RESUMEN
Tumor acidosis is one of the hallmarks indicating the initiation and progression of various cancers. Here, we present a protocol for preparing a hyperpolarized (HP) 13C-bicarbonate tissue pH MRI imaging contrast agent to detect aggressive tumors. We describe the steps for the formulation and polarization of a precursor molecule 13C-glycerol carbonate (13C-GLC), the post-dissolution reaction, and converting HP 13C-GLC to an injectable HP 13C-bicarbonate solution. We then detail procedures for MRI data acquisition to generate tumor pH maps for assessing tumor aggressiveness. For complete details on the use and execution of this protocol, please refer to Mu et al.1.
RESUMEN
Hyperpolarized (HP) 13C MRI has shown promise as a valuable modality for in vivo measurements of metabolism and is currently in human trials at 15 research sites worldwide. With this growth, it is important to adopt standardized data storage practices as it will allow sites to meaningfully compare data. In this paper, we (1) describe data that we believe should be stored and (2) demonstrate pipelines and methods that utilize the Digital Imaging and Communications in Medicine (DICOM) standard. This includes proposing a set of minimum set of information that is specific to HP 13C MRI studies. We then show where the majority of these can be fit into existing DICOM attributes, primarily via the "Contrast/Bolus" module. We also demonstrate pipelines for utilizing DICOM for HP 13C MRI. DICOM is the most common standard for clinical medical image storage and provides the flexibility to accommodate the unique aspects of HP 13C MRI, including the HP agent information but also spectroscopic and metabolite dimensions. The pipelines shown include creating DICOM objects for studies on human and animal imaging systems with various pulse sequences. We also show a python-based method to efficiently modify DICOM objects to incorporate the unique HP 13C MRI information that is not captured by existing pipelines. Moreover, we propose best practices for HP 13C MRI data storage that will support future multi-site trials, research studies, and technical developments of this imaging technique.
RESUMEN
PURPOSE: Metabolite-specific balanced SSFP (MS-bSSFP) sequences are increasingly used in hyperpolarized [1-13C]Pyruvate (HP 13C) MRI studies as they improve SNR by refocusing the magnetization each TR. Currently, pharmacokinetic models used to fit conversion rate constants, kPL and kPB, and rate constant maps do not account for differences in the signal evolution of MS-bSSFP acquisitions. METHODS: In this work, a flexible MS-bSSFP model was built that can be used to fit conversion rate constants for these experiments. The model was validated in vivo using paired animal (healthy rat kidneys n = 8, transgenic adenocarcinoma of the mouse prostate n = 3) and human renal cell carcinoma (n = 3) datasets. Gradient echo (GRE) acquisitions were used with a previous GRE model to compare to the results of the proposed GRE-bSSFP model. RESULTS: Within simulations, the proposed GRE-bSSFP model fits the simulated data well, whereas a GRE model shows bias because of model mismatch. For the in vivo datasets, the estimated conversion rate constants using the proposed GRE-bSSFP model are consistent with a previous GRE model. Jointly fitting the lactate T2 with kPL resulted in less precise kPL estimates. CONCLUSION: The proposed GRE-bSSFP model provides a method to estimate conversion rate constants, kPL and kPB, for MS-bSSFP HP 13C experiments. This model may also be modified and used for other applications, for example, estimating rate constants with other hyperpolarized reagents or multi-echo bSSFP.
Asunto(s)
Isótopos de Carbono , Imagen por Resonancia Magnética , Ácido Pirúvico , Animales , Ácido Pirúvico/farmacocinética , Ácido Pirúvico/metabolismo , Ratas , Imagen por Resonancia Magnética/métodos , Ratones , Isótopos de Carbono/farmacocinética , Humanos , Masculino , Riñón/diagnóstico por imagen , Riñón/metabolismo , Simulación por Computador , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/metabolismo , Procesamiento de Imagen Asistido por Computador/métodos , Algoritmos , Relación Señal-Ruido , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/metabolismo , Ratones TransgénicosRESUMEN
Hyperpolarized (HP) 13C MRI has shown promise as a valuable modality for in vivo measurements of metabolism and is currently in human trials at 15 research sites worldwide. With this growth it is important to adopt standardized data storage practices as it will allow sites to meaningfully compare data. In this paper we (1) describe data that we believe should be stored and (2) demonstrate pipelines and methods that utilize the Digital Imaging and Communications in Medicine (DICOM) standard. This includes proposing a set of minimum set of information that is specific to HP 13C MRI studies. We then show where the majority of these can be fit into existing DICOM Attributes, primarily via the "Contrast/Bolus" module. We also demonstrate pipelines for utilizing DICOM for HP 13C MRI. DICOM is the most common standard for clinical medical image storage and provides the flexibility to accommodate the unique aspects of HP 13C MRI, including the HP agent information but also spectroscopic and metabolite dimensions. The pipelines shown include creating DICOM objects for studies on human and animal imaging systems with various pulse sequences. We also show a python-based method to efficiently modify DICOM objects to incorporate the unique HP 13C MRI information that is not captured by existing pipelines. Moreover, we propose best practices for HP 13C MRI data storage that will support future multi-site trials, research studies and technical developments of this imaging technique.
RESUMEN
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.
Asunto(s)
Imagen por Resonancia Magnética , Ácido Pirúvico , Humanos , Ácido Pirúvico/metabolismo , Imagen por Resonancia Magnética/métodos , Procesamiento de Imagen Asistido por Computador , Corazón , Hígado/diagnóstico por imagen , Hígado/metabolismo , Isótopos de Carbono/metabolismoRESUMEN
PURPOSE: This study aimed to develop a new high-resolution MRI sequence for the imaging of the ultra-short transverse relaxation time (uT2) components in the brain, while simultaneously providing proton density (PD) contrast for reference and quantification. THEORY: The sequence combines low flip angle balanced SSFP (bSSFP) and UTE techniques, together with a 3D dual-echo rosette k-space trajectory for readout. METHODS: The expected image contrast was evaluated by simulations. A study cohort of six healthy volunteers and eight multiple sclerosis (MS) patients was recruited to test the proposed sequence. Subtraction between two TEs was performed to extract uT2 signals. In addition, conventional longitudinal relaxation time (T1) weighted, T2-weighted, and PD-weighted MRI sequences were also acquired for comparison. RESULTS: Typical PD-contrast was found in the second TE images, while uT2 signals were selectively captured in the first TE images. The subtraction images presented signals primarily originating from uT2 components, but only if the first TE is short enough. Lesions in the MS subjects showed hyperintense signals in the second TE images but were hypointense signals in the subtraction images. The lesions had significantly lower signal intensity in subtraction images than normal white matter (WM), which indicated a reduction of uT2 components likely associated with myelin. CONCLUSION: 3D isotropic sub-millimeter (0.94 mm) spatial resolution images were acquired with the novel bSSFP UTE sequence within 3 min. It provided easy extraction of uT2 signals and PD-contrast for reference within a single acquisition.
Asunto(s)
Encéfalo , Imagenología Tridimensional , Imagen por Resonancia Magnética , Esclerosis Múltiple , Humanos , Imagenología Tridimensional/métodos , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Esclerosis Múltiple/diagnóstico por imagen , Adulto , Masculino , Femenino , Algoritmos , Persona de Mediana Edad , Procesamiento de Imagen Asistido por Computador/métodos , Interpretación de Imagen Asistida por Computador/métodos , Voluntarios Sanos , Simulación por ComputadorRESUMEN
Non-invasive prostate cancer classification from MRI has the potential to revolutionize patient care by providing early detection of clinically significant disease, but has thus far shown limited positive predictive value. To address this, we present a image-based deep learning method to predict clinically significant prostate cancer from screening MRI in patients that subsequently underwent biopsy with results ranging from benign pathology to the highest grade tumors. Specifically, we demonstrate that mixed supervision via diverse histopathological ground truth improves classification performance despite the cost of reduced concordance with image-based segmentation. Where prior approaches have utilized pathology results as ground truth derived from targeted biopsies and whole-mount prostatectomy to strongly supervise the localization of clinically significant cancer, our approach also utilizes weak supervision signals extracted from nontargeted systematic biopsies with regional localization to improve overall performance. Our key innovation is performing regression by distribution rather than simply by value, enabling use of additional pathology findings traditionally ignored by deep learning strategies. We evaluated our model on a dataset of 973 (testing n=198 ) multi-parametric prostate MRI exams collected at UCSF from 2016-2019 followed by MRI/ultrasound fusion (targeted) biopsy and systematic (nontargeted) biopsy of the prostate gland, demonstrating that deep networks trained with mixed supervision of histopathology can feasibly exceed the performance of the Prostate Imaging-Reporting and Data System (PI-RADS) clinical standard for prostate MRI interpretation (71.6% vs 66.7% balanced accuracy and 0.724 vs 0.716 AUC).
Asunto(s)
Aprendizaje Profundo , Interpretación de Imagen Asistida por Computador , Imagen por Resonancia Magnética , Próstata , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Imagen por Resonancia Magnética/métodos , Interpretación de Imagen Asistida por Computador/métodos , Próstata/diagnóstico por imagen , Próstata/patologíaRESUMEN
Magnetic resonance imaging is subject to slow acquisition times due to the inherent limitations in data sampling. Recently, supervised deep learning has emerged as a promising technique for reconstructing sub-sampled MRI. However, supervised deep learning requires a large dataset of fully-sampled data. Although unsupervised or self-supervised deep learning methods have emerged to address the limitations of supervised deep learning approaches, they still require a database of images. In contrast, scan-specific deep learning methods learn and reconstruct using only the sub-sampled data from a single scan. Here, we introduce Scan-Specific Self-Supervised Bayesian Deep Non-Linear Inversion (DNLINV) that does not require an auto calibration scan region. DNLINV utilizes a Deep Image Prior-type generative modeling approach and relies on approximate Bayesian inference to regularize the deep convolutional neural network. We demonstrate our approach on several anatomies, contrasts, and sampling patterns and show improved performance over existing approaches in scan-specific calibrationless parallel imaging and compressed sensing.
Asunto(s)
Teorema de Bayes , Aprendizaje Profundo , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Imagen por Resonancia Magnética/métodos , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Encéfalo/diagnóstico por imagen , Algoritmos , Aprendizaje Automático SupervisadoRESUMEN
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.
Asunto(s)
Imagen por Resonancia Magnética , Ácido Pirúvico , Humanos , Ácido Pirúvico/metabolismo , Abdomen/diagnóstico por imagen , Lactatos , Alanina , Isótopos de Carbono/metabolismoRESUMEN
This study aimed to implement a multimodal 1H/HP-13C imaging protocol to augment the serial monitoring of patients with glioma, while simultaneously pursuing methods for improving the robustness of HP-13C metabolic data. A total of 100 1H/HP [1-13C]-pyruvate MR examinations (104 HP-13C datasets) were acquired from 42 patients according to the comprehensive multimodal glioma imaging protocol. Serial data coverage, accuracy of frequency reference, and acquisition delay were evaluated using a mixed-effects model to account for multiple exams per patient. Serial atlas-based HP-13C MRI demonstrated consistency in volumetric coverage measured by inter-exam dice coefficients (0.977 ± 0.008, mean ± SD; four patients/11 exams). The atlas-derived prescription provided significantly improved data quality compared to manually prescribed acquisitions (n = 26/78; p = 0.04). The water-based method for referencing [1-13C]-pyruvate center frequency significantly reduced off-resonance excitation relative to the coil-embedded [13C]-urea phantom (4.1 ± 3.7 Hz vs. 9.9 ± 10.7 Hz; p = 0.0007). Significantly improved capture of tracer inflow was achieved with the 2-s versus 5-s HP-13C MRI acquisition delay (p = 0.007). This study demonstrated the implementation of a comprehensive multimodal 1H/HP-13C MR protocol emphasizing the monitoring of steady-state/dynamic metabolism in patients with glioma.
RESUMEN
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.
Asunto(s)
Encéfalo , Protones , Humanos , Voluntarios Sanos , Fantasmas de Imagen , Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética/métodos , FosfolípidosRESUMEN
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.
Asunto(s)
Miocardio , Ácido Pirúvico , Humanos , Ácido Pirúvico/metabolismo , Miocardio/metabolismo , Glucosa/metabolismo , Acetilcarnitina/metabolismo , Miocitos Cardíacos , Ácido Glutámico/metabolismo , Lactatos/metabolismo , Isótopos de Carbono/metabolismoRESUMEN
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.
Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Humanos , Ácido Pirúvico/metabolismo , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/patología , Bicarbonatos/metabolismo , Imagen por Resonancia Magnética/métodos , Encéfalo/metabolismo , Riñón/diagnóstico por imagen , Riñón/metabolismo , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/patología , Lactatos/metabolismo , Isótopos de Carbono/metabolismoRESUMEN
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.
RESUMEN
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.
Asunto(s)
Bicarbonatos , Ácido Pirúvico , Humanos , Valor Predictivo de las Pruebas , Imagen por Resonancia Magnética/métodos , Glucosa , Ácido Láctico/metabolismo , Isótopos de CarbonoRESUMEN
Purpose: To evaluate methods for quantification of pulmonary ventilation with ultrashort echo time (UTE) MRI. Methods: We performed a reproducibility study, acquiring two free-breathing 1H UTE lung MRIs on the same day for six healthy volunteers. The 1) 3D + t cyclic b-spline and 2) symmetric image normalization (SyN) methods for image registration were applied after respiratory phase-resolved image reconstruction. Ventilation maps were calculated using 1) Jacobian determinant of the deformation fields minus one, termed regional ventilation, and 2) intensity percentage difference between the registered and fixed image, termed specific ventilation. We compared the reproducibility of all four method combinations via statistical analysis. Results: Split violin plots and Bland-Altman plots are shown for whole lungs and lung sections. The cyclic b-spline registration and Jacobian determinant regional ventilation quantification provide total ventilation volumes that match the segmentation tidal volume, smooth and uniform ventilation maps. The cyclic b-spline registration and specific ventilation combination yields the smallest standard deviation in the Bland-Altman plot. Conclusion: Cyclic registration performs better than SyN for respiratory phase-resolved 1H UTE MRI ventilation quantification. Regional ventilation correlates better with segmentation lung volume, while specific ventilation is more reproducible.
RESUMEN
Solid tumors such as prostate cancer (PCa) commonly develop an acidic microenvironment with pH 6.5-7.2, owing to heterogeneous perfusion, high metabolic activity, and rapid cell proliferation. In preclinical prostate cancer models, disease progression is associated with a decrease in tumor extracellular pH, suggesting that pH imaging may reflect an imaging biomarker to detect aggressive and high-risk disease. Therefore, we developed a hyperpolarized carbon-13 MRI method to image the tumor extracellular pH (pHe) and prepared it for clinical translation for detection and risk stratification of PCa. This method relies on the rapid breakdown of hyperpolarized (HP) 1,2-glycerol carbonate (carbonyl-13C) via base-catalyzed hydrolysis to produce HP 13CO32-, which is neutralized and converted to HP H13CO3-. After injection, HP H13CO3- equilibrates with HP 13CO2 in vivo and enables the imaging of pHe. Using insights gleaned from mechanistic studies performed in the hyperpolarized state, we solved issues of polarization loss during preparation in a clinical polarizer system. We successfully customized a reaction apparatus suitable for clinical application, developed clinical standard operating procedures, and validated the radiofrequency pulse sequence and imaging data acquisition with a wide range of animal models. The results demonstrated that we can routinely produce a highly polarized and safe HP H13CO3- contrast agent suitable for human injection. Preclinical imaging studies validated the reliability and accuracy of measuring acidification in healthy kidney and prostate tumor tissue. These methods were used to support an Investigational New Drug application to the U.S. Food and Drug Administration. This methodology is now ready to be implemented in human trials, with the ultimate goal of improving the management of PCa.
Asunto(s)
Bicarbonatos , Neoplasias de la Próstata , Estados Unidos , Masculino , Animales , Humanos , Bicarbonatos/metabolismo , Reproducibilidad de los Resultados , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Imagen por Resonancia Magnética/métodos , Concentración de Iones de Hidrógeno , Microambiente TumoralRESUMEN
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.
RESUMEN
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.
RESUMEN
BACKGROUND: This study aimed to develop a time-efficient method of acquiring simultaneous, dual-slice MR spectroscopic imaging (MRSI) for the evaluation of brain metabolism. METHODS: Adaptive Hadamard-encoded pulses were developed and integrated with atlas-based automatic prescription. The excitation profiles were evaluated via simulation, phantom and volunteer experiments. The feasibility of γ-aminobutyric acid (GABA)-edited dual-slice MRSI was also assessed. RESULTS: The signal between slices in the dual-band MRSI was less than 1% of the slice profiles. Data from a homemade phantom containing separate, interfacing compartments of creatine and acetate solutions demonstrated ~0.4% acetate signal contamination relative to the amplitude in the excited creatine compartment. The normalized signal-to-noise ratios from atlas-based acquisitions in volunteers were found to be comparable between dual-slice, Hadamard-encoded MRSI and 3D acquisitions. The mean and standard deviation of the coefficients of variation for NAA/Cho from the repeated volunteer scans were 8.2% ± 0.8% and 10.1% ± 3.7% in the top and bottom slices, respectively. GABA-edited, dual-slice MRSI demonstrated simultaneous detection of signals from GABA and coedited macromolecules (GABA+) from both superior grey and deep grey regions of volunteers. CONCLUSION: This study demonstrated a fully automated dual-slice MRSI acquisition using atlas-based automatic prescription and adaptive Hadamard-encoded pulses.