Synopsis

Keywords: Hyperpolarized MR (Gas), Lung

¹²⁹Xe gas exchange MRI is commonly quantified by binning images of ventilation, membrane uptake (M/gas), and red blood cell transfer (RBC/gas) according to thresholds established using healthy reference distributions. To date, reference values have been based on small samples and do not account for hemoglobin concentration (Hb), which is known to vary by sex. We apply a Hb correction to data from 15 young, healthy volunteers (age=25.2±3.3 yrs., 6 female). After correction, there was no significant difference in individual mean M/gas and RBC/gas between males and females. The resulting reference distributions have less dispersion and skew than previously established distributions.

Introduction

Hyperpolarized ¹²⁹Xe MRI maps ¹²⁹Xe signal distribution within airspaces (gas), membrane tissues (M), and red blood cells (RBCs) and has emerged as a means of characterizing pulmonary diseases^1-3. A common method of quantifying these images involves classifying the M/gas and RBC/gas maps into color bins according to thresholds established by healthy reference distributions^4,5. Recent findings show that ¹²⁹Xe gas exchange metrics are affected by age and hemoglobin concentration (Hb) and may differ between males and females^6–8. However, current reference thresholds are based on small population samples with a wide range of ages and no consideration of differences in sex and Hb^4,5. Since males tend to have higher Hb than females, accounting for Hb is essential to examining sex differences in ¹²⁹Xe MRI⁹. Here we apply a Hb correction⁸ to images from 15 young, healthy subjects to assess sex-specific differences in measures of gas exchange and establish improved reference distributions.

Methods

22 healthy subjects underwent pulmonary function tests (PFTs) and ¹²⁹Xe gas exchange MRI according to established protocols¹⁰. Hb was measured using an optical sensor at the finger. Seven subjects were excluded due to abnormal PFTs, poor scan SNR, insufficient Hb sensor signal, or subsequent pulmonary disease diagnosis, leaving a final sample of 15 (age=25.2±3.3, 6 female).

Ventilation maps were corrected for B1 inhomogeneity using the N4ITK method and then normalized¹¹. Maps of M/gas and RBC/gas were constructed using the RBC/M ratio from spectroscopy, as described previously⁴. These maps were then corrected for T₂*, which for the gas signal was approximated as a constant 18ms¹² and for the membrane and RBC signals was estimated by 1/(πw), where w is the FWHM of Lorentzian fits to their respective spectral peaks (T₂*_M=1.20±0.05ms, T₂*_RBC=1.09±0.02ms). Maps were corrected for Hb using previously established correction factors derived from the model of xenon gas exchange (MOXE) (Figure 1)⁸. Each voxel of the M/gas and RBC/gas images was multiplied by the corresponding membrane ($$$Z_{M}$$$) and RBC ($$$Z_{RBC}$$$) Hb scalar correction factor. To compare to previously established reference distributions⁵, the previous non T₂*-corrected M/gas and RBC/gas data⁵ were scaled by the average T₂* factors from our sample. Sex-specific distributions were compared using a t-test on the set of subject means.

Thresholds for color binning were calculated from normalized cumulative distributions of all subjects, as done previously⁵. The ventilation and RBC/gas distributions were Box-Cox transformed to account for skew, thresholds were calculated from the mean and standard deviation of the transformed data and then inverse transformed⁵. These final thresholds were used to identify regions of defect (<two SD below mean), low intensity (<one SD below mean), and high intensity (>two SD above mean). To illustrate the impact of these new thresholds, we applied T₂* and Hb corrections to images from a 69 y/o patient with idiopathic pulmonary fibrosis (IPF) and compared the resulting color-binned images with the uncorrected images binned using the previous thresholds⁵.

Results

Figure 2 shows the cumulative ventilation, M/gas, and RBC/gas distributions with and without Hb correction, along with the thresholds and mean±SD determined from the Hb-corrected distributions. Hb correction changed individual M/gas and RBC/gas signal by an average of 3.4% and 6.4%, respectively, but had minimal impact on the cumulative distributions. The new distributions have less spread and skew than previous distributions⁵. Figure 3 shows images from the example IPF patient binned using the new and old methods. The new method reveals more ventilation defects, higher membrane uptake, and improved RBC transfer.

Figure 4 shows sex-specific distributions of individual ventilation means along with RBC/gas means both pre and post Hb correction. The gas signal averages were lower in males than females (p<0.01). Hb was significantly higher in the male cohort (14.6±1.4 vs 12.8±1.4 g/dL, p<0.05). Before Hb correction, the individual subject means of the RBC/gas distributions were higher for males (p<0.05), although there was no significant difference in M/gas means. After Hb correction, there was no significant difference in either metric across sexes. However, even with Hb correction, the cumulative sex-specific distributions suggest lower membrane uptake and higher RBC transfer in males (Figure 5).

Discussion

While Hb correction can cause large changes in some individual distributions (greater than 10% in 3/15 subjects), most subjects demonstrated only minor changes and the effect on the cumulative distributions was minimal. We suspect that this is primarily the result of the relatively tight distribution of sample Hb (13.9±1.6 g/dL) about the reference Hb⁰=14 g/dL.

We expect that these narrower distributions will allow greater sensitivity to abnormalities in ventilation, membrane uptake, and RBC transfer. This is demonstrated in the IPF patient images where the new thresholds reveal higher membrane uptake, a key biomarker of interstitial lung disease^13–15.

The reason for the observed higher gas signal in females is unclear but could relate to differences in lung inflation states, which can impact ¹²⁹Xe imaging markers^7,16. Increased RBC/gas in males was only observed prior to Hb correction, indicating that this apparent difference was likely driven by sex differences in Hb and highlights how Hb correction reduces perceived sex-specific differences. Hemoglobin correction is an essential step to ensure meaningful comparisons of ¹²⁹Xe MRI measurements of gas exchange function across subjects.

Acknowledgements

R01HL105643, R01HL12677, NSF GRFP DGE-1644868

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