3D diffusion‐weighted 129Xe MRI for whole lung morphometry

Purpose To obtain whole lung morphometry measurements from 129Xe in a single breath‐hold with 3D multiple b‐value 129Xe diffusion‐weighted MRI (DW‐MRI) with an empirically optimized diffusion time and compressed sensing for scan acceleration. Methods Prospective three‐fold undersampled 3D multiple b‐value hyperpolarized 129Xe DW‐MRI datasets were acquired, and the diffusion time (Δ) was iterated so as to provide diffusive length scale (LmD) estimates from the stretched exponential model (SEM) that are comparable to those from 3He. The empirically optimized 129Xe diffusion time was then implemented with a four‐fold undersampling scheme and was prospectively benchmarked against 3He measurements in a cohort of five healthy volunteers, six ex‐smokers, and two chronic obstructive pulmonary disease patients using both SEM‐derived LmD and cylinder model (CM)‐derived mean chord length (Lm). Results Good agreement between the mean 129Xe and 3He LmD (mean difference, 2.2%) and Lm (mean difference, 1.1%) values was obtained in all subjects at an empirically optimized 129Xe Δ = 8.5 ms. Conclusion Compressed sensing has facilitated single‐breath 3D multiple b‐value 129Xe DW‐MRI acquisitions, and results at 129Xe Δ = 8.5 ms indicate that 129Xe provides a viable alternative to 3He for whole lung morphometry mapping with either the SEM or CM. Magn Reson Med 79:2986–2995, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.


INTRODUCTION
The apparent diffusion coefficient (ADC) calculated from hyperpolarized 3 He diffusion-weighted MRI (DW-MRI) has been shown to be sensitive to changes in lung microstructure (1,2). The non-Gaussian diffusion behavior of the gas in the lungs results in a non-monoexponential signal attenuation with increasing b-value (3). The signal decay is determined by experimental and physiological factors including gas diffusivity, diffusion gradient strengths and timings, and the complexity of alveolar microstructure, which together influence the measurement of ADC (4,5). Theoretical diffusion models, such as the cylinder model (CM) (6,7), stretched exponential model (SEM) (8), and q-space analysis (9), have been proposed to model this non-Gaussian diffusion behavior and derive estimates of alveolar length scales (i.e., morphometry) from multiple b-value DW-MRI acquisitions. Compressed sensing (CS) has enabled multiple b-value 3 He DW-MRI for 3D whole lung morphometry mapping in a single breath-hold (10) for quantitative regional assessment of lung microstructure.
With the limited availability of 3 He gas (11), 129 Xe provides a more cost-effective alternative for pulmonary MRI, and with advancements in polarization levels (12,13), recent studies have shown that comparable ventilation and microstructural information can be obtained using both nuclei (14)(15)(16)(17). DW-MRI with 129 Xe is, however, inherently more challenging due to the lower diffusivity and gyromagnetic ratio of 129 Xe compared with 3 He, resulting in longer diffusion gradient times, longer sequence echo time (TE) and repetition time (TR), and lower image SNR. Despite these challenges, theoretical models have been proposed for interpreting the 129 Xe DW-MRI signal from multiple b-value acquisitions (18), and estimates of alveolar length scales have been derived from healthy subjects and chronic obstructive pulmonary disease (COPD) patients (19)(20)(21). However, the multiple b-value interleaves in previous studies were acquired using noncontiguous, relatively thick 2D slices without whole lung coverageand in some cases in separate breath-holds-due to the associated long scan times. Furthermore, to our knowledge, no direct comparison of alveolar length scales derived from application of theoretical diffusion models of 3 He and 129 Xe in vivo have yet been presented.
In this study, compressed sensing acceleration methods developed for 3 He (10) were adapted for 3D multiple b-value 129 Xe DW-MRI in a single breath-hold, and 3D morphometric maps of mean diffusive length scale (Lm D ) were generated using the SEM. Results were compared against equivalent 3D 3 He Lm D morphometric maps acquired with CS, and an optimal 129 Xe diffusion time of D ¼ 8.5 ms was derived empirically. Prospective acquisitions with the optimal 129 Xe diffusion time were then benchmarked in healthy volunteers, ex-smokers, and COPD patients with both SEM-derived Lm D and CMderived mean chord length (Lm) measurements.

The Stretched Exponential Model
The non-Gaussian signal decay from an imaging voxel can be modeled as the superposition of signals with different apparent diffusivities (D): where S 0 is the signal when b ¼ 0, S b is the signal corresponding to a non-zero b-value, D are all possible apparent diffusivities between 0 and D 0 (the free diffusion coefficient of 3 He or 129 Xe in air/N 2 ), and pðDÞ is the probability distribution associated with the apparent diffusivities. The non-Gaussian HP gas diffusion signal decay in the lungs can be well described by an SEM fit (Equation [2]) (22).
With 3 He DW-MRI, the SEM-derived parameters of distributed diffusivity coefficient (DDC) and heterogeneity index (a) have been shown to be sensitive to changes in lung microstructure and are valid over a range of experimental conditions. DDC is dependent on diffusion time, while a has been demonstrated to be insensitive to lung inflation and experimental diffusion time (23). A numerical expression for pðDÞ can be estimated from the SEM-derived parameters using the approach developed by Berberan-Santos et al. (24): Dt 0 a=ð1ÀaÞ Á f ðDÞ; where t 0 is 1/DDC, and f ðDÞ is defined by ½1 þ CðDt 0 Þ d ; d ¼ aða À 0:5Þ=ð1 À aÞ; a > 0:5; : The parameters B and C are functions related to a, and parameters at specific a values can be found in Table 1 of Berberan-Santos et al. (24). Interpolation can be used to derive the corresponding parameters B and C for other a values. The expression for pðDÞ can subsequently be related to a distribution of diffusion length scales pðL D Þ associated with the different apparent diffusivities through the 1D diffusion equation L D 5 (2DD) 1 =2 (i.e., root mean squared displacements, where D is the diffusion time). The pðL D Þ distributions should then represent the distribution of microscopic dimensions of the airways (i.e., the diffusion-restricting boundaries) contained within a given voxel. These distributions can then be used to calculate the mean diffusion length scale (Lm D ) as a quantitative estimate of the mean acinar airway dimensions within a given voxel. The Lm D metric should therefore be analogous to the calculation of mean linear intercept length (L x ) from histology.
This method of calculating Lm D differs from the method used to derive mean chord length (Lm) with the CM. In the CM, the underlying assumptions are that the acinar airways are considered cylindrical objects and thus the HP gas diffusion signal can be described by two anisotropic diffusion coefficients, longitudinal (D L ) and transverse (D T ). Phenomenological expressions were empirically optimized from Monte Carlo simulations to relate D L and D T to the cylindrical lung airway parameters, outer airway radii (R) and alveolar sleeve depth (h) (6,25). Lm is subsequently derived from the alveoli surface area and volume based upon the geometrical parameters of R and h (7).

METHODS
All in vivo MRI experiments were performed under the approval of the UK National Research Ethics Committee  (18). This time was derived theoretically such that acinar airway geometrical parameters from the CM for 129 Xe would be the same as those obtained with 3 He (18), and these values have been subsequently used in 2D 129 Xe DW-MRI experimental studies (20,21). Retrospective CS simulations of the fully sampled dataset with acceleration factors (AF) between 2 and 5 were implemented using the methodology described previously for 3 He (10). The Wilcoxon signedrank test was employed to assess differences in fully sampled and retrospectively reconstructed ADC maps for each AF on a pixel-by-pixel basis.
The optimum k-space sampling pattern for three-fold undersampling was chosen based on the simulation results and was used for prospective acquisition of 3D 129 Xe multiple b-value DW-MRI data from four healthy volunteers (HV1, HV2, HV3, HV4). Prospective data were acquired with an inhaled gas mixture of 750 mL 129 Xe and 250 mL nitrogen, with imaging parameters as for the fully sampled acquisition other than the following: four interleaves (b ¼ 0, 12, 20, 30 s/cm 2 ); TE/TR ¼ 11.7/15.0 ms; D ¼ 5 ms (maximum diffusion gradient strength ¼ 31.9 mT/m, ramp time ¼ 0.3 ms, plateau time-¼ 3.5 ms, gap ¼ 0.9 ms); and flip angle ¼ 2.7 . The AF of 3 reduces the scan time from 57 to 19 s. 129 Xe Lm D maps were calculated using the SEM, and results were compared with Lm D maps derived from the same volunteers' lungs using 3 He DW-MRI as described by Chan et al. (10). 3 He Lm D at 3 He D ¼ 1.6 ms was chosen for comparison because healthy and COPD Lm D values derived at this diffusion time have been demonstrated to match histologically derived healthy and COPD mean linear intercept values (26).

Empirical Determination of Optimal 129 Xe Diffusion Time
With the aim of obtaining the best agreement between 129 Xe and 3 He lung morphometry results [rather than simply using the 129 Xe D ¼ 5 ms proposed by Sukstanskii and Yablonskiy (18)], HV1 was imaged at additional diffusion times (D ¼ 5, 7, 8, and 10 ms). 129 Xe D ¼ 10 ms was chosen as it corresponds to the same 1D characteristic free diffusion length ( ffiffiffiffiffiffiffiffiffiffiffi ffi 2D 0 D p $530 mm) as experienced in the benchmark 3 He experiment (assuming D Xe-air 0 ¼ 0:14 cm 2 =s; D He-air 0 ¼ 0:88 cm 2 =s, and D He ¼ 1.6 ms). Each additional scan was acquired with the same gas mixture and b-values as the previous prospective CS acquisitions at 129 Xe D ¼ 5 ms, and Lm D maps were calculated from each dataset.

Benchmarking of Empirically Optimized 129 Xe Diffusion Time
The empirically optimized diffusion time ( 129 Xe D ¼ 8.5 ms [see Results]) was then benchmarked against 3 He equivalent measurements for lung morphometry mapping over different ranges of acinar length scales that are experienced with smoking-related emphysema. Five healthy volunteers (age, 31.0 6 3.1 years), six ex-smokers (age, 51.3 6 2.7 years), and two COPD patients (age, 63.0 6 1.4 years, GOLD II-IV) were recruited for this preliminary study. Subject demographics and pulmonary function test (PFT) data for each subject are summarized in Table 1.
Each subject was imaged with 3D multiple b-value 129 Xe DW-MRI, using 750 mL of inhaled 129 Xe and the following imaging parameters: TE/TR ¼ 14.0/17.3 ms; maximum DW gradient strength ¼ 32.6 mT/m; D ¼ 8.5 ms; ramp time ¼ 0.3 ms; plateau time ¼ 2.3 ms; gap ¼ 5.6 ms; and flip angle ¼ 3.1 . Using 129 Xe D ¼ 8.5 ms, the duration of three-fold undersampled CS scans was increased by 3 s due to the increased diffusion time. Therefore, four-fold undersampling (AF ¼ 4) was now implemented in the subsequent prospective CS acquisitions to further reduce the breath-hold to 16 s, similar to the 15 s acquisition for 3 He (10), and to demonstrate the clinical viability of this sequence. 3D 3 He DW-MRI was acquired in same-day scan sessions for all subjects (except for HV1-HV3, for whom 3 He data were acquired approximately 1 year previously), with experimental parameters described previously (10). 129 Xe and 3 He Lm D maps were derived and compared in each subject.
Finally, the applicability of 129 Xe D ¼ 8.5 ms to CM derivations of lung morphometry parameters was assessed. The 129 Xe-based CM phenomenological expressions are optimized for 129 Xe D ¼ 5 ms; however, if the same theoretical free diffusion length is probed with both nuclei (i.e., D He ¼ 1.6 ms and D Xe ¼ 10 ms), the original 3 He-based phenomenological expressions should in theory be applicable for derivation of 129 Xe lung morphometry parameters (18). Initial CM analysis of 129 Xe DW-MRI data in healthy subjects at 129 Xe D ¼ 8.5 ms and 129 Xe D ¼ 10 ms, suggested that, as with the SEM, more consistent 129 Xe lung morphometry results were obtained with 129 Xe D ¼ 8.5 ms (see Discussion). The 3D multiple b-value 129 Xe DW-MRI data at 129 Xe D ¼ 8.5 ms was therefore analyzed using the 3 He-based CM phenomenological expressions (7), and the 129 Xe mean chord length (Lm) was hence derived and compared with 3 He-derived Lm for each subject in the preliminary study.

3D Multiple b-Value 129 Xe DW-MRI with CS
The SNR of the fully sampled 129 Xe DW-MRI dataset was 25. Optimal k-space undersampling patterns for different AFs were determined through CS simulations. Retrospectively reconstructed datasets from each optimal undersampling pattern showed a small increase in mean absolute error (MAE) of normalized signal intensity value for the b ¼ 0 data (from 2.27% at AF ¼ 2 to 4.25% at AF ¼ 5), indicating a good preservation of image details with increased AF (Fig. 1). Whole lung mean ADC histograms and single slice ADC maps generated from the reconstructed CS datasets also demonstrated a good preservation of quantitative information and low MAE ADC (Fig. 2). Wilcoxon signed-rank tests for each AF found no significant differences (P > 0.05) between CSreconstructed and fully sampled ADC maps on a pixelby-pixel basis, confirming preservation of quantitative information and indicating that CS is suitable for 3D 129 Xe multiple b-value DW-MRI.
Prospective 3D 129 Xe multiple b-value DW-MRI was acquired in four healthy volunteers with AF ¼ 3 and 129 Xe D ¼ 5 ms, and resulting ADC and Lm D maps were compared with previously calculated lung microstructural maps acquired using 3D 3 He multiple b-value DW-MRI. Mean SNR for the four prospective 129 Xe datasets was 40. The prospective CS whole lung mean 129 Xe ADC value for volunteer HV1 (0.0329 cm 2 /s) was very similar (þ1.2% difference) to the fully sampled mean ADC value (0.0325 cm 2 /s) that was obtained for CS simulations. Example 129 Xe and 3 He Lm D maps from the comparative slices in HV1 are shown in Figure 3 and a summary of mean ADC and Lm D values for each volunteer is provided in Table 2. At 129 Xe D ¼ 5 ms, mean 129 Xe Lm D values for all subjects were $50 mm smaller than the corresponding mean 3 He values.

Empirical Determination of Optimal 129 Xe Diffusion Time
A strong positive linear correlation (r ¼ 0.998, P < 0.001) was established between 129 Xe Lm D and diffusion times, and at D ¼ 8.5 ms the 129 Xe Lm D value best matched the volunteer's 3 He Lm D value (Fig. 4a). In contrast to Lm D , mean 129 Xe ADC decreased with increasing diffusion time; a 12.5% decrease in mean 129 Xe ADC was observed from D ¼ 5 ms to 10 ms. The relationship between 129 Xe ADC and diffusion time was nonlinear, however, and best fitted a logarithmic function (R 2 ¼ 0.961) (Fig. 4b).

Benchmarking of Empirically Optimized 129 Xe Diffusion Time
The mean 3 He and 129 Xe SNR of the b ¼ 0 image for all preliminary study subjects was 32 and 65, respectively. A summary of 129 Xe Lm D and corresponding 3 He Lm D values are shown in Table 3. An improved matching of mean 129 Xe and 3 He Lm D was obtained with the empirically optimized diffusion time, and this is visible in example Lm D maps from three representative subjects (Fig. 5). A difference in Lm D of less than 7% was observed in all subjects, with a mean difference ( 129 Xe À 3 He) in all subjects of À2.2%. Figure 6a shows a very strong correlation (r ¼ 0.987, P < 0.001) between individual lung 3 He and 129 Xe mean Lm D values in all subjects. Lm D values fall around the line of equality, and this good agreement was confirmed by Bland-Altman analysis (Fig. 6b) of individual lung Lm D values, where a mean bias of À2.1% (À4.8 mm) for 129 Xe mean Lm D with a 95% confidence interval of À6.7% to 2.5% (À14.8 to 5.2 mm) was observed.
The mean difference in 129 Xe and 3 He CM Lm values was þ1.1% (Table 3), demonstrating a similar level of agreement in CM-derived Lm at 129 Xe D ¼ 8.5 ms as SEM-derived Lm D . 3 He and 129 Xe CM single lung Lm values were also strongly correlated (r ¼ 0.980, P < 0.001) (Fig. 6c), and Bland-Altman analysis of mean single lung Lm values indicates a mean bias of þ2.3% in 129 Xe Lm values with a 95% confidence interval of À15.2% to 19.9% (Fig. 6d).   (10). The presence of image blurring in the fully sampled 129 Xe images is likely the result of elliptical-centric phase encode ordering used with 129 Xe in contrast to sequential encoding used previously with 3 He. Elliptical-centric phase encoding maximizes SNR at the consequence of increased image blurring with a RF depolarization k-space filter that originates from the center of k-space (27). The full width at half maximum values of retrospectively undersampled 129 Xe ADC histograms decreased with AF; this trend matches the results of 3 He CS simulations (10) and demonstrates decreased spatial heterogeneity associated with the denoising reconstruction process of CS. However, this loss of spatial heterogeneity did not result in a statistically significant difference between fully sampled ADC and undersampled CS ADC maps. Prospective three-fold undersampled 3D multiple bvalue 129 Xe DW-MRI was acquired in four healthy volunteers at D ¼ 5 ms. The difference of þ 1.2% between CS (0.0329 cm 2 /s) and fully sampled mean 129 Xe ADC (0.0325 cm 2 /s) for one volunteer (HV1) was similar to the small differences we reported previously between fully sampled and CS undersampled 2D and 3D 3 He ADC values (10,28). The whole lung mean 129 Xe ADC value for all four healthy volunteers ($0.033 cm 2 /s) was also consistent with previously reported healthy subject ADC values, with b ¼ 12 s/cm 2 at 1.5 T (29). The observed mean Lm D mismatch of approximately 50 mm between 3 He and 129 Xe suggests that the 129 Xe diffusion time of D ¼ 5 ms, previously proposed for in vivo lung morphometry with the CM (18), is not applicable for 129 Xe lung diffusion length scale measurements derived from the SEM.

Empirical Determination of Optimal 129 Xe Diffusion Time
Mean 129 Xe ADC values (at b ¼ 12 s/cm 2 ) decreased nonlinearly with increasing diffusion time; a trend observed previously in 3 He ADC measurements (4,30). The logarithmic relationship observed between 129 Xe ADC and diffusion time also matches the trend observed for 3 He  ADC (30). The SEM-derived Lm D values exhibited a strong positive linear dependence with D over the range of 5-10 ms. The dependence of Lm D on D reflects the changes in the theoretical characteristic free diffusion lengths probed for each experiment. At D ¼ 10 ms, corresponding to the characteristic free diffusion length of 129 Xe ( ffiffiffiffiffiffiffiffiffiffiffi ffi 2D 0 D p ¼ 530 mm) which is identical to the free diffusion length of 3 He in air for the diffusion times used by Chan et al. (10), a mismatch of Lm D values was still observed in the data from three healthy volunteers (Fig. 7).
This mismatch suggests that even at the same characteristic free diffusion length there may be inherent differences in the specific diffusion dephasing regime of the respective gas in the lung alveoli which makes this assumption of Gaussian relation between diffusion length and diffusion time inexact. The differences in diffusion dephasing regime stems from intrinsic properties (i.e., gyromagnetic ratio and diffusivity) of each gas, and thus leads to different mechanisms that contribute to non-Gaussian diffusion signal behaviors that are not accounted for in the calculation of characteristic free diffusion length. For example, differences in the diffusional dephasing regime due to microscopic background susceptibility gradients may exist between 129 Xe and 3 He at the same field strength due to the smaller gyromagnetic ratio of 129 Xe. These effects on diffusive length scales are similar to the effect of different B 0 field strengths on 3 He ADC values (5).

Benchmarking of Empirically Optimized 129 Xe Diffusion Time
The decision to further accelerate with four-fold undersampling was motivated by the need to reduce the breath-hold duration incurred with 129 Xe diffusion times > 5 ms. To verify that good agreement in Lm D values was obtained with three-and four-fold undersampling, all five healthy volunteers were imaged with an additional AF ¼ 3 129 Xe CS acquisition at 129 Xe D ¼ 8.5 ms. A slice-by-slice comparison of mean Lm D values for the five healthy volunteers was performed, and Bland-Altman analysis confirmed a mean bias of þ1.5% (þ2.9 mm) for AF ¼ 4. The 95% confidence interval of À6.9% to þ 10.0% (À13.4 to 19.3 mm) was within typical standard deviation values of lung Lm D values in healthy volunteers. This slight increase in mean slice Lm D values obtained with AF ¼ 4 is likely the result of CS reconstruction error associated with increased undersampling. In addition, the broad 95% confidence interval range could also be explained by inexact coregistration of image slices due to slight changes in subject position between the AF ¼ 3 and AF ¼ 4 scan sessions. However, the small increase in Lm D justifies that implementation of AF ¼ 4 in prospective acquisitions with 129 Xe D ¼ 8.5 ms. The reduction of scan time to within 16 s is more tolerable for a wider range of subjects, therefore AF ¼ 4 will be used in all subsequent 3D multiple b-value 129 Xe DW-MRI acquisitions.
Using the empirically optimized diffusion time, 129 Xederived Lm D values demonstrated improved matching with 3 He Lm D at 129 Xe D ¼ 8.5 ms than at 129 Xe D ¼ 5 ms. The mean difference between whole lung 129 Xe and 3 He Lm D values across all subjects was À2.2%, and the mean bias in individual lung 129 Xe Lm D values was À2.1%. 129 Xe D ¼ 8.5 ms was derived from preliminary data, and this small bias may suggest that a different optimal diffusion time (slightly longer than D ¼ 8.5 ms) could be used to bring the bias toward 0%. Considering D ¼ 8.5 ms Lm D for HV1, a 129 Xe D ¼ 9.1 ms was found to match the volunteer's 3 He Lm D value (Fig. 7). Additionally, when the previous 129 Xe D ¼ 5 and 8.5 ms results for HV2 and HV3 are considered in conjunction with an additional acquisition at 129 Xe D ¼ 10 ms, a similar optimal diffusion time of around 9 ms was obtained as well (Fig. 7).  Nevertheless, the observed bias of À2.1% is equivalent to the same-day reproducibility error (2.1%) (31) of Lm values calculated from multiple b-value 3 He DW-MRI using the CM. This indicates that any mismatch between 3 He and 129 Xe Lm D values at the 129 Xe D ¼ 8.5 ms is of the order of same-day reproducibility error, and we conclude that comparable lung morphometry maps can be obtained with 129 Xe.
One limitation of this study is that the 129 Xe diffusion time was optimized based upon the Lm D results from healthy volunteers only. In subjects with emphysematous changes to alveolar length scales, a different relationship between 129 Xe Lm D and diffusion time may exist. However, the strong agreement between 129 Xe and 3 He Lm D results from the subsequent prospective acquisitions in healthy volunteers, ex-smokers, and COPD patients suggests that 129 Xe D ¼ 8.5-9 ms is valid across a range of alveolar sizes subject to age and smokingrelated emphysema.
The empirically optimized 129 Xe D ¼ 8.5 ms used in our study is significantly longer than the diffusion time used in other 129 Xe lung morphometry studies. In Sukstanskii and Yablonskiy (18), 129 Xe D ¼ 5 ms was chosen and CM phenomenological expressions for acinar airway geometrical parameters were also recalibrated for 129 Xe such that lung morphometry results matched those of 3 He. However, it was noted that if the same theoretical free diffusion length is probed with both nuclei, the 3 Hebased phenomenological expressions can be applied to derive 129 Xe lung morphometry parameters (18). In a small subset of the preliminary study cohort (HV1-HV4), the assumption that, like the SEM, the CM will yield more comparable lung morphometry results at 129 Xe D ¼ 8.5 ms than with 129 Xe D ¼ 10 ms was explored. 129 Xe D ¼ 8.5 and 10 ms data were analyzed with 3 Hebased CM parameters, and derived Lm was compared with 3 He-derived Lm values. A mean difference of 4.3% was obtained between 129 Xe D ¼ 8.5 ms Lm and 3 He Lm, whereas at 129 Xe D ¼ 10 ms the difference was larger (11.5%). These results, albeit in a small subset of subjects, support the implementation of the 3 He-based CM with 129 Xe DW-MRI at 129 Xe D ¼ 8.5 ms.
The mean 3 He Lm values for healthy volunteers ($180 mm), ex-smokers ($250 mm), and COPD patients ($500 mm) were consistent with previously reported 3 He Lm values (7,32,33). The mean 129 Xe Lm for ex-smokers (with 129 Xe D ¼ 8.5 ms) are also in agreement with previous 129 Xe Lm values reported at 3 T obtained with 129 Xe D ¼ 5 ms (20,21). The 129 Xe Lm for the GOLD II COPD subject (318 mm) is also comparable to the 129 Xe Lm ($350 mm) reported in COPD patients (GOLD I-III) (20,21). When 129 Xe Lm from the 129 Xe D ¼ 8.5 ms data was evaluated with 3 He-based CM, an overall mean difference of þ1.1% and þ2.3% was obtained for whole lung and individual lung 129 Xe and 3 He Lm values, respectively. This small bias is of a similar magnitude as that observed with SEM-derived Lm D and therefore suggests that 129 Xe lung morphometry results obtained with 129 Xe D ¼ 8.5 ms are comparable to 3 He results analyzed with both the cylinder and stretched exponential models.

CONCLUSIONS
With limited availability of 3 He, there is a strong motivation to evaluate functional and structural information that can be derived from the readily available and cheaper 129 Xe gas isotope. Compressed sensing has facilitated acquisition of single-breath 3D multiple b-value 129 Xe DW-MRI for whole lung morphometry mapping. SEM-derived Lm D demonstrated a linear dependence with diffusion time, and the best agreement between 129 Xe and 3 He Lm D results was obtained with an empirically optimized 129 Xe D ¼ 8.5 ms. Prospective CS acquisitions were used to validate 129 Xe D ¼ 8.5 ms in healthy volunteers, ex-smokers, and COPD patients, and a strong agreement (mean Lm D bias of À2.2%) in 129 Xe and 3 He Lm D values was obtained. A similar level of agreement (mean Lm bias of þ1.1%) was obtained with CM-derived Lm, indicating that 129 Xe DW-MRI acquired with 129 Xe D ¼ 8.5 ms is a viable alternative to 3 He for 3D whole lung morphometry assessment with both cylinder and stretched exponential models.