric septal/apical hypertrophy. METHODS: We developed and applied methods for whole-heart imaging of 13C-pyruvate, 13C-lactate and 13C-bicarbonate, following intravenous administration of [1-13C]-pyruvate. The image acquisition used an autonomous scanning method including bolus tracking, real-time magnetic field calibrations and metabolite-specific imaging. For quantification of metabolism, we evaluated 13C metabolite images, ratio metrics, and pharmacokinetic modeling to provide measurements of myocardial lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) mediated metabolic conversion in 5 healthy volunteers (fasting & 30 min following oral glucose load). RESULTS: We demonstrate whole heart coverage for dynamic measurement of pyruvate-to-lactate conversion via LDH and pyruvate-to-bicarbonate conversion via PDH at a resolution of 6 × 6 × 21 mm3 (13C-pyruvate) and 12 × 12 × 21 mm3 (13C-lactate, 13C-bicarbonate). 13C-pyruvate and 13C-lactate were detected simultaneously in the RV blood pool, immediately after intravenous injection, reflecting LDH activity in blood. In healthy volunteers, myocardial 13C-pyruvate-SNR, 13C-lactate-SNR, 13C-bicarbonate-SNR, 13C-lactate/pyruvate ratio, 13C-pyruvate-to-lactate conversion rate, kPL, and 13C-pyruvate-to-bicarbonate conversion rate, kPB, all had statistically significant increases following oral glucose challenge. kPB, reflecting PDH activity and pyruvate entering the Krebs Cycle, had the highest correlation with blood glucose levels and was statistically significant. CONCLUSIONS: We demonstrate first-in-human regional quantifications of cardiac metabolism by HP 13C-pyruvate MRI that aims to reflect LDH and PDH activity.

Regional quantification of cardiac metabolism with hyperpolarized [1-13C]-pyruvate MRI evaluated in an oral glucose challenge.

Background: The heart has metabolic flexibility, which is influenced by fed/fasting states, and pathologies such as myocardial ischemia and hypertrophic cardiomyopathy (HCM). Hyperpolarized (HP) 13C-pyruvate MRI is a promising new tool for non-invasive quantification of myocardial glycolytic and Krebs cycle flux. However, human studies of HP 13C-MRI have yet to demonstrate regional quantification of metabolism, which is important in regional ischemia and HCM patients with asymmetric septal/apical hypertrophy. Methods: We developed and applied methods for whole-heart imaging of 13C-pyruvate, 13C-lactate and 13C-bicarbonate, following intravenous administration of [1-13C]-pyruvate. The image acquisition used an autonomous scanning method including bolus tracking, real-time magnetic field calibrations and metabolite-specific imaging. For quantification of metabolism, we evaluated 13C metabolite images, ratio metrics, and pharmacokinetic modeling to provide measurements of myocardial lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH) mediated metabolic conversion in 5 healthy volunteers (fasting & 30 min following oral glucose load). Results: We demonstrate whole heart coverage for dynamic measurement of pyruvate-to-lactate conversion via LDH and pyruvate-to-bicarbonate conversion via PDH at a resolution of 6×6×21 mm3 (13C-pyruvate) and 12×12×21 mm3 (13C-lactate, 13C-bicarbonate) . 13C-pyruvate and 13C-lactate were detected simultaneously in the RV blood pool, immediately after intravenous injection, reflecting LDH activity in blood. In healthy volunteers, myocardial 13C-pyruvate-SNR, 13C-lactate-SNR, 13C-bicarbonate-SNR, 13C-lactate/pyruvate ratio, 13C-pyruvate-to-lactate conversion rate, kPL, and 13C-pyruvate-to-bicarbonate conversion rate, kPB, all had statistically significant increases following oral glucose challenge. kPB, reflecting PDH activity and pyruvate entering the Krebs Cycle, had the highest correlation with blood glucose levels and was statistically significant. Conclusions: We demonstrate first-in-human regional quantifications of cardiac metabolism by HP 13C-pyruvate MRI that aims to reflect LDH and PDH activity.

Probing Human Heart TCA Cycle Metabolism and Response to Glucose Load using Hyperpolarized [2-13C]Pyruvate MR Spectroscopy.

Introduction: The normal heart has remarkable metabolic flexibility that permits rapid switching between mitochondrial glucose oxidation and fatty acid (FA) oxidation to generate ATP. Loss of metabolic flexibility has been implicated in the genesis of contractile dysfunction seen in cardiomyopathy. Metabolic flexibility has been imaged in experimental models, using hyperpolarized (HP) [2-13C]pyruvate MRI, which enables interrogation of metabolites that reflect tricarboxylic acid (TCA) cycle flux in cardiac myocytes. This study aimed to develop methods, demonstrate feasibility for [2-13C]pyruvate MRI in the human heart for the first time, and assess cardiac metabolic flexibility. Methods: Good Manufacturing Practice [2-13C]pyruvic acid was polarized in a 5T polarizer for 2.5-3 hours. Following dissolution, QC parameters of HP pyruvate met all safety and sterility criteria for pharmacy release, prior to administration to study subjects. Three healthy subjects each received two HP injections and MR scans, first under fasting conditions, followed by oral glucose load. A 5cm axial slab-selective spectroscopy approach was prescribed over the left ventricle and acquired at 3s intervals on a 3T clinical MRI scanner. Results: The study protocol which included HP substrate injection, MR scanning and oral glucose load, was performed safely without adverse events. Key downstream metabolites of [2-13C]pyruvate metabolism in cardiac myocytes include the glycolytic derivative [2-13C]lactate, TCA-associated metabolite [5-13C]glutamate, and [1-13C]acetylcarnitine, catalyzed by carnitine acetyltransferase (CAT). After glucose load, 13C-labeling of lactate, glutamate, and acetylcarnitine from 13C-pyruvate increased by 39.3%, 29.5%, and 114%, respectively in the three subjects, that could result from increases in lactate dehydrogenase (LDH), pyruvate dehydrogenase (PDH), and CAT enzyme activity as well as TCA cycle flux (glucose oxidation). Conclusions: HP [2-13C]pyruvate imaging is safe and permits non-invasive assessment of TCA cycle intermediates and the acetyl buffer, acetylcarnitine, which is not possible using HP [1-13C]pyruvate. Cardiac metabolite measurement in the fasting/fed states provides information on cardiac metabolic flexibility and the acetylcarnitine pool.

Optimization in the space domain for density compensation with the nonuniform FFT.

The non-uniform Discrete Fourier Transform algorithm has shown great utility for reconstructing images from non-uniformly spaced Fourier samples in several imaging modalities. Due to the non-uniform spacing, some correction for the variable density of the samples must be made. Common methods for generating density compensation values are either sub-optimal or only consider a finite set of points in the optimization. This manuscript presents an algorithm for generating density compensation values from a set of Fourier samples that takes into account the point spread function over an entire rectangular region in the image domain. We show that the reconstructed images using the density compensation values of this method are of superior quality when compared to other standard methods. Results are shown with a numerical phantom and with magnetic resonance images of the abdomen and the knee.

Utilizing the Wavelet Transform's Structure in Compressed Sensing.

Compressed sensing has empowered quality image reconstruction with fewer data samples than previously thought possible. These techniques rely on a sparsifying linear transformation. The Daubechies wavelet transform is commonly used for this purpose. In this work, we take advantage of the structure of this wavelet transform and identify an affine transformation that increases the sparsity of the result. After inclusion of this affine transformation, we modify the resulting optimization problem to comply with the form of the Basis Pursuit Denoising problem. Finally, we show theoretically that this yields a lower bound on the error of the reconstruction and present results where solving this modified problem yields images of higher quality for the same sampling patterns using both magnetic resonance and optical images.

Specialized computational methods for denoising, B1 correction, and kinetic modeling in hyperpolarized 13 C MR EPSI studies of liver tumors.

PURPOSE: To develop a novel post-processing pipeline for hyperpolarized (HP) 13 C MRSI that integrates tensor denoising and B1+ correction to measure pyruvate-to-lactate conversion rates (kPL ) in patients with liver tumors. METHODS: Seven HP 13 C MR scans of progressing liver tumors were acquired using a custom 13 C surface transmit/receive coil and the echo-planar spectroscopic imaging (EPSI) data analysis included B0 correction, tensor rank truncation, and zero- and first-order phase corrections to recover metabolite signals that would otherwise be obscured by spectral noise as well as a correction for inhomogeneous transmit ( B1+ ) using a B1+ map aligned to the coil position for each patient scan. Processed HP data and corrected flip angles were analyzed with an inputless two-site exchange model to calculate kPL . RESULTS: Denoising averages SNR increases of pyruvate, lactate, and alanine were 37.4-, 34.0-, and 20.1-fold, respectively, with lactate and alanine dynamics most noticeably recovered and better defined. In agreement with Monte Carlo simulations, over-flipped regions underestimated kPL and under-flipped regions overestimated kPL . B1+ correction addressed this issue. CONCLUSION: The new HP 13 C EPSI post-processing pipeline integrated tensor denoising and B1+ correction to measure kPL in patients with liver tumors. These technical developments not only recovered metabolite signals in voxels that did not receive the prescribed flip angle, but also increased the extent and accuracy of kPL estimations throughout the tumor and adjacent regions including normal-appearing tissue and additional lesions.

Di-chromatic interpolation of magnetic resonance metabolic images.

OBJECTIVE: Magnetic resonance imaging with hyperpolarized contrast agents can provide unprecedented in vivo measurements of metabolism, but yields images that are lower resolution than that achieved with proton anatomical imaging. In order to spatially localize the metabolic activity, the metabolic image must be interpolated to the size of the proton image. The most common methods for choosing the unknown values rely exclusively on values of the original uninterpolated image. METHODS: In this work, we present an alternative method that uses the higher-resolution proton image to provide additional spatial structure. The interpolated image is the result of a convex optimization algorithm which is solved with the fast iterative shrinkage threshold algorithm (FISTA). RESULTS: Results are shown with images of hyperpolarized pyruvate, lactate, and bicarbonate using data of the heart and brain from healthy human volunteers, a healthy porcine heart, and a human with prostate cancer.

Fast Imaging for Hyperpolarized MR Metabolic Imaging.

MRI with hyperpolarized carbon-13 agents has created a new type of noninvasive, in vivo metabolic imaging that can be applied in cell, animal, and human studies. The use of 13 C-labeled agents, primarily [1-13 C]pyruvate, enables monitoring of key metabolic pathways with the ability to image substrate and products based on their chemical shift. Over 10 sites worldwide are now performing human studies with this new approach for studies of cancer, heart disease, liver disease, and kidney disease. Hyperpolarized metabolic imaging studies must be performed within several minutes following creation of the hyperpolarized agent due to irreversible decay of the net magnetization back to equilibrium, so fast imaging methods are critical. The imaging methods must include multiple metabolites, separated based on their chemical shift, which are also undergoing rapid metabolic conversion (via label exchange), further exacerbating the challenges of fast imaging. This review describes the state-of-the-art in fast imaging methods for hyperpolarized metabolic imaging. This includes the approach and tradeoffs between three major categories of fast imaging methods-fast spectroscopic imaging, model-based strategies, and metabolite specific imaging-as well additional options of parallel imaging, compressed sensing, tailored RF flip angles, refocused imaging methods, and calibration methods that can improve the scan coverage, speed, signal-to-noise ratio (SNR), resolution, and/or robustness of these studies. To date, these approaches have produced extremely promising initial human imaging results. Improvements to fast hyperpolarized metabolic imaging methods will provide better coverage, SNR, resolution, and reproducibility for future human imaging studies. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY STAGE: 1.

Fast variable density Poisson-disc sample generation with directional variation for compressed sensing in MRI.

We present a fast method for generating random samples according to a variable density poisson-disc distribution. A minimum parameter value is used to create a background grid array for keeping track of those points that might affect any new candidate point; this reduces the number of conflicts that must be checked before acceptance of a new point, thus reducing the number of computations required. We demonstrate the algorithm's ability to generate variable density poisson-disc sampling patterns according to a parameterized function, including patterns where the variations in density are a function of direction. We further show that these sampling patterns are appropriate for compressed sensing applications. Finally, we present a method to generate patterns with a specific acceleration rate.

Rosette Trajectories Enable Ungated, Motion-Robust, Simultaneous Cardiac and Liver T2 * Iron Assessment.

BACKGROUND: Quantitative T2 * MRI is the standard of care for the assessment of iron overload. However, patient motion corrupts T2 * estimates. PURPOSE: To develop and evaluate a motion-robust, simultaneous cardiac and liver T2 * imaging approach using non-Cartesian, rosette sampling and a model-based reconstruction as compared to clinical-standard Cartesian MRI. STUDY TYPE: Prospective. PHANTOM/POPULATION: Six ferumoxytol-containing phantoms (26-288 µg/mL). Eight healthy subjects and 18 patients referred for clinically indicated iron overload assessment. FIELD STRENGTH/SEQUENCE: 1.5T, 2D Cartesian and rosette gradient echo (GRE) ASSESSMENT: GRE T2 * values were validated in ferumoxytol phantoms. In healthy subjects, test-retest and spatial coefficient of variation (CoV) analysis was performed during three breathing conditions. Cartesian and rosette T2 * were compared using correlation and Bland-Altman analysis. Images were rated by three experienced radiologists on a 5-point scale. STATISTICAL TESTS: Linear regression, analysis of variance (ANOVA), and paired Student's t-testing were used to compare reproducibility and variability metrics in Cartesian and rosette scans. The Wilcoxon rank test was used to assess reader score comparisons and reader reliability was measured using intraclass correlation analysis. RESULTS: Rosette R2* (1/T2 *) was linearly correlated with ferumoxytol concentration (r2 = 1.00) and not significantly different than Cartesian values (P = 0.16). During breath-holding, ungated rosette liver and heart T2 * had lower spatial CoV (liver: 18.4 ± 9.3% Cartesian, 8.8% ± 3.4% rosette, P = 0.02, heart: 37.7% ± 14.3% Cartesian, 13.4% ± 1.7% rosette, P = 0.001) and higher-quality scores (liver: 3.3 [3.0-3.6] Cartesian, 4.7 [4.1-4.9] rosette, P = 0.005, heart: 3.0 [2.3-3] Cartesian, 4.5 [3.8-5.0] rosette, P = 0.005) compared to Cartesian values. During free-breathing and failed breath-holding, Cartesian images had very poor to average image quality with significant artifacts, whereas rosette remained very good, with minimal artifacts (P = 0.001). DATA CONCLUSION: Rosette k-sampling with a model-based reconstruction offers a clinically useful motion-robust T2 * mapping approach for iron quantification. J. MAGN. RESON. IMAGING 2020;52:1688-1698.

Automatically Determining the Confocal Parameters From OCT B-Scans for Quantification of the Attenuation Coefficients.

The attenuation coefficient is a relevant biomarker for many diagnostic medical applications. Recently, the Depth-Resolved Confocal (DRC) technique was developed to automatically estimate the attenuation coefficients from Optical Coherence Tomography (OCT) data with pixel-level resolution. However, DRC requires that the confocal function parameters (i.e., focal plane location and apparent Rayleigh range) be known a priori. In this paper, we present the autoConfocal algorithm: a simple, automatic method for estimating those parameters directly from OCT imagery when the focal plane is within the sample. We present autoConfocal+DRC results on phantom data, ex-vivo biological tissue data, and in-vivo clinical data.

Rapid compressed sensing reconstruction of 3D non-Cartesian MRI.

PURPOSE: Conventional non-Cartesian compressed sensing requires multiple nonuniform Fourier transforms every iteration, which is computationally expensive. Accordingly, time-consuming reconstructions have slowed the adoption of undersampled 3D non-Cartesian acquisitions into clinical protocols. In this work we investigate several approaches to minimize reconstruction times without sacrificing accuracy. METHODS: The reconstruction problem can be reformatted to exploit the Toeplitz structure of matrices that are evaluated every iteration, but it requires larger oversampling than what is strictly required by nonuniform Fourier transforms. Accordingly, we investigate relative speeds of the two approaches for various nonuniform Fourier transform kernel sizes and oversampling for both GPU and CPU implementations. Second, we introduce a method to minimize matrix sizes by estimating the image support. Finally, density compensation weights have been used as a preconditioning matrix to improve convergence, but this increases noise. We propose a more general approach to preconditioning that allows a trade-off between accuracy and convergence speed. RESULTS: When using a GPU, the Toeplitz approach was faster for all practical parameters. Second, it was found that properly accounting for image support can prevent aliasing errors with minimal impact on reconstruction time. Third, the proposed preconditioning scheme improved convergence rates by an order of magnitude with negligible impact on noise. CONCLUSION: With the proposed methods, 3D non-Cartesian compressed sensing with clinically relevant reconstruction times (<2 min) is feasible using practical computer resources. Magn Reson Med 79:2685-2692, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Formulation of image fusion as a constrained least squares optimization problem.

Fusing a lower resolution color image with a higher resolution monochrome image is a common practice in medical imaging. By incorporating spatial context and/or improving the signal-to-noise ratio, it provides clinicians with a single frame of the most complete information for diagnosis. In this paper, image fusion is formulated as a convex optimization problem that avoids image decomposition and permits operations at the pixel level. This results in a highly efficient and embarrassingly parallelizable algorithm based on widely available robust and simple numerical methods that realizes the fused image as the global minimizer of the convex optimization problem.

Robust dipstick urinalysis using a low-cost, micro-volume slipping manifold and mobile phone platform.

We introduce a novel manifold and companion software for dipstick urinalysis that eliminate many of the aspects that are traditionally plagued by user error: precise sample delivery, accurate readout timing, and controlled lighting conditions. The proposed all-acrylic slipping manifold is reusable, reliable, and low in cost. A simple timing mechanism ensures results are read out at the appropriate time. Results are obtained by capturing videos using a mobile phone and by analyzing them using custom-designed software. We show that the results obtained with the proposed device are as accurate and consistent as a properly executed dip-and-wipe method, the industry gold-standard, suggesting the potential for this strategy to enable confident urinalysis testing in home environments.

Automated, Depth-Resolved Estimation of the Attenuation Coefficient From Optical Coherence Tomography Data.

We present a method for automated, depth-resolved extraction of the attenuation coefficient from Optical Coherence Tomography (OCT) data. In contrast to previous automated, depth-resolved methods, the Depth-Resolved Confocal (DRC) technique derives an invertible mapping between the measured OCT intensity data and the attenuation coefficient while considering the confocal function and sensitivity fall-off, which are critical to ensure accurate measurements of the attenuation coefficient in practical settings (e.g., clinical endoscopy). We also show that further improvement of the estimated attenuation coefficient is possible by formulating image denoising as a convex optimization problem that we term Intensity Weighted Horizontal Total Variation (iwhTV). The performance and accuracy of DRC alone and DRC+iwhTV are validated with simulated data, optical phantoms, and ex-vivo porcine tissue. Our results suggest that implementation of DRC+iwhTV represents a novel way to improve OCT contrast for better tissue characterization through quantitative imaging.