Enabling SENSE accelerated 2D CSI for hyperpolarized carbon-13 imaging.

As hyperpolarized (HP) carbon-13 (13C) metabolic imaging is clinically translated, there is a need for easy-to-implement, fast, and robust imaging techniques. However, achieving high temporal resolution without decreasing spatial and/or spectral resolution, whilst maintaining the usability of the imaging sequence is challenging. Therefore, this study looked to accelerate HP 13C MRI by combining a well-established and robust sequence called two-dimensional Chemical Shift Imaging (2D CSI) with prospective under sampling and SENSitivity Encoding (SENSE) reconstruction. Due to the low natural abundance of 13C, the sensitivity maps cannot be pre-acquired for the reconstruction. As such, the implementation of sodium (23Na) sensitivity maps for SENSE reconstructed 13C CSI was demonstrated in a phantom and in vivo in the pig kidney. Results showed that SENSE reconstruction using 23Na sensitivity maps corrected aliased images with a four-fold acceleration. With high temporal resolution, the kidney spectra produced a detailed metabolic arrival and decay curve, useful for further metabolite kinetic modelling or denoising. Metabolic ratio maps were produced in three pigs demonstrating the technique's ability for repeat metabolic measurements. In cases with unknown metabolite spectra or limited HP MRI specialist knowledge, this robust acceleration method ensures comprehensive capture of metabolic signals, mitigating the risk of missing spectral data.

3D quantitative myocardial perfusion imaging with hyperpolarized HP001(bis-1,1-(hydroxymethyl)-[1-13C]cyclopropane-d8): Application of gradient echo and balanced SSFP sequences.

PURPOSE: This study aims to show the viability of conducting three-dimensional (3D) myocardial perfusion quantification covering the entire heart using both GRE and bSSFP sequences with hyperpolarized HP001. METHODS: A GRE sequence and a bSSFP sequence, both with a stack-of-spirals readout, were designed and applied to three pigs. The images were reconstructed using 13 $$ {}^{13} $$ C coil sensitivity maps measured in a phantom experiment. Perfusion was quantified using a constrained decomposition method, and the estimated rest/stress perfusion values from 13 $$ {}^{13} $$ C GRE/bSSFP and Dynamic contrast-enhanced MRI (DCE-MRI) were individually analyzed through histograms and the mean perfusion values were compared with reference values obtained from PET( 15 $$ {}^{15} $$ O-water). The Myocardial Perfusion Reserve Index (MPRI) was estimated for 13 $$ {}^{13} $$ C GRE/bSSFP and DCE-MRI and compared with the reference values. RESULTS: Perfusion values, estimated by both DCE and 13 $$ {}^{13} $$ C MRI, were found to be lower than reference values. However, DCE-MRI's estimated perfusion values were closer to the reference values than those obtained from 13 $$ {}^{13} $$ C MRI. In the case of MPRI estimation, the 13 $$ {}^{13} $$ C estimated MPRI values (GRE/bSSFP: 2.3/2.0) more closely align with the literature value (around 3) than the DCE estimated MPRI value (1.6). CONCLUSION: This study demonstrated the feasibility of 3D whole-heart myocardial perfusion quantification using hyperpolarized HP001 with both GRE and bSSFP sequences. The 13 $$ {}^{13} $$ C perfusion measurements underestimated perfusion values compared to the 15 $$ {}^{15} $$ O PET literature value, while the 13 $$ {}^{13} $$ C estimated MPRI value aligned better with the literature. This preliminary result indicates 13 $$ {}^{13} $$ C imaging may more accurately estimate MPRI values compared to DCE-MRI.

Hyperpolarized [1-13C]pyruvate Magnetic Resonance Imaging Identifies Metabolic Phenotypes in Patients with Heart Failure.

BACKGROUND: Hyperpolarized [1-13C]pyruvate magnetic resonance imaging (HP MRI) visualizes key steps in myocardial metabolism. The present study aimed to examine patients with heart (HF) using HP MRI. METHODS: A cross-sectional study of patients with HF and healthy controls using HP MRI. Metabolic imaging was obtained using a cardiac-gated spectral-spatial excitation with spiral read-out acquisition. The metabolite signal was analyzed for lactate, bicarbonate, and the alanine signal. Metabolite signal was normalized to the total carbon signal (TC). At the one-year follow-up, echocardiography was performed in all patients and HP MRI in two patients. RESULTS: We included six patients with ischemic heart disease (IHD), six with dilated cardiomyopathy and six healthy controls. In patients, left ventricular ejection fraction (LVEF) correlated with lactate/bicarbonate (r = -0.6, p = 0.03) and lactate/TC (r = -0.7, p = 0.01). In patients with LVEF < 30%, lactate/TC was increased (p = 0.01) and bicarbonate/TC reduced (p = 0.03). Circumferential strain correlated with metabolite ratios: lactate/bicarbonate, r = 0.87 (p = 0.0002); lactate/TC, r = 0.85 (p = 0.0005); bicarbonate/TC, r = -0.82 (p = 0.001). In patients with IHD, a strong correlation was found between baseline metabolite ratios and the change in LVEF at follow-up: lactate/bicarbonate (p = 0.001); lactate/TC (p = 0.011); and bicarbonate/TC (p = 0.012). CONCLUSIONS: This study highlighted the ability of HP MRI to detect changes in metabolism in HF. HP MRI has potential for metabolic phenotyping of patients with HF and for predicting treatment response. TRIAL REGISTRATION: EUDRACT, 2018-003533-15. Registered 4 December 2018, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2018-003533-15.

Differentiating leukemia subtypes based on metabolic signatures using hyperpolarized 13C NMR.

Leukemia is a group of blood cancers that are classified in four major classes. Within these four classes, many different subtypes exists with similar origin, genetic mutations, and level of maturity, which can make them difficult to distinguish. Despite their similarities, they might respond differently to treatment, and therefore distinguishing between them is of crucial importance. A deranged metabolic phenotype (Warburg effect) is often seen in cancer cells, leukemia cells included, and is increasingly a target for improved diagnosis and treatment. In this study, hyperpolarized 13C NMR spectroscopy was used to characterize the metabolic signatures of the six leukemia cell lines ML-1, CCRF-CEM, THP-1, MOLT-4, HL-60, and K562. This was done using [1-13C]pyruvate and [1-13C]alanine as bioprobes for downstream metabolite quantification and kinetic analysis on cultured cells with and without 2-deoxy-D-glucose treatment. The metabolic signatures of similar leukemia subtypes could be readily distinguished. This includes ML-1 and THP-1, which are of the similar M4 and M5 AML subtypes, CCRF-CEM and MOLT-4, which are of the similar T-ALL lineage at different maturation states, and HL-60 and K562, which are of the closely related M1 and M2 AML subtypes. The data presented here demonstrate the potential of hyperpolarized 13C NMR spectroscopy as a method to differentiate between leukemia subtypes of similar origin. Combining this method with bioreactor setups could potentially allow for better leukemia disease management as metabolic signatures could be acquired from a single biopsy through repeated experimentation and intervention.

Hyperpolarized Water for Coronary Artery Angiography and Whole-Heart Myocardial Perfusion Quantification.

Purpose: Water freely diffuses across cell membranes, making it suitable for measuring absolute tissue perfusion. In this study, we introduce an imaging method for conducting coronary artery angiography and quantifying myocardial perfusion across the entire heart using hyperpolarized water. Methods:1H was hyperpolarized using dissolution dynamic nuclear polarization (dDNP) with UV-generated radicals. Submillimeter resolution coronary artery images were acquired as 2D projections using a spoiled GRE (SPGRE) sequence gated on diastole. Dynamic perfusion images were obtained with a multi-slice SPGRE with diastole gating, covering the entire heart. Perfusion values were analyzed through histograms, and the most frequent estimated perfusion value (the mode of the distribution), was compared with the average values for 15O water PET from the literature. Results: A liquid state polarization of 10% at the time of the injection and a 30 s T1 in D2O TRIS buffer were measured. Both coronary artery and dynamic perfusion images exhibited good quality. The main and small coronary artery branches were well resolved. The most frequent estimated perfusion value is around 0.6 mL/g/min, which is lower than the average values obtained from the literature for 15O-water PET (around 1.1 and 1.5 mL/g/min). Conclusions: The study successfully demonstrated the feasibility of achieving high-resolution, motion-free coronary artery angiography and 3D whole-heart quantitative myocardial perfusion using hyperpolarized water.

Effects of semaglutide, empagliflozin and their combination on renal diffusion-weighted MRI and total kidney volume in patients with type 2 diabetes: a post hoc analysis from a 32 week randomised trial.

AIMS/HYPOTHESIS: The apparent diffusion coefficient (ADC) derived from diffusion-weighted MRI (DWI-MRI) has been proposed as a measure of changes in kidney microstructure, including kidney fibrosis. In advanced kidney disease, the kidneys often become atrophic; however, in the initial phase of type 2 diabetes, there is an increase in renal size. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors both provide protection against progression of kidney disease in diabetes. However, the mechanisms are incompletely understood. To explore this, we examined the effects of semaglutide, empagliflozin and their combination on renal ADC and total kidney volume (TKV). METHODS: This was a substudy of a randomised clinical trial on the effects of semaglutide and empagliflozin alone or in combination. Eighty patients with type 2 diabetes and high risk of CVD were randomised into four groups (n=20 in each) receiving either tablet placebo, empagliflozin, a combination of semaglutide and tablet placebo (herein referred to as the 'semaglutide' group), or the combination of semaglutide and empagliflozin (referred to as the 'combination-therapy' group). The semaglutide and the combination-therapy group had semaglutide treatment for 16 weeks and then had either tablet placebo or empagliflozin added to the treatment, respectively, for a further 16 weeks; the placebo and empagliflozin groups were treated with the respective monotherapy for 32 weeks. We analysed the effects of treatment on changes in ADC (cortical, medullary and the cortico-medullary difference [ΔADC; medullary ADC subtracted from cortical ADC]), as well as TKV measured by MRI. RESULTS: Both semaglutide and empagliflozin decreased cortical ADC significantly compared with placebo (semaglutide: -0.20×10-3 mm2/s [95% CI -0.30, -0.10], p<0.001; empagliflozin: -0.15×10-3 mm2/s [95% CI -0.26, -0.04], p=0.01). No significant change was observed in the combination-therapy group (-0.05×10-3 mm2/s [95%CI -0.15, 0.05]; p=0.29 vs placebo). The changes in cortical ADC were not associated with changes in GFR, albuminuria, TKV or markers of inflammation. Further, there were no changes in medullary ADC in any of the groups compared with placebo. Only treatment with semaglutide changed ΔADC significantly from placebo, showing a decrease of -0.13×10-3 mm2/s (95% CI -0.22, -0.04; p=0.01). Compared with placebo, TKV decreased by -3% (95% CI -5%, -0.3%; p=0.04), -3% (95% CI -5%, -0.4%; p=0.02) and -5% (95% CI -8%, -2%; p<0.001) in the semaglutide, empagliflozin and combination-therapy group, respectively. The changes in TKV were associated with changes in GFR, albuminuria and HbA1c. CONCLUSIONS/INTERPRETATION: In a population with type 2 diabetes and high risk of CVD, semaglutide and empagliflozin significantly reduced cortical ADC compared with placebo, indicating microstructural changes in the kidneys. These changes were not associated with changes in GFR, albuminuria or inflammation. Further, we found a decrease in TKV in all active treatment groups, which was possibly mediated by a reduction in hyperfiltration. Our findings suggest that DWI-MRI may serve as a promising tool for investigating the underlying mechanisms of medical interventions in individuals with type 2 diabetes but may reflect effects not related to fibrosis. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) 2019-000781-38.

Metabolic MRI With Hyperpolarized 13 C-Pyruvate for Early Detection of Fibrogenic Kidney Metabolism.

OBJECTIVES: Fibrosis is the final common pathway for chronic kidney disease and the best predictor for disease progression. Besides invasive biopsies, biomarkers for its detection are lacking. To address this, we used hyperpolarized 13 C-pyruvate MRI to detect the metabolic changes associated with fibrogenic activity of myofibroblasts. MATERIALS AND METHODS: Hyperpolarized 13 C-pyruvate MRI was performed in 2 pig models of kidney fibrosis (unilateral ureteral obstruction and ischemia-reperfusion injury). The imaging data were correlated with histology, biochemical, and genetic measures of metabolism and fibrosis. The porcine experiments were supplemented with cell-line experiments to inform the origins of metabolic changes in fibrogenesis. Lastly, healthy and fibrotic human kidneys were analyzed for the metabolic alterations accessible with hyperpolarized 13 C-pyruvate MRI. RESULTS: In the 2 large animal models of kidney fibrosis, metabolic imaging revealed alterations in amino acid metabolism and glycolysis. Conversion from hyperpolarized 13 C-pyruvate to 13 C-alanine decreased, whereas conversion to 13 C-lactate increased. These changes were shown to reflect profibrotic activity in cultured epithelial cells, macrophages, and fibroblasts, which are important precursors of myofibroblasts. Importantly, metabolic MRI using hyperpolarized 13 C-pyruvate was able to detect these changes earlier than fibrosis-sensitive structural imaging. Lastly, we found that the same metabolic profile is present in fibrotic tissue from human kidneys. This affirms the translational potential of metabolic MRI as an early indicator of fibrogenesis associated metabolism. CONCLUSIONS: Our findings demonstrate the promise of hyperpolarized 13 C-pyruvate MRI for noninvasive detection of fibrosis development, which could enable earlier diagnosis and intervention for patients at risk of kidney fibrosis.

Magnetic resonance imaging as a noninvasive adjunct to conventional assessment of functional differences between kidneys in vivo and during ex vivo normothermic machine perfusion.

Normothermic machine perfusion (NMP) is increasingly considered for pretransplant kidney quality assessment. However, fundamental questions about differences between in vivo and ex vivo renal function, as well as the impact of ischemic injury on ex vivo physiology, remain unanswered. This study utilized magnetic resonance imaging (MRI), alongside conventional parameters to explore differences between in vivo and ex vivo renal function and the impact of warm ischemia on a kidney's behavior ex vivo. Renal MRI scans and samples were obtained from living pigs (n = 30) in vivo. Next, kidney pairs were procured and exposed to minimal, or 75 minutes of warm ischemia, followed by 6 hours of hypothermic machine perfusion. Both kidneys simultaneously underwent 6-hour ex vivo perfusion in MRI-compatible NMP circuits to obtain multiparametric MRI data. Ischemically injured ex vivo kidneys showed a significantly altered regional blood flow distribution compared to in vivo and minimally damaged organs. Both ex vivo groups showed diffusion restriction relative to in vivo. Our findings underscore the differences between in vivo and ex vivo MRI-based renal characteristics. Therefore, when assessing organ viability during NMP, it should be considered to incorporate parameters beyond the conventional functional markers that are common in vivo.

Mice and minipigs with compromised expression of the Alzheimer's disease gene SORL1 show cerebral metabolic disturbances on hyperpolarized [1-13C]pyruvate and sodium MRI.

The sortilin-related receptor 1 (SORL1) gene, encoding the cellular endosomal sorting-related receptor with A-type repeats (SORLA), is now established as a causal gene for Alzheimer's disease. As the latest addition to the list of causal genes, the pathophysiological effects and biomarker potential of SORL1 variants remain relatively undiscovered. Metabolic dysfunction is, however, well described in patients with Alzheimer's disease and is used as an imaging biomarker in clinical diagnosis settings. To understand the metabolic consequences of loss-of-function SORL1 mutations, we applied two metabolic MRI technologies, sodium (23Na) MRI and MRI with hyperpolarized [1-13C]pyruvate, in minipigs and mice with compromised expression of SORL1. At the age analysed here, both animal models display no conventional imaging evidence of neurodegeneration but show biochemical signs of elevated amyloid production, thus representing the early preclinical disease. With hyperpolarized MRI, the exchange from [1-13C]pyruvate to [1-13C]lactate and 13C-bicarbonate was decreased by 32 and 23%, respectively, in the cerebrum of SORL1-haploinsufficient minipigs. A robust 11% decrease in the sodium content was observed with 23Na-MRI in the same minipigs. Comparably, the brain sodium concentration gradually decreased from control to SORL1 haploinsufficient (-11%) to SORL1 knockout mice (-23%), suggesting a gene dose dependence in the metabolic dysfunction. The present study highlights that metabolic MRI technologies are sensitive to the functional, metabolic consequences of Alzheimer's disease and Alzheimer's disease-linked genotypes. Further, the study suggests a potential avenue of research into the mechanisms of metabolic alterations by SORL1 mutations and their potential role in neurodegeneration.

Effects of power training in older patients with multiple sclerosis on neurodegeneration, neuromuscular function, and physical function. A study protocol for the "power training in older multiple sclerosis patients (PoTOMS) randomized control trial.

Introduction: Approximately one-third of all persons with multiple sclerosis (pwMS) are older, i.e., having an age ≥60 years. Whilst ageing and MS separately elicit deteriorating effects on brain morphology, neuromuscular function, and physical function, the combination of ageing and MS may pose a particular challenge. To counteract such detrimental changes, power training (i.e., a type of resistance exercise focusing on moderate-to-high loading at maximal intended movement velocity) presents itself as a viable and highly effective solution. Power training is known to positively impact physical function, neuromuscular function, as well as brain morphology. Existing evidence is promising but limited to young and middle-aged pwMS, with the effects of power training remaining to be elucidated in older pwMS. Methods: The presented 'Power Training in Older MS patients (PoTOMS)' trial is a national, multi-center, parallel-group, randomized controlled trial. The trial compares 24 weeks of usual care(n = 30) to 24 weeks of usual care and power training (n = 30). The primary outcome is whole brain atrophy rate. The secondary outcomes include changes in brain micro and macro structures, neuromuscular function, physical function, cognitive function, bone health, and patient-reported outcomes. Ethics and dissemination: The presented study is approved by The Regional Ethics Committee (reference number 1-10-72-222-20) and registered at the Danish Data Protection Agency (reference number 2016-051-000001). All study findings will be published in scientific peer-reviewed journals and presented at relevant scientific conferences independent of the results. The www.clinicaltrials.gov identifier is NCT04762342.

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.

Repeatability of deuterium metabolic imaging of healthy volunteers at 3 T.

BACKGROUND: Magnetic resonance (MR) imaging of deuterated glucose, termed deuterium metabolic imaging (DMI), is emerging as a biomarker of pathway-specific glucose metabolism in tumors. DMI is being studied as a useful marker of treatment response in a scan-rescan scenario. This study aims to evaluate the repeatability of brain DMI. METHODS: A repeatability study was performed in healthy volunteers from December 2022 to March 2023. The participants consumed 75 g of [6,6'-2H2]glucose. The delivery of 2H-glucose to the brain and its conversion to 2H-glutamine + glutamate, 2H-lactate, and 2H-water DMI was imaged at baseline and at 30, 70, and 120 min. DMI was performed using MR spectroscopic imaging on a 3-T system equipped with a 1H/2H-tuned head coil. Coefficients of variation (CoV) were computed for estimation of repeatability and between-subject variability. In a set of exploratory analyses, the variability effects of region, processing, and normalization were estimated. RESULTS: Six male participants were recruited, aged 34 ± 6.5 years (mean ± standard deviation). There was 42 ± 2.7 days between sessions. Whole-brain levels of glutamine + glutamate, lactate, and glucose increased to 3.22 ± 0.4 mM, 1.55 ± 0.3 mM, and 3 ± 0.7 mM, respectively. The best signal-to-noise ratio and repeatability was obtained at the 120-min timepoint. Here, the within-subject whole-brain CoVs were -10% for all metabolites, while the between-subject CoVs were -20%. CONCLUSIONS: DMI of glucose and its downstream metabolites is feasible and repeatable on a clinical 3 T system. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05402566 , registered the 25th of May 2022. RELEVANCE STATEMENT: Brain deuterium metabolic imaging of healthy volunteers is repeatable and feasible at clinical field strengths, enabling the study of shifts in tumor metabolism associated with treatment response. KEY POINTS: • Deuterium metabolic imaging is an emerging tumor biomarker with unknown repeatability.  • The repeatability of deuterium metabolic imaging is on par with FDG-PET.  • The study of deuterium metabolic imaging in clinical populations is feasible.

Hyperpolarized 13C magnetic resonance imaging in neonatal hypoxic-ischemic encephalopathy: First investigations in a large animal model.

Early biomarkers of cerebral damage are essential for accurate prognosis, timely intervention, and evaluation of new treatment modalities in newborn infants with hypoxia and ischemia at birth. Hyperpolarized 13C magnetic resonance imaging (MRI) is a novel method with which to quantify metabolism in vivo with unprecedented sensitivity. We aimed to investigate the applicability of hyperpolarized 13C MRI in a newborn piglet model and whether this method may identify early changes in cerebral metabolism after a standardized hypoxic-ischemic (HI) insult. Six piglets were anesthetized and subjected to a standardized HI insult. Imaging was performed prior to and 2 h after the insult on a 3-T MR scanner. For 13C studies, [1-13C]pyruvate was hyperpolarized in a commercial polarizer. Following intravenous injection, images were acquired using metabolic-specific imaging. HI resulted in a metabolic shift with a decrease in pyruvate to bicarbonate metabolism and an increase in pyruvate to lactate metabolism (lactate/bicarbonate ratio, mean [SD]; 2.28 [0.36] vs. 3.96 [0.91]). This is the first study to show that hyperpolarized 13C MRI can be used in newborn piglets and applied to evaluate early changes in cerebral metabolism after an HI insult.

The effects of semaglutide, empagliflozin and their combination on the kidney sodium signal from magnetic resonance imaging: A prespecified, secondary analysis from a randomized, clinical trial.

AIMS: To evaluate the effect of treatment with semaglutide and empagliflozin on the cortico-medullary sodium gradient (MCR; medulla/cortex ratio), urine sodium/creatinine ratio (UNACR), and estimated plasma volume (ePV) and to compare the MCR between persons with and without type 2 diabetes. METHODS: Using the 23Na magnetic resonance imaging (23Na-MRI) technique, we investigated the effects of 32 weeks of treatment with semaglutide, empagliflozin or their combination on MCR in 65 participants with type 2 diabetes and high risk of cardiovascular disease. The participants were recruited from a randomized, controlled interventional trial and further characterized by UNACR and ePV. In addition, in a cross-sectional design, we compared MCR by 23Na-MRI in 12 persons with type 2 diabetes and 17 matched controls. Data from the interventional trial were analyzed using a single, multivariate linear mixed model strategy for repeated measurements. Data from the cross-sectional study were analyzed by fitting a linear regression model adjusted for age and sex. RESULTS: Compared to placebo, semaglutide, but not empagliflozin, significantly decreased the MCR (-9 %, 95%CI (-18, -0.06)%, p = 0.035 and -0.05 %, 95%CI(-0.15, 0.05)%, p = 0.319, respectively). The UNACR decreased in the semaglutide group(-35 %, 95 % CI(-52, -14) %, p = 0.003) but not in the empagliflozin group (7 %, 95 % CI(-21, 44)%, p = 0.657), whereas the ePV decreased in the combination group. The MCR was not different between persons with and without type 2 diabetes. CONCLUSION: 23Na magnetic resonance imaging can identify drug induced changes in the MCR in persons with type 2 diabetes, and 32 weeks of semaglutide decreases the MCR in such persons. There is no difference in the MCR between persons with and without type 2 diabetes. TRIAL NUMBER AND REGISTRY: EUDRACT 2019-000781-38, clinicaltrialsregister.eu.

A continuous flow bioreactor system for high-throughput hyperpolarized metabolic flux analysis.

Hyperpolarized carbon-13 labeled compounds are increasingly being used in medical MR imaging (MRI) and MR imaging (MRI) and spectroscopy (MRS) research, due to its ability to monitor tissue and cell metabolism in real-time. Although radiological biomarkers are increasingly being considered as clinical indicators, biopsies are still considered the gold standard for a large variety of indications. Bioreactor systems can play an important role in biopsy examinations because of their ability to provide a physiochemical environment that is conducive for therapeutic response monitoring ex vivo. We demonstrate here a proof-of-concept bioreactor and microcoil receive array setup that allows for ex vivo preservation and metabolic NMR spectroscopy on up to three biopsy samples simultaneously, creating an easy-to-use and robust way to simultaneously run multisample carbon-13 hyperpolarization experiments. Experiments using hyperpolarized [1-13C]pyruvate on ML-1 leukemic cells in the bioreactor setup were performed and the kinetic pyruvate-to-lactate rate constants ( k PL ) extracted. The coefficient of variation of the experimentally found k PL s for five repeated experiments was C V = 35 % . With this statistical power, treatment effects of 30%-40% change in lactate production could be easily differentiable with only a few hyperpolarization dissolutions on this setup. Furthermore, longitudinal experiments showed preservation of ML-1 cells in the bioreactor setup for at least 6 h. Rat brain tissue slices were also seen to be preserved within the bioreactor for at least 1 h. This validation serves as the basis for further optimization and upscaling of the setup, which undoubtedly has huge potential in high-throughput studies with various biomarkers and tissue types.

Daytime Variation in Kidney Perfusion, Oxygenation, and Sodium Concentration Assessed by Multiparametric MRI in Healthy Volunteers.

BACKGROUND: MRI can provide information on kidney structure, perfusion, and oxygenation. Furthermore, it allows for the assessment of kidney sodium concentrations and handling, allowing multiparametric evaluation of kidney physiology. Multiparametric MRI is promising for establishing prognosis and monitoring treatment responses in kidney diseases, but its intraindividual variation during the day is unresolved. PURPOSE: To investigate the variation in multiparametric MRI measurements from the morning to the evening. STUDY TYPE: Prospective. POPULATION: Ten healthy volunteers, aged 29 ± 5 without history of kidney disease. FIELD STRENGTH/SEQUENCE: 3 T/T1 mapping, blood-oxygen level dependent imaging, arterial spin labeling perfusion imaging, diffusion weighted imaging, and sodium imaging. ASSESSMENT: A multiparametric MRI protocol, yielding T1, R2*, ADC, renal blood flow and renal sodium levels, was acquired in the morning, noon, and evening. The participants were fasting prior to the first examination. Urine biochemical analyses were performed to complement MRI data. The cortex and medulla were analyzed separately in a semi-automatic fashion, and gradients of total sodium concentration (TSC) and R2* gradients were calculated from outer cortex to inner medulla. STATISTICAL TEST: Analyses of variance and mixed-effects models to estimate differences from time of day. Coefficients of variation to assess variability within and between participants. A P-value <0.05 was considered statistically significant. RESULTS: The coefficients of variation varied from 5% to 18% for proton-based parametric sequences, while it was 38% for TSC over a day. DATA CONCLUSION: Multiparametric MRI is stable over the day. The coefficients of variation over a day were lower for proton multiparametric MRI, but higher for sodium MRI. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

New Horizons in Hyperpolarized 13C MRI.

Hyperpolarization techniques significantly enhance the sensitivity of magnetic resonance (MR) and thus present fascinating new directions for research and applications with in vivo MR imaging and spectroscopy (MRI/S). Hyperpolarized 13C MRI/S, in particular, enables real-time non-invasive assessment of metabolic processes and holds great promise for a diverse range of clinical applications spanning fields like oncology, neurology, and cardiology, with a potential for improving early diagnosis of disease, patient stratification, and therapy response assessment. Despite its potential, technical challenges remain for achieving clinical translation. This paper provides an overview of the discussions that took place at the international workshop "New Horizons in Hyperpolarized 13C MRI," in March 2023 at the Bavarian Academy of Sciences and Humanities, Munich, Germany. The workshop covered new developments, as well as future directions, in topics including polarization techniques (particularly focusing on parahydrogen-based methods), novel probes, considerations related to data acquisition and analysis, and emerging clinical applications in oncology and other fields.