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Purpose: To develop a high spatiotemporal resolution 3D dynamic pulse sequence for preclinical imaging of hyperpolarized [1- 13 C]pyruvate-to-[1- 13 C]lactate metabolism at 7T., Methods: A standard 3D balanced SSFP (bSSFP) sequence was modified to enable alternating-frequency excitations. RF pulses with 2.33 ms duration and 900 Hz FWHM were placed off-resonance of the target metabolites, [1- 13 C]pyruvate (by approximately -245 Hz) and [1- 13 C]lactate (by approximately 735 Hz), to selectively excite those resonances. Relatively broad bandwidth (compared to those metabolites' chemical shift offset) permits a short TR of 6.29 ms, enabling higher spatiotemporal resolution. Bloch equation simulations of the bSSFP response profile guided the sequence parameter selection to minimize spectral contamination between metabolites and preserve magnetization over time., Results: Bloch equation simulations, phantom studies, and in vivo studies demonstrated that the two target resonances could be cleanly imaged without substantial bSSFP banding artifacts and with little spectral contamination between lactate and pyruvate and from pyruvate hydrate. High spatiotemporal resolution 3D images were acquired of in vivo pyruvate-lactate metabolism in healthy wild-type and endogenous pancreatic tumor-bearing mice, with 1.212 s acquisition time per single-metabolite image and (1.75 mm) 3 isotropic voxels with full mouse abdomen 56 × 28 × 21 mm 3 FOV and fully-sampled k-space. Kidney and tumor lactate/pyruvate ratios of two consecutive measurements in one animal, 1 h apart, were consistent., Conclusion: Spectrally selective bSSFP using off-resonant RF excitations can provide high spatio-temporal resolution 3D dynamic images of pyruvate-lactate metabolic conversion., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

pH alterations are a hallmark of many pathologies including cancer and kidney disease. Here, we introduce [1,5- 13 C 2 ]Z-OMPD as a hyperpolarized extracellular pH and perfusion sensor for MRI which allows to generate a multiparametric fingerprint of renal disease status and to detect local tumor acidification. Exceptional long T 1 of two minutes at 1 T, high pH sensitivity of up to 1.9 ppm per pH unit and suitability of using the C 1 -label as internal frequency reference enables pH imaging in vivo of three pH compartments in healthy rat kidneys. Spectrally selective targeting of both 13 C-resonances enables simultaneous imaging of perfusion and filtration in 3D and pH in 2D within one minute to quantify renal blood flow, glomerular filtration rates and renal pH in healthy and hydronephrotic kidneys with superior sensitivity compared to clinical routine methods. Imaging multiple biomarkers within a single session renders [1,5- 13 C 2 ]Z-OMPD a promising new hyperpolarized agent for oncology and nephrology., (© 2023. Springer Nature Limited.)

Background: Hyperpolarization enhances the sensitivity of nuclear magnetic resonance experiments by between four and five orders of magnitude. Several hyperpolarized sensor molecules have been introduced that enable high sensitivity detection of metabolism and physiological parameters. However, hyperpolarized magnetic resonance spectroscopy imaging (MRSI) often suffers from poor signal-to-noise ratio and spectral analysis is complicated by peak overlap. Here, we study measurements of extracellular pH (pH e ) by hyperpolarized zymonic acid, where multiple pH e compartments, such as those observed in healthy kidney or other heterogeneous tissue, result in a cluster of spectrally overlapping peaks, which is hard to resolve with conventional spectroscopy analysis routines., Methods: We investigate whether deep learning methods can yield improved pH e prediction in hyperpolarized zymonic acid spectra of multiple pH e compartments compared to conventional line fitting. As hyperpolarized 13 C-MRSI data sets are often small, a convolutional neural network (CNN) and a multilayer perceptron (MLP) were trained with either a synthetic or a mixed (synthetic and augmented) data set of acquisitions from the kidneys of healthy mice., Results: Comparing the networks' performances compartment-wise on a synthetic test data set and eight real kidney data shows superior performance of CNN compared to MLP and equal or superior performance compared to conventional line fitting. For correct prediction of real kidney pH e values, training with a mixed data set containing only 0.5% real data shows a large improvement compared to training with synthetic data only. Using a manual segmentation approach, pH maps of kidney compartments can be improved by neural network predictions for voxels including three pH compartments., Conclusion: The results of this study indicate that CNNs offer a reliable, accurate, fast and non-interactive method for analysis of hyperpolarized 13 C MRS and MRSI data, where low amounts of acquired data can be complemented to achieve suitable network training., (© 2022. The Author(s).)

Hyperpolarized 13 C nuclear magnetic resonance spectroscopy can characterize in vivo tissue metabolism, including preclinical models of cancer and inflammatory disease. Broad bandwidth radiofrequency excitation is often paired with free induction decay readout for spectral separation, but quantification of low-signal downstream metabolites using this method can be impeded by spectral peak overlap or when frequency separation of the detected peaks exceeds the excitation bandwidth. In this work, alternating frequency narrow bandwidth (250 Hz) slice-selective excitation was used for 13 C spectroscopy at 7 T in a subcutaneous xenograft rat model of human pancreatic cancer (PSN1) to improve quantification while measuring the dynamics of injected hyperpolarized [1- 13 C]lactate and its metabolite [1- 13 C]pyruvate. This method does not require sophisticated pulse sequences or specialized radiofrequency and gradient pulses, but rather uses nominally spatially offset slices to produce alternating frequency excitation with simpler slice-selective radiofrequency pulses. Additionally, point-resolved spectroscopy was used to calibrate the 13 C frequency from the thermal proton signal in the target region. This excitation scheme isolates the small [1- 13 C]pyruvate peak from the similar-magnitude tail of the much larger injected [1- 13 C]lactate peak, facilitates quantification of the [1- 13 C]pyruvate signal, simplifies data processing, and could be employed for other substrates and preclinical models.

The aim of this study was to acquire the transient MRI signal of hyperpolarized tracers and their metabolites efficiently, for which specialized imaging sequences are required. In this work, a multi-echo balanced steady-state free precession (me-bSSFP) sequence with Iterative Decomposition with Echo Asymmetry and Least squares estimation (IDEAL) reconstruction was implemented on a clinical 3 T positron-emission tomography/MRI system for fast 2D and 3D metabolic imaging. Simulations were conducted to obtain signal-efficient sequence protocols for the metabolic imaging of hyperpolarized biomolecules. The sequence was applied in vitro and in vivo for probing the enzymatic exchange of hyperpolarized [1- 13 C]pyruvate and [1- 13 C]lactate. Chemical shift resolution was achieved using a least-square, iterative chemical species separation algorithm in the reconstruction. In vitro, metabolic conversion rate measurements from me-bSSFP were compared with NMR spectroscopy and free induction decay-chemical shift imaging (FID-CSI). In vivo, a rat MAT-B-III tumor model was imaged with me-bSSFP and FID-CSI. 2D metabolite maps of [1- 13 C]pyruvate and [1- 13 C]lactate acquired with me-bSSFP showed the same spatial distributions as FID-CSI. The pyruvate-lactate conversion kinetics measured with me-bSSFP and NMR corresponded well. Dynamic 2D metabolite mapping with me-bSSFP enabled the acquisition of up to 420 time frames (scan time: 180-350 ms/frame) before the hyperpolarized [1- 13 C]pyruvate was relaxed below noise level. 3D metabolite mapping with a large field of view (180 × 180 × 48 mm 3 ) and high spatial resolution (5.6 × 5.6 × 2 mm 3 ) was conducted with me-bSSFP in a scan time of 8.2 seconds. It was concluded that Me-bSSFP improves the spatial and temporal resolution for metabolic imaging of hyperpolarized [1- 13 C]pyruvate and [1- 13 C]lactate compared with either of the FID-CSI or EPSI methods reported at 3 T, providing new possibilities for clinical and preclinical applications., (© 2020 The Authors. NMR in Biomedicine published by John Wiley & Sons Ltd.)

Hyperpolarization is an emerging method in magnetic resonance imaging that allows nuclear spin polarization of gases or liquids to be temporarily enhanced by up to five or six orders of magnitude at clinically relevant field strengths and administered at high concentration to a subject at the time of measurement. This transient gain in signal has enabled the non-invasive detection and imaging of gas ventilation and diffusion in the lungs, perfusion in blood vessels and tissues, and metabolic conversion in cells, animals, and patients. The rapid development of this method is based on advances in polarizer technology, the availability of suitable probe isotopes and molecules, improved MRI hardware and pulse sequence development. Acquisition strategies for hyperpolarized nuclei are not yet standardized and are set up individually at most sites depending on the specific requirements of the probe, the object of interest, and the MRI hardware. This review provides a detailed introduction to spatially resolved detection of hyperpolarized nuclei and summarizes novel and previously established acquisition strategies for different key areas of application.

Spin-exchange optical pumping (SEOP) can enhance the NMR sensitivity of noble gases by up to five orders of magnitude at Tesla-strength magnetic fields. SEOP-generated hyperpolarised (HP) 129 Xe is a promising contrast agent for lung imaging but an ongoing barrier to widespread clinical usage has been economical production of sufficient quantities with high 129 Xe polarisation. Here, the 'standard model' of SEOP, which was previously used in the optimisation of continuous-flow 129 Xe polarisers, is modified for validation against two Xe-rich stopped-flow SEOP datasets. We use this model to examine ways to increase HP Xe production efficiency in stopped-flow 129 Xe polarisers and provide further insight into the underlying physics of Xe-rich stopped-flow SEOP at high laser fluxes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Eduard Chekmenev, Boyd Goodson and Panayiotis Nikolaou each declare they have a stake in XeUS Technologies LTD. All other authors declare they have no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Since reaching the clinic, magnetic resonance imaging (MRI) has become an irreplaceable radiological tool because of the macroscopic information it provides across almost all organs and soft tissues within the human body, all without the need for ionising radiation. The sensitivity of MR, however, is too low to take full advantage of the rich chemical information contained in the MR signal. Hyperpolarisation techniques have recently emerged as methods to overcome the sensitivity limitations by enhancing the MR signal by many orders of magnitude compared to the thermal equilibrium, enabling a new class of metabolic and molecular X-nuclei based MR tracers capable of reporting on metabolic processes at the cellular level. These hyperpolarised (HP) tracers have the potential to elucidate the complex metabolic processes of many organs and pathologies, with studies so far focusing on the fields of oncology and cardiology. This review presents an overview of hyperpolarisation techniques that appear most promising for clinical use today, such as dissolution dynamic nuclear polarisation (d-DNP), parahydrogen-induced hyperpolarisation (PHIP), Brute force hyperpolarisation and spin-exchange optical pumping (SEOP), before discussing methods for tracer detection, emerging metabolic tracers and applications and progress in preclinical and clinical application.

Hyperpolarized (HP) tracers dramatically increase the sensitivity of magnetic resonance imaging (MRI) to monitor metabolism non-invasively and in vivo. Their production, however, requires an extra polarizing device (polarizer) whose complexity, operation and cost can exceed that of an MRI system itself. Furthermore, the lifetime of HP tracers is short and some of the enhancement is lost during transfer to the application site. Here, we present the production of HP tracers in water without an external polarizer: by Synthesis Amid the Magnet Bore, A Dramatically Enhanced Nuclear Alignment (SAMBADENA) is achieved within seconds, corresponding to a hyperpolarization of ∼20%. As transfer of the tracer is no longer required, SAMBADENA may permit a higher polarization at the time of detection at a fraction of the cost and complexity of external polarizers. This development is particularly promising in light of the recently extended portfolio of biomedically relevant para-hydrogen-tracers and may lead to new diagnostic applications.

Acute phase proteins (APPs) such as haptoglobin, serum amyloid A and pig major acute phase protein are plasma proteins that increase in concentration following infection, inflammation, or trauma. The circulating concentrations of these proteins in pigs and cattle can provide an objective measure of the health status of an animal and are increasingly being used as markers of animal health and welfare. Plasma concentrations of APPs are related to the severity of the underlying condition, and provide a ready means of evaluating both the presence and extent of disease. Haptoglobin, for example, has been used to identify both clinical and subclinical disease in animals, and for objectively monitoring antibiotic therapy in experimentally infected animals. Interpretative benefit can be further enhanced by the "acute phase index", derived from a mathematical formula that uses both positive- and negative-reacting APPs. Research suggests that in the future, assays for APPs will be used routinely to assess animal health, optimize production rates, monitor antibiotic therapy, detect diseases such as mastitis in dairy cows, and assess the health of animals at slaughter. These applications have considerable benefit for human food safety. Before APP assays can be applied in animal production on a worldwide basis, however, the calibration of assay methods must be harmonized to ensure that results obtained in the laboratory or on the farm are universally comparable and of consistent quality. In February 2000 the European Commission Directorate General Research Concerted Action was established to fulfill the task of international standardization of APPs. The Concerted Action Group consists of a network of 14 institutions representing 9 European countries. In this report, the background and goals of the Concerted Action Group, and scientific presentations from the group's first colloquium are described. In addition, the progress of the group to date and the standardization plan for the full 30-month duration of the Concerted Action are summarized.

An automated method for the estimation of the acute phase protein haptoglobin was developed and used to compare the blood haptoglobin concentrations of 42 sheep examined post mortem with other haematological findings in infectious and non-infectious conditions. Haptoglobin was also assayed in 863 sheep from nine apparently normal flocks; of these sheep seven per cent had significantly raised haptoglobin levels. The studies showed that haptoglobin was useful as a marker for the presence of bacterial infection in sheep, and was more sensitive, specific and efficient and less likely to give false positive and negative results than a haematological examination.

In order to assess the usefulness of haptoglobin as a measure of the acute phase response in cattle, the concentration of serum haptoglobin was estimated in the non-infectious conditions of milk fever and ketosis, and in the infectious conditions of severe mastitis, acute severe metritis, retained placenta and chronic endometritis. Mean haptoglobin concentrations were normal in cattle with non-infectious conditions and chronic endometritis but significantly increased in cattle with infectious conditions.