Hyperpolarized Magnetic Resonance Imaging Research Articles

A Study on the Diazo-Transfer Reaction Using o-Nitrobenzenesulfonyl Azide

Abstract 15N-Labeled azides have a great potential as practical and effective tags for vibrational probing and hyperpolarized magnetic resonance imaging of biomolecules. They can be synthesized by reaction of primary amines with a 15N-labeled diazo-transfer reagent. TfNN15N, a γ-15N-labeled diazo-transfer reagent, was developed to prepare β-15N-labeled azides; these are vibrational probes devoid of strong spectral interference by Fermi resonance. To overcome the stability and safety problems associated with TfNN15N, there is a strong demand for the development of a novel γ-15N-labeled diazo-transfer reagent. We present a study on the diazo-transfer reaction using o-nitrobenzenesulfonyl azide (o-NsN3). o-NsNN15N, a γ-15N-labeled diazo-transfer reagent, was newly developed and found to be better than TfNN15N with respect to its physicochemical properties and ease of synthesis. Unlike TfNN15N, however, o-NsNN15N was found to afford a mixture of β- and γ-15N-labeled azides rather than the β-15N-labeled azide alone. A mechanism for the diazo-transfer reaction of o-NsNN15N with primary amines is proposed to explain the formation of such isotopomeric mixtures.

Imaging immunomodulatory treatment responses in a multiple sclerosis mouse model using hyperpolarized 13C metabolic MRI

BackgroundIn recent years, the ability of conventional magnetic resonance imaging (MRI), including T1 contrast-enhanced (CE) MRI, to monitor high-efficacy therapies and predict long-term disability in multiple sclerosis (MS) has been challenged. Therefore, non-invasive methods to improve MS lesions detection and monitor therapy response are needed.MethodsWe studied the combined cuprizone and experimental autoimmune encephalomyelitis (CPZ-EAE) mouse model of MS, which presents inflammatory-mediated demyelinated lesions in the central nervous system as commonly seen in MS patients. Using hyperpolarized 13C MR spectroscopy (MRS) metabolic imaging, we measured cerebral metabolic fluxes in control, CPZ-EAE and CPZ-EAE mice treated with two clinically-relevant therapies, namely fingolimod and dimethyl fumarate. We also acquired conventional T1 CE MRI to detect active lesions, and performed ex vivo measurements of enzyme activities and immunofluorescence analyses of brain tissue. Last, we evaluated associations between imaging and ex vivo parameters.ResultsWe show that hyperpolarized [1-13C]pyruvate conversion to lactate is increased in the brain of untreated CPZ-EAE mice when compared to the control, reflecting immune cell activation. We further demonstrate that this metabolic conversion is significantly decreased in response to the two treatments. This reduction can be explained by increased pyruvate dehydrogenase activity and a decrease in immune cells. Importantly, we show that hyperpolarized 13C MRS detects dimethyl fumarate therapy, whereas conventional T1 CE MRI cannot.ConclusionsIn conclusion, hyperpolarized MRS metabolic imaging of [1-13C]pyruvate detects immunological responses to disease-modifying therapies in MS. This technique is complementary to conventional MRI and provides unique information on neuroinflammation and its modulation.

Developing a metabolic clearance rate framework as a translational analysis approach for hyperpolarized 13C magnetic resonance imaging

Hyperpolarized carbon-13 magnetic resonance imaging is a promising technique for in vivo metabolic interrogation of alterations between health and disease. This study introduces a formalism for quantifying the metabolic information in hyperpolarized imaging. This study investigated a novel perfusion formalism and metabolic clearance rate (MCR) model in pre-clinical stroke and in the healthy human brain. Simulations showed that the proposed model was robust to perturbations in T1, transmit B1, and kPL. A significant difference in ipsilateral vs contralateral pyruvate derived cerebral blood flow (CBF) was detected in rats (140 ± 2 vs 89 ± 6 mL/100 g/min, p < 0.01, respectively) and pigs (139 ± 12 vs 95 ± 5 mL/100 g/min, p = 0.04, respectively), along with an increase in fractional metabolism (26 ± 5 vs 4 ± 2%, p < 0.01, respectively) in the rodent brain. In addition, a significant increase in ipsilateral vs contralateral MCR (0.034 ± 0.007 vs 0.017 ± 0.02/s, p = 0.03, respectively) and a decrease in mean transit time (31 ± 8 vs 60 ± 2 s, p = 0.04, respectively) was observed in the porcine brain. In conclusion, MCR mapping is a simple and robust approach to the post-processing of hyperpolarized magnetic resonance imaging.

Gas exchange and ventilation imaging of healthy and COPD subjects using hyperpolarized xenon-129 MRI and a 3D alveolar gas-exchange model.

To investigate the utility of hyperpolarized xenon-129 (HPX) gas-exchange magnetic resonance imaging (MRI) and modeling in a chronic obstructive pulmonary disease (COPD) cohort in comparison to a minimal CT-diagnosed emphysema (MCTE) cohort and a healthy cohort. A total of 25 subjects were involved in this study including COPD (n = 8), MCTE (n = 3), and healthy (n = 14) subjects. The COPD subjects were scanned using HPX ventilation, gas-exchange MRI, and volumetric CT. The healthy subjects were scanned using the same HPX gas-exchange MRI protocol with 9 of them scanned twice, 3 weeks apart. The coefficient of variation (CV) was used to quantify image heterogeneities. A three-dimensional computational fluid dynamic (CFD) model of gas exchange was used to derive functional volumes of pulmonary tissue, capillaries, and veins. The CVs of gas distributions in the images showed that there was a statistically significant difference between the COPD and healthy subjects (p < 0.0001). The functional volumes of pulmonary tissue, capillaries, and veins were significantly lower in the subjects with COPD than in the healthy subjects (p < 0.001). The functional volume of pulmonary tissue was found to be (i) statistically different between the healthy and MCTE groups (p = 0.02) and (ii) dependent on the age of the subjects in the healthy group (p = 0.0008) while their CVs (p = 0.13) were not. The novel HPX gas-exchange MRI and CFD model distinguished the healthy cohort from the MCTE and COPD cohorts. The proposed technique also showed that the functional volume of pulmonary tissue decreases with aging in the healthy group. • The ventilation and gas-exchange imaging with hyperpolarized xenon-129 MRI has enabled the identification of gas-exchange variation between COPD and healthy groups. • This novel technique was promising to be sensitive to minimal CT-diagnosed emphysema and age-related changes in gas-exchange parameter in a small pilot cohort.

Xenon-enhanced dual-energy tomosynthesis for functional imaging of respiratory disease-Concept and phantom study.

Xenon-enhanced dual-energy (DE) computed tomography (CT) and hyperpolarized noble-gas magnetic resonance imaging (MRI) provide maps of lung ventilation that can be used to detect chronic obstructive pulmonary disease (COPD) early in its development and predict respiratory exacerbations. However, xenon-enhanced DE-CT requires high radiation doses and hyper-polarized noble-gas MRI is expensive and only available at a handful of institutionsglobally. To present xenon-enhanced dual-energy tomosynthesis (XeDET) for low-dose, low-cost functional imaging of respiratory disease in an experimental phantomstudy. We propose using digital tomosynthesis to produce Xe-enhanced low-energy (LE) and high-energy (HE) coronal images. DE subtraction of the LE and HE images is used to suppress soft tissues. We used an imaging phantom to investigate image quality in terms of the area under the reciever operating characteristic curve (AUC) for the Non-PreWhitening model observer with an Eye filter and internal noise (NPWEi). The phantom simulated anatomic clutter due to lung parenchyma and attenuation due to soft tissue and lung tissue. Aluminum slats were used to simulate rib structures. A stepwedge consisting of an acrylic casing with sealed cylindrical air-filled cavities was used to simulate ventilation defects with step thicknesses of 0.5, 1, and 2cm and cylindrical radii of 0.5, 0.75, and 1cm. The phantom was ventilated with Xe and projection data were acquired using a flat-panel detector, a tube-voltage combination of 60/140kV with 1.2 mm of copper filtration on the HE spectrum and an angular range of in 1° increments. The AUC of a NPWEi observer that has access only to a single coronal slice was calculated from measurements of the three-dimensional noise power spectrum and signal template. The AUC was calculated as a function of ventilation defect thickness and radius for total patient entrance air kermas ranging from 1.42 to 2.84mGy with and without rib-simulating Al slats. For the AUC analysis, the observer internal noise level was obtained from an ad hoc calibration to a high-dose dataset. XeDET was able to suppress parenchyma-simulating clutter in coronal images enabling visualization of the simulated ventilation defects, but the limited angle acquisition resulted in residual clutter due to out-of-plane bone-mimmicking structures. The signal power of the defects increased linearly with defect radius and showed a ten-fold to fifteen-fold increase in signal power when the defect thickness increased from 0.5 to 2cm. These trends agreed with theoretical predictions. Along the depth dimension, the power of the defects decreased exponentially with distance from the center of the defects with full-width half maxima that varied from 1.85to 2.85cm depending on the defect thickness and radius. The AUCs of the 1-cm-radius defect that was 2cm in thickness ranged from good (0.8-0.9) to excellent (0.9-1.0) over the range of air kermasconsidered. Xenon-enhanced DE tomosynthesis has the potential to enable functional imaging of respiratory disease and should be further investigated as a low-cost alternative to MRI-based approaches and a low-dose alternative to CT-basedapproaches.

Hyperpolarized 13C magnetic resonance imaging-a window into metabolism : High-resolution images of human metabolism

Despite being one of the main pillars of modern diagnostics, magnetic resonance imaging (MRI) uses only atiny fraction of its potential: no more than amillionth of all nuclear spins contribute to the MRI signal. In order to increase this fraction, called polarization, MRI scanners with stronger magnetic fields are being developed. However, even the most modern scanners do not exploit the potential of MRI. To make full use of this potential, hyperpolarized MRI (HP-MRI) is an excellent tool: quantum mechanical tricks can be used to generate contrast agents whose nuclear spins can deliver a MRI signal that is up to a100,000 times stronger. This signal enhancement allows imaging of in vivo processes that would be otherwise impossible to measure. It is particularly interesting to introduce these magnetically labeled nuclei into metabolic processes so that the metabolism can be investigated non-invasively and in vivo. Small but diagnostically important changes in metabolism could be found before macroscopic tissue changes were otherwise visible. High-resolution images can be acquired within afew 100 ms, enabling metabolic monitoring in real-time. Heart, brain, and prostate are among the organs that have already been investigated in over 90clinical trials using this emerging technology. So far, displaying tissue in asimilar manner was only possible using nuclear medicine, e.g., positron emission tomography (PET) utilizing radionuclides and without resolution of various metabolic steps. Achange in tumor metabolism following treatment was shown within hours in HP-MRI. These applications coupled with background information about the technology are the subject of this review.

Multimodality Advanced Cardiovascular and Molecular Imaging for Early Detection and Monitoring of Cancer Therapy-Associated Cardiotoxicity and the Role of Artificial Intelligence and Big Data.

Cancer mortality has improved due to earlier detection via screening, as well as due to novel cancer therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitions. However, similarly to older cancer therapies such as anthracyclines, these therapies have also been documented to cause cardiotoxic events including cardiomyopathy, myocardial infarction, myocarditis, arrhythmia, hypertension, and thrombosis. Imaging modalities such as echocardiography and magnetic resonance imaging (MRI) are critical in monitoring and evaluating for cardiotoxicity from these treatments, as well as in providing information for the assessment of function and wall motion abnormalities. MRI also allows for additional tissue characterization using T1, T2, extracellular volume (ECV), and delayed gadolinium enhancement (DGE) assessment. Furthermore, emerging technologies may be able to assist with these efforts. Nuclear imaging using targeted radiotracers, some of which are already clinically used, may have more specificity and help provide information on the mechanisms of cardiotoxicity, including in anthracycline mediated cardiomyopathy and checkpoint inhibitor myocarditis. Hyperpolarized MRI may be used to evaluate the effects of oncologic therapy on cardiac metabolism. Lastly, artificial intelligence and big data of imaging modalities may help predict and detect early signs of cardiotoxicity and response to cardioprotective medications as well as provide insights on the added value of molecular imaging and correlations with cardiovascular outcomes. In this review, the current imaging modalities used to assess for cardiotoxicity from cancer treatments are discussed, in addition to ongoing research on targeted molecular radiotracers, hyperpolarized MRI, as well as the role of artificial intelligence (AI) and big data in imaging that would help improve the detection and prognostication of cancer-treatment cardiotoxicity.

Aiding Airway Obstruction Diagnosis With Computational Fluid Dynamics and Convolutional Neural Network: A New Perspective and Numerical Case Study

AbstractIt is challenging to locate small-airway obstructions induced by chronic obstructive pulmonary disease (COPD) directly from visualization using available medical imaging techniques. Accordingly, this study proposes an innovative and noninvasive diagnostic method to detect obstruction locations using computational fluid dynamics (CFD) and convolutional neural network (CNN). Specifically, expiratory airflow velocity contours were obtained from CFD simulations in a subject-specific 3D tracheobronchial tree. One case representing normal airways and 990 cases associated with different obstruction sites were investigated using CFD. The expiratory airflow velocity contours at a selected cross section in the trachea were labeled and stored as the database for training and testing two CNN models, i.e., ResNet50 and YOLOv4. Gradient-weighted class activation mapping (Grad-CAM) and the Pearson correlation coefficient were employed and calculated to classify small-airway obstruction locations and pulmonary airflow pattern shifts and highlight the highly correlated regions in the contours for locating the obstruction sites. Results indicate that the airflow velocity pattern shifts are difficult to directly visualize based on the comparisons of CFD velocity contours. CNN results show strong relevance exists between the locations of the obstruction and the expiratory airflow velocity contours. The two CNN-based models are both capable of classifying the left lung, right lung, and both lungs obstructions well using the CFD simulated airflow contour images with total accuracy higher than 95.07%. The two automatic classification algorithms are highly transformative to clinical practice for early diagnosis of obstruction locations in the lung using the expiratory airflow velocity distributions, which could be imaged using hyperpolarized magnetic resonance imaging.

Initial Experience on Hyperpolarized [1-13C]Pyruvate MRI Multicenter Reproducibility-Are Multicenter Trials Feasible?

Background: Magnetic resonance imaging (MRI) with hyperpolarized [1-13C]pyruvate allows real-time and pathway specific clinical detection of otherwise unimageable in vivo metabolism. However, the comparability between sites and protocols is unknown. Here, we provide initial experiences on the agreement of hyperpolarized MRI between sites and protocols by repeated imaging of same healthy volunteers in Europe and the US. Methods: Three healthy volunteers traveled for repeated multicenter brain MRI exams with hyperpolarized [1-13C]pyruvate within one year. First, multisite agreement was assessed with the same echo-planar imaging protocol at both sites. Then, this was compared to a variable resolution echo-planar imaging protocol. In total, 12 examinations were performed. Common metrics of 13C-pyruvate to 13C-lactate conversion were calculated, including the kPL, a model-based kinetic rate constant, and its model-free equivalents. Repeatability was evaluated with intraclass correlation coefficients (ICC) for absolute agreement computed using two-way random effects models. Results: The mean kPL across all examinations in the multisite comparison was 0.024 ± 0.0016 s−1. The ICC of the kPL was 0.83 (p = 0.14) between sites and 0.7 (p = 0.09) between examinations of the same volunteer at any of the two sites. For the model-free metrics, the lactate Z-score had similar site-to-site ICC, while it was considerably lower for the lactate-to-pyruvate ratio. Conclusions: Estimation of metabolic conversion from hyperpolarized [1-13C]pyruvate to lactate using model-based metrics such as kPL suggests close agreement between sites and examinations in volunteers. Our initial results support harmonization of protocols, support multicenter studies, and inform their design.

A pilot study of function-based radiation therapy planning for lung cancer using hyperpolarized xenon-129 ventilation MRI.

PurposeRadiation‐induced lung injury (RILI) is a common side effect in patients with non‐small cell lung cancer (NSCLC) treated with radiotherapy. Minimizing irradiation into highly functional areas of the lung may reduce the occurrence of RILI. The aim of this study is to evaluate the feasibility and utility of hyperpolarized xenon‐129 magnetic resonance imaging (MRI), an imaging tool for evaluation of the pulmonary function, to guide radiotherapy planning.MethodsTen locally advanced NSCLC patients were recruited. Each patient underwent a simulation computed tomography (CT) scan and hyperpolarized xenon‐129 MRI, then received 64 Gyin 32 fractions for radiotherapy. Clinical contours were drawn on CT. Lung regions with good ventilation were contoured based on the MRI. Two intensity‐modulated radiation therapy plans were made for each patient: an anatomic plan (Plan‐A) based on CT alone and a function‐based plan (Plan‐F) based on CT and MRI results. Compared to Plan‐A, Plan‐F was generated with two additional steps: (1) beam angles were carefully chosen to minimize direct radiation entering well‐ventilated areas, and (2) additional optimization criteria were applied to well‐ventilated areas to minimize dose exposure. V20Gy, V10Gy, V5Gy, and the mean dose in the lung were compared between the two plans.ResultsPlan‐A and Plan‐F were both clinically acceptable and met similar target coverage and organ‐at‐risk constraints (p > 0.05) except for the ventilated lungs. Compared with Plan‐A, V5Gy (Plan‐A: 30.7 ± 11.0%, Plan‐F: 27.2 ± 9.3%), V10Gy (Plan‐A: 22.0 ± 8.6%, Plan‐F: 19.3 ± 7.0%), and V20Gy (Plan‐A: 12.5 ± 5.6%, Plan‐F: 11.0 ± 4.1%) for well‐ventilated lung areas were significantly reduced in Plan‐F (p < 0.05).ConclusionIn this pilot study, function‐based radiotherapy planning using hyperpolarized xenon‐129 MRI is demonstrated to be feasible in 10 patients with NSCLC with the potential to reduce radiation exposure in well‐ventilated areas of the lung defined by hyperpolarized xenon‐129 MRI.

29Si Isotope-Enriched Silicon Nanoparticles for an Efficient Hyperpolarized Magnetic Resonance Imaging Probe.

Silicon particles have garnered attention as promising biomedical probes for hyperpolarized 29Si magnetic resonance imaging and spectroscopy. However, due to the limited levels of hyperpolarization for nanosized silicon particles, microscale silicon particles have primarily been the focus of dynamic nuclear polarization (DNP) applications, including in vivo magnetic resonance imaging (MRI). To address these current challenges, we developed a facile synthetic method for partially 29Si-enriched porous silicon nanoparticles (NPs) (160 nm) and examined their usability in hyperpolarized 29Si MRI agents with enhanced signals in spectroscopy and imaging. Hyperpolarization characteristics, such as the build-up constant, the depolarization time (T1), and the overall enhancement of the 29Si-enriched silicon NPs (10 and 15%), were thoroughly investigated and compared with those of a naturally abundant NP (4.7%). During optimal DNP conditions, the 15% enriched silicon NPs showed more than 16-fold higher enhancements─far beyond the enrichment ratio─than the naturally abundant sample, further improving the signal-to-noise ratio in in vivo 29Si MRI. The 29Si-enriched porous silicon NPs used in this work are potentially capable to serve as drug-delivery vehicles in addition to hyperpolarized 29Si in vivo, further enabling their potential future applicability as a theragnostic platform.

Hypoxia Imaging As a Guide for Hypoxia-Modulated and Hypoxia-Activated Therapy.

Significance: Oxygen imaging techniques, which can probe the spatiotemporal heterogeneity of tumor oxygenation, could be of significant clinical utility in radiation treatment planning and in evaluating the effectiveness of hypoxia-activated prodrugs. To fulfill these goals, oxygen imaging techniques should be noninvasive, quantitative, and capable of serial imaging, as well as having sufficient temporal resolution to detect the dynamics of tumor oxygenation to distinguish regions of chronic and acute hypoxia. Recent Advances: No current technique meets all these requirements, although all have strengths in certain areas. The current status of positron emission tomography (PET)-based hypoxia imaging, oxygen-enhanced magnetic resonance imaging (MRI), 19F MRI, and electron paramagnetic resonance (EPR) oximetry are reviewed along with their strengths and weaknesses for planning hypoxia-guided, intensity-modulated radiation therapy and detecting treatment response for hypoxia-targeted prodrugs. Critical Issues: Spatial and temporal resolution emerges as a major concern for these areas along with specificity and quantitative response. Although multiple oxygen imaging techniques have reached the investigative stage, clinical trials to test the therapeutic effectiveness of hypoxia imaging have been limited. Future Directions: Imaging elements of the redox environment besides oxygen by EPR and hyperpolarized MRI may have a significant impact on our understanding of the basic biology of the reactive oxygen species response and may extend treatment possibilities.

Dynamic Nuclear Polarization of Silicon Carbide Micro- and Nanoparticles.

Two dominant crystalline phases of silicon carbide (SiC): α-SiC and β-SiC, differing in size and chemical composition, were investigated regarding their potential for dynamic nuclear polarization (DNP). 29Si nuclei in α-SiC micro- and nanoparticles with sizes ranging from 650 nm to 2.2 μm and minimal oxidation were successfully hyperpolarized without the use of free radicals, while β-SiC samples did not display appreciable degrees of polarization under the same polarization conditions. Long T1 relaxation times in α-SiC of up to 1600 s (∼27 min) were recorded for the 29Si nuclei after 1 h of polarization at a temperature of 4 K. Interestingly, these promising α-SiC particles allowed for direct hyperpolarization of both 29Si and 13C nuclei, resulting in comparably strong signal amplifications. Moreover, the T1 relaxation time of 13C nuclei in 750 nm-sized α-SiC particles was over 33 min, which far exceeds T1 times of conventional 13C DNP probes with values in the order of 1–2 min. The present work demonstrates the feasibility of DNP on SiC micro- and nanoparticles and highlights their potential as hyperpolarized magnetic resonance imaging agents.

Metabolic MRI with hyperpolarized [1-13C]pyruvate separates benign oligemia from infarcting penumbra in porcine stroke

Acute ischemic stroke patients benefit from reperfusion in a short time-window after debut. Later treatment may be indicated if viable brain tissue is demonstrated and this outweighs the inherent risks of late reperfusion. Magnetic resonance imaging (MRI) with hyperpolarized [1-13C]pyruvate is an emerging technology that directly images metabolism. Here, we investigated its potential to detect viable tissue in ischemic stroke. Stroke was induced in pigs by intracerebral injection of endothelin 1. During ischemia, the rate constant of pyruvate-to-lactate conversion, kPL, was 52% larger in penumbra and 85% larger in the infarct compared to the contralateral hemisphere (P = 0.0001). Within the penumbra, the kPL was 50% higher in the regions that later infarcted compared to non-progressing regions (P = 0.026). After reperfusion, measures of pyruvate-to-lactate conversion were slightly decreased in the infarct compared to contralateral. In addition to metabolic imaging, we used hyperpolarized pyruvate for perfusion-weighted imaging. This was consistent with conventional imaging for assessment of infarct size and blood flow. Lastly, we confirmed the translatability of simultaneous assessment of metabolism and perfusion with hyperpolarized MRI in healthy volunteers. In conclusion, hyperpolarized [1-13C]pyruvate may aid penumbral characterization and increase access to reperfusion therapy for late presenting patients.

L-Carnitine Stimulates In Vivo Carbohydrate Metabolism in the Type 1 Diabetic Heart as Demonstrated by Hyperpolarized MRI.

The diabetic heart is energetically and metabolically abnormal, with increased fatty acid oxidation and decreased glucose oxidation. One factor contributing to the metabolic dysfunction in diabetes may be abnormal handling of acetyl and acyl groups by the mitochondria. L-carnitine is responsible for their transfer across the mitochondrial membrane, therefore, supplementation with L-carnitine may provide a route to improve the metabolic state of the diabetic heart. The primary aim of this study was to use hyperpolarized magnetic resonance imaging (MRI) to investigate the effects of L-carnitine supplementation on the in vivo metabolism of [1-13C]pyruvate in diabetes. Male Wistar rats were injected with either vehicle or streptozotocin (55 mg/kg) to induce type-1 diabetes. Three weeks of daily i.p. treatment with either saline or L-carnitine (3 g/kg/day) was subsequently undertaken. In vivo cardiac function and metabolism were assessed with CINE and hyperpolarized MRI, respectively. L-carnitine supplementation prevented the progression of hyperglycemia, which was observed in untreated streptozotocin injected animals and led to reductions in plasma triglyceride and ß-hydroxybutyrate concentrations. Hyperpolarized MRI revealed that L-carnitine treatment elevated pyruvate dehydrogenase flux by 3-fold in the diabetic animals, potentially through increased buffering of excess acetyl-CoA units in the mitochondria. Improved functional recovery following ischemia was also observed in the L-carnitine treated diabetic animals.

Peripheral and proximal lung ventilation in asthma: Short-term variation and response to bronchodilator inhalation

The relative involvement of the large and small airways in asthma is not clear. Hyperpolarized gas magnetic resonance imaging (MRI) provides high-resolution 3-dimensional images of ventilation distribution that can be quantified by the ventilated volume percentage (VV%) of the lungs. Our aims were to (1) quantify the baseline reproducibility of VV%, (2) assess the ventilation distribution between the proximal and peripheral lungs, and (3) investigate regional ventilation response to bronchodilator inhalation in a cohort of patients with asthma. A total of 33 patients with poorly controlled, moderate-to-severe asthma were scanned with hyperpolarized 3He MRI. Two image data sets were acquired at baseline, and 1 image data set was acquired after bronchodilator inhalation. Images were divided into proximal and peripheral regions for analysis. Bland-Altman analysis showed strong reproducibility of VV% (bias= 0.12%; LOA= -1.86% to 2.10%). VV% variation at baseline was greater in the periphery than in the proximal lung. The proximal lung was better ventilated than the peripheral lung. Ventilation increased significantly in response to bronchodilator inhalation, globally and regionally, and the ventilation increase in response to bronchodilator inhalation was greater in the peripheral lung than in the proximal lung. Hyperpolarized gas MRI was more sensitive to changes in response to bronchodilator inhalation (58%) than spirometry (33%). The peripheral lung showed reduced ventilation and a greater response to bronchodilator inhalation than the proximal lung. The high level of baseline reproducibility and sensitivity of hyperpolarized gas MRI to bronchodilator reversibility suggests that it is suitable for low subject number studies of therapy response.

Hyperpolarized 13 C magnetic resonance imaging for noninvasive assessment of tissue inflammation.

Inflammation is a central mechanism underlying numerous diseases and incorporates multiple known and potential future therapeutic targets. However, progress in developing novel immunomodulatory therapies has been slowed by a need for improvement in noninvasive biomarkers to accurately monitor the initiation, development and resolution of immune responses as well as their response to therapies. Hyperpolarized magnetic resonance imaging (MRI) is an emerging molecular imaging technique with the potential to assess immune cell responses by exploiting characteristic metabolic reprogramming in activated immune cells to support their function. Using specific metabolic tracers, hyperpolarized MRI can be used to produce detailed images of tissues producing lactate, a key metabolic signature in activated immune cells. This method has the potential to further our understanding of inflammatory processes across different diseases in human subjects as well as in preclinical models. This review discusses the application of hyperpolarized MRI to the imaging of inflammation, as well as the progress made towards the clinical translation of this emerging technique.

Early detection of doxorubicin-induced cardiotoxicity in rats by its cardiac metabolic signature assessed with hyperpolarized MRI

Doxorubicin (DOX) is a widely used chemotherapeutic agent that can cause serious cardiotoxic side effects culminating in congestive heart failure (HF). There are currently no clinical imaging techniques or biomarkers available to detect DOX-cardiotoxicity before functional decline. Mitochondrial dysfunction is thought to be a key factor driving functional decline, though real-time metabolic fluxes have never been assessed in DOX-cardiotoxicity. Hyperpolarized magnetic resonance imaging (MRI) can assess real-time metabolic fluxes in vivo. Here we show that cardiac functional decline in a clinically relevant rat-model of DOX-HF is preceded by a change in oxidative mitochondrial carbohydrate metabolism, measured by hyperpolarized MRI. The decreased metabolic fluxes were predominantly due to mitochondrial loss and additional mitochondrial dysfunction, and not, as widely assumed hitherto, to oxidative stress. Since hyperpolarized MRI has been successfully translated into clinical trials this opens up the potential to test cancer patients receiving DOX for early signs of cardiotoxicity.

Hyperpolarized 129Xe Time-of-Flight MR Imaging of Perfusion and Brain Function.

Perfusion measurements can provide vital information about the homeostasis of an organ and can therefore be used as biomarkers to diagnose a variety of cardiovascular, renal, and neurological diseases. Currently, the most common techniques to measure perfusion are 15O positron emission tomography (PET), xenon-enhanced computed tomography (CT), single photon emission computed tomography (SPECT), dynamic contrast enhanced (DCE) MRI, and arterial spin labeling (ASL) MRI. Here, we show how regional perfusion can be quantitively measured with magnetic resonance imaging (MRI) using time-resolved depolarization of hyperpolarized (HP) xenon-129 (129Xe), and the application of this approach to detect changes in cerebral blood flow (CBF) due to a hemodynamic response in response to brain stimuli. The investigated HP 129Xe Time-of-Flight (TOF) technique produced perfusion images with an average signal-to-noise ratio (SNR) of 10.35. Furthermore, to our knowledge, the first hemodynamic response (HDR) map was acquired in healthy volunteers using the HP 129Xe TOF imaging. Responses to visual and motor stimuli were observed. The acquired HP TOF HDR maps correlated well with traditional proton blood oxygenation level-dependent functional MRI. Overall, this study expands the field of HP MRI with a novel dynamic imaging technique suitable for rapid and quantitative perfusion imaging.

Organ-specific metabolic profiles of the liver and kidney during brain death and afterwards during normothermic machine perfusion of the kidney.

We investigated metabolic changes during brain death (BD) using hyperpolarized magnetic resonance (MR) spectroscopy and ex vivo graft glucose metabolism during normothermic isolated perfused kidney (IPK) machine perfusion. BD was induced in mechanically ventilated rats by inflation of an epidurally placed catheter; sham‐operated rats served as controls. Hyperpolarized [1‐13C]pyruvate MR spectroscopy was performed to quantify pyruvate metabolism in the liver and kidneys at 3 time points during BD, preceded by injecting hyperpolarized[1‐13C]pyruvate. Following BD, glucose oxidation was measured using tritium‐labeled glucose (d‐6‐3H‐glucose) during IPK reperfusion. Quantitative polymerase chain reaction and biochemistry were performed on tissue/plasma. Immediately following BD induction, lactate increased in both organs (liver: eµd0.21, 95% confidence interval [CI] [−0.27, −0.15]; kidney: eµd0.26, 95% CI [−0.40, −0.12]. After 4 hours of BD, alanine production decreased in the kidney (eµd0.14, 95% CI [0.03, 0.25], P < .05). Hepatic lactate and alanine profiles were significantly different throughout the experiment between groups (P < .01). During IPK perfusion, renal glucose oxidation was reduced following BD vs sham animals (eµd0.012, 95% CI [0.004, 0.03], P < .001). No differences in enzyme activities were found. Renal gene expression of lactate‐transporter MCT4 increased following BD (P < .01). In conclusion, metabolic processes during BD can be visualized in vivo using hyperpolarized magnetic resonance imaging and with glucose oxidation during ex vivo renal machine perfusion. These techniques can detect differences in the metabolic profiles of the liver and kidney following BD.