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Assessing Cross-Site Variability in 129Xe Spectroscopy Measurements Across Major Scanner Platforms1Biomedical Engineering, Duke University, DURHAM, NC, United States, 2Radiology, Duke University, DURHAM, NC, United States, 3Medical Physics Graduate Program, Duke University, DURHAM, NC, United States, 4Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States, 5Radiology, University of Iowa, Iowa City, IA, United States
Synopsis
Keywords: Hyperpolarized MR (Gas), Hyperpolarized MR (Gas)
Motivation: Hyperpolarized 129Xe gas exchange magnetic resonance spectroscopy (MRS) lacks standardized healthy reference values.
Goal(s): To standardize 129Xe gas exchange MRS biomarker reference values across different MRI systems and estimate a T2* for consistent analysis of 129Xe gas exchange MRI.
Approach: Healthy 18-30 yr old non-smokers underwent 129Xe MRS using the consortium recommended protocol across three research centers and three different MRI vendors.
Results: Findings indicated consistent RBC-to-membrane ratios across sites but slight differences in RBC shifts, oscillation amplitudes, and T2* values.
Impact: Establishing healthy reference values for multi-site 129Xe spectroscopy will facilitate its incorporation into collaborative respiratory research.
INTRODUCTION
Hyperpolarized 129Xe is a promising emergent tool in pulmonary MRS, due to its capacity to detect distinct resonance signals as 129Xe diffuses from the airspaces to membrane tissues, and subsequently into red blood cells (RBCs), thus characterizing the stages of gas exchange. Three principal biomarkers are often extracted from 129Xe gas exchange MRS: the RBC-to-membrane ratio (RBC:M), reflecting gas exchange efficiency; the RBC chemical shift, assessing blood oxygenation levels[1]; and the RBC Oscillation Amplitude, reflecting pulmonary hemodynamics[2]. This amplitude, linked to pulsatile, cardiogenic blood flow through the pulmonary capillary bed, intensifies in patients with post-capillary pulmonary hypertension (PH) and is reduced in pre-capillary PH[3]. Collectively, these static and dynamic spectral parameters from 129Xe MR spectroscopy offer a non-invasive approach to categorize distinct cardiopulmonary disease states. However, the absence of standardized healthy reference values limits their clinical utility and suitability as endpoints in clinical trials. Our study therefore aims to characterize these 129Xe MRS biomarkers across MRI systems. We further establish a standardized estimate of T2* for the membrane and RBC resonances at 3-Tesla, an important value for correcting the corresponding images of those compartments on 129Xe gas exchange MRI.METHODS
Three research centers, Duke University[4] (Siemens, N=13, 7M/6F), Cincinnati Children’s Hospital[5] (Philips, N=19, 10M/9F), and University of Iowa[6] (General Electric, N=11, 5M/6F), recruited healthy, non-smoking adults aged 18-30. Participants underwent pulmonary function tests (PFTs) and 129Xe MRS according to the consortium protocol [7], with the exception of RF excitation occurring between the membrane and RBC resonances (208 ppm from the gas-phase) rather than 218 ppm. All subjects had FEV1>80%, FEV1/FVC>0.70, and DLCO>80%, and no history of cardiopulmonary disease. Subjects inhaled the 129Xe gas dose from FRC tailored to ~20% of their FVC. Inclusion criteria for spectroscopic evaluation were based on signal-to-noise ratio (SNR) benchmarks and comparison against Duke's established healthy reference data [2]. After these exclusion criteria, 38 subjects remained for static analysis (Duke: 10, Cincinnati: 18, Iowa: 10), while 34 subjects remained for dynamic analysis (Duke:10, Cincinnati:14, Iowa:10). Figure 1 illustrates the methodologies employed for analyzing static and dynamic spectroscopy. RBC and membrane resonances were fit in the time-domain to Lorentzian and Voigt line shapes, respectively. For each complex resonance, the amplitude, chemical shift, linewidth(s), and phase were calculated. Static spectra were averaged over 1-second (67 FIDS) and used to calculate the RBC:M, the RBC chemical shift, and the full width at half maximum (FWHM) for both resonances. T2* was estimated from spectral FHWM using $$$T2^*=1⁄(π*FHWM)$$$. Since Siemens scanners operate at 2.9T, all T2* values were adjusted, assuming $$$T2^*∝1⁄B_0$$$, to a standard B0 field of exactly 3T[8]. Dynamic spectra were analyzed using established methods[2], and oscillations were quantified with a peak-finding algorithm[9]. All metrics were compared across sites using Kruskal-Wallis analysis[10] with Bonferroni-corrected Dunn's test[11].RESULTS
Figure 2 shows key static and dynamic spectroscopy metrics from the three sites. Across all sites, differences were observed in the RBC shift (p=0.042), RBC oscillation amplitude (p=0.013), and RBC T2* (p=0.038), but not in the RBC:M or membrane T2*. Specifically, significant but modest pairwise differences were observed in RBC shift between Cincinnati/Iowa (p=0.024) and RBC oscillation amplitude between Duke/Iowa (p=0.0053). Figure 3 depicts the T2* values adjusted to 3T across the sites, with average values for RBC and membrane of 1.05ms and 1.14ms. While membrane T2* values did not differ significantly between sites, RBC T2* differed modestly between Duke/Iowa and Cincinnati/Iowa (p=0.035 and p=0.038, respectively). Table 1 shows a summary of the reference values derived from the multi-center study. The RBC:M value of 0.51±0.13 is specific both to the fitting procedure and excitation at 208 ppm. Using published approaches [12] this value can be used to estimate a multi-site reference for 218-ppm excitation via a correction factor of 1.12, suggesting a reference RBC:M of 0.59±0.20 for the consortium protocol.DISCUSSION
The consistency of RBC:M across multiple sites suggests this marker can be used reliably for cross-site comparisons of 129Xe MRS. Moreover, the estimated value at 218 ppm of 0.59±0.20 aligns closely with the reported directly measured value of 0.59±0.08 [12]. However, the minor but significant differences in RBC shift, T2*, and oscillation amplitude reveal some residual heterogeneity of 129Xe MRS across the sites. This variability could stem from factors including but not limited to differences in MRI hardware, calibration procedures, local magnetic field inhomogeneities, variations in subject sex distributions, or physiology. To enhance the accuracy and reliability of biomarkers for lung function assessment, a deeper understanding of the causes for this variability is needed to guide and refine standardization methods.Acknowledgements
Acknowledgements: R01HL105643, R01HL12677, NSF GRFP DGE-2139754References
[1] G. Norquay, G. Leung, N. J. Stewart, J. Wolber, and J. M. Wild, "129Xe chemical shift in human blood and pulmonary blood oxygenation measurement in humans using hyperpolarized 129Xe NMR," Magn Reson Med, vol. 77, no. 4, pp. 1399-1408, Apr 2017, doi: 10.1002/mrm.26225.
[2] E. A. Bier et al., "A protocol for quantifying cardiogenic oscillations in dynamic 129Xe gas exchange spectroscopy: The effects of idiopathic pulmonary fibrosis," NMR Biomed, vol. 32, no. 1, p. e4029, Jan 2019, doi: 10.1002/nbm.4029.
[3] Z. Wang et al., "Diverse cardiopulmonary diseases are associated with distinct xenon magnetic resonance imaging signatures," Eur Respir J, vol. 54, no. 6, Dec 2019, doi: 10.1183/13993003.00831-2019.
[4] Z. Wang et al., "Quantitative analysis of hyperpolarized 129Xe gas transfer MRI," Med Phys, vol. 44, no. 6, pp. 2415-2428, Jun 2017, doi: https://doi.org/10.1002/mp.12264.
[5] M. M. Willmering et al., "Improved pulmonary 129Xe ventilation imaging via 3D-spiral UTE MRI," Magn Reson Med, vol. 84, no. 1, pp. 312-320, Jul 2020, doi: https://doi.org/10.1002/mrm.28114.
[6] A. D. Hahn et al., "Functional xenon-129 magnetic resonance imaging response to antifibrotic treatment in idiopathic pulmonary fibrosis," ERJ Open Res, vol. 9, no. 3, May 2023, doi: 10.1183/23120541.00080-2023.
[7] P. J. Niedbalski et al., "Protocols for multi-site trials using hyperpolarized 129Xe MRI for imaging of ventilation, alveolar-airspace size, and gas exchange: A position paper from the 129Xe MRI clinical trials consortium," Magnetic Resonance in Medicine, vol. 86, no. 6, pp. 2966-2986, 2021, doi: https://doi.org/10.1002/mrm.28985.
[8] E. M. Haacke, Magnetic resonance imaging : physical principles and sequence design. J. Wiley & Sons, 1999.
[9] A. Costelle et al., "Quantifying Cardiogenic Oscillations of Hyperpolarized 129Xe Gas Exchange MR Spectra in a Healthy Reference Cohort," ISMRM, 2023.
[10] W. H. Kruskal and W. A. Wallis, "Use of Ranks in One-Criterion Variance Analysis," Journal of the American Statistical Association, vol. 47, no. 260, pp. 583-621, 1952, doi: 10.2307/2280779.
[11] O. J. Dunn, "Multiple Comparisons Among Means," Journal of the American Statistical Association, vol. 56, no. 293, pp. 52-64, 1961, doi: 10.2307/2282330.
[12] A. Bechtel et al., "Establishing a hemoglobin adjustment for 129Xe gas exchange MRI and MRS," Magn Reson Med, vol. 90, no. 4, pp. 1555-1568, Oct 2023, doi: 10.1002/mrm.29712.
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