Comparison of ³He and ¹²⁹Xe MRI for evaluation of lung microstructure and ventilation at 1.5T

Abstract

Background

To support translational lung MRI research with hyperpolarized ¹²⁹Xe gas, comprehensive evaluation of derived quantitative lung function measures against established measures from ³He MRI is required. Few comparative studies have been performed to date, only at 3T, and multisession repeatability of ¹²⁹Xe functional metrics have not been reported.

Purpose/Hypothesis

To compare hyperpolarized ¹²⁹Xe and ³He MRI‐derived quantitative metrics of lung ventilation and microstructure, and their repeatability, at 1.5T.

Study Type

Retrospective.

Population

Fourteen healthy nonsmokers (HN), five exsmokers (ES), five patients with chronic obstructive pulmonary disease (COPD), and 16 patients with nonsmall‐cell lung cancer (NSCLC).

Field Strength/Sequence

1.5T. NSCLC, COPD patients and selected HN subjects underwent 3D balanced steady‐state free‐precession lung ventilation MRI using both ³He and ¹²⁹Xe. Selected HN, all ES, and COPD patients underwent 2D multislice spoiled gradient‐echo diffusion‐weighted lung MRI using both hyperpolarized gas nuclei.

Assessment

Ventilated volume percentages (VV%) and mean apparent diffusion coefficients (ADC) were derived from imaging. COPD patients performed the whole MR protocol in four separate scan sessions to assess repeatability. Same‐day pulmonary function tests were performed.

Statistical Tests

Intermetric correlations: Spearman's coefficient. Intergroup/internuclei differences: analysis of variance / Wilcoxon's signed rank. Repeatability: coefficient of variation (CV), intraclass correlation (ICC) coefficient.

Results

A significant positive correlation between ³He and ¹²⁹Xe VV% was observed (r = 0.860, P < 0.001). VV% was larger for ³He than ¹²⁹Xe (P = 0.001); average bias, 8.79%. A strong correlation between mean ³He and ¹²⁹Xe ADC was obtained (r = 0.922, P < 0.001). MR parameters exhibited good correlations with pulmonary function tests. In COPD patients, mean CV of ³He and ¹²⁹Xe VV% was 4.08% and 13.01%, respectively, with ICC coefficients of 0.541 (P = 0.061) and 0.458 (P = 0.095). Mean ³He and ¹²⁹Xe ADC values were highly repeatable (mean CV: 2.98%, 2.77%, respectively; ICC: 0.995, P < 0.001; 0.936, P < 0.001).

Data Conclusion

¹²⁹Xe lung MRI provides near‐equivalent information to ³He for quantitative lung ventilation and microstructural MRI at 1.5T.

Level of Evidence: 3

Technical Efficacy Stage 2

J. Magn. Reson. Imaging 2018;48:632–642.

THE MAJORITY of hyperpolarized gas lung magnetic resonance imaging (MRI) studies that have been performed to date in patients with lung diseases have used ³He gas, exploiting its intrinsically stronger MRI signal when compared to ¹²⁹Xe. However, recent years have seen an increase in ¹²⁹Xe lung MRI1 studies in patients for assessment of lung ventilation,2, 3, 4, 5 microstructure,6, 7 and regional gas exchange8 with this naturally abundant isotope. This renewed interest is attributable to the relative scarcity of ³He gas,9 and parallel developments in ¹²⁹Xe gas polarization technology10, 11, 12, 13 and MRI pulse sequences14 that have helped bridge the gap in image quality due to the difference in gyromagnetic ratio between the two nuclei.

Previous comparisons of the sensitivity of ³He and ¹²⁹Xe MRI for assessment of lung ventilation and microstructure have been reported in healthy subjects, former smokers,7 patients with chronic obstructive pulmonary disease (COPD),3, 15 and asthma.16 Generally, lung ventilation and microstructural information of similar diagnostic quality has been obtained with the two nuclei, despite their different diffusivity in the lung airspaces. However, all of these reported studies were carried out at 3T, at relatively modest spatial resolution (15 mm and 30 mm slice thickness for ventilation and diffusion‐weighted microstructural MRI, respectively), and at a single site.3, 7, 15, 16 Magnetic susceptibility differences at 1.5T and 3T have been shown to have some impact on lung ventilation and diffusion‐weighted microstructural MRI with both gases17, 18; however, quantitative information derived from ³He and ¹²⁹Xe techniques at the most‐reported field strength to date for lung MRI (1.5T) has yet to be systematically compared. This information is critical for multisite implementation and widespread clinical dissemination of ¹²⁹Xe MRI in the future.

In addition, future clinical use of ¹²⁹Xe will require quantitative data regarding the repeatability and robustness of associated MRI biomarkers of lung disease. The most commonly reported quantitative metrics of lung ventilation from conventional, static hyperpolarized gas images are percentage ventilated volume (VV%) and ventilation defect percentage (VDP = 100% – VV%). Same‐day ³He VDP measurements were reported to be highly repeatable at 3T in patients with COPD,19, 20 while 1‐week repeatability was relatively poorer. Good same‐day and same‐week repeatability of ³He VV% has been reported in cystic fibrosis (CF) patients at 1.5T21 and 3T,22 respectively. One report of high same‐session repeatability of ¹²⁹Xe VDP in healthy subjects and asthma patients has been published recently23; however, multisession, multiday variability in quantitative lung ventilation metrics derived from ¹²⁹Xe MRI has not been assessed. Delivery of several doses of ¹²⁹Xe gas for ventilation imaging on the same/subsequent day to subjects with a variety of pulmonary conditions has been reported.2, 24 However, the primary purpose of those studies was to assess safety and tolerability, and ventilation volume repeatability was not evaluated.

The global mean ³He apparent diffusion coefficient (ADC) in the lung airspaces derived from diffusion‐weighted MRI is a well‐established marker of alveolar microstructural change. Comprehensive investigations of same‐session25 and multiday26 repeatability of mean ³He ADC values have demonstrated a high intra‐individual repeatability in healthy subjects and patients with emphysema. Furthermore, studies at 3T have highlighted a higher repeatability of ³He ADC when compared to ³He VDP in patients with COPD.19, 20 However, to our knowledge, interscan repeatability of ¹²⁹Xe ADC has not been assessed to date. Evaluation of the repeatability of lung ventilation and microstructural metrics derived from ¹²⁹Xe MRI against ³He MRI and pulmonary functional tests is therefore necessary to facilitate the clinical dissemination of these methods.

Taking the gaps in the literature discussed above into account, the purpose of this work was to evaluate the applicability and repeatability of quantitative metrics of ¹²⁹Xe ventilation and diffusion‐weighted MRI as compared to the equivalent ³He measurements made at a field strength of 1.5T.

Materials and Methods

Subjects

We present an analysis of MR data obtained from several distinct studies. Two groups of healthy nonsmokers: a) 11 participants (age = 43 ± 6 years), and b) three participants (age = 31 ± 4 years), all with no history of smoking or respiratory disorders; five ex‐smokers with a pack history of ≥10 years and no history of respiratory disorders (age = 51 ± 2 years); five patients with COPD (GOLD stage: 3D [n = 4], 3B [n = 1]; age = 67 ± 7 years); and 16 patients with nonsmall‐cell lung cancer (NSCLC) (age = 67 ± 12 years) were recruited for separate studies approved by the National Research Ethics Committee, with governance approval from the local National Health Service research committee. All subjects provided written informed consent. Patient demographics and pulmonary function test (PFT) results are summarized in Table 1. Subjects with a resting oxygen saturation of <90%, unstable cardiac disease, or (for NSCLC patients) comorbid conditions that precluded radiotherapy, were excluded.

Table 1.

Summary of Subject Demographics, PFT Results, and ³He and ¹²⁹Xe MRI Parameters

	Subject group
	Healthy nonsmokers
Parameter	a	b	Healthy ex‐smokers	NSCLC patients	COPD patients
Age (yrs) (# of Subjects)	43.0 ± 6.4 (6M, 5F)	30.7 ± 3.5 (3M)	51.0 ± 2.3 (3M, 2F)	66.9 ± 12.0 (10M, 6F)	67.4 ± 6.5 (2M, 3F)
FEV1 (%‐pred)	101.0 ± 12.5	92.6 ± 15.9	94.9 ± 9.8	72.7 ± 25.0	38.0 ± 6.6
FEV1/FVC (%)	77.1 ± 7.2	77.0 ± 7.6	75.1 ± 13.2	57.1 ± 16.5	29.7 ± 5.9
DLCO (%‐pred)	89.6 ± 17.8	102.3 ± 9.3	103.5 ± 16.2	56.6 ± 31.0	42.5 ± 32.4
3He VV%	—	98.4 ± 0.60	—	79.6 ± 11.7	71.4 ± 7.8
129Xe VV%	—	96.6 ± 0.32	—	70.8 ± 13.3	59.8 ± 10.4
3He ADCglob (cm2.s−1)	0.190 ± 0.017	—	0.211 ± 0.022	—	0.432 ± 0.127
129Xe ADCglob (cm2.s−1)	0.038 ± 0.003	—	0.043 ± 0.004	—	0.073 ± 0.019

FEV₁ = forced expiratory volume in 1 second; FVC = forced vital capacity; D_LCO = diffusing capacity of the lung for carbon monoxide; %‐pred = PFTs expressed as a percentage of a predicted value, based on the subject's age, height, and other demographic factors.

MRI Technique

All subjects underwent MRI at 1.5T (GE HDx, GE Healthcare, Milwaukee, WI). Flexible quadrature radiofrequency coils were employed for transmission and reception of MR signals at the Larmor frequencies of ³He and ¹²⁹Xe (Clinical MR Solutions, Brookfield, WI). ³He and ¹²⁹Xe gas was polarized by collisional spin‐exchange optical pumping, using a prototype commercial ³He polarizer (MITI, Durham, NC) (average polarization ∼25%) and a home‐built ¹²⁹Xe polarizer12, 27 (average polarization ∼10–15%), respectively.

Patients with NSCLC and COPD, and three healthy nonsmokers (group b) underwent 3D lung ventilation MRI with a steady‐state free precession (SSFP) sequence at breath‐hold after inhalation of ³He or ¹²⁹Xe gas.14, 28 ¹H images of the thorax were also acquired for anatomical reference and calculation of total lung volume. As illustrated in Fig. 1 (right), ¹H images were acquired in both the same breath‐hold29 and a separate breath‐hold as ³He ventilation images (same breath‐hold for ease of image registration; separate breath‐hold in case same breath‐hold acquisition failed or could not be registered). Due to the length of the ¹²⁹Xe ventilation imaging breath‐hold, ¹H images were acquired in a separate breath‐hold. VV% was derived by segmentation (and registration if required) of paired sets of hyperpolarized gas and corresponding ¹H images as described previously28 (VV% = volume of "ventilated" regions from segmentation of hyperpolarized gas images / total lung volume from segmentation of ¹H images). In addition to calculation of VV%, images were qualitatively assessed for size and number of ventilation defects (regions of unventilated signal, defined as falling below 2 standard deviations of the noise) and signal heterogeneity in ventilated areas. Hyperpolarized gas and ¹H pulse sequence parameters are listed in Table 2. In each case, a dose of ³He (99.25% of 100% ³He isotope, 0.75% N₂) or 129‐enriched xenon (86% ¹²⁹Xe) gas was balanced to 1 L with N₂ in a Tedlar bag and inhaled via a sterilized air filter. Prior to image acquisition, subjects inhaled from functional residual capacity (FRC) after a period of steady breathing. Target inhaled gas doses were achieved to within a tolerance of ± 10 mL for ³He and ± 20 mL for ¹²⁹Xe. Images with a signal‐to‐noise ratio (SNR) of <5 were not included in quantitative analysis. This threshold was determined by quantitative evaluation of the effect of SNR on ventilation heterogeneity30 by incrementally adding noise to high SNR ventilation images.

Figure 1.

Left: Comparison of ³He and ¹²⁹Xe MR ventilation images of i. a healthy nonsmoker (group b), ii. a patient with NSCLC (white arrows indicate the location of a lesion), and iii. a patient with COPD. (Note: The slice thickness of ³He images is half that of ¹²⁹Xe images; see Table 2). Right: Corresponding breath‐hold scheme for ventilation imaging scans. Scans were acquired in the order shown, with a change of RF coil and repositioning of the patient between ³He and ¹²⁹Xe scans.

Table 2.

Summary of MR Pulse Sequence Acquisition Parameters

Metric	3He VV%		129Xe VV%		3He ADC	129Xe ADC
Pulse sequence	3He 3D SSFP	1H 3D SPGR	129Xe 3D SSFP	1H 3D SPGR	DW 2D SPGR	DW 2D SPGR
FOV (cm)	∼40	∼40	∼40	∼40	∼40	∼40
Phase FOV	0.8	1.0	0.8	1.0	0.75	0.75
Matrix	100 × 80	100 × 100	100 × 80	100 × 100	64 × 64	64 × 48
Pixel size (mm)	4 × 4	4 × 4	4 × 4	4 × 4	6.25 × 6.25	6.25 × 8.33
# of slices	∼48	∼48	∼24	∼24	5	4
Slice thickness (mm)	5	5	10	10	15 (10 mm gap)	15 (10 mm gap)
Flip angle (°)	9	5	9/10a	5	4.8	6.7
TE/TR (msec)	0.6/1.9	0.6/1.9	2.2/6.7	0.6/1.9	4.8/10.0	12.5/27.0
BW(kHz)	±83.3	±83.3	±8	±83.3	±31.25	±2
Gas dose (ml)	200	N/A	600	N/A	300	600
Breath‐hold (s)	5	4	14	4	16	16
	∼14 (3He+gap+1H)		—		—	—
Δ (ms)	—		—		1.6 (τ=0.3;	5.0 (τ=0.3;
	—		—		δ=1.0; X=0)	δ=3.0; X=1.4)
ND	—		—		6	4
G m (mT.m−1)	—		—		31.6	32.2
b 1,2 (s.cm−2)	—		—		0; 1.6	0; 8.0

SSFP: steady‐state free precession; SPGR: spoiled gradient echo; FOV: field of view; TE: echo time; TR: repetition time; BW: bandwidth; Δ: diffusion time, τ: ramp time, δ: plateau time; X: separation of gradient lobes; N_D: number of diffusion‐weighted interleaves; G_m: maximum gradient amplitude; b _1,2: b values of first two interleaves.

FOV and ventilation # of slices were increased if necessary to cover the whole lungs of larger patients.

^aFlip angle was 9 ° for COPD patients, 10 ° for NSCLC patients.

Healthy nonsmokers (group a), ex‐smokers, and COPD patients underwent 2D multislice ³He and ¹²⁹Xe diffusion‐weighted lung MRI to acquire ADC maps of the lungs. ADC values were calculated from the first two interleaves of a multiple b‐value 2D diffusion‐weighted spoiled gradient echo sequence. Acquisition parameters and bipolar diffusion gradient timing parameters are summarized in Table 2. Gradients were designed to achieve comparable diffusion weighting for the two nuclei, and slice locations were matched (with an additional anterior slice for ³He acquisitions). The same SNR threshold as ventilation imaging was applied to diffusion‐weighted MRI data. Note: Healthy nonsmokers (group a) and ex‐smokers did not undergo ventilation imaging in this study. Likewise, patients with NSCLC and healthy group b did not undergo diffusion‐weighted MRI.

Patients with COPD underwent the complete MR protocol on four separate scan sessions in total: twice on day 1; once on day 2; and once 2 weeks after day 1, to assess the repeatability of ³He and ¹²⁹Xe metrics.

Pulmonary Function Testing

PFTs, including the diffusing capacity of the lung for carbon monoxide (D_LCO) and spirometry, were performed by each COPD patient, once on the same day as each MR session (three times in total, always following MRI). Healthy nonsmokers and ex‐smokers performed the same tests immediately after their single‐timepoint diffusion‐weighted MR scans, and NSCLC patients performed PFTs within ±1 week of MRI.

Statistical Analysis

VV% and global mean ADC (ADC_glob) values derived from ³He and ¹²⁹Xe MRI were compared for differences in each metric between two, or more than two, subject groups with conventional t‐tests or analyses of variance (ANOVA), respectively. Differences in metrics derived between gas nuclei were analyzed using Wilcoxon signed rank tests. Spearman's rank correlation coefficients were derived to quantify the relationship between ³He and ¹²⁹Xe datasets, and Bland–Altman analysis was used to visualize systematic differences in VV% between the two nuclei. MRI metrics were compared and correlated against PFT results by calculating Spearman's rank coefficients. The mean of repeated measurements from each COPD patient was used to represent a single datapoint for the above statistical tests.

Where repeatability data were available, the coefficient of variation (CV) of each parameter was calculated as the ratio of the standard deviation (SD) to the mean over all repeated measurements, expressed as a percentage. In addition, two‐way mixed intraclass correlation (ICC) coefficients were calculated for absolute agreement between repeat measurements. Statistical analyses were performed using IBM SPSS Statistics (v. 23, Armonk, NY) and R (R3.4, R Foundation for Statistical Computing, Vienna, Austria), and statistical significance level was set to P < 0.05.

Results

Imaging Data Quality

From the healthy nonsmokers cohort, ¹²⁹Xe diffusion‐weighted MR images from one subject exhibited insufficient SNR for accurate calculation of ADC maps. From the COPD cohort, one ³He and one ¹²⁹Xe ADC dataset, and two ³He and two ¹²⁹Xe VV% datasets (each out of a total of 20 datasets for each nucleus, each metric) were either not successfully acquired or image SNR was unsatisfactory. From the NSCLC patient cohort, one ³He dataset and one ¹H dataset was not acquired successfully, and two ¹²⁹Xe datasets showed low SNR.

All other recorded data were of sufficient SNR for analysis: ie, for ³He, >95% of ADC data and >90% of VV% data were acceptable; for ¹²⁹Xe, 95% of ADC data and >85% of VV% data were acceptable. All gas doses were well‐tolerated and no significant side effects or adverse events were reported. Mean MR parameters and PFT results are shown in Table 1.

Ventilation Imaging

Representative ³He and ¹²⁹Xe coronal ventilation images and corresponding structural ¹H images from patients with NSCLC and COPD are shown in Fig. 1 (left), alongside images from a healthy nonsmoker. Considerable ventilation abnormalities were observed in patients with NSCLC, with most patients exhibiting a heterogeneous distribution of ventilated airspaces and complete absences of ventilation in the region of the lung associated with malignancies (as identified on structural ¹H MRI). Severe ventilation defects were detected in most COPD patients, and entire lobes of the lungs were often observed to be completely unventilated.

By pooling data from healthy nonsmokers (group b) and patients with NSCLC and COPD, a significant positive correlation between ³He and ¹²⁹Xe VV%, was identified (Spearman's correlation coefficient, r = 0.860, P < 0.001). Derived VV% values were larger on average for ³He when compared with ¹²⁹Xe (mean over all healthy group b, NSCLC, and COPD subjects); P < 0.001 (Wilcoxon signed rank) and qualitatively, typically larger and more numerous ventilation defects could be observed in ¹²⁹Xe images. A Bland–Altman plot of the systematic differences between ³He and ¹²⁹Xe VV% is shown in Fig. 2, indicating a bias of +8.79% towards higher ³He VV%. Analyzing data from COPD and NSCLC patients separately, intragroup correlations between ³He and ¹²⁹Xe VV% were statistically significant for NSCLC patients (r = 0.657, P = 0.024) but not COPD patients (r = 0.700, P = 0.233). Additionally, ³He VV% values were found to be higher than ¹²⁹Xe VV% values when COPD (P = 0.063, close to significant) and NSCLC (P = 0.002, significant) patient data were analyzed separately. There were no significant differences in either mean ³He VV% (P = 0.095) or mean ¹²⁹Xe VV% (P = 0.085) values between the two patient groups, although the VV% trended to be lower in COPD patients compared with NSCLC patients.

Figure 2.

Bland–Altman analysis of ³He and ¹²⁹Xe VV% values in patients with NSCLC and COPD and healthy nonsmokers group b. The solid gray line indicates the mean difference (bias) between ³He and ¹²⁹Xe VV%, and dashed lines represent ±1.96 standard deviations from the mean. Datapoints and error bars for COPD patients denote intrasubject means and standard deviations of repeated acquisitions, respectively.

Diffusion‐Weighted Imaging

Examples of ³He and ¹²⁹Xe ADC maps obtained from a healthy nonsmoker and a patient with COPD are shown in Fig. 3. ADC_glob values of both nuclei were significantly elevated in COPD patients when compared to both healthy nonsmokers (group a) and ex‐smokers: ³He ADC_glob = 0.432 ± 0.127 cm².s⁻¹ in COPD patients, 0.211 ± 0.022 cm².s⁻¹ in ex‐smokers (P = 0.036 vs. COPD patients) and 0.190 ± 0.017 cm².s⁻¹ in healthy nonsmokers (P = 0.028 vs. COPD patients); mean ¹²⁹Xe ADC_glob = 0.073 ± 0.019 cm².s⁻¹ in COPD patients, 0.042 ± 0.004 cm².s⁻¹ in ex‐smokers (P = 0.045 vs. COPD patients) and 0.038 ± 0.003 cm².s⁻¹ in healthy nonsmokers (P = 0.029 vs. COPD patients). Ex‐smoker and healthy nonsmoker ADC_glob values were statistically indistinguishable; P = 0.214 and P = 0.114 for ³He and ¹²⁹Xe data, respectively.

Figure 3.

Representative dataset of ³He and ¹²⁹Xe ADC maps obtained from a healthy nonsmoker (group a) and a patient with COPD. The mean ADC over all slices is quoted underneath each dataset.

A strong positive correlation between ³He and ¹²⁹Xe ADC_glob was found when pooling data from healthy nonsmokers group a, ex‐smokers and COPD patients together (Fig. 4: Spearman's r = 0.922, P < 0.001). Analyzing the three subject groups separately, significant correlations between ³He and ¹²⁹Xe ADC_glob were observed for each of the three groups (P < 0.05).

Figure 4.

Correlation between mean ³He and ¹²⁹Xe ADC_glob in healthy nonsmokers (group a), ex‐smokers, and patients with COPD, with associated Spearman's correlation coefficient (r) and P value of statistical significance. The dashed line represents a linear fit to the data and error bars represent the standard deviation of repeated scans for each COPD patient.

MR Metrics vs. PFTs

A summary of the statistical analyses of relationships between MR metrics and PFTs is presented in Table 3. Both ³He and ¹²⁹Xe VV% exhibited significant correlations with FEV₁ and FEV₁/FVC at P < 0.001 (except ¹²⁹Xe VV% vs. FEV₁, P < 0.05 significance level). Correlations of VV% values derived from both nuclei with D_LCO were relatively weaker, although still significant at the P < 0.05 level. Note: One significant outlying datapoint from a patient with NSCLC with %‐predicted spirometry ∼90% but low VV% values, ∼50% for both nuclei, was excluded from the analysis presented in Table 3. When these outlying data were included in the analysis, the correlation statistics were severely affected; correlations of VV% with D_LCO were no longer significant (P > 0.05) and all other correlations were significant at the P < 0.05 level, rather than P < 0.001 (Table 3 caption).

Table 3.

Correlations Between MRI‐Derived ³He and ¹²⁹Xe VV% and ADC Measurements and PFTs

r (P)	3He ADC	129Xe ADC	3He VV%	129Xe VV%
DLCO (%‐pred)	−0.537 (0.018a)	−0.628 (0.005a)	0.524c (0.019a)	0.476c (0.035a)
FEV1 (%‐pred)	(−0.724 <0.001b)	−0.834 (<0.001b)	0.732 (<0.001b)	0.648 (0.002a)
FEV1/FVC	−0.747 (<0.001b)	−0.672 (0.001a)	0.819 (<0.001b)	0.744 (<0.001b)

^aCorrelations at the statistical significance level of P < 0.05.

^bCorrelations at the statistical significance level of P < 0.001.

^cResults of correlating VV% values with PFTs represent the statistics obtained when outlying data associated with one NSCLC patient was excluded. When this data‐point was included, the correlation coefficients (P values) for VV% altered as follows: ³He, 3 rows: 0.432 (0.052); 0.592 (0.005^a); 0.559 (0.012^a); ¹²⁹Xe, 3 rows: 0.387 (0.084); 0.531 (0.012^a); 0.529 (0.015^a).

%‐pred: %‐predicted pulmonary function test result.

ADC_glob values also showed strong correlations with PFTs; notably, correlations of ³He ADC_glob with both FEV₁ and FEV₁/FVC were significant at the P < 0.001 level, while correlations with D_LCO were significant at the P < 0.05 level (Table 3). Similarly, correlations of ¹²⁹Xe ADC_glob with FEV₁ were significant to P < 0.001, and correlations with FEV₁/FVC and D_LCO were significant to P < 0.05.

Repeatability

In COPD patients, both ³He and ¹²⁹Xe ventilation images appeared qualitatively similar (in terms of visual ventilation defect prevalence and ventilation homogeneity) at each of the four scan timepoints, as shown for a representative example in Fig. 5. Mean CV values of ³He and ¹²⁹Xe VV% between all repeated scans were 4.08% and 13.01%, respectively (Table 4). According to ICC analysis, both ³He VV% (ICC coefficient 0.541, P = 0.061) and ¹²⁹Xe VV% (coefficient 0.458, P = 0.095) repeatability—calculated by considering data from all scan timepoints—was classified as just beyond the 95% confidence level. The CV of ³He VV% was comparable to that of PFTs, while the ¹²⁹Xe VV% CV was higher.

Figure 5.

Selected ³He and ¹²⁹Xe ventilation image slices acquired at each of the four scan timepoints of the repeatability study from a COPD patient. Calculated ventilated volume percentages (VV%) are quoted underneath each respective set of images.

Table 4.

Repeatability of PFTs and MRI Metrics in Patients With COPD

	ICC (P value)	CV mean (%)	CV range (%)
FEV1 (%‐pred)	0.934 (<0.001a)	4.22	2.16–6.35
FEV1/FVC	0.987 (<0.001a)	2.34	1.49–3.80
DLCO (%‐pred)	0.992 (<0.001a)	8.73	3.91–16.15
3He VV%	0.541 (0.061)	4.08	2.21–8.86
129Xe VV%	0.458 (0.095)	13.01	9.62–25.28
3He ADCglob	0.995 (<0.001a)	2.98	1.48–5.61
129Xe ADCglob	0.936 (<0.001a)	2.77	1.68–5.88

ICC = intraclass correlation coefficient; CV = coefficient of variation.

Statistical significance level of P < 0.05.

^aStatistical significance level of P < 0.001.

Good agreement in the appearance of both ³He and ¹²⁹Xe ADC maps was observed for each scan timepoint, as illustrated in Fig. 6. ³He and ¹²⁹Xe ADC_glob values were highly repeatable over all scan sessions, with ICC coefficients for interscan agreement (0.995 and 0.936 for ³He and ¹²⁹Xe, respectively) significant at the P < 0.001 level, and mean CV values of <3% in both cases (see Table 4). ICC coefficients and CVs of ADC_glob values were comparable to those of FEV₁ and FEV₁/FVC, and considerably less than those of D_LCO and VV%.

Figure 6.

Representative ³He and ¹²⁹Xe ADC maps acquired at each of the four scan timepoints of the repeatability study from a COPD patient. Global mean ADC values (ADC_glob) are quoted underneath each respective set of maps.

Discussion

This work indicates that ¹²⁹Xe lung MRI can provide equivalent regional information on lung ventilation and microstructure to ³He MRI at to‐date the most‐reported field strength for lung MRI, 1.5T. Specifically, we demonstrated a clear agreement between ¹²⁹Xe ventilation and diffusion MRI measurements and ³He equivalent measurements; these findings substantiate previous work from the Robarts group that was performed at 3T with lower spatial resolution imaging.3, 15, 16 We also quantified the repeatability of ¹²⁹Xe ventilation and diffusion‐weighted MRI metrics against ³He equivalent measurements in COPD patients.

³He and ¹²⁹Xe VV% correlated strongly, with a positive bias towards increased VV% for ³He. Discrepancies can likely be attributed to differences in image slice thickness, gas polarization, and the fundamental properties of the gases as discussed below. The generally lower VV% of ¹²⁹Xe may be explained by the ∼5‐fold lower diffusion coefficient of xenon in air (as confirmed by the mean ADCs of the two gases measured in healthy lungs here), and the resulting slower penetration of partially obstructed airways, although the relatively lower mean SNR of ¹²⁹Xe ventilation images may also contribute to this observation. In patients with severe disease, partially obstructed airways may cause an accentuation of this diffusion‐related effect, leading to observation of further ventilation abnormalities with ¹²⁹Xe when compared with ³He. We note that a time‐dependent diffusive effect of delayed filling of ventilation defects and collateral ventilation has been observed in COPD patients by ³He MRI,31 but the equivalent measurements has not yet been reported for ¹²⁹Xe. A reduced VV% for ¹²⁹Xe when compared with ³He was also reported previously at 3T3, 16 and attributed to lower diffusivity. Furthermore, systematically higher absolute ventilated volumes have been reported for ³He when compared with ¹²⁹Xe at 3T,15 wherein it was suggested that ³He has a higher propensity to flow through collateral channels in COPD patients. Nevertheless, this property of ¹²⁹Xe could prove useful in the assessment of early (ie, small‐scale) structural abnormalities of distal airways and lung parenchyma in a variety of pulmonary diseases, provided that equivalent image SNR and spatial resolution can be achieved as that of ³He MRI.

The lower CV values (and higher ICC coefficients) of ³He VV% when compared with ¹²⁹Xe VV% are likely attributable to the generally lower and more variable SNR of ¹²⁹Xe images acquired at the time of the study (mean ± standard deviation of SNR over all NSCLC and COPD patients: 23.6 ± 16.8 for ¹²⁹Xe; 30.6 ± 10.8 for ³He), and the differences in lung inflation level in some cases between ¹²⁹Xe and anatomical ¹H images acquired in a separate breath‐hold.28 As mentioned in the Materials and Methods, polarization levels, and thus image SNR, affect the ventilation heterogeneity and therefore images with low SNR (<5) can significantly distort the physiological interpretation of the data. The relatively lower SNR may be explained by the fact that a prototype ¹²⁹Xe polarizer (producing ¹²⁹Xe polarization ∼10–15%) was used for most ¹²⁹Xe experiments in this work.12 We have since developed and optimized a clinical‐scale polarizer capable of rapidly producing ¹²⁹Xe polarized to ∼40%, which will enable improved ¹²⁹Xe image SNR in future studies.27 Nevertheless, the CV of ¹²⁹Xe VV% is severely biased by an outlying subject (CV of 25%); the CV in all other COPD patients was ∼10%. The ¹²⁹Xe images from the first scan session in this outlying subject were excluded from analysis because of insufficient SNR. Despite this observation, no other metrics showed abnormally high CV for that patient and no differences in the patient's clinical status were noted.

The high regional heterogeneity of COPD may explain the increased CV of VV% when compared with ADC_glob (ADC maps are of lower resolution than ventilation images), although we note that, qualitatively, the prominent areas of ventilation defect were observed repeatedly over scan sessions. Furthermore, the variability of bronchodilator therapy applied on a day‐to‐day basis will potentially impact VV% more severely than ADC. Nonetheless, both ³He and ¹²⁹Xe VV% CV values calculated from COPD patient data are similar to week‐to‐week percentage variability in FEV₁ and D_LCO,32 and same‐day ³He VV% variability in pediatric CF patients,21 as reported earlier, although poorer than or comparable to the repeatability of PFTs measured in the present work. Our ICC values for ¹²⁹Xe VV% are considerably lower than same‐session (10 minutes apart) ¹²⁹Xe VDP ICCs reported by Ebner et al23; however, the differences can potentially be explained by the fact that in that work, patients did not leave the scanner between scans, no multisession/multiday data were recorded, and the number of patients was significantly higher than in the present work. Otherwise, the results of ¹²⁹Xe VV% and ADC repeatability have, to our knowledge, not been previously reported, and hence our measurements can only be assessed against literature data for equivalent ³He measurements. Resolution of some of the issues discussed herein, including utilization of the higher performance polarizer, should lead to improvements in the repeatability of ¹²⁹Xe VV% to a similar level as ³He, thus facilitating translation to large‐scale clinical studies.

Typically, lower imaging bandwidths and larger diffusion gradients are required for ¹²⁹Xe when compared with ³He lung MRI, necessitating longer breath‐hold times or lower spatial resolutions. Additionally, until recently, ¹²⁹Xe polarizer performance has not been adequate to overcome the inherent MR signal disadvantages compared with ³He. As such, a compromise was reached in this work, such that the in‐plane resolution of ¹²⁹Xe ventilation imaging acquisitions matched that of ³He, but the slice resolution was halved. Developments in compressed sensing (CS) and parallel imaging acquisition strategies for accelerated imaging33, 34 should help permit equivalent, isotropic resolution ¹²⁹Xe, and ³He ventilation imaging within a clinically feasible breath‐hold in the near future, and facilitate same‐breath ¹²⁹Xe and ¹H imaging for improved ¹²⁹Xe ventilation volumetry. Moreover, it has recently been demonstrated that 3D multiple b‐value diffusion‐weighted CS‐based acquisition strategies for whole‐lung morphometric analysis developed for diffusion‐weighted ³He MRI35 are readily transferable to ¹²⁹Xe.36 Although the through‐plane ¹²⁹Xe ventilation and diffusion image resolution in this work is already superior to previous reports at 3T, the adoption of CS methods for both applications should enable these resolution limits to be pushed further towards those attainable with ³He.

Mean ADC_glob values of both nuclei exhibited excellent correlation with each other and high repeatability in COPD patients, with comparable or lower interscan CVs than conventional PFTs, suggesting that ¹²⁹Xe diffusion‐weighted MR has approximately equal sensitivity to ³He for quantitative assessment of lung microstructural changes, and sufficient reliability for routine clinical application.

The observation of elevated ADC_glob in COPD patients agrees with previous reports for both ³He3, 26 and ¹²⁹Xe,6, 7 and has been well characterized. Similarly, increased ADC_glob in subjects with smoking history is consistent with previous observations,7 although the ¹²⁹Xe b‐values used in those works differ from this work. As a consequence of the non‐Gaussian phase dispersion of the ³He and ¹²⁹Xe diffusion regime experienced in the lungs, ADC_glob exhibits some variation with b‐value,37 which constrains the validity of interstudy comparisons. As such, we recommend that for ease of implementation and comparison across sites, a standardized b‐value and diffusion time should be adopted for ¹²⁹Xe diffusion‐weighted MRI, similar to the value of 1.6 s.cm⁻² now widely used for ³He.

CV values of both ³He and ¹²⁹Xe ADC_glob are less than those of previously reported same‐day variability in FEV₁,32 and substantially lower than measured variability in D_LCO (∼9%)38. D_LCO is perhaps the most relevant PFT to compare with ADC, since both measurements rely on gas diffusion within the alveoli, albeit for studying different lung physiology. Thus, the observed repeatability is extremely promising for advancing ¹²⁹Xe diffusion‐weighted MRI to large‐scale multisite trials with the goal of routine clinical implementation. Additionally, our reported CV values of both ³He and ¹²⁹Xe ADC_glob are less than ³He ADC CVs reported for healthy subjects and patients with emphysema at 1.5T,26 and are comparable to ³He CVs measured at 3T.20

The design of the present study has some limitations that could be effectively resolved in future studies. Although a reasonable number of patients were included in this study (37 in total), repeatability experiments were only performed on five patients and, thus, a follow‐up comprehensive, repeatability‐specific study is required with an increased number of subjects, including both patients and volunteers. In such a study, it may be statistically meaningful to distinguish same‐day from 2‐week repeatability, and therefore better identify potential sources of physiological variability between different scan sessions. Due to a few missing datasets, the current data is insufficient in quantity for such statistically sound intertimepoint repeatability analysis; hence, the repeatability was only analyzed over all scan sessions. Data regarding day‐to‐day and week‐to‐week repeatability is critical for understanding the natural physiological variability in VV% and ADC_glob in patients and discriminating this from measurement uncertainty.

In conclusion, the findings reported herein demonstrate that ¹²⁹Xe is approaching readiness as a clinically viable alternative to ³He for quantitative lung ventilation and microstructural MRI studies. For future dissemination and multisite cross‐platform clinical trials, the fact that our results agree with many of the trends seen in prior studies that benchmarked ³He and ¹²⁹Xe MRI measurements at 3T is encouraging. Although quantitative measurements of ventilation and ADC will be biased by magnetic susceptibility effects at the two field strengths, we believe that equivalent functional information can be achieved with both gases at both field strengths. In addition, the high repeatability of both ³He and ¹²⁹Xe ADC observed here is perhaps the most convincing evidence to date that ¹²⁹Xe ADC imaging has developed into a robust microstructural imaging methodology. Moreover, this report builds upon previous measurements at 3T in terms of improved spatial resolution of ¹²⁹Xe imaging, and the realization of 3D DW‐MRI with both nuclei35, 36 is extremely promising for further validation and clinical application in the near future. The preliminary assessment of the repeatability of ¹²⁹Xe ventilation and diffusion MRI biomarkers addresses a gap in knowledge that was not considered prior to this work and paves the way for further, more comprehensive multisite repeatability studies.

Conflict of Interest

Dr. Yates was involved in the study design and imaging protocol for the COPD imaging metric repeatability study. She is part of the Novartis imaging biomarker team and this work was not related to a clinical trial of a therapeutic.