Hyperpolarized ³He and ¹²⁹Xe magnetic resonance imaging apparent diffusion coefficients: physiological relevance in older never‐ and ex‐smokers

Abstract

Noble gas pulmonary magnetic resonance imaging (MRI) is transitioning away from ³He to ¹²⁹Xe gas, but the physiological/clinical relevance of ¹²⁹Xe apparent diffusion coefficient (ADC) parenchyma measurements is not well understood. Therefore, our objective was to generate ¹²⁹Xe MRI ADC for comparison with ³He ADC and with well‐established measurements of alveolar structure and function in older never‐smokers and ex‐smokers with chronic obstructive pulmonary disease (COPD). In four never‐smokers and 10 COPD ex‐smokers, ³He (b = 1.6 sec/cm²) and ¹²⁹Xe (b = 12, 20, and 30 sec/cm²) ADC, computed tomography (CT) density‐threshold measurements, and the diffusing capacity for carbon monoxide (DL_CO) were measured. To understand regional differences, the anterior–posterior (AP_G) and superior–inferior (∆SI) ADC differences were evaluated. Compared to never‐smokers, COPD ex‐smokers showed greater ³He ADC (P = 0.006), ¹²⁹Xe ADC_b12 (P = 0.006), and ADC_b20 (P = 0.006), but not for ADC_b30 (P > 0.05). Never‐smokers and COPD ex‐smokers had significantly different AP_G for ³He ADC (P = 0.02), ¹²⁹Xe ADC_b12 (P = 0.006), and ADC_b20 (P = 0.01), but not for ADC_b30 (P > 0.05). ∆SI for never‐ and ex‐smokers was significantly different for ³He ADC (P = 0.046), but not for ¹²⁹Xe ADC (P > 0.05). There were strong correlations for DL_CO with ³He ADC and ¹²⁹Xe ADC_b12 (both r = −0.95, P < 0.05); in a multivariate model ¹²⁹Xe ADC_b12 was the only significant predictor of DL_CO (P = 0.049). For COPD ex‐smokers, CT relative area <−950 HU (RA₉₅₀) correlated with ³He ADC (r = 0.90, P = 0.008) and ¹²⁹Xe ADC_b12 (r = 0.85, P = 0.03). In conclusion, while ¹²⁹Xe ADC_b30 may be appropriate for evaluating subclinical or mild emphysema, in this small group of never‐smokers and ex‐smokers with moderate‐to‐severe emphysema, ¹²⁹Xe ADC_b12 provided a physiologically appropriate estimate of gas exchange abnormalities and alveolar microstructure.

We aimed to better understand how ¹²⁹Xe MRI measurements might explain well‐established measurements of emphysema, and explored different ¹²⁹Xe MRI apparent diffusion coefficients (ADCs) in a small group of older never‐smokers and ex‐smokers with chronic obstructive pulmonary disease (COPD). In the same visit, ³He ADC, the diffusing capacity of carbon monoxide and computed tomography (CT) emphysema measurements were acquired. In this small group of older never‐smokers and ex‐smokers with COPD, ¹²⁹Xe ADCb12 provided a physiologically appropriate estimate of gas exchange abnormalities and alveolar microstructure.

Introduction

Magnetic resonance imaging (MRI) using hyperpolarized noble gases ³He and ¹²⁹Xe provides high spatial and temporal resolution images of pulmonary gas distribution (Kauczor et al. 1997; de Lange et al. 1999; Moller et al. 2002). Parenchymal microstructure can also be probed using diffusion‐weighted (DW) imaging. DW imaging takes advantage of the gases rapid molecular diffusion to generate ³He and ¹²⁹Xe apparent diffusion coefficients (ADCs; Saam et al. 2000; Salerno et al. 2002). Although the first demonstrations of inhaled hyperpolarized gas MRI used ¹²⁹Xe gas (Albert et al. 1994; Mugler et al. 1997), until recently, most examinations in subjects with chronic obstructive pulmonary disease (COPD) used ³He gas mainly due to the nearly threefold higher gyromagnetic ratio and higher polarizations – both of which independently contribute to greater image quality for ³He MRI. These previous studies showed that ³He ADC values are reproducible in emphysematous subjects (Morbach et al. 2005; Diaz et al. 2008; Mathew et al. 2008), sensitive to lung microstructure and airspace size (Saam et al. 2000; Salerno et al. 2002), and correlate with spirometry (Salerno et al. 2002; Diaz et al. 2009), diffusing capacity of carbon monoxide (DL_CO; Fain et al. 2006), and x‐ray computed tomography (CT) measurements of emphysema (Diaz et al. 2009). Importantly, ³He MRI ADC measurements were directly compared with stereological measurements of fixed lung tissue and this showed the high sensitivity of ³He MRI ADC to lung surface area abnormalities in emphysematous tissue (Woods et al. 2006). Despite these important findings, ³He MRI is unlikely to be used clinically because of its relatively high cost and low abundance (Fain et al. 2010). On the other hand, ¹²⁹Xe gas is substantially more abundant, relatively inexpensive, and clinical quantities may be polarized in 30–60 min (Mugler et al. 1997, 2004). Because of this, there is considerable interest in transitioning to ¹²⁹Xe MRI.

Although ¹²⁹Xe gas is capable of transmembrane diffusion (Cleveland et al. 2010) this leads to adverse systemic effects when used in high concentrations; Xe has been widely and safely used in pulmonary CT (Chae et al. 2008; Honda et al. 2012), cerebral blood flow imaging (Carlson et al. 2011), and lung scintigraphy (Suga 2002). Recent ¹²⁹Xe MRI safety studies demonstrated that the gas concentrations compatible with MRI are well tolerated in healthy subjects and those with respiratory disease (Driehuys et al. 2012; Shukla et al. 2012). Previous work showed that ¹²⁹Xe ADC (b = 12 sec/cm²; Kaushik et al. 2011) and ¹²⁹Xe ADC morphometry measurements (Ouriadov et al. 2013) provide a way to distinguish between age‐matched subjects with and without COPD. Moreover, although strong and significant correlations for ³He ADC with ¹²⁹Xe ADC (b = 12 sec/cm²) were reported (Kirby et al. 2012d), significantly lower ¹²⁹Xe as compared to ³He MRI ventilation was observed in COPD ex‐smokers (Kirby et al. 2013) and asthmatics (Svenningsen et al. 2013). Regions of diminished ¹²⁹Xe as compared to ³He ventilation are spatially related to emphysematous regions (Kirby et al. 2013) in COPD subjects.

It is important to consider the different self‐diffusion coefficients of ³He and ¹²⁹Xe gases. For example, ¹²⁹Xe gas has a much lower diffusion coefficient than ³He and, therefore, in order to achieve sufficient diffusion weighting for ¹²⁹Xe MRI to derive meaningful lung microstructural information, appropriately large b values and diffusion times must be applied (Sukstanskii and Yablonskiy 2012). However, increasing the diffusion weighting is coupled with a reduction in image signal‐to‐noise ratio (SNR); therefore it is important to experimentally demonstrate the ¹²⁹Xe ADC b value that provides the optimal balance between sensitivity to the lung microstructural abnormalities and feasibility with respect to image SNR. It is also essential to investigate the different ¹²⁹Xe MRI ADC b values and their associations with other emphysema measurements in order to better understand how imaging estimates are related to physiological measurements in COPD patients. Previous studies have focused on ¹²⁹Xe ADC generated with a b value of 12 sec/cm² (Kaushik et al. 2011; Kirby et al. 2012d), and therefore here we aimed to (i) determine whether ¹²⁹Xe ADC generated using b values of 12, 20, and 30 sec/cm² and contemporaneously acquired ³He ADC (Kirby et al. 2013), distinguishes older never‐smokers from ex‐smokers with COPD, (ii) compare ³He and ¹²⁹Xe ADC in the superior–inferior (SI) and anterior–posterior (AP) lung regions to better understand potential dependencies for b value with regional ADC, and (iii) determine the significant associations of ¹²⁹Xe ADC with b values of 12, 20, and 30 sec/cm² with DL_CO and CT measurements of emphysema, similar to those recently used in the COPDGene (Regan et al. 2010), CanCOLD (Bourbeau and Saad 2013), ECLIPSE (Vestbo and Anderson 2008), and SPIROMICS (Couper et al. 2014) studies.

Materials and Methods

Subjects

All subjects provided written informed consent to the study protocol that was approved by the local research ethics board and Health Canada. COPD subjects were ex‐smokers with a smoking history of at least 10 pack‐years between 50 and 85 years of age and categorized according to the Global Initiative for Chronic Lung Disease (2013) (GOLD) spirometry criteria. Healthy older never‐smokers (<1 pack‐year over their lifetime and no smoking in last 20 years) were enrolled who had no history of previous chronic or current respiratory disease.

Pulmonary function tests

A body plethysmograph (MedGraphics Corporation, Saint Paul, MN) with the attached gas analyzer was used to measure airflow, lung volumes, and DL_CO according to ATS/ERS guidelines (Macintyre et al. 2005; Miller et al. 2005; Wanger et al. 2005).

Image acquisition

Magnetic resonance imaging was performed on a whole body 3.0 Tesla Discovery 750MR (General Electric Health Care, Milwaukee, WI) MRI system with broadband imaging capability. Subjects were instructed to inhale a gas mixture from a 1.0L Tedlar^® bag (Jensen Inert Products, Coral Springs, FL) from functional residual capacity (FRC) and image acquisition was performed under breath‐hold conditions (Parraga et al. 2007).

Hyperpolarized ³He MRI was enabled using a linear bird‐cage transmit/receive chest coil (RAPID Biomedical GmbH, Wuerzburg, Germany; Farag et al. 2012). A turn‐key system (HeliSpin^™, Polarean Inc, Durham, NC) was used to polarize ³He gas to 30–40% and doses (5 mL/kg body weight) diluted with N₂ were administered in 1.0L Tedlar^® bags. Hyperpolarized ³He MRI diffusion‐weighted imaging was performed using a 2D multislice fast gradient‐recalled echo sequence (FGRE; 14 sec total data acquisition, repetition time [TR]/echo time [TE]/flip angle = 7.6 msec/3.7 msec/8°, field of view [FOV] = 40 × 40 cm, matrix 128 × 128, seven slices, 30 mm slice thickness, 0 gap) during breath hold (Parraga et al. 2007) for acquisition of two interleaved images with and without additional diffusion sensitization with b = 1.6 sec/cm² (maximum gradient amplitude [G] = 1.94 G/cm, rise and fall time = 0.5 msec, gradient duration = 0.46 msec, diffusion time = 1.46 msec).

Hyperpolarized ¹²⁹Xe MRI was enabled using a custom‐made, quadrature‐asymmetric bird‐cage coil model tuned to 35.34 MHz, as described previously (Farag et al. 2012). The XeBox‐E10 polarizer system (XeBox‐E10; Xemed LLC, Durham, NH) was used to polarize the ¹²⁹Xe gas (86% enriched) to 10–60%. In contrast to the ³He gas doses which were determined according to the subjects’ body weight, for ¹²⁹Xe MRI a 50/50 mixture of ¹²⁹Xe and ⁴He gas was obtained by dispensing ¹²⁹Xe directly into 1.0L Tedlar^® bags prefilled with ⁴He. Polarization of the diluted dose was quantified with use of a Polarimeter (Polarean, Durham, NC). ¹²⁹Xe MRI DW images were obtained using a 2D multislice FGRE sequence; two interleaved images (16 sec total data acquisition, TE/TR/flip angle = 9.8 msec/11.0 msec/5°, bandwidth = 31.25 kHz, FOV = 40 × 40 cm, matrix 128 × 80, seven slices, 30 mm slice thickness, 0 gap) with and without additional diffusion sensitization with b = 12 sec/cm² (G = 2.90 G/cm, rise and fall time = 0.5 msec, gradient separation = 2.0 msec, gradient duration = 2.0 msec, diffusion time = 5 msec), b = 20 sec/cm² (G = 3.75 G/cm, rise and fall time = 0.5 msec, gradient separation = 2.0 msec, gradient duration = 2.0 msec, diffusion time = 5 msec), and b = 30 sec/cm² (G = 4.60 G/cm, rise and fall time = 0.5 msec, gradient separation = 2 msec, gradient duration = 2.0 msec, diffusion time = 5 msec) were acquired in separate image acquisitions, as described previously (Kirby et al. 2012d; Boudreau et al. 2013).

Computed tomography was performed on a 64‐slice Lightspeed VCT scanner (GEHC, Milwaukee, WI). A single spiral acquisition of the entire lung was acquired from apex to base with subjects in breath‐hold condition after inhalation of N₂ from a 1.0L Tedlar^® bag (detector configuration of 64 × 0.625 mm, 120 kVp, 100 effective mA, tube rotation time of 500 msec, and a pitch of 1.0). Reconstruction of the data was performed using a standard convolution kernel and a slice thickness of 1.25 mm.

Image analysis

³He ADC and ¹²⁹Xe ADC with b values of 12 sec/cm² (ADC_b12), 20 sec/cm² (ADC_b20), and 30 sec/cm² (ADC_b30) were generated as described previously (Kirby et al. 2012b). Briefly, we first segmented the ³He MRI non‐DW images using k‐means cluster algorithm as described previously for ³He MRI segmentation (Kirby et al. 2012a). The segmented binary mask for the non‐DW images was applied to the DW images. The ADC maps were generated on a voxel‐by‐voxel basis according to equation 1:

where b = 1.6 sec/cm², S₀ = the segmented non‐DW image, and S = the diffusion‐weighted image. The regional differences in ADC were evaluated for all AP coronal slices and for each coronal slice in three SI regions of interest (ROIs). The AP gradient (AP_G) was defined as the slope of the line of best fit that described the change in ADC as a function of distance in centimeters for all slices in the anterior to posterior direction. The three SI ROI were generated by dividing the center coronal slice into three equivalent ROIs from apex to base and applying those boundaries to all slices. ∆SI was the mean change in ADC in the superior and inferior ROI. To compare ³He and ¹²⁹Xe ADC ∆SI and AP_G to better understand any dependency on b value for regional ADC differences in the respective gases, we compared the older never‐smokers to the COPD subjects, as well as to only the COPD ex‐smokers with emphysema. COPD subjects without emphysema are unlikely to show an increased ³He or ¹²⁹Xe ADC ∆SI and AP_G difference compared to the older never‐smokers. The SNR for ³He and ¹²⁹Xe DW images and nondiffusion‐weighted (NDW) images were determined by calculating the mean voxel value within a 5 × 5 voxel ROI for four representative ROI within the lung parenchyma, and dividing by the standard deviation of the mean voxel values for four representative 5 × 5 voxel ROI within the image background where there was no lung structure, for each slice. SNR was determined for each slice and then averaged to obtain a single SNR value for each subject image.

Quantitative CT measurements were performed using the Pulmonary Workstation 2.0 (VIDA Diagnostics, Inc., Coralville, IA); the relative area with attenuation values below −950 Hounsfield Units (HU; RA₉₅₀), −910 HU (RA₉₁₀), and −856 HU (RA₈₅₆) were generated (Gevenois et al. 1996) as well as the CT HU value at which 15% of the voxels in the frequency distribution histogram have a lower density (HU_15%). A CT density threshold for emphysema of RA₉₅₀ > 6.8% was adopted based on a previous study that reported RA₉₅₀ = 6.8% as the upper 95% limit of predicted normal values (Gevenois et al. 1996).

Qualitative visual scoring was also performed by an expert chest radiologist (R. E.‐R.) using a method adapted from Bankier et al. (1996). Emphysema scores were based on the percentage of low attenuation, tissue destruction, and vascular disruption.

Statistical methods

A Mann–Whitney unpaired two‐tailed t‐test was performed for statistical comparison of all pulmonary function measurements, ³He and ¹²⁹Xe ADC, ³He and ¹²⁹Xe ADC AP_G, and ³He and ¹²⁹Xe ADC SI using GraphPad Prism version 4.00 (GraphPad Software Inc., San Diego, CA). A one‐way analysis of variance (ANOVA) was used for statistical comparison of the mean SNR values for ADC DW images for ³He and ¹²⁹Xe with all three b values using IBM SPSS Statistics 20.0 (SPSS Inc., Chicago, IL). Linear regression (r²) and Pearson correlation coefficients (r) were used to determine the relationships between imaging and other measurements using GraphPad. A Holm–Bonferroni correction (Van Bell et al. 2004) was used to correct for multiple tests. Multivariate linear regression modeling was used to evaluate the relationship between DL_CO and ³He ADC, ¹²⁹Xe ADC_b12, ¹²⁹Xe ADC_b20, and ¹²⁹Xe ADC_b30 as well as between CT density measurements and ³He ADC, ¹²⁹Xe ADC_b12, ¹²⁹Xe ADC_b20, and ¹²⁹Xe ADC_b30 using PROC REG in SAS ^® 9.2 Software (SAS Institute Inc., Cary, NC). In all statistical analyses, results were considered significant when the probability of making a Type I error was <5% (P < 0.05).

Results

Study subjects and pulmonary function

Table 1 shows all demographic and pulmonary function measurements for four older never‐smokers and 10 COPD ex‐smokers (GOLD Class I: n = 1; GOLD Class II: n = 6; GOLD Class III: n = 2; GOLD Class IV: n = 1). Although there were no significant differences in age, sex, or BMI, the never‐smokers and COPD ex‐smokers were significantly different with respect to FEV₁ (P = 0.01), FEV₁/FVC (P = 0.002), TLC (P = 0.02), RV (P = 0.02), FRC (P = 0.01), and DL_CO (P = 0.006).

Table 1.

Subject demographics and pulmonary function measurements

	Older never‐smokers (n = 4)	All COPD (n = 10)	COPD with emphysema (n = 7)
Age years (±SD)	67 (13)	74 (4)	74 (4)
Female sex	2	2	2
Weight kg (±SD)	72 (11)	77 (22)	68 (18)
BMI kg/m2 (±SD)	26.4 (2.8)	25.4 (5.0)	23.6 (4.6)
FEV1%pred (±SD)	103 (6)	57 (24)*	52 (27)*
FVC%pred (±SD)	102 (8)	91 (19)	92 (22)
FEV1/FVC (±SD)	0.76 (0.02)	0.46 (0.14)*	0.40 (0.13)*
TLC%pred (±SD)	102 (8)	115 (8)*	118 (7)*
RV%pred (±SD)	102 (9)	159 (46)*	167 (54)
RV/TLC (±SD)	0.39 (0.09)	0.53 (0.14)	0.55 (0.16)
IC%pred (±SD)	113 (16)	85 (31)	77 (32)
FRC%pred (±SD)	93 (15)	141 (35)*	154 (34)*
DLCO%pred (±SD)	104 (12)	41 (17)*	36 (13)*

SD, standard deviation; BMI, body mass index; FEV₁, forced expiratory volume in 1 sec; %_pred, percent predicted; FVC, forced vital capacity; TLC, total lung capacity; RV, reserve volume; IC, inspiratory capacity; FRC, functional residual capacity; DL_CO, carbon monoxide diffusion capacity of the lung.

^*Significant difference (P < 0.05) between older never‐smokers and chronic obstructive pulmonary disease (COPD) subjects.

CT measurements of emphysema

Table 2 shows mean CT density thresholds (RA₉₅₀, RA₉₁₀, RA₈₅₆, HU_15%) and CT emphysema scores for the COPD ex‐smokers, by subject. For all COPD ex‐smokers, mean RA₉₅₀, RA₉₁₀, RA₈₅₆, HU_15%, and emphysema score were 18.8 ± 14.1%, 39.6 ± 20.6%, 65.0 ± 16.0%, −948 ± 30 HU, and 1.1 ± 0.7, respectively, consistent with mild emphysema. Subjects 2 (RA₉₅₀ = 5.3%), 4 (RA₉₅₀ = 1.5%), and 9 (RA₉₅₀ = 2.1%) did not have CT evidence of emphysema (RA₉₅₀ < 6.8%). For only the COPD ex‐smokers with emphysema, mean RA₉₅₀, RA₉₁₀, RA₈₅₆, HU_15%, and visual CT scoring measurements were 25.5 ± 10.9%, 48.9 ± 15.8%, 71.1 ± 12.4%, −964 ± 16 HU, and 1.4 ± 0.6, respectively.

Table 2.

Subject listing of ³He and ¹²⁹Xe magnetic resonance imaging ADC and computed tomography (CT) measurements

Subject	ADC measurements				CT measurements
	3He ADCb = 1.6 (cm2/sec)	129Xe ADCb = 12 (cm2/sec)	129Xe ADCb = 20 (cm2/sec)	129Xe ADCb = 30 (cm2/sec)	RA950 (HU)	RA910 (HU)	RA856 (HU)	HU15% (HU)	Visual score
Older never‐smokers
1	0.247	0.048	0.048	0.040	–	–	–	–	–
2	0.230	0.049	0.049	0.035	–	–	–	–	–
3	0.215	0.049	0.049	0.036	–	–	–	–	–
4	0.242	0.053	0.053	0.042	–	–	–	–	–
All (±SD)	0.223 (0.014)	0.050 (0.002)	0.044 (0.002)	0.038 (0.003)	–	–	–	–	–
Chronic obstructive pulmonary disease Ex‐Smokers
1	0.611	0.096	0.081	–	33.33	49.35	67.78	−981	2.35
2	0.305	0.057	0.057	–	5.26	30.43	67.90	−930	0.16
3	0.531	0.087	0.078	–	32.07	65.81	85.86	−972	1.55
4	0.320	0.058	0.050	–	1.53	9.13	36.68	−895	0.43
5	0.591	0.095	0.088	–	36.83	66.19	84.28	−975	0.89
6	0.617	0.095	0.070	–	34.25	60.48	79.03	−977	–
7	0.504	0.085	0.079	0.064	12.12	31.56	60.64	−943	0.83
8	0.474	0.083	0.072	0.055	16.77	40.14	66.75	−954	1.40
9	0.283	0.056	0.046	–	2.12	13.38	47.61	−907	0.34
10	0.526	0.092	0.076	0.052	13.22	29.00	53.02	−945	1.49
All (±SD)	0.476 (0.128)	0.080 (0.017)	0.070 (0.014)	0.057 (0.006)	18.75 (14.11)	39.55 (20.56)	64.95 (15.95)	−948 (30)	1.05 (0.71)

ADC, apparent diffusion coefficient; SNR, signal‐to‐noise ratio; RA₉₅₀, relative area with attenuation values below −950 HU; RA₉₁₀, relative area with attenuation values below −910 HU; RA₈₅₆, relative area with attenuation values below −856 HU; HU_15%, the hounsfield unit value at which 15% of the voxels in the frequency distribution histogram have a lower density.

Hyperpolarized MRI ADC

Figure 1 shows the central coronal ³He ADC, ¹²⁹Xe ADC_b12, ¹²⁹Xe ADC_b20, and ¹²⁹Xe ADC_b30 maps for an older never‐smoker and two COPD ex‐smokers. ADC maps appear brighter and more heterogeneous for the COPD ex‐smokers in comparison with the healthy never‐smoker for ³He MRI as well as for ¹²⁹Xe MRI for all b values. As shown in Figure 2, there were statistically significantly greater ADC values for all COPD ex‐smokers as well as only those COPD ex‐smokers with emphysema in comparison to the older never‐smokers for ³He ADC (all COPD: P = 0.002; COPD with emphysema: P = 0.006), ¹²⁹Xe ADC_b12 (all COPD: P = 0.002; COPD with emphysema: P = 0.006), and ¹²⁹Xe ADC_b20 (all COPD: P = 0.04; COPD with emphysema: P = 0.006), but not for ¹²⁹Xe ADC_b30 (P = 0.06).

Figure 1.

Hyperpolarized ³He apparent diffusion coefficient (ADC) and ¹²⁹Xe ADC maps for a representative older never‐smoker and two chronic obstructive pulmonary disease (COPD) ex‐smokers. ³He ADC and ¹²⁹Xe ADC maps with b value of 12 sec/cm² (ADC_{b = 12}), 20 sec/cm² (ADC_{b = 20}), and 30 sec/cm² (ADC_{b = 30}) of the coronal center slice for an older never‐smoker (79‐year‐old male, FEV₁ = 96%_pred, FEV₁/FVC = 74%) and two COPD ex‐smokers (top: 71‐year‐old male, FEV₁ = 107%_pred, FEV₁/FVC = 58%; bottom: 76‐year‐old male, FEV₁ = 35%_pred, FEV₁/FVC = 31%).

Figure 2.

³He and ¹²⁹Xe magnetic resonance imaging apparent diffusion coefficient (ADC) measurements for older never‐smokers, all chronic obstructive pulmonary disease (COPD) ex‐smokers, and COPD ex‐smokers with emphysema. Box‐and‐Whisker plot where box extends from the 25th to 75th percentiles of ADC values, the line within the box is the median ADC value and error bars are the minimum and maximum ADC values. Significance of difference (P < 0.05) determined using a Mann–Whitney unpaired two‐tailed t‐test.

For all subjects, mean SNR was statistically significantly greater for ³He DW images (³He DW SNR = 34 ± 19) in comparison with ¹²⁹Xe DW images with b value = 12 sec/cm² (¹²⁹Xe DW SNR = 12 ± 7, P < 0.0001), b value = 20 sec/cm² (¹²⁹Xe DW SNR = 10 ± 7, P < 0.0001), and b value = 30 sec/cm² (¹²⁹Xe DW SNR = 4 ± 1, P < 0.0001), however, there was no significant difference between mean ¹²⁹Xe DW SNR for all b values (P > 0.05). Importantly, for all subjects there was no significant correlation between SNR and ADC for ³He (r = 0.32, P = 0.27), ¹²⁹Xe ADC_b12 (r = 0.47, P = 0.09), and ¹²⁹Xe ADC_b20 (r = 0.50, P = 0.07), however, there was a significant correlation between SNR and ¹²⁹Xe ADC_b30 (r = 0.84, P = 0.02). For all subjects, mean SNR was statistically significantly greater for ³He NDW, or b =0, images (³He NDW SNR = 65 ± 39) than for ¹²⁹Xe NDW images with b value = 12 sec/cm² (¹²⁹Xe NDW SNR = 29 ± 21, P = 0.008), b value = 20 sec/cm² (¹²⁹Xe NDW SNR = 33 ± 26, P = 0.02), and b value = 30 sec/cm² (¹²⁹Xe NDW SNR = 18 ± 11, P = 0.003), however, there was no significant difference between mean ¹²⁹Xe NDW SNR for all b values (P > 0.05).

ADC regional differences

Figure 3 shows the ³He and ¹²⁹Xe MRI ADC anterior–posterior gradients (AP_G) for older never‐smokers as well as all COPD ex‐smokers and only the COPD ex‐smokers with emphysema. There were statistically significantly greater AP_G for the COPD ex‐smokers than the older never‐smokers for ¹²⁹Xe ADC_b12 (P = 0.04) and ¹²⁹Xe ADC_b20 (P = 0.04), but not for ³He ADC (P > 0.05) or ¹²⁹Xe ADC_b30 (P > 0.05); there were also statistically significantly greater AP_G for the COPD ex‐smokers with emphysema than the older never‐smokers for ³He ADC (P = 0.02), ¹²⁹Xe ADC_b12 (P = 0.006), and ¹²⁹Xe ADC_b20 (P = 0.01), but not for ¹²⁹Xe ADC_b30 (P > 0.05).

Figure 3.

³He and ¹²⁹Xe magnetic resonance imaging apparent diffusion coefficient (ADC) anterior–posterior gradients (AP_G) for older never‐smokers, all chronic obstructive pulmonary disease (COPD) ex‐smokers, and COPD ex‐smokers with emphysema. Box‐and‐Whisker plot where box extends from the 25th to 75th percentiles of ADC values, the line within the box is the median ADC AP_G value and error bars are the minimum and maximum ADC AP_G values. Significance of difference (P < 0.05) determined using a Mann–Whitney unpaired two‐tailed t‐test.

Figure 4 shows the ADC in the superior and inferior ROI for the older never‐smokers, all COPD ex‐smokers and only the COPD ex‐smokers with emphysema. For the COPD ex‐smokers with emphysema, mean ³He ADC was statistically significantly greater in the superior ROI than the inferior ROI (P = 0.04), however, there were no other significant SI ADC differences in ³He or ¹²⁹Xe MRI.

Figure 4.

³He and ¹²⁹Xe magnetic resonance imaging (MRI) apparent diffusion coefficient (ADC) for superior and inferior regions of interest in older never‐smokers, all chronic obstructive pulmonary disease (COPD) ex‐smokers, and COPD ex‐smokers with emphysema. There was a significant difference in mean ADC in the superior to inferior lung regions between the older never‐smokers and the COPD ex‐smokers with emphysema for ³He MRI ADC (P = 0.04), but there were no other significant differences. Significance of difference (P < 0.05) determined using a Mann–Whitney unpaired two‐tailed t‐test.

ADC relationships with pulmonary function and CT

Figure 5 shows Pearson correlations for DL_CO with ³He ADC, ¹²⁹Xe ADC_b12, ¹²⁹Xe ADC_b20, and ¹²⁹Xe ADC_b30 for all subjects. There were significant correlations for D_LCO with ³He ADC (r = −0.95, P = 0.003), ¹²⁹Xe ADC_b12 (r = −0.95, P = 0.002), and ¹²⁹Xe ADC_b20 (r = −0.87, P = 0.01), however, the correlation for DL_CO with ¹²⁹Xe ADC_b30 (r = −0.89, P = 0.008 uncorrected, P = 0.10 corrected) was no longer significant following Holm–Bonferroni correction.

Figure 5.

Correlations for ³He and ¹²⁹Xe apparent diffusion coefficient (ADC) with DL_CO in all subjects. D_LCO was significantly correlated with ³He ADC (r = −0.95, r² = 0.90, P < 0.0001, Holm–Bonferroni corrected P = 0.003, y = −0.0044x + 0.69), ¹²⁹Xe ADC_{b = 12} (r = −0.95, r² = 0.90, P < 0.0001, Holm–Bonferroni corrected P = 0.002, y = −0.00056x + 0.11), ¹²⁹Xe ADC_{b = 20} (r = −0.87, r² = 0.76, P = 0.0005, Holm–Bonferroni corrected P = 0.01, y = −0.00042x + 0.088), and ¹²⁹Xe ADC_{b = 30} (r = −0.89, r² = 0.78, P = 0.008, Holm–Bonferroni corrected P = 0.10, y = −0.00029x + 0.069). Dotted lines indicate the 95% limits of agreement.

The Pearson correlation coefficients between CT lung density thresholds (RA₉₅₀, RA₉₁₀, RA₈₅₆, HU_15%) and visual CT emphysema scores are shown in Table 3. Following Holm–Bonferroni correction, ³He ADC was significantly correlated with RA₉₅₀ (r = 0.90, P = 0.008) and HU_15% (r = −0.92, P = 0.004); ¹²⁹Xe ADC_b12 was significantly correlated with RA₉₅₀ (r = 0.85, P = 0.03) and HU_15% (r = −0.90, P = 0.008); ¹²⁹Xe ADC_b20 was significantly correlated with HU_15% (r = −0.86, P = 0.02); ¹²⁹Xe ADC_b30 was not significantly correlated with any CT emphysema measurements.

Table 3.

Correlations for ³He and ¹²⁹Xe apparent diffusion coefficient (ADC) with computed tomography emphysema measurements for chronic obstructive pulmonary disease ex‐smokers

	Pearson correlation coefficients r (p/p1)
	3He ADC (cm2/sec)	129Xe ADCb12 (cm2/sec)	129Xe ADCb20 (cm2/sec)	129Xe ADCb30 (cm2/sec)
RA950 (HU)	0.90 (0.0004/0.008)	0.85 (0.002/0.03)	0.79 (0.006/0.09)	−0.49 (0.68/1.00)
RA910 (HU)	0.82 (0.004/0.06)	0.77 (0.009/0.11)	0.78 (0.008/0.11)	−0.06 (0.96/0.96)
RA856 (HU)	0.67 (0.04/0.32)	0.63 (0.05/0.35)	0.69 (0.03/0.27)	0.30 (0.81/1.00)
HU15% (HU)	−0.92 (0.0002/0.004)	−0.90 (0.0004/0.008)	−0.86 (0.001/0.02)	0.44 (0.71/1.00)
Visual Score	0.79 (0.01/0.11)	0.76 (0.02/0.20)	0.66 (0.05/0.30)	−0.38 (0.75/1.00)

¹Holm–Bonferroni adjusted significance values.

Table 4 shows the results of multiple linear regression models with ³He ADC, ¹²⁹Xe ADC_b12, ¹²⁹Xe ADC_b20, and ¹²⁹Xe ADC_b30 as the predictor variables. In the multivariate regression model for DL_CO with ³He and all ¹²⁹Xe ADC values included, ¹²⁹Xe ADC_b12 (P = 0.049) was the only significant predictor. In the multivariate regression model for RA₉₅₀ with ³He and all ¹²⁹Xe ADC values included, the only significant predictor was ³He ADC (P = 0.03). We also evaluated the multivariate regression model for HU_15%, and although the overall model was statistically significant (P < 0.05), ³He ADC, ¹²⁹Xe ADC_b12, or ¹²⁹Xe ADC_b20 were not significant predictors.

Table 4.

Multivariate linear regression model for DL_CO and computed tomography RA₉₅₀ with ³He and ¹²⁹Xe apparent diffusion coefficient (ADC)

Variable	Parameter estimate	Standard error	Fold change	P‐value
Model 1: DLCO
3He ADCb1.6	663.85	218.63	3.04	0.09
129Xe ADCb12	−4974.20	1153.94	−4.31	0.049
129Xe ADCb20	−1165.39	795.22	−1.47	0.28
129Xe ADCb30	−935.27	539.89	−1.73	0.23
Model 2: RA950
3He ADCb1.6	306.93	107.64	2.85	0.03
129Xe ADCb12	−1821.20	929.23	−1.96	0.10
129Xe ADCb20	292.72	370.07	0.79	0.46
129Xe ADCb30	–	–	–	–

Statistically significant P‐values (P < 0.05) are presented in bold.

Discussion

The low and variable polarization levels and low diffusivity of ¹²⁹Xe gas results in technical challenges for extracting physiologically meaningful pulmonary microstructural information based on ¹²⁹Xe MRI. Moreover, although previous studies (Kaushik et al. 2011; Kirby et al. 2013, 2012d) reported ¹²⁹Xe ADC based on a b value of 12 sec/cm², it is still unclear how to provide the optimal balance between sensitivity to the lung microstructural abnormalities in emphysematous patients and feasibility with respect to image quality. Moreover, ¹²⁹Xe MRI ADC generated using different b values may access different regions of the lung and likely probe different lung microstructure length scales thereby providing somewhat different spatial information relative to ³He ADC. For a better understanding of these measurements, we investigated the different ¹²⁹Xe MRI ADC b values and their associations with anatomical and physiological measurements of COPD in a small but well‐characterized group of older never‐smokers and COPD ex‐smokers.

We observed (i) significantly greater ADC values for COPD ex‐smokers compared to older never‐smokers for ³He ADC, ¹²⁹Xe ADC_b12, and ADC_b20, but not for ¹²⁹Xe ADC_b30, (ii) significantly greater anterior–posterior ADC differences in COPD ex‐smokers with emphysema compared to older never‐smokers for ³He ADC, ¹²⁹Xe ADC_b12, and ADC_b20, but not for ¹²⁹Xe ADC_b30, (iii) significantly different mean ADC in the superior as compared to inferior lung regions between older never‐smokers and COPD ex‐smokers for ³He ADC, but not for ¹²⁹Xe ADC, and finally, (iv) strong and significant correlations for ³He and ¹²⁹Xe ADC with DL_CO and CT measurements of emphysema, but in a multivariate model, ¹²⁹Xe ADC_b12 was the only significant predictor of DL_CO and ³He ADC was the only significant predictor of CT measured RA₉₅₀.

As expected, we observed significantly greater (worse) ADC for COPD ex‐smokers than for older never‐smokers for ³He, and as well for ¹²⁹Xe ADC_b12 and ADC_b20, but not for ¹²⁹Xe ADC_b30. There was a large difference in mean ADC between subject subgroups for both ³He and ¹²⁹Xe MRI, and this important finding suggested that both ¹²⁹Xe MRI generated using b values of 12 and 20 sec/cm² provide adequate sensitivity to lung microstructural abnormalities. These data are also in agreement with previous findings (Kaushik et al. 2011) that ¹²⁹Xe ADC_b12 can be used to distinguish between older never‐smokers and COPD subjects with emphysema. However, we must point out that ¹²⁹Xe ADC_b30 was not significantly different between subject subgroups and this may have been due to the low sample size as well as low SNR. For ADC_b30, we demonstrated that the diffusion attenuation curves deviate from single exponential behavior after b = 20 sec/cm², suggesting greater diffusion anisotropy (Ouriadov et al. 2013) compared to ADC_b12 and ADC_b20, and this greatly influences image quality, which was poor for ADC_b30 images here. It is important to note that while SNR was not significantly different for ¹²⁹Xe MRI acquired at all three b values, there was a significant correlation between image SNR and ADC for ¹²⁹Xe ADC_b30 only, suggesting that there may have been inadequate image quality to derive reliable ADC measurements. Clearly these are important considerations when optimizing and selecting pulse sequence parameters since image signal is expected to be reduced when the gradient amplitude is increased.

Second, there were statistically significantly greater AP_G for the COPD ex‐smokers with emphysema than the older never‐smokers for ³He ADC, ¹²⁹Xe ADC_b12, and ADC_b20, but not for ¹²⁹Xe ADC_b30. DW MRI is sensitive to changes in the lung microstructure (Saam et al. 2000; Salerno et al. 2002) and is therefore an indirect measure of airspace size. Since the DW images were acquired in breath‐hold condition in the supine position, the measurement of the ADC on a slice‐by‐slice basis can be exploited to measure compression of the dependent lung due to gravity. Several studies have reported lower ADC values in the dependent (or posterior) lung slices relative to the nondependent anterior lung slices for ³He MRI (Fichele et al. 2004; Evans et al. 2007; Diaz et al. 2008) and ¹²⁹Xe MRI with b = 12 sec/cm² (Kaushik et al. 2011), which is expected due to compression of the lung parenchyma in healthy never‐smokers. However, in subjects with emphysema, the gradient in alveolar expansion in the gravity‐dependent direction is reduced, in part, because of gas trapping (Evans et al. 2007; Diaz et al. 2008). The finding that ¹²⁹Xe ADC_b12 anterior–posterior gradients were also reduced in the COPD ex‐smokers with emphysema in comparison to healthy never‐smokers is in agreement with these previous studies (Evans et al. 2007; Diaz et al. 2008; Kaushik et al. 2011). Furthermore, the finding that ¹²⁹Xe ADC_b20 anterior–posterior gradients were also reduced in the COPD ex‐smokers with emphysema in comparison to healthy never‐smokers suggests that ¹²⁹Xe MRI with b =20 sec/cm² also provides a way to evaluate microstructural abnormalities.

Third, there was a significant difference in mean ADC in the superior as compared to inferior lung regions between the older never‐smokers and the COPD ex‐smokers with emphysema for ³He ADC, but not for any ¹²⁹Xe ADC. It is important to note that in contrast with the results reported here, previous studies evaluating the ¹²⁹Xe ADC SI gradients in older never‐smokers demonstrated elevated ADC values in the inferior lung regions (Sindile et al. 2007) or elevated ADC values the superior lung regions (Kaushik et al. 2011). It is clear that because of the lower diffusion coefficient of pure ¹²⁹Xe gas, more heterogeneous gas mixing within the lung is likely to occur during image acquisition and this may, in part, explain the discrepancies in these previous reports. However, the ¹²⁹Xe/⁴He gas mixture used in this study may have allowed more homogeneous mixing within the lung resulting in the lower SI gradient seen in the older never‐smokers, which is to be expected in healthy volunteers without emphysema. Although it is unclear why elevated ADC was demonstrated in the superior lung regions in comparison to the inferior lung regions for ³He MRI, but not for ¹²⁹Xe MRI in the COPD ex‐smokers with emphysema, these differences may be explained by the different lung regions accessed by the gases, as shown in Figure 1, due to the different densities and viscosities of the gas mixtures. In this regard, we previously demonstrated significantly greater ventilation abnormalities for ¹²⁹Xe MRI than ³He MRI in the same COPD ex‐smokers (Kirby et al. 2012d). In a regional evaluation of ³He and ¹²⁹Xe ADC, we showed that mean ADC in lung regions accessed by ³He gas only were significantly greater than in the remaining lung (Kirby et al. 2013), suggesting that the more emphysematous lung regions filled more readily with ³He as compared to ¹²⁹Xe gas. By extension therefore, if here the ³He gas more readily filled the centrilobular emphysematous regions within the upper lobe, this may explain the greater SI differences for ³He MRI. However, it is important to note that based on the estimated self‐diffusion coefficients for the ³He and ¹²⁹Xe gas mixtures (0.211 and 0.826 cm²/sec for ¹²⁹Xe/⁴He and ³He/N₂, respectively; Kirby et al. 2012d), ¹²⁹Xe gas is a better estimate of room air, which has an estimated self‐diffusion coefficient of 0.218 cm²/sec, as compared to the ³He gas mixture. Taken together this suggests that due to the different physical properties of ¹²⁹Xe, the distribution of the ¹²⁹Xe gas mixture that is imaged during a breath‐hold condition may more accurately reflect the regional distribution of oxygen gas mixed in room air as compared to ³He gas mixtures used during imaging.

Finally, we demonstrated strong and significant correlations for ³He ADC, ¹²⁹Xe ADC_b12, and ADC_b20 with DL_CO and CT measurements of emphysema. DW gradients and diffusion time influence the measured ADC, and more importantly, they influence the spatial scale that the gas is probing (Woods et al. 2005). Therefore, ³He ADC and ¹²⁹Xe ADC with different b‐values may provide different sensitivities to different lung microstructural environments and abnormalities. We investigated this by evaluating the relationship for DL_CO and CT lung density thresholds with ³He and ¹²⁹Xe ADC. We observed strong correlations for ³He ADC, ¹²⁹Xe ADC_b12, and ADC_b20, further suggesting that ¹²⁹Xe DW imaging is sensitive to the same lung microstructural abnormalities as ³He ADC with b value 1.6 cm²/sec. However, we must also note that although strong and significant univariate correlations were observed for ³He and ¹²⁹Xe ADC with DL_CO, in the multivariate regression model ¹²⁹Xe ADC_b12 was the only significant predictor of DL_CO. In contrast, ³He ADC was the only significant predictor of RA₉₅₀. Although CT density‐threshold measurements correlate with pathology measurements of emphysema on resected lung specimens (Avni et al. 1996), it has been suggested that CT is not sensitive to subclinical or more mild emphysema (Muller et al. 1988; Miller et al. 1989). DL_CO, on the other hand, despite low reproducibility, has been shown to be a very sensitive measure of early or mild subclinical emphysematous abnormalities. A recent study demonstrated elevated levels of endothelial microparticles in smokers with abnormally low DL_CO but normal spirometry (Gordon et al. 2011). Furthermore, in ex‐smokers without COPD, elevated ³He ADC, worse symptoms and exercise capacity were reported in subjects with abnormal as compared to normal DL_CO (Kirby et al. 2013). Since ¹²⁹Xe gas has a lower diffusivity than ³He, we hypothesized that ¹²⁹Xe MRI with greater diffusion weighting may be more sensitive to early or mild emphysema. The finding that ¹²⁹Xe MRI was the only significant predictor of DL_CO lends support to this notion.

The diffusion time of 5 msec was selected for ¹²⁹Xe MRI (Sukstanskii and Yablonskiy 2012; Boudreau et al. 2013) in order to probe a similar spatial length scale as ³He, and using this diffusion time, the characteristic diffusion lengths were approximately 0.49 and 0.46 mm for ³He and ¹²⁹Xe, respectively. For these diffusion lengths, it is likely that both ³He and ¹²⁹Xe gas atoms diffused beyond a single alveolus (diameter ~0.20 mm; Ochs et al. 2004) to a distal respiratory bronchiole (diameter ~0.40 mm; Horsfield and Cumming 1968). Although the majority of the COPD subjects evaluated in this study had moderate‐to‐severe emphysema, future studies, perhaps with improved polarization levels, should investigate the sensitivity of different ¹²⁹Xe MRI imaging parameters, including different diffusion weighting and diffusion times, for evaluating emphysematous changes in subjects with more mild disease. Importantly, in our previous investigations we have demonstrated ¹²⁹Xe MRI gas distribution measurements were more sensitive to airway wall abnormalities in asthmatics (Svenningsen et al. 2013) and to emphysematous bullae in COPD (Kirby et al. 2013). These findings suggest that due to the different physical properties of ¹²⁹Xe gas compared to ³He gas, ¹²⁹Xe may be more sensitive for the detection of airway obstruction and may therefore also be more sensitive for the detection of airway obstruction in patients with early or subclinical disease. However, this will need to be confirmed in future ¹²⁹Xe MRI investigations.

We also believe that ¹²⁹Xe MRI DW imaging may provide increased sensitivity for evaluating emphysematous changes in subjects with more mild disease. In this regard, we must acknowledge that ¹²⁹Xe ADC_b30 may not provide an appropriate estimate of emphysema in subjects with moderate‐to‐severe disease. In regions of the lung with significant emphysema, the ¹²⁹Xe gas diffusion coefficient is likely strong enough to destroy the MRI signal in that region due to the greater ¹²⁹Xe diffusion weighting, and the only signal remaining in the lung will be from the nonemphysematous lung microstructure. Therefore, the measured ADC values will reflect the healthier lung parenchyma, and not the emphysematous regions. However, in very early or mild subclinical disease, this may in fact be advantageous, as any small increase in airspace size will result in a reduction in signal intensity in the DW images. ¹²⁹Xe ADC_b30, due to the greater diffusion weighting may therefore provide greater sensitivity to mild microstructural changes than ³He ADC or ¹²⁹Xe ADC_b12, although this cannot be ascertained by the current study.

We recognize that this work was limited by several factors. First, the small number of subjects evaluated and in particular the small number of subjects in the ¹²⁹Xe ADC_b30 group, certainly limits the generalizability of these results. Another important limitation for both ³He and ¹²⁹Xe ADC measurements is that these cannot be reported for the regions of the lung that are poorly or not ventilated. Such unventilated or poorly ventilated lung regions may be due to small airway occlusion, mucous plugs, airway wall thickening and inflammation, severe emphysema, or bullous disease. Previous studies (Kaushik et al. 2011; Kirby et al. 2012a) comparing ³He and ¹²⁹Xe in COPD suggest that ¹²⁹Xe gas distribution is sensitive to emphysematous bullae, and this is another consideration when performing ¹²⁹Xe DW imaging in COPD subjects.

In summary, we evaluated ¹²⁹Xe ADC b values of 12, 20, and 30 sec/cm² in the same older never‐smokers and COPD ex‐smokers and compared these with ³He ADC, DL_CO, and CT measurements of emphysema. We showed that ³He ADC and ¹²⁹Xe ADC_b12 or ADC_b20 distinguished subjects with and without COPD. Although strong correlations for both ³He and ¹²⁹Xe ADC were observed with DL_CO and CT measurements of emphysema, in a multivariate analysis ¹²⁹Xe ADC_b12 was the only significant predictor of DL_CO. However, ¹²⁹Xe ADC_b30 may be appropriate for evaluating subclinical or mild emphysema, in this small group of older never‐smokers and ex‐smokers with moderate‐to‐severe emphysema, ¹²⁹Xe ADC_b12 provided a physiologically appropriate estimate of gas exchange abnormalities and alveolar microstructure, providing good evidence to support future ¹²⁹Xe MRI studies of emphysema.

Acknowledgments

We thank S. McKay and S. Blamires for subject recruitment, clinical coordination, and clinical database management; A. Wheatley for production and dispensing of ³He gas; and T. Szekeres for MRI of research volunteers.