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.

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.

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.

A Framework for Predicting X-Nuclei Transmitter Gain Using 1H Signal.

Commercial human MR scanners are optimised for proton imaging, containing sophisticated prescan algorithms with setting parameters such as RF transmit gain and power. These are not optimal for X-nuclear application and are challenging to apply to hyperpolarised experiments, where the non-renewable magnetisation signal changes during the experiment. We hypothesised that, despite the complex and inherently nonlinear electrodynamic physics underlying coil loading and spatial variation, simple linear regression would be sufficient to accurately predict X-nuclear transmit gain based on concomitantly acquired data from the proton body coil. We collected data across 156 scan visits at two sites as part of ongoing studies investigating sodium, hyperpolarised carbon, and hyperpolarised xenon. We demonstrate that simple linear regression is able to accurately predict sodium, carbon, or xenon transmit gain as a function of position and proton gain, with variation that is less than the intrasubject variability. In conclusion, sites running multinuclear studies may be able to remove the time-consuming need to separately acquire X-nuclear reference power calibration, inferring it from the proton instead.

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. METHODS: Denoising approaches were compared on human acquisitions of sodium (23 Na) brain, deuterium (2 H) brain, carbon (13 C) heart and brain, and simulated dynamic hyperpolarized 13 C brain scans, with and without additional noise. The current state-of-the-art denoising method Global-local higher order singular value decomposition (GL-HOSVD) was compared to the few-input method tensor Marchenko-Pastur principal component analysis (tMPPCA). Noise-removal was quantified by residual distributions, and statistical analyses evaluated the differences in mean-square-error and Bland-Altman analysis to quantify agreement between original and denoised results of noise-added data. RESULTS: GL-HOSVD and tMPPCA showed similar performance for the variety of x-nuclei data analyzed in this work, with tMPPCA removing ˜5% more noise on average over GL-HOSVD. The mean ratio between noise-added and denoising reproducibility coefficients of the Bland-Altman analysis when compared to the original are also similar for the two methods with 3.09 ± 1.03 and 2.83 ± 0.79 for GL-HOSVD and tMPPCA, respectively. CONCLUSION: The strength of tMPPCA lies in the few-input approach, which generalizes well to different data sources. This makes the use of tMPPCA denoising a robust and versatile tool in x-nuclei imaging improvements and the preferred denoising method.

Considering whole-body metabolism in hyperpolarized MRI through 13 C breath analysis-An alternative way to quantification and normalization?

PURPOSE: Hyperpolarized [1-13 C]pyruvate MRI is an emerging clinical tool for metabolic imaging. It has the potential for absolute quantitative metabolic imaging. However, the method itself is not quantitative, limiting comparison of images across both time and between individuals. Here, we propose a simple signal normalization to the whole-body oxidative metabolism to overcome this limitation. THEORY AND METHODS: A simple extension of the model-free ratiometric analysis of hyperpolarized [1-13 C]pyruvate MRI is presented, using the expired 13 CO2 in breath for normalization. The proposed framework was investigated in two porcine cohorts (N = 11) subjected to local renal hypoperfusion defects and subsequent [1-13 C]pyruvate MRI. A breath sample was taken before the [1-13 C]pyruvate injection and 5 min after. The raw MR signal from both the healthy and intervened kidney in the two cohorts was normalized using the 13 CO2 in the expired air. RESULTS: 13 CO2 content in the expired air was significantly different between the two cohorts. Normalization to this reduced the coefficients of variance in the aerobic metabolic sensitive pathways by 25% for the alanine/pyruvate ratio, and numerical changes were observed in the bicarbonate/pyruvate ratio. The lactate/pyruvate ratio was largely unaltered (<2%). CONCLUSION: Our results indicate that normalizing the hyperpolarized 13 C-signal ratios by the 13 CO2 content in expired air can reduce variation as well as improve specificity of the method by normalizing the metabolic readout to the overall metabolic status of the individual. The method is a simple and cheap extension to the hyperpolarized 13 C exam.

Fibrosis imaging with multiparametric proton and sodium MRI in pig injury models.

Chronic kidney disease (CKD) is common and has huge implications for health and mortality. It is aggravated by intrarenal fibrosis, but the assessment of fibrosis is limited to kidney biopsies, which carry a risk of complications and sampling errors. This calls for a noninvasive modality for diagnosing and staging intrarenal fibrosis. The current, exploratory study evaluates a multiparametric MRI protocol including sodium imaging (23 Na-MRI) to determine the opportunities within this modality to assess kidney injury as a surrogate endpoint of fibrosis. The study includes 43 pigs exposed to ischemia-reperfusion injury (IRI) or unilateral ureteral obstruction (UUO), or serving as healthy controls. Fibrosis was determined using gene expression analysis of collagen. The medulla/cortex ratio of 23 Na-MRI decreased in the injured kidney in the IRI pigs, but not in the UUO pigs (p = 0.0180, p = 0.0754). To assess the combination of MRI parameters in estimating fibrosis, we created a linear regression model consisting of the cortical apparent diffusion coefficient, ΔR2*, ΔT1, the 23 Na medulla/cortex ratio, and plasma creatinine (R2  = 0.8009, p = 0.0117). The 23 Na medulla/cortex ratio only slightly improved the fibrosis prediction model, leaving 23 Na-MRI in an ambiguous place for evaluation of intrarenal fibrosis. Use of multiparametric MRI in combination with plasma creatinine shows potential for the estimation of fibrosis in human kidney disease, but more translational and clinical work is warranted before MRI can contribute to earlier diagnosis and evaluation of treatment for acute kidney injury and CKD.

A genetically modified minipig model for Alzheimer's disease with SORL1 haploinsufficiency.

The established causal genes in Alzheimer's disease (AD), APP, PSEN1, and PSEN2, are functionally characterized using biomarkers, capturing an in vivo profile reflecting the disease's initial preclinical phase. Mutations in SORL1, encoding the endosome recycling receptor SORLA, are found in 2%-3% of individuals with early-onset AD, and SORL1 haploinsufficiency appears to be causal for AD. To test whether SORL1 can function as an AD causal gene, we use CRISPR-Cas9-based gene editing to develop a model of SORL1 haploinsufficiency in Göttingen minipigs, taking advantage of porcine models for biomarker investigations. SORL1 haploinsufficiency in young adult minipigs is found to phenocopy the preclinical in vivo profile of AD observed with APP, PSEN1, and PSEN2, resulting in elevated levels of ß-amyloid (Aß) and tau preceding amyloid plaque formation and neurodegeneration, as observed in humans. Our study provides functional support for the theory that SORL1 haploinsufficiency leads to endosome cytopathology with biofluid hallmarks of autosomal dominant AD.

Imaging Neurodegenerative Metabolism in Amyotrophic Lateral Sclerosis with Hyperpolarized [1-13C]pyruvate MRI.

The cause of amyotrophic lateral sclerosis (ALS) is still unknown, and consequently, early diagnosis of the disease can be difficult and effective treatment is lacking. The pathology of ALS seems to involve specific disturbances in carbohydrate metabolism, which may be diagnostic and therapeutic targets. Magnetic resonance imaging (MRI) with hyperpolarized [1-13C]pyruvate is emerging as a technology for the evaluation of pathway-specific changes in the brain's metabolism. By imaging pyruvate and the lactate and bicarbonate it is metabolized into, the technology is sensitive to the metabolic changes of inflammation and mitochondrial dysfunction. In this study, we performed hyperpolarized MRI of a patient with newly diagnosed ALS. We found a lateralized difference in [1-13C]pyruvate-to-[1-13C]lactate exchange with no changes in exchange from [1-13C]pyruvate to 13C-bicarbonate. The 40% increase in [1-13C]pyruvate-to-[1-13C]lactate exchange corresponded with the patient's symptoms and presentation with upper-motor neuron affection and cortical hyperexcitability. The data presented here demonstrate the feasibility of performing hyperpolarized MRI in ALS. They indicate potential in pathway-specific imaging of dysfunctional carbohydrate metabolism in ALS, an enigmatic neurodegenerative disease.

Lactate saturation limits bicarbonate detection in hyperpolarized 13 C-pyruvate MRI of the brain.

PURPOSE: To investigate the potential effects of [1-13 C]lactate RF saturation pulses on [13 C]bicarbonate detection in hyperpolarized [1-13 C]pyruvate MRI of the brain. METHODS: Thirteen healthy rats underwent MRI with hyperpolarized [1-13 C]pyruvate of either the brain (n = 8) or the kidneys, heart, and liver (n = 5). Dynamic, metabolite-selective imaging was used in a cross-over experiment in which [1-13 C]lactate was excited with either 0° or 90° flip angles. The [13 C]bicarbonate SNR and apparent [1-13 C]pyruvate-to-[13 C]bicarbonate conversion (kPB ) were determined. Furthermore, simulations were performed to identify the SNR optimal flip-angle scheme for detection of [1-13 C]lactate and [13 C]bicarbonate. RESULTS: In the brain, the [13 C]bicarbonate SNR was 64% higher when [1-13 C]lactate was not excited (5.8 ± 1.5 vs 3.6 ± 1.3; 1.2 to 3.3-point increase; p = 0.0027). The apparent kPB decreased 25% with [1-13 C]lactate saturation (0.0047 ± 0.0008 s-1 vs 0.0034 ± 0.0006 s-1 ; 95% confidence interval, 0.0006-0.0019 s-1 increase; p = 0.0049). These effects were not present in the kidneys, heart, or liver. Simulations suggest that the optimal [13 C]bicarbonate SNR with a TR of 1 s in the brain is obtained with [13 C]bicarbonate, [1-13 C]lactate, and [1-13 C]pyruvate flip angles of 60°, 15°, and 10°, respectively. CONCLUSIONS: Radiofrequency saturation pulses on [1-13 C]lactate limit [13 C]bicarbonate detection in the brain specifically, which could be due to shuttling of lactate from astrocytes to neurons. Our results have important implications for experimental design in studies in which [13 C]bicarbonate detection is warranted.

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.

Visualization of sodium dynamics in the kidney by magnetic resonance imaging in a multi-site study.

Sodium magnetic resonance imaging (MRI) is a powerful, non-invasive technique to assess sodium distribution within the kidney. Here we undertook pre-clinical and clinical studies to quantify the corticomedullary sodium gradient in healthy individuals and in a porcine model of diuresis. The results demonstrated that sodium MRI could detect spatial differences in sodium biodistribution across the kidney. The sodium gradient of the kidney changed significantly after diuresis in the pig model and was independent of blood electrolyte measurements. Thus, rapid sodium MRI can be used to dynamically quantify sodium biodistribution in the porcine and human kidney.

Increasing carbohydrate oxidation improves contractile reserves and prevents hypertrophy in porcine right heart failure.

In heart failure, myocardial overload causes vast metabolic changes that impair cardiac energy production and contribute to deterioration of contractile function. However, metabolic therapy is not used in heart failure care. We aimed to investigate the interplay between cardiac function and myocardial carbohydrate metabolism in a large animal heart failure model. Using magnetic resonance spectroscopy with hyperpolarized pyruvate and magnetic resonance imaging at rest and during pharmacological stress, we investigated the in-vivo cardiac pyruvate metabolism and contractility in a porcine model of chronic pulmonary insufficiency causing right ventricular volume overload. To assess if increasing the carbohydrate metabolic reserve improves the contractile reserve, a group of animals were fed dichloroacetate, an activator of pyruvate oxidation. Volume overload caused heart failure with decreased pyruvate dehydrogenase flux and poor ejection fraction reserve. The animals treated with dichloroacetate had a larger contractile response to dobutamine stress than non-treated animals. Further, dichloroacetate prevented myocardial hypertrophy. The in-vivo metabolic data were validated by mitochondrial respirometry, enzyme activity assays and gene expression analyses. Our results show that pyruvate dehydrogenase kinase inhibition improves the contractile reserve and decreases hypertrophy by augmenting carbohydrate metabolism in porcine heart failure. The approach is promising for metabolic heart failure therapy.

Creating a clinical platform for carbon-13 studies using the sodium-23 and proton resonances.

PURPOSE: Calibration of hyperpolarized 13 C-MRI is limited by the low signal from endogenous carbon-containing molecules and consequently requires 13 C-enriched external phantoms. This study investigated the feasibility of using either 23 Na-MRI or 1 H-MRI to calibrate the 13 C excitation. METHODS: Commercial 13 C-coils were used to estimate the transmit gain and center frequency for 13 C and 23 Na resonances. Simulations of the transmit B1 profile of a Helmholtz loop were performed. Noise correlation was measured for both nuclei. A retrospective analysis of human data assessing the use of the 1 H resonance to predict [1-13 C]pyruvate center frequency was also performed. In vivo experiments were undertaken in the lower limbs of 6 pigs following injection of hyperpolarized 13 C-pyruvate. RESULTS: The difference in center frequencies and transmit gain between tissue 23 Na and [1-13 C]pyruvate was reproducible, with a mean scale factor of 1.05179 ± 0.00001 and 10.4 ± 0.2 dB, respectively. Utilizing the 1 H water peak, it was possible to retrospectively predict the 13 C-pyruvate center frequency with a standard deviation of only 11 Hz sufficient for spectral-spatial excitation-based studies. CONCLUSION: We demonstrate the feasibility of using the 23 Na and 1 H resonances to calibrate the 13 C transmit B1 using commercially available 13 C-coils. The method provides a simple approach for in vivo calibration and could improve clinical workflow.

Radiofrequency ablation lesions in low-, intermediate-, and normal-voltage myocardium: an in vivo study in a porcine heart model.

AIMS: Contact force (CF) between radiofrequency (RF) ablation catheter and myocardium and ablation index (AI) correlates with RF lesion depth and width in normal-voltage (>1.5 mV) myocardium (NVM). We investigate the impact of CF on RF lesion depth and width in low (<0.5 mV) (LVM) and intermediate-voltage (0.5-1.5 mV) myocardium (IVM) following myocardial infarction. Correlation between RF lesion depth and width evaluated by native contrast magnetic resonance imaging (ncMRI) and gross anatomical evaluation was investigated. METHODS AND RESULTS: Twelve weeks after myocardial infarction, 10 pigs underwent electroanatomical mapping and endocardial RF ablations were deployed in NVM, IVM, and LVM myocardium. In vivo ncMRI was performed before the heart was excised and subjected to gross anatomical evaluation. Ninety (82%) RF lesions were evaluated. Radiofrequency lesion depth and width were smaller in IVM and LVM compared with NVM (P < 0.001). Radiofrequency lesion depth and width correlated with CF, AI, and impedance drop in NVM (CF and AI P < 0.001) and IVM (CF and AI depths P < 0.001; CF and AI widths P < 0.05). Native contrast magnetic resonance imaging evaluated RF lesion depth and width correlated with gross anatomical depth and width (NVM and IVM P < 0.001; LVM P < 0.05). CONCLUSIONS: Radiofrequency lesions deployed by similar duration, power and CF are smaller in IVM and LVM than in NVM. Radiofrequency lesion depth and width correlated with CF, AI, and impedance drop in NVM and IVM but not in LVM. Native contrast magnetic resonance imaging may be useful to assess RF lesion depth and width in NVM, IVM, and LVM.

Hyperpolarized 13 C,15 N2 -Urea MRI for assessment of the urea gradient in the porcine kidney.

PURPOSE: A decline in cortico-medullary osmolality gradient of the kidney may serve as an early indicator of pathological disruption of the tubular reabsorption process. The purpose of this study was to investigate the feasibility of hyperpolarized 13 C,15 N2 -urea MRI as a biomarker of renal function in healthy porcine kidneys resembling the human physiology. METHODS: Five healthy female Danish domestic pigs (weight 30 kg) were scanned at 3 Tesla (T) using a 13 C 3D balanced steady-state MR pulse sequence following injection of hyperpolarized 13 C,15 N2 -urea via a femoral vein catheter. Images were acquired at different time points after urea injection, and following treatment with furosemide. RESULTS: A gradient in cortico-medullary urea was observed with an intramedullary accumulation 75 s after injection of hyperpolarized 13 C,15 N2 -urea, whereas images acquired at earlier time points postinjection were dominated by cortical perfusion. Furosemide treatment resulted in an increased urea accumulation in the cortical space, leading to a reduction of the medullary-to-cortical signal ratio of 49%. CONCLUSION: This study demonstrates that hyperpolarized 13 C,15 N2 -urea MRI is capable of identifying the intrarenal accumulation of urea and can differentiate acute renal functional states in multipapillary kidneys, highlighting the potential for human translation. Magn Reson Med 76:1895-1899, 2016. © 2016 International Society for Magnetic Resonance in Medicine.

Assessment of intramyocardial hemorrhage by T1-weighted cardiovascular magnetic resonance in reperfused acute myocardial infarction.

BACKGROUND: Intramyocardialhemorrhage (IMH) reflects severe reperfusion injury in acute myocardial infarction. Non-invasive detection of IMH by cardiovascular magnetic resonance (CMR) may serve as a surrogate marker to evaluate the effect of preventive measures to reduce reperfusion injury and hence provide additional prognostic information. We sought to investigate whether IMH could be detected by CMR exploiting the T1 shortening effect of methemoglobin in an experimental model of acute myocardial infarction. The results were compared to T2-weighthed short tau inversion recovery (T2-STIR), and T2*-weighted(T2*W) sequences. METHODS AND RESULTS: IMH was induced in ten 40 kg pigs by 50-min balloon occlusion of the mid LAD followed by reperfusion. Between 4-9 days (average 4.8) post-injury, the left ventricular myocardium was assessed by T1-weigthed Inversion Recovery(T1W-IR), T2-STIR, and T2*W sequences. All CMR images were matched to histopathology and compared with the area of IMH. The difference between the size of the IMH area detected on T1W-IR images and pathology was -1.6 ± 11.3% (limits of agreement, -24%-21%), for the T2*W images the difference was -0.1 ± 18.3% (limits of agreement, -36.8%-36.6%), and for T2-STIR the difference was 8.0 ± 15.5% (limits of agreement, -23%-39%). By T1W IR the diagnostic sensitivity of IMH was 90% and specificity 70%, for T2*W imaging the sensitivity was 70% and specificity 50%, and for T2-STIR sensitivity for imaging IMH was 50% and specificity 60%. CONCLUSION: T1-weigthed non-contrast enhanced CMR detects IMH with high sensitivity and specificity and may become a diagnostic tool for detection of IMH in patients with myocardial infarction.