Increasing the sensitivity of hyperpolarized [15 N2 ]urea detection by serial transfer of polarization to spin-coupled protons.

PURPOSE: Hyperpolarized 15 N-labeled molecules have been proposed as imaging agents for investigating tissue perfusion and pH. However, the sensitivity of direct 15 N detection is limited by the isotope's low gyromagnetic ratio. Sensitivity can be increased by transferring 15 N hyperpolarization to spin-coupled protons provided that there is not significant polarization loss during transfer. However, complete polarization transfer would limit the temporal window for imaging to the order of the proton T1 (2-3 s). To exploit the long T1 offered by storing polarization in 15 N and the higher sensitivity of 1 H detection, we have developed a pulse sequence for partial polarization transfer. METHODS: A polarization transfer pulse sequence was modified to allow partial polarization transfer, as is required for dynamic measurements, and that can be implemented with inhomogeneous B1 fields, as is often the case in vivo. The sequence was demonstrated with dynamic spectroscopy and imaging measurements with [15 N2 ]urea. RESULTS: When compared to direct 15 N detection, the sequence increased the signal-to-noise ratio (SNR) by a factor of 1.72 ± 0.25, where both experiments depleted ~20% of the hyperpolarization (>10-fold when 100% of the hyperpolarization is used). Simulations with measured cross relaxation rates showed that this sequence gave up to a 50-fold increase in urea proton polarization when compared to spontaneous polarization transfer via cross relaxation. CONCLUSION: The sequence gave an SNR increase that was close to the theoretical limit and can give a significant SNR benefit when compared to direct 13 C detection of hyperpolarized [13 C]urea

In vivo magnetic resonance imaging of glucose - initial experience

A new noninvasive, nonradioactive approach for glucose imaging using spin hyperpolarization technology and stable isotope labeling is presented. A glucose analog labeled with 13C at all six positions increased the overall hyperpolarized imaging signal; deuteration at all seven directly bonded proton positions prolonged the spin-lattice relaxation time. High-bandwidth 13C imaging overcame the large glucose carbon chemical shift dispersion. Hyperpolarized glucose images in the live rat showed time-dependent organ distribution patterns. At 8s after the start of bolus injection, the inferior vena cava was demonstrated at angiographic quality. Distribution of hyperpolarized glucose in the kidneys, vasculature, and heart was demonstrated at 12 and 20s. The heart-to-vasculature intensity ratio at 20s suggests myocardial uptake. Cancer imaging, currently performed with 18F-deoxyglucose positron emission tomography (FDG-PET), warrants further investigation, and glucose imaging could be useful in a vast range of clinical conditions and research fields where the radiation associated with the FDG-PET examination limits its use. © 2012 John Wiley & Sons, Ltd

Tolerance of Rodents to an Intravenous Bolus Injection of Sodium Nitrate in a High Concentration

Nitrate, the inorganic anion NO3−, is found in many foods and is an endogenous mammalian metabolite, which is supplied mostly through the diet. Although much is known about the safety of sodium nitrate when given per os, methodological safety data on intravenous bolus injection of sodium nitrate to rodents are lacking. Recently, we have proposed a new use for nitrate, as a contrast agent for magnetic resonance imaging that will be metal free and leave no traces in the body and the environment further to the imaging examination. It was shown that a stable isotope-labelled analog of this ion (15NO3−), in a sodium nitrate solution form and hyperpolarized state, produces a high magnetic resonance signal with prolonged visibility. Therefore, sodium nitrate was targeted for further preclinical development in this context. In the absence of methodological safety data on the potential effects of a high concentration sodium nitrate bolus intravenous injection into rodents, we carried out such an investigation in mice and rats (n = 12 of each, 6 males and 6 females in each group, altogether 24 animals). We show here that an intravenous bolus administration of sodium nitrate at a concentration of 150 mM and a dose of 51 mg/Kg does not lead to adverse effects in mice and rats. This is the first investigation of the tolerance of rodents to an intravenous injection of sodium nitrate

Hyperpolarized [15N]nitrate as a potential long lived hyperpolarized contrast agent for MRI

Primary data for DOI: 10.1016/j.jmr.2019.01.001 Title: Hyperpolarized [15N]nitrate as a potential long lived hyperpolarized contrast agent for MRI Authors: Ayelet Gamliel, Sivaranjan Uppala, Gal Sapir, Talia Harris, Atara Nardi-Schreiber, David Shaul, Jacob Sosna, J. Moshe Gomori, Rachel Katz-Brull Description: The primary datasets in this archive contain data presented in the above publication and consist of 15N-NMR spectra in solutions. Please consult the Archive Guide

Higher levels of myelin phospholipids in brains of neuronal α-Synuclein transgenic mice precede myelin loss

Abstract α-Synuclein is a protein involved in the pathogenesis of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). We investigated the role of neuronal α-Syn in myelin composition and abnormalities. The phospholipid content of purified myelin was determined by 31P NMR in two mouse lines modeling PD, PrP-A53T α-Syn and Thy-1 wt-α-Syn. Significantly higher levels of phospholipids were detected in myelin purified from brains of these α-Syn transgenic mouse models than in control mice. Nevertheless, myelin ultrastructure appeared intact. To further investigate the effect of α-Syn on myelin abnormalities, we systematically analyzed the striatum, a brain region associated with neurodegeneration in PD. An age and disease-dependent loss of myelin basic protein (MBP) signal was detected by immunohistochemistry in striatal striosomes (patches). The age-dependent loss of MBP signal was associated with lower P25α levels in oligodendrocytes. In addition, we found that α-Syn inhibited oligodendrocyte maturation and the formation of membranous sheets in vitro. Based on these results we concluded that neuronal α-Syn is involved in the regulation and/or maintenance of myelin phospholipid. However, axonal hypomyelination in the PD models is evident only in progressive stages of the disease and associated with α-Syn toxicity

Differentiation of Heterogeneous Mouse Liver from HCC by Hyperpolarized ¹³C Magnetic Resonance

The clinical characterization of small hepatocellular carcinoma (HCC) lesions in the liver and differentiation from heterogeneous inflammatory or fibrotic background is important for early detection and treatment. Metabolic monitoring of hyperpolarized 13C-labeled substrates has been suggested as a new avenue for diagnostic magnetic resonance. The metabolism of hyperpolarized [1-13C]pyruvate was monitored in mouse precision-cut liver slices (PCLS) of aged MDR2-KO mice, which served as a model for heterogeneous liver and HCC that develops similarly to the human disease. The relative in-cell activities of lactate dehydrogenase (LDH) to alanine transaminase (ALT) were found to be 0.40 ± 0.06 (n = 3) in healthy livers (from healthy mice), 0.90 ± 0.27 (n = 3) in heterogeneously inflamed liver, and 1.84 ± 0.46 (n = 3) in HCC. Thus, the in-cell LDH/ALT activities ratio was found to correlate with the progression of the disease. The results suggest that the LDH/ALT activities ratio may be useful in the assessment of liver disease. Because the technology used here is translational to both small liver samples that may be obtained from image-guided biopsy (i.e., ex vivo investigation) and to the intact liver (i.e., in a noninvasive MRI scan), these results may provide a path for differentiating heterogeneous liver from HCC in human subjects