Dynamic T 2 * relaxometry of hyperpolarized [1-13 C]pyruvate MRI in the human brain and kidneys.

PURPOSE: This study aimed to quantify T 2 * $$ {T}_2^{\ast } $$ for hyperpolarized [1-13 C]pyruvate and metabolites in the healthy human brain and renal cell carcinoma (RCC) patients at 3 T. METHODS: Dynamic T 2 * $$ {T}_2^{\ast } $$ values were measured with a metabolite-specific multi-echo spiral sequence. The dynamic T 2 * $$ {T}_2^{\ast } $$ of [1-13 C]pyruvate, [1-13 C]lactate, and 13 C-bicarbonate was estimated in regions of interest in the whole brain, sinus vein, gray matter, and white matter in healthy volunteers, as well as in kidney tumors and the contralateral healthy kidneys in a separate group of RCC patients. T 2 * $$ {T}_2^{\ast } $$ was fit using a mono-exponential function; and metabolism was quantified using pyruvate-to-lactate conversion rate maps and lactate-to-pyruvate ratio maps, which were compared with and without an estimated T 2 * $$ {T}_2^{\ast } $$ correction. RESULTS: The T 2 * $$ {T}_2^{\ast } $$ of pyruvate was shown to vary during the acquisition, whereas the T 2 * $$ {T}_2^{\ast } $$ of lactate and bicarbonate were relatively constant through time and across the organs studied. The T 2 * $$ {T}_2^{\ast } $$ of lactate was similar in gray matter (29.75 ± 1.04 ms), white matter (32.89 ± 0.9 ms), healthy kidney (34.61 ± 4.07 ms), and kidney tumor (33.01 ± 2.31 ms); and the T 2 * $$ {T}_2^{\ast } $$ of bicarbonate was different between whole-brain (108.17 ± 14.05 ms) and healthy kidney (58.45 ± 6.63 ms). The T 2 * $$ {T}_2^{\ast } $$ of pyruvate had similar trends in both brain and RCC studies, reducing from 75.56 ± 2.23 ms to 22.24 ± 1.24 ms in the brain and reducing from 122.72 ± 9.86 ms to 57.38 ± 7.65 ms in the kidneys. CONCLUSION: Multi-echo dynamic imaging can quantify T 2 * $$ {T}_2^{\ast } $$ and metabolism in a single integrated acquisition. Clear differences were observed in the T 2 * $$ {T}_2^{\ast } $$ of metabolites and in their behavior throughout the timecourse.

Hyperpolarized 13 C metabolic imaging of the human abdomen with spatiotemporal denoising.

PURPOSE: Improving the quality and maintaining the fidelity of large coverage abdominal hyperpolarized (HP) 13 C MRI studies with a patch based global-local higher-order singular value decomposition (GL-HOVSD) spatiotemporal denoising approach. METHODS: Denoising performance was first evaluated using the simulated [1-13 C]pyruvate dynamics at different noise levels to determine optimal kglobal and klocal parameters. The GL-HOSVD spatiotemporal denoising method with the optimized parameters was then applied to two HP [1-13 C]pyruvate EPI abdominal human cohorts (n = 7 healthy volunteers and n = 8 pancreatic cancer patients). RESULTS: The parameterization of kglobal = 0.2 and klocal = 0.9 denoises abdominal HP data while retaining image fidelity when evaluated by RMSE. The kPX (conversion rate of pyruvate-to-metabolite, X = lactate or alanine) difference was shown to be <20% with respect to ground-truth metabolic conversion rates when there is adequate SNR (SNRAUC > 5) for downstream metabolites. In both human cohorts, there was a greater than nine-fold gain in peak [1-13 C]pyruvate, [1-13 C]lactate, and [1-13 C]alanine apparent SNRAUC . The improvement in metabolite SNR enabled a more robust quantification of kPL and kPA . After denoising, we observed a 2.1 ± 0.4 and 4.8 ± 2.5-fold increase in the number of voxels reliably fit across abdominal FOVs for kPL and kPA quantification maps. CONCLUSION: Spatiotemporal denoising greatly improves visualization of low SNR metabolites particularly [1-13 C]alanine and quantification of [1-13 C]pyruvate metabolism in large FOV HP 13 C MRI studies of the human abdomen.

Current methods for hyperpolarized [1-13C]pyruvate MRI human studies.

MRI with hyperpolarized (HP) 13C agents, also known as HP 13C MRI, can measure processes such as localized metabolism that is altered in numerous cancers, liver, heart, kidney diseases, and more. It has been translated into human studies during the past 10 years, with recent rapid growth in studies largely based on increasing availability of HP agent preparation methods suitable for use in humans. This paper aims to capture the current successful practices for HP MRI human studies with [1-13C]pyruvate-by far the most commonly used agent, which sits at a key metabolic junction in glycolysis. The paper is divided into four major topic areas: (1) HP 13C-pyruvate preparation; (2) MRI system setup and calibrations; (3) data acquisition and image reconstruction; and (4) data analysis and quantification. In each area, we identified the key components for a successful study, summarized both published studies and current practices, and discuss evidence gaps, strengths, and limitations. This paper is the output of the "HP 13C MRI Consensus Group" as well as the ISMRM Hyperpolarized Media MR and Hyperpolarized Methods and Equipment study groups. It further aims to provide a comprehensive reference for future consensus, building as the field continues to advance human studies with this metabolic imaging modality.

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.

Hyperpolarized [2-13C]pyruvate MR molecular imaging with whole brain coverage.

Hyperpolarized (HP) 13C Magnetic Resonance Imaging (MRI) was applied for the first time to image and quantify the uptake and metabolism of [2-13C]pyruvate in the human brain to provide new metabolic information on cerebral energy metabolism. HP [2-13C]pyruvate was injected intravenously and imaged in 5 healthy human volunteer exams with whole brain coverage in a 1-minute acquisition using a specialized spectral-spatial multi-slice echoplanar imaging (EPI) pulse sequence to acquire 13C-labeled volumetric and dynamic images of [2-13C]pyruvate and downstream metabolites [5-13C]glutamate and [2-13C]lactate. Metabolic ratios and apparent conversion rates of pyruvate-to-lactate (kPL) and pyruvate-to-glutamate (kPG) were quantified to investigate simultaneously glycolytic and oxidative metabolism in a single injection.

A user independent denoising method for x-nuclei MRI and MRS.

PURPOSE: X-nuclei (also called non-proton MRI) MRI and spectroscopy are limited by the intrinsic low SNR as compared to conventional proton imaging. Clinical translation of x-nuclei examination warrants the need of a robust and versatile tool improving image quality for diagnostic use. In this work, we compare a novel denoising method with fewer inputs to the current state-of-the-art denoising method. METHODS: Denoising approaches were compared on human acquisitions of sodium (23 Na) brain, deuterium (2 H) brain, carbon (13 C) heart and brain, and simulated dynamic hyperpolarized 13 C brain scans, with and without additional noise. The current state-of-the-art denoising method Global-local higher order singular value decomposition (GL-HOSVD) was compared to the few-input method tensor Marchenko-Pastur principal component analysis (tMPPCA). Noise-removal was quantified by residual distributions, and statistical analyses evaluated the differences in mean-square-error and Bland-Altman analysis to quantify agreement between original and denoised results of noise-added data. RESULTS: GL-HOSVD and tMPPCA showed similar performance for the variety of x-nuclei data analyzed in this work, with tMPPCA removing ˜5% more noise on average over GL-HOSVD. The mean ratio between noise-added and denoising reproducibility coefficients of the Bland-Altman analysis when compared to the original are also similar for the two methods with 3.09 ± 1.03 and 2.83 ± 0.79 for GL-HOSVD and tMPPCA, respectively. CONCLUSION: The strength of tMPPCA lies in the few-input approach, which generalizes well to different data sources. This makes the use of tMPPCA denoising a robust and versatile tool in x-nuclei imaging improvements and the preferred denoising method.

Model-constrained reconstruction accelerated with Fourier-based undersampling for hyperpolarized [1-13 C] pyruvate imaging.

PURPOSE: Model-constrained reconstruction with Fourier-based undersampling (MoReFUn) is introduced to accelerate the acquisition of dynamic MRI using hyperpolarized [1-13 C]-pyruvate. METHODS: The MoReFUn method resolves spatial aliasing using constraints introduced by a pharmacokinetic model that describes the signal evolution of both pyruvate and lactate. Acceleration was evaluated on three single-channel data sets: a numerical digital phantom that is used to validate the accuracy of reconstruction and model parameter restoration under various SNR and undersampling ratios, prospectively and retrospectively sampled data of an in vitro dynamic multispectral phantom, and retrospectively undersampled imaging data from a prostate cancer patient to test the fidelity of reconstructed metabolite time series. RESULTS: All three data sets showed successful reconstruction using MoReFUn. In simulation and retrospective phantom data, the restored time series of pyruvate and lactate maintained the image details, and the mean square residual error of the accelerated reconstruction increased only slightly (< 10%) at a reduction factor up to 8. In prostate data, the quantitative estimation of the conversion-rate constant of pyruvate to lactate was achieved with high accuracy of less than 10% error at a reduction factor of 2 compared with the conversion rate derived from unaccelerated data. CONCLUSION: The MoReFUn technique can be used as an effective and reliable imaging acceleration method for metabolic imaging using hyperpolarized [1-13 C]-pyruvate.

Investigating cerebral perfusion with high resolution hyperpolarized [1-13 C]pyruvate MRI.

PURPOSE: To investigate high-resolution hyperpolarized (HP) 13 C pyruvate MRI for measuring cerebral perfusion in the human brain. METHODS: HP [1-13 C]pyruvate MRI was acquired in five healthy volunteers with a multi-resolution EPI sequence with 7.5 × 7.5 mm2 resolution for pyruvate. Perfusion parameters were calculated from pyruvate MRI using block-circulant singular value decomposition and compared to relative cerebral blood flow calculated from arterial spin labeling (ASL). To examine regional perfusion patterns, correlations between pyruvate and ASL perfusion were performed for whole brain, gray matter, and white matter voxels. RESULTS: High resolution 7.5 × 7.5 mm2 pyruvate images were used to obtain relative cerebral blood flow (rCBF) values that were significantly positively correlated with ASL rCBF values (r = 0.48, 0.20, 0.28 for whole brain, gray matter, and white matter voxels respectively). Whole brain voxels exhibited the highest correlation between pyruvate and ASL perfusion, and there were distinct regional patterns of relatively high ASL and low pyruvate normalized rCBF found across subjects. CONCLUSION: Acquiring HP 13 C pyruvate metabolic images at higher resolution allows for finer spatial delineation of brain structures and can be used to obtain cerebral perfusion parameters. Pyruvate perfusion parameters were positively correlated to proton ASL perfusion values, indicating a relationship between the two perfusion measures. This HP 13 C study demonstrated that hyperpolarized pyruvate MRI can assess cerebral metabolism and perfusion within the same study.

Hyperpolarized 13 C Metabolic MRI of Patients with Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is the third leading cause of cancer-related death in the United States. However, early response assessment using the current approach of measuring changes in tumor size on computed tomography (CT) or MRI is challenging. PURPOSE: To investigate the feasibility of hyperpolarized (HP) [1-13 C]pyruvate MRI to quantify metabolism in the normal appearing pancreas and PDA, and to assess changes in PDA metabolism following systemic chemotherapy. STUDY TYPE: Prospective. SUBJECTS: Six patients (65.0 ± 7.6 years, 2 females) with locally advanced or metastatic PDA enrolled prior to starting a new line of systemic chemotherapy. FIELD STRENGTH/SEQUENCE: 3-T, T1-weighted gradient echo, metabolite-selective 13 C echoplanar imaging. ASSESSMENT: Time-resolved HP [1-13 C]pyruvate data were acquired before (N = 6) and 4-weeks after (N = 3) treatment initiation. Pyruvate metabolism, as quantified by pharmacokinetic modeling and metabolite area-under-the-curve ratios, was assessed in manually segmented PDA and normal appearing pancreas ROIs (N = 5). The change in tumor metabolism before and 4-weeks after treatment initiation was assessed in primary PDA (N = 2) and liver metastases (N = 1), and was compared to objective tumor response defined by response evaluation criteria in solid tumors (RECIST) on subsequent CTs. STATISTICAL TESTS: Descriptive tests (mean ± standard deviation), model fit error for pharmacokinetic rate constants. RESULTS: Primary PDA showed reduced alanine-to-lactate ratios when compared to normal pancreas, due to increased lactate-to-pyruvate or reduced alanine-to-pyruvate ratios. Of the three patients who received HP [1-13 C]pyruvate MRI before and 4-weeks after treatment initiation, one patient had a primary tumor with early metabolic response (increase in alanine-to-lactate) and subsequent partial response according to RECIST, one patient had a primary tumor with relatively stable metabolism and subsequent stable disease by RECIST, and one patient had metastatic PDA with increase in lactate-to-pyruvate of the liver metastases and corresponding progressive disease according to RECIST. DATA CONCLUSION: Altered pyruvate metabolism with increased lactate or reduced alanine was observed in the primary tumor. Early metabolic response assessed at 4-weeks after treatment initiation correlated with subsequent objective tumor response assessed using RECIST. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

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.

Sodium in the skin: a summary of the physiology and a scoping review of disease associations.

A large and growing body of research suggests that the skin plays an important role in regulating total body sodium, challenging traditional models of sodium homeostasis that focused exclusively on blood pressure and the kidney. In addition, skin sodium may help to prevent water loss and facilitate macrophage-driven antimicrobial host defence, but may also trigger immune dysregulation via upregulation of proinflammatory markers and downregulation of anti-inflammatory processes. We performed a systematic search of PubMed for published literature on skin sodium and disease outcomes and found that skin sodium concentration is increased in patients with cardiometabolic conditions including hypertension, diabetes and end-stage renal disease; autoimmune conditions including multiple sclerosis and systemic sclerosis; and dermatological conditions including atopic dermatitis, psoriasis and lipoedema. Several patient characteristics are associated with increased skin sodium concentration including older age and male sex. Animal evidence suggests that increased salt intake results in higher skin sodium levels; however, there are conflicting results from small trials in humans. Additionally, limited data suggest that pharmaceuticals such as diuretics and sodium-glucose co-transporter-2 inhibitors approved for diabetes, as well as haemodialysis may reduce skin sodium levels. In summary, emerging research supports an important role for skin sodium in physiological processes related to osmoregulation and immunity. With the advent of new noninvasive magnetic resonance imaging measurement techniques and continued research on skin sodium, it may emerge as a marker of immune-mediated disease activity or a potential therapeutic target.

Kinetic analysis of multi-resolution hyperpolarized 13 C human brain MRI to study cerebral metabolism.

PURPOSE: To investigate multi-resolution hyperpolarized (HP) 13 C pyruvate MRI for measuring kinetic conversion rates in the human brain. METHODS: HP [1-13 C]pyruvate MRI was acquired in 6 subjects with a multi-resolution EPI sequence at 7.5 × 7.5 mm2 resolution for pyruvate and 15 × 15 mm2 resolution for lactate and bicarbonate. With the same lactate data, 2 quantitative maps of pyruvate-to-lactate conversion (kPL ) maps were generated: 1 using 7.5 × 7.5 mm2 resolution pyruvate data and the other using synthetic 15 × 15 mm2 resolution pyruvate data to simulate a standard constant resolution acquisition. To examine local kPL values, 4 voxels were manually selected in each study representing brain tissue near arteries, brain tissue near veins, white matter, and gray matter. RESULTS: High resolution 7.5 × 7.5 mm2 pyruvate images increased the spatial delineation of brain structures and decreased partial volume effects compared to coarser resolution 15 × 15 mm2 pyruvate images. Voxels near arteries, veins and in white matter exhibited higher calculated kPL for multi-resolution images. CONCLUSION: Acquiring HP 13 C pyruvate metabolic data with a multi-resolution approach minimized partial volume effects from vascular pyruvate signals while maintaining the SNR of downstream metabolites. Higher resolution pyruvate images for kinetic fitting resulted in increased kinetic rate values, particularly around the superior sagittal sinus and cerebral arteries, by reducing extracellular pyruvate signal contributions from adjacent blood vessels. This HP 13 C study showed that acquiring pyruvate with finer resolution improved the quantification of kinetic rates throughout the human brain.

Development of specialized magnetic resonance acquisition techniques for human hyperpolarized [13 C,15 N2 ]urea + [1-13 C]pyruvate simultaneous perfusion and metabolic imaging.

PURPOSE: This study aimed to develop and demonstrate the in vivo feasibility of a 3D stack-of-spiral balanced steady-state free precession(3D-bSSFP) urea sequence, interleaved with a metabolite-specific gradient echo (GRE) sequence for pyruvate and metabolic products, for improving the SNR and spatial resolution of the first hyperpolarized 13 C-MRI human study with injection of co-hyperpolarized [1-13 C]pyruvate and [13 C,15 N2 ]urea. METHODS: A metabolite-specific bSSFP urea imaging sequence was designed using a urea-specific excitation pulse, optimized TR, and 3D stack-of-spiral readouts. Simulations and phantom studies were performed to validate the spectral response of the sequence. The image quality of urea data acquired by the 3D-bSSFP sequence and the 2D-GRE sequence was evaluated with 2 identical injections of co-hyperpolarized [1-13 C]pyruvate and [13 C,15 N2 ]urea formula in a rat. Subsequently, the feasibility of the acquisition strategy was validated in a prostate cancer patient. RESULTS: Simulations and phantom studies demonstrated that 3D-bSSFP sequence achieved urea-only excitation, while minimally perturbing other metabolites (<1%). An animal study demonstrated that compared to GRE, bSSFP sequence provided an ∼2.5-fold improvement in SNR without perturbing urea or pyruvate kinetics, and bSSFP approach with a shorter spiral readout reduced blurring artifacts caused by J-coupling of [13 C,15 N2 ]urea. The human study demonstrated the in vivo feasibility and data quality of the acquisition strategy. CONCLUSION: The 3D-bSSFP urea sequence with a stack-of-spiral acquisition demonstrated significantly increased SNR and image quality for [13 C,15 N2 ]urea in co-hyperpolarized [1-13 C]pyruvate and [13 C,15 N2 ]urea imaging studies. This work lays the foundation for future human studies to achieve high-quality and high-SNR metabolism and perfusion images.

Clinical translation of hyperpolarized 13 C pyruvate and urea MRI for simultaneous metabolic and perfusion imaging.

PURPOSE: The combined hyperpolarized (HP) 13 C pyruvate and urea MRI has provided a simultaneous assessment of glycolytic metabolism and tissue perfusion for improved cancer diagnosis and therapeutic evaluation in preclinical studies. This work aims to translate this dual-probe HP imaging technique to clinical research. METHODS: A co-polarization system was developed where [1-13 C]pyruvic acid (PA) and [13 C, 15 N2 ]urea in water solution were homogeneously mixed and polarized on a 5T SPINlab system. Physical and chemical characterizations and toxicology studies of the combined probe were performed. Simultaneous metabolic and perfusion imaging was performed on a 3T clinical MR scanner by alternatively applying a multi-slice 2D spiral sequence for [1-13 C]pyruvate and its downstream metabolites and a 3D balanced steady-state free precession (bSSFP) sequence for [13 C, 15 N2 ]urea. RESULTS: The combined PA/urea probe has a glass-formation ability similar to neat PA and can generate nearly 40% liquid-state 13 C polarization for both pyruvate and urea in 3-4 h. A standard operating procedure for routine on-site production was developed and validated to produce 40 mL injection product of approximately 150 mM pyruvate and 35 mM urea. The toxicology study demonstrated the safety profile of the combined probe. Dynamic metabolite-specific imaging of [1-13 C]pyruvate, [1-13 C]lactate, [1-13 C]alanine, and [13 C, 15 N2 ]urea was achieved with adequate spatial (2.6 mm × 2.6 mm) and temporal resolution (4.2 s), and urea images showed reduced off-resonance artifacts due to the JCN coupling. CONCLUSION: The reported technical development and translational studies will lead to the first-in-human dual-agent HP MRI study and mark the clinical translation of the first HP 13 C MRI probe after pyruvate.

Improving multiparametric MR-transrectal ultrasound guided fusion prostate biopsies with hyperpolarized 13 C pyruvate metabolic imaging: A technical development study.

PURPOSE: To develop techniques and establish a workflow using hyperpolarized carbon-13 (13 C) MRI and the pyruvate-to-lactate conversion rate (kPL ) biomarker to guide MR-transrectal ultrasound fusion prostate biopsies. METHODS: The integrated multiparametric MRI (mpMRI) exam consisted of a 1-min hyperpolarized 13 C-pyruvate EPI acquisition added to a conventional prostate mpMRI exam. Maps of kPL values were calculated, uploaded to a picture archiving and communication system and targeting platform, and displayed as color overlays on T2 -weighted anatomic images. Abdominal radiologists identified 13 C research biopsy targets based on the general recommendation of focal lesions with kPL >0.02(s-1 ), and created a targeting report for each study. Urologists conducted transrectal ultrasound-guided MR fusion biopsies, including the standard 1 H-mpMRI targets as well as 12-14 core systematic biopsies informed by the research 13 C-kPL targets. All biopsy results were included in the final pathology report and calculated toward clinical risk. RESULTS: This study demonstrated the safety and technical feasibility of integrating hyperpolarized 13 C metabolic targeting into routine 1 H-mpMRI and transrectal ultrasound fusion biopsy workflows, evaluated via 5 men (median age 71 years, prostate-specific antigen 8.4 ng/mL, Cancer of the Prostate Risk Assessment score 2) on active surveillance undergoing integrated scan and subsequent biopsies. No adverse event was reported. Median turnaround time was less than 3 days from scan to 13 C-kPL targeting, and scan-to-biopsy time was 2 weeks. Median number of 13 C targets was 1 (range: 1-2) per patient, measuring 1.0 cm (range: 0.6-1.9) in diameter, with a median kPL of 0.0319 s-1 (range: 0.0198-0.0410). CONCLUSIONS: This proof-of-concept work demonstrated the safety and feasibility of integrating hyperpolarized 13 C MR biomarkers to the standard mpMRI workflow to guide MR-transrectal ultrasound fusion biopsies.

Whole-Abdomen Metabolic Imaging of Healthy Volunteers Using Hyperpolarized [1-13 C]pyruvate MRI.

BACKGROUND: Hyperpolarized 13 C MRI quantitatively measures enzyme-catalyzed metabolism in cancer and metabolic diseases. Whole-abdomen imaging will permit dynamic metabolic imaging of several abdominal organs simultaneously in healthy and diseased subjects. PURPOSE: Image hyperpolarized [1-13 C]pyruvate and products in the abdomens of healthy volunteers, overcoming challenges of motion, magnetic field variations, and spatial coverage. Compare hyperpolarized [1-13 C]pyruvate metabolism across abdominal organs of healthy volunteers. STUDY TYPE: Prospective technical development. SUBJECTS: A total of 13 healthy volunteers (8 male), 21-64 years (median 36). FIELD STRENGTH/SEQUENCE: A 3 T. Proton: T1 -weighted spoiled gradient echo, T2 -weighted single-shot fast spin echo, multiecho fat/water imaging. Carbon-13: echo-planar spectroscopic imaging, metabolite-specific echo-planar imaging. ASSESSMENT: Transmit magnetic field was measured. Variations in main magnetic field (ΔB0 ) determined using multiecho proton acquisitions were compared to carbon-13 acquisitions. Changes in ΔB0 were measured after localized shimming. Improvements in metabolite signal-to-noise ratio were calculated. Whole-organ regions of interests were drawn over the liver, spleen, pancreas, and kidneys by a single investigator. Metabolite signals, time-to-peak, decay times, and mean first-order rate constants for pyruvate-to-lactate (kPL ) and alanine (kPA ) conversion were measured in each organ. STATISTICAL TESTS: Linear regression, one-sample Kolmogorov-Smirnov tests, paired t-tests, one-way ANOVA, Tukey's multiple comparisons tests. P ≤ 0.05 considered statistically significant. RESULTS: Proton ΔB0 maps correlated with carbon-13 ΔB0 maps (slope = 0.93, y-intercept = -2.88, R2  = 0.73). Localized shimming resulted in mean frequency offset within ±25 Hz for all organs. Metabolite SNR significantly increased after denoising. Mean kPL and kPA were highest in liver, followed by pancreas, spleen, and kidneys (all comparisons with liver were significant). DATA CONCLUSION: Whole-abdomen coverage with hyperpolarized carbon-13 MRI was feasible despite technical challenges. Multiecho gradient echo 1 H acquisitions accurately predicted chemical shifts observed using carbon-13 spectroscopy. Carbon-13 acquisitions benefited from local shimming. Metabolite energetics in the abdomen compiled for healthy volunteers can be used to design larger clinical trials in patients with metabolic diseases. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 1.

Metabolic imaging with hyperpolarized 13 C pyruvate magnetic resonance imaging in patients with renal tumors-Initial experience.

BACKGROUND: Optimal treatment selection for localized renal tumors is challenging because of their variable biologic behavior and limitations in the preoperative assessment of tumor aggressiveness. The authors investigated the emerging hyperpolarized (HP) 13 C magnetic resonance imaging (MRI) technique to noninvasively assess tumor lactate production, which is strongly associated with tumor aggressiveness. METHODS: Eleven patients with renal tumors underwent HP 13 C pyruvate MRI before surgical resection. Tumor 13 C pyruvate and 13 C lactate images were acquired dynamically. Five patients underwent 2 scans on the same day to assess the intrapatient reproducibility of HP 13 C pyruvate MRI. Tumor metabolic data were compared with histopathology findings. RESULTS: Eight patients had tumors with a sufficient metabolite signal-to-noise ratio for analysis; an insufficient tumor signal-to-noise ratio was noted in 2 patients, likely caused by poor tumor perfusion and, in 1 patient, because of technical errors. Of the 8 patients, 3 had high-grade clear cell renal cell carcinoma (ccRCC), 3 had low-grade ccRCC, and 2 had chromophobe RCC. There was a trend toward a higher lactate-to-pyruvate ratio in high-grade ccRCCs compared with low-grade ccRCCs. Both chromophobe RCCs had relatively high lactate-to-pyruvate ratios. Good reproducibility was noted across the 5 patients who underwent 2 HP 13 C pyruvate MRI scans on the same day. CONCLUSIONS: The current results demonstrate the feasibility of HP 13 C pyruvate MRI for investigating the metabolic phenotype of localized renal tumors. The initial data indicate good reproducibility of metabolite measurements. In addition, the metabolic data indicate a trend toward differentiating low-grade and high-grade ccRCCs, the most common subtype of renal cancer. LAY SUMMARY: Renal tumors are frequently discovered incidentally because of the increased use of medical imaging, but it is challenging to identify which aggressive tumors should be treated. A new metabolic imaging technique was applied to noninvasively predict renal tumor aggressiveness. The imaging results were compared with tumor samples taken during surgery and showed a trend toward differentiating between low-grade and high-grade clear cell renal cell carcinomas, which are the most common type of renal cancers.

55 Mn-based fiducial markers for rapid and automated RF coil localization for hyperpolarized 13 C MRI.

PURPOSE: To use fiducial markers containing manganese 55 to rapidly localize carbon 13 (13 C) RF coils for correcting images for B1 variation. METHODS: Hollow high-density polyethylene spheres were filled with 3M sodium permanganate and affixed to a rectangular 13 C-tuned RF coil. The relative positions of the markers and coil conductors were mapped using CT. Marker positions were measured by MRI using a series of 1D projections and automated peak detection. Once the coil location was determined, coil sensitivity was estimated using a quasi-static calculation. Simulations were performed to determine the minimum number of projections required for robust localization. Phantom experiments were used to confirm the accuracy of marker localization as well as the calculated coil sensitivity. Finally, in vivo validation was performed using hyperpolarized 13 C pyruvate in a rat model. RESULTS: In simulations, our algorithm was accurate in determining marker positions when at least 6 projections were used (RMSE 1.4 ± 0.9 mm). These estimates were verified in phantom experiments, where markers locations were determined with an RMS accuracy of 1.3 mm. A minimum SNR of 4 was required for automated detection to perform accurately. Computed coil sensitivity had a median error of 17% when taken over the entire measured area and 5.7% over a central region. In a rat, correction for nonuniform reception and flip angle was able to normalize the signals arising from asymmetrically positioned kidneys. CONCLUSION: Manganese 55 fiducial markers are an inexpensive and reliable method for rapidly localizing 13 C RF coils and correcting 13 C images for B1 variation without user intervention.

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.

Denoising of hyperpolarized 13 C MR images of the human brain using patch-based higher-order singular value decomposition.

PURPOSE: To improve hyperpolarized 13 C (HP-13 C) MRI by image denoising with a new approach, patch-based higher-order singular value decomposition (HOSVD). METHODS: The benefit of using a patch-based HOSVD method to denoise dynamic HP-13 C MR imaging data was investigated. Image quality and the accuracy of quantitative analyses following denoising were evaluated first using simulated data of [1-13 C]pyruvate and its metabolic product, [1-13 C]lactate, and compared the results to a global HOSVD method. The patch-based HOSVD method was then applied to healthy volunteer HP [1-13 C]pyruvate EPI studies. Voxel-wise kinetic modeling was performed on both non-denoised and denoised data to compare the number of voxels quantifiable based on SNR criteria and fitting error. RESULTS: Simulation results demonstrated an 8-fold increase in the calculated SNR of [1-13 C]pyruvate and [1-13 C]lactate with the patch-based HOSVD denoising. The voxel-wise quantification of kPL (pyruvate-to-lactate conversion rate) showed a 9-fold decrease in standard errors for the fitted kPL after denoising. The patch-based denoising performed superior to the global denoising in recovering kPL information. In volunteer data sets, [1-13 C]lactate and [13 C]bicarbonate signals became distinguishable from noise across captured time points with over a 5-fold apparent SNR gain. This resulted in >3-fold increase in the number of voxels quantifiable for mapping kPB (pyruvate-to-bicarbonate conversion rate) and whole brain coverage for mapping kPL . CONCLUSIONS: Sensitivity enhancement provided by this denoising significantly improved quantification of metabolite dynamics and could benefit future studies by improving image quality, enabling higher spatial resolution, and facilitating the extraction of metabolic information for clinical research.