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Enhanced ¹²⁹Xe T₁ relaxation in blood and in presence of SPIONs at low field strengths

Nicholas Bryden¹, Sebastian William Atalla¹, Michele Kelley¹, Leah R Holmes¹, and Rosa Tamara Branca¹
¹Physics and Astronomy, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States

Synopsis

Keywords: Hyperpolarized MR (Non-Gas), Relaxometry

We demonstrate enhanced T₁ relaxation of hyperpolarized ¹²⁹Xe spins in blood and in the presence of superparamagnetic iron oxide nanoparticles (SPIONs) at low field strengths.

Introduction

Most applications of hyperpolarized ¹²⁹Xe gas at high field can be grouped in two main categories, depending on whether the gas phase or the dissolved phase is detected. In vivo gas-phase imaging applications generally include lung ventilation imaging and molecular lung imaging, where the gas is used in combination with iron oxide nanoparticles that yield enhanced sensitivity and molecular specificity to the detection^1,2. In vivo dissolved-phase imaging applications at high field, enabled by the relatively long relaxation time of xenon in blood and the recent improvements in gas polarization efficiency, range from the detection of gas exchange in the lungs, to brain perfusion, kidney perfusion, and temperature imaging^3-5.
At low magnetic field strengths, hyperpolarized gases have been used only for lung ventilation studies, despite the wide difference in chemical shift between the dissolved phase and gas phase resonances, which could in principle enable both gas phase and dissolved-phase imaging^6-8. Here, by performing a set of in vivo and in vitro measurements, we assess the feasibility of extending some of the hyperpolarized ¹²⁹Xe gas applications from high field to low field. In particular, by performing relaxation studies at high and low field strengths, we assess the sensitivity of hyperpolarized gases to SPIONs that have been used at high field for molecular imaging in the lungs, and more recently have been shown to predominately affect the longitudinal relaxation of nearby spins at low field^9-11. Then, to assess the feasibility of dissolved-phase ¹²⁹Xe MRI at low field, we perform in vivo experiments at variable field strengths to determine the relaxation properties of xenon in blood.

Methods

SPION-induced ¹H and ¹²⁹Xe relaxivities were measured on samples of deionized water containing SPIONs at different concentrations, using a Varian NMR spectrometer operating at 11.7T, as well as a home-made MRI system operating at 2.1mT¹². ¹H measurements at high field were performed by using an inversion recovery sequence, while a variable delay was placed between gas delivery and excitation to measure the relaxation of dissolved ¹²⁹Xe¹³. For ¹H measurements performed at 0.6mT, the sample was first placed in a 0.4T permanent magnet to polarize the ¹H spins, and then rapidly transported to 2.1mT, where a variable delay was placed before excitation and detection to allow for T₁ relaxation to occur. For ¹²⁹Xe at 2.1mT, the protocol used at high field was followed exactly.
Imaging of SPION samples was also performed by using the low field MRI system and a 9.4T Bruker Biospect MRI system. For imaging, a modified gradient echo sequence was used with additional delay times to allow for varied durations of longitudinal relaxation to occur. Basic image subtraction was used to calculate the contrast obtained as a result of the increased delay time.
¹²⁹Xe depolarization studies in blood were performed by using the same 9.4T MR system used to image the SPION samples. For these experiments, the mouse was placed on a rail system concentric with the bore of the magnet. A surface coil was placed on the back of the mouse such that a relatively large dissolved-phase signal could be detected from xenon dissolved in the interscapular brown fat of the animal (Fig. 1). Before each acquisition, the mouse was ventilated with hyperpolarized xenon gas for one minute, while sitting in the fringe field of the 9.4T magnet, at field strengths ranging from 0.02 - 2T, before the signal was detected at 9.4T. Control experiments were performed to account for ¹²⁹Xe depolarization during the transport of the animal in and out of the magnet.

Results

At low field, both ¹H and ¹²⁹Xe spins experienced a much larger increase in their respective longitudinal relaxation rates as a result of their interactions with the unsaturated magnetization of SPIONs (Fig. 2). More specifically, the SPION relaxivity increased from 0.92 ± 0.06 to 31.5 ± 1.8 mM s^-1 for ¹H and from 0.13 ± 0.03 to 7.32 ± 0.71 mM s^-1 for ¹²⁹Xe. This enhanced T₁ relaxivity led to increased MRI contrast consistent with the spectroscopic results. While at high field (left column of Fig. 3 and 4) SPIONs do not generate detectable contrast at the low concentration used here (top and bottom images appear almost identical), at low field (right column) significant T₁ contrast is achieved.
Total signal loss is reported for in vivo dissolved ¹²⁹Xe when the animal was ventilated at fields lower than 200mT, suggesting depolarization of xenon in blood on a time scale of milliseconds (Fig. 5).
These results, together with additional results obtained at low field using mixtures of water and blood, suggest an increased depolarization effect of the paramagnetic deoxyhemoglobin molecules found in blood at low field compared to high field^14,15.

Conclusions

As with ¹H, dissolved ¹²⁹Xe experiences accelerated longitudinal relaxation in the presence of SPIONs at low field strengths. As a result, SPIONs serve as effective T₁ contrast agents in this regime for both ¹H and dissolved ¹²⁹Xe MRI and could be used for molecular imaging applications of combined hyperpolarized xenon gas and SPIONs in the lungs at low field. The enhanced depolarization of xenon in blood observed at low field effectively prevents the extension of dissolved-phase imaging and spectroscopy applications in this regime.

Acknowledgements

This work was partially supported by the NIH grants R01DK108231, R01DK123206, and R21EB031319; and the NSFGraduate Research FellowshipDGE-1650116.

References

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2. Vignaud, A. et al. Magnetic susceptibility matching at the air-tissue interface in rat lung by using a superparamagnetic intravascular contrast agent: Influence on transverse relaxation time of hyperpolarized helium-3. Magn. Reson. Med. 54, 28–33 (2005). 10.1002/mrm.20576

3. Branca, R. T. et al. Detection of brown adipose tissue and thermogenic activity in mice by hyperpolarized xenon MRI. Proc. Natl. Acad. Sci. U. S. A. 111, 18001–18006 (2014). 10.1073/pnas.1403697111

4. Myc, L. et al. Characterisation of gas exchange in COPD with dissolved-phase hyperpolarised xenon-129 MRI. Thorax 76, 178–181 (2021). 10.1136/thoraxjnl-2020-214924

5. Chacon-Caldera, J. et al. Dissolved hyperpolarized xenon-129 MRI in human kidneys. Magn. Reson. Med. 83, 262–270 (2020). 10.1002/mrm.27923

6. Venkatesh, A. K. et al. MRI of the lung gas-space at very low-field using hyperpolarized noble gases. Magn. Reson. Imaging 21, 773–776 (2003). 10.1016/S0730-725X(03)00178-4

7. Domingues-Viqueira, William; Juan Parra-Robles; Fox, M. A Variable Field Strength System for Hyperpolarized Noble Gas MR Imaging of Rodent Lungs. Concepts Magn. Reson. Part B Magn. Reson. Eng. 33B, 124–137 (2008). 10.1002/cmr.b.20111

8. Tsai, L. L., Mair, R. W., Rosen, M. S., Patz, S. & Walsworth, R. L. An open-access, very-low-field MRI system for posture-dependent 3He human lung imaging. J. Magn. Reson. 193, 274–285 (2008). 10.1016/j.jmr.2008.05.016

9. Yin, X. et al. Large T1 contrast enhancement using superparamagnetic nanoparticles in ultra-low field MRI. Sci. Rep. 8, 1–10 (2018). 10.1038/s41598-018-30264-5

10. Rodriguez, G. G. & Erro, E. M. Fast iron oxide-induced low-field magnetic resonance imaging. J. Phys. D. Appl. Phys. 54, (2021). 10.1088/1361-6463/abbe4d

11. Waddington, D. E. J., Boele, T., Maschmeyer, R., Kuncic, Z. & Rosen, M. S. High-sensitivity in vivo contrast for ultra-low field magnetic resonance imaging using superparamagnetic iron oxide nanoparticles. Sci. Adv. 6, (2020). 10.1126/sciadv.abb0998

12. Bryden, N., McHugh, C. T., Kelley, M. & Branca, R. T. Longitudinal nuclear spin relaxation of 129Xe in solution and in hollow fiber membranes at low and high magnetic field strengths.

13. Bryden, N., Antonacci, M., Kelley, M. & Branca, R. T. An open-source, low-cost NMR spectrometer operating in the mT field regime. J. Magn. Reson. 332, 107076 (2021). 10.1016/j.jmr.2021.107076

14. Wolber, J., Cherubini, A., Dzik-Jurasz, A. S. K., Leach, M. O. & Bifone, A. Spin-lattice relaxation of laser-polarized xenon in human blood. Proc. Natl. Acad. Sci. U. S. A. 96, 3664–3669 (1999). 10.1073/pnas.96.7.3664

15. Norquay, G. et al. Relaxation and exchange dynamics of hyperpolarized 129Xe in human blood. Magn. Reson. Med. 74, 303–311 (2015). 10.1002/mrm.25417

Figures

Figure 1: Experimental setup for in vivo ¹²⁹Xe blood depolarization study. A rail system was used to move the mouse, positioned on a ¹²⁹Xe surface coil, in and out of the 9.4T magnet bore. The field along the rail was mapped using a gaussmeter and ranged in strength from 0.02 – 2T. The mouse was ventilated at various positions along the rail for one minute and relocated to isocenter for signal detection. After each measurement, the mouse was then ventilated at 9.4T to monitor the gas relaxation in the reservoir (seen on the table in the illustration).

Figure 2: Increased ¹H and ¹²⁹Xe T1 relaxation rates with SPIONs. A representative sample of T₁ relaxation data and fits for the two nuclei at various SPION concentrations obtained at low and high magnetic field strengths. At low field, both ¹H and ¹²⁹Xe spins experienced a much larger increase in their respective longitudinal relaxation rates as a result of interactions with SPIONs. Consequently, the SPION relaxivity (seen as the slope of the lines in the bottom row) is 34- and 56- fold larger for ¹H and ¹²⁹Xe, respectively.

Figure 3: ¹H images acquired at 0.6mT and 9.4T showing the SPION contrast in both regimes. A control and 2.5 μg/mL SPION sample of identical volume were imaged. All images were collected at a 64x64 resolution and have been interpolated here for clarity. A FLASH sequence with varied TR (1 – 4 s) was used at 9.4T to allow for T₁ recovery between acquisition of each line of k-space. Low field images were obtained by polarizing the samples in a 0.4T permanent magnet before acquisition of each line of k-space. .

Figure 4: ¹²⁹Xe images acquired at 2.1mT and 9.4T showing the attainable SPION contrast in both regimes. Both a control and 2.5 μg/mL SPION sample of identical volume were imaged. All images were collected at a 64x32 resolution and have been interpolated here for clarity. All images were collected with a modified gradient echo sequence to filter out any effect from gas relaxation in the reservoir. Images of the same sample with different delay times were collected simultaneously by alternating lines of k-space. Delays refer to the time between end of gas delivery and spin excitation.

Figure 5: (A) Spectra showing detected lipid-dissolved ¹²⁹Xe signal in a live mouse ventilated at different field strengths (red) and their corresponding control spectra (black). No signal was recovered at 20mT, and significant line broadening was required to resolve signal above noise at 200mT. Bottom right plot demonstrates the effect of passing animal through magnetic field gradients post ventilation and was used to correct all other control data. (B) All signal intensities plotted as a function of ventilation field strength. The dashed line is included to guide the eye.

Proc. Intl. Soc. Mag. Reson. Med. 31 (2023)

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DOI: https://doi.org/10.58530/2023/4510