Clinical Translation of Hyperpolarized C Metabolic Probes for Glioma Imaging.

Hyperpolarized carbon-13 (HP-C) MRI enables the real-time measurement of dynamic metabolism by utilizing molecular probes whose magnetization has been transiently enhanced via dynamic nuclear polarization of C labels. Based on pre-clinical and clinical investigations demonstrating Warburg-related metabolic dysfunction and tricarboxylic acid (TCA)-cycle alterations in gliomas, HPC techniques appear very promising for overcoming conventional challenges to evaluating tumor burden and extent, early therapeutic response and progression among patients non-invasively. This article surveys the multi-faceted translational development of HP-C MRI in the context of glioma imaging, while emphasizing innovation concerning the pharmacy production of HP probes - [1-C]/[2-C]-pyruvate and [1-C,5-C]-alpha-ketoglutarate - that serve as non-radioactive metabolic contrast agents.

A data-driven approach for improved quantification of in vivo metabolic conversion rates of hyperpolarized [1-C]pyruvate.

Purpose: Accurate quantification of metabolism in hyperpolarized (HP) C MRI is essential for clinical applications. However, kinetic model parameters are often confounded by uncertainties in radiofrequency flip angles and other model parameters.

Methods: A data-driven kinetic fitting approach for HP C-pyruvate MRI was proposed that compensates for uncertainties in the B field.

Spatially constrained hyperpolarized 13C MRI pharmacokinetic rate constant map estimation using a digital brain phantom and a U-Net.

Fitting rate constants to Hyperpolarized [1-C]Pyruvate (HP C13) MRI data is a promising approach for quantifying metabolism in vivo. Current methods typically fit each voxel of the dataset using a least-squares objective. With these methods, each voxel is considered independently, and the spatial relationships are not considered during fitting.

Brain metabolism after therapeutic hypothermia for murine hypoxia-ischemia using hyperpolarized [1-C] pyruvate magnetic resonance spectroscopy.

Hypoxic-ischemic encephalopathy (HIE) is a common neurological syndrome in newborns with high mortality and morbidity. Therapeutic hypothermia (TH), which is standard of care for HIE, mitigates brain injury by suppressing anaerobic metabolism. However, more than 40% of HIE neonates have a poor outcome, even after TH.

Advanced Hyperpolarized C Metabolic Imaging Protocol for Patients with Gliomas: A Comprehensive Multimodal MRI Approach.

This study aimed to implement a multimodal H/HP-C imaging protocol to augment the serial monitoring of patients with glioma, while simultaneously pursuing methods for improving the robustness of HP-C metabolic data. A total of 100 H/HP [1-C]-pyruvate MR examinations (104 HP-C 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.

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

Purpose: Improving the quality and maintaining the fidelity of large coverage abdominal hyperpolarized (HP) 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- C]pyruvate dynamics at different noise levels to determine optimal k and k parameters. The GL-HOSVD spatiotemporal denoising method with the optimized parameters was then applied to two HP [1- C]pyruvate EPI abdominal human cohorts (n = 7 healthy volunteers and n = 8 pancreatic cancer patients).

Hyperpolarized [1- C] pyruvate MRSI to detect metabolic changes in liver in a methionine and choline-deficient diet rat model of fatty liver disease.

Purpose: Nonalcoholic fatty liver disease is an important cause of chronic liver disease. There are limited methods for monitoring metabolic changes during progression to steatohepatitis. Hyperpolarized C MRSI (HP C MRSI) was used to measure metabolic changes in a rodent model of fatty liver disease.

Monitoring response to a clinically relevant IDH inhibitor in glioma-Hyperpolarized C magnetic resonance spectroscopy approaches.

Background: Mutant isocitrate dehydrogenase (IDHmut) catalyzes 2-hydroxyglutarate (2HG) production and is considered a therapeutic target for IDHmut tumors. However, response is mostly associated with inhibition of tumor growth. Response assessment via anatomic imaging is therefore challenging.

Parallel detection of chemical reactions in a microfluidic platform using hyperpolarized nuclear magnetic resonance.

The sensitivity of NMR may be enhanced by more than four orders of magnitude dissolution dynamic nuclear polarization (dDNP), potentially allowing real-time, analysis of chemical reactions. However, there has been no widespread use of the technique for this application and the major limitation has been the low experimental throughput caused by the time-consuming polarization build-up process at cryogenic temperatures and fast decay of the hyper-intense signal post dissolution. To overcome this limitation, we have developed a microfluidic device compatible with dDNP-MR spectroscopic imaging methods for detection of reactants and products in chemical reactions in which up to 8 reactions can be measured simultaneously using a single dDNP sample.

Clinically Translatable Hyperpolarized C Bicarbonate pH Imaging Method for Use in Prostate Cancer.

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.

Multi-parametric hyperpolarized C/H imaging reveals Warburg-related metabolic dysfunction and associated regional heterogeneity in high-grade human gliomas.

Background: Dynamic hyperpolarized (HP)-C MRI has enabled real-time, non-invasive assessment of Warburg-related metabolic dysregulation in glioma using a [1-C]pyruvate tracer that undergoes conversion to [1-C]lactate and [C]bicarbonate. Using a multi-parametric H/HP-C imaging approach, we investigated dynamic and steady-state metabolism, together with physiological parameters, in high-grade gliomas to characterize active tumor.

Methods: Multi-parametric H/HP-C MRI data were acquired from fifteen patients with progressive/treatment-naïve glioblastoma [prog/TN GBM, IDH-wildtype (n = 11)], progressive astrocytoma, IDH-mutant, grade 4 (G4A, n = 2) and GBM manifesting treatment effects (n = 2).

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.

Peptidylarginine Deiminase 2 Autoantibodies Are Linked to Less Severe Disease in Multiple Sclerosis and Post-treatment Lyme Disease.

Background: Peptidylarginine deiminase 2 (PAD2) mediates the post-translational conversion of arginine residues in proteins to citrullines and is highly expressed in the central nervous system (CNS). Dysregulated PAD2 activity has been implicated in the pathogenesis of several neurologic diseases, including multiple sclerosis (MS). In this study, we sought to define the cellular and regional expression of the gene encoding for PAD2 (i.

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

Background: Hyperpolarized 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- C]pyruvate and products in the abdomens of healthy volunteers, overcoming challenges of motion, magnetic field variations, and spatial coverage.

Time- and site-resolved kinetic NMR for real-time monitoring of off-equilibrium reactions by 2D spectrotemporal correlations.

Nuclear magnetic resonance (NMR) spectroscopy provides detailed information about dynamic processes through line-shape changes, which are traditionally limited to equilibrium conditions. However, a wealth of information is available by studying chemical reactions under off-equilibrium conditions-e.g.

Intraindividual variability in executive and motor control tasks in children with attention deficit hyperactivity disorder.

Objective: Emerging evidence highlights intraindividual variability (IIV) during executive function (EF) tasks as a reliable endophenotype of Attention Deficit/Hyperactivity Disorder (ADHD) and as contributing to motor dysregulation and hyperactive-impulsive behaviors. This study examined the relationship between EF and motor control in children with and without ADHD.

Method: Ninety-seven children (6-13 years) completed standardized and experimental tasks of executive and motor control.

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

Purpose: To improve hyperpolarized C (HP- 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- C MR imaging data was investigated. Image quality and the accuracy of quantitative analyses following denoising were evaluated first using simulated data of [1- C]pyruvate and its metabolic product, [1- C]lactate, and compared the results to a global HOSVD method.

Polyolefin catalysis of propene, 1-butene and isobutene monitored using hyperpolarized NMR.

Polymerization reactions of the dissolved gases propene, 1-butene, and isobutene catalyzed by [Zr(Cp)Me][B(CF)] were characterized using NMR. Hyperpolarization of C spins by the dissolution dynamic nuclear polarization (DNP) technique provided a signal enhancement of up to 5000-fold for these monomers. For DNP hyperpolarization, liquid aliquots containing monomers were prepared at a temperature between the freezing point of the solvent toluene and the boiling point of the monomer, mixed with the polarizing agent α,γ-bis-diphenylene-β-phenylallyl free radical, and subsequently frozen.

Dynamic Nuclear Polarization Using 3D Aromatic Boron Cluster Radicals.

A set of two dodecaborate [B(OR)] radical cluster anions containing a dense layer of fluorinated end-groups provides nuclear spin hyperpolarization via the dissolution dynamic nuclear polarization (D-DNP) technique. We show that these clusters can enhance F nuclear magnetic resonance (NMR) signals. Importantly, given the inherent radical delocalization in dodecaborate-based clusters, these species are compatible with reactive compounds such as Lewis acids, providing ∼1000-2000 times of signal enhancement for B(CF) in liquid state NMR spectroscopy experiments at 9.

Indirect detection of intermediate in decarboxylation reaction of phenylglyoxylic acid by hyperpolarized C NMR.

The decarboxylation reaction of phenylglyoxylic acid with hydrogen peroxide is studied by real-time hyperpolarized carbon-13 nuclear magnetic resonance (13C NMR) spectroscopy at room temperature. A non-observable reaction intermediate is identified using blind selective saturation pulses in the expected chemical shift range, thereby revealing information on the reaction mechanism.