Discrimination of COPD Patients, Healthy Smokers and Age-matched Normals with Hyperpolarized Xenon-129 MR Spectroscopy
Kai Ruppert1,2, Kun Qing2, Talissa A. Altes2,3, and John P. Mugler III2

1Cincinnati Children's Hospital, Cincinnati, OH, United States, 2University of Virginia, Charlottesville, VA, United States, 3University of Missouri, Columbia, MO, United States

Synopsis

Chemical Shift Saturation Recovery (CSSR) MR Spectroscopy permits the in-vivo measurement of the alveolar septal wall thickness (SWT) by quantifying the uptake of hyperpolarized xenon-129 by lung parenchyma on a millisecond timescale. In this study we correlated the SWT with apparent diffusion coefficient (ADC) measurements in patients with chronic-obstructive pulmonary disease (COPD), healthy smokers and age-matched normals. While the ADC measurements and conventional pulmonary function tests could detect statistically significant differences between the COPD and non-COPD subjects, only CSSR spectroscopy could, in addition, discriminate healthy smokers from the age-matched normals.

Purpose

Apparent diffusion coefficient (ADC) MRI of the lung using hyperpolarized gases has been demonstrated as being highly sensitive to detect the breakdown of pulmonary tissue structures during the formation of emphysema in patients with chronic-obstructive pulmonary disease (COPD)1,2. However, since the ADC parameter is linked to the morphologic dimensions and interconnectivity of the acinar airspaces, it is inherently much less suitable for the quantification of preclinical COPD disease stages before actual lung-tissue destruction has begun. More recently, it has been shown that chemical-shift selective saturation recovery (CSSR) MR spectroscopy using hyperpolarized xenon-129 (HXe) indicates an increase in the pulmonary septal wall thickness (SWT) in COPD patients compared to healthy control subjects3. Unfortunately, many of the healthy subjects in this study were considerably younger than the COPD patients, and hence the possibility remained that some of the observed differences were age-related4. To address this concern, we investigated the correlation between SWT, ADC and the results of various pulmonary function tests for three cohorts of similar age ranges: COPD patients, healthy smokers (HS) and age-matched normal (AMN) subjects.

Methods

Gaussian RF pulses (2-ms duration) were applied to saturate the dissolved-phase magnetization. Following a delay time τ, a 1.2-ms Gaussian RF excitation pulse was used to generate a free induction decay. Fitting the spectral peak areas to the Patz gas-uptake model5 and assuming an HXe diffusion constant in tissue of 3.3×10-6 cm2/s 6 permitted calculation of the alveolar SWT. All MR studies were performed at 1.5T (Avanto; Siemens), using a flexible (Clinical MR Solutions) xenon-129 chest RF coil, under a physician’s IND for HXe MRI. Informed consent was obtained in all cases and a physician supervised each study. Enriched xenon gas (87% Xe129) was polarized to approximately 40% using a prototype commercial system (XeBox-E10, Xemed). The study group included 8 AMNs (age 63 ± 10), 8 HS (age 60 ± 9), and 13 COPD subjects (age 67 ± 8) who underwent pulmonary function tests including spirometry and Diffusion Capacity of Lung for Carbon Monoxide (DLCO), as well as HXe ADC MRI in addition to CSSR MR spectroscopy at total lung capacity. The measured quantities of interest were compared pairwise with 2-tailed t-tests for unequal variances to assess statistically significant differences between the three subject groups.

Results and Discussion

Figure 1 depicts the correlation between the alveolar SWT obtained from the CSSR studies and the HXe ADC averaged over the entire lung. While the two quantities are moderately well correlated (R2 = 0.48; p = 3×10-5), for the ADC studies there were only statistically significant differences between the AMN and COPD groups (ADCAMN = 0.043 cm2/s, ADCCOPD = 0.061 cm2/s, p = 7×10-5) as well as between the HS and COPD groups (ADCHS = 0.042 cm2/s, ADCCOPD = 0.061 cm2/s, p = 8×10-5), but not between the HS and AMN groups (ADCHS = 0.042 cm2/s, ADCAMN = 0.043 cm2/s, p = 0.91). In contrast, the SWT measurements exhibited statistically significant differences between all groups (AMN vs. COPD: SWTAMN = 9.0 μm, SWTCOPD = 12.8 μm, p = 4×10-5; HS vs. COPD: SWTHS = 10.6 μm, SWTCOPD = 12.8 μm, p = 0.01; and AMN vs. HS: SWTAMN = 9.0 μm, SWTHS = 10.6 μm, p = 0.02). These differences would probably be even more significant if it was not for the two oldest AMN subjects (both 79 years old) with SWTs above 10 μm. Further, many of the pulmonary function tests including FEV1, DLCO, FRC, and 6-min walk could detect statistically significant differences between the COPD and non-COPD groups, but not one could discriminate the AMN and HS groups.

Although this study is cross-sectional and not longitudinal, our findings indicate a disease etiology wherein inhalation of cigarette smoke induces a thickening of the pulmonary septal walls, most likely due to inflammation (left-to-right progression in Fig. 1). As the inflammation persists or even increases over time, septa begin to break down and pulmonary emphysema develops (bottom-to-top progression in Fig. 1). Thus, by combining SWT measurements with structural assessments through HXe ADC MRI, it might be feasible to monitor and quantify all stages of COPD development starting from preclinical inflammation to full-blown lung-tissue destruction.

Conclusion

HXe ADC MRI, SWT as assessed by CSSR spectroscopy, and many of the conventional pulmonary function tests found statistically significant differences between COPD patients and non-COPD subjects. However, only CSSR spectroscopy detected a statistically significant difference between the AMN and the HS groups, thereby potentially extending the characterization of early-stage COPD into the preclinical realm.

Acknowledgements

Supported by NIH grant R01 HL109618 and Siemens Medical Solutions.

References

1. Salerno et al. Radiology 2002;222(1):252-260.

2. Swift et al. Eur J Radiol 2005;54(3):352-358.

3. Qing et al. NMR in Biomed 2014;27(12):1490-1501.

4. Stewart et al. MRM 2014;epub.

5. Patz et al. Eur J Radiol. 2007 Dec;64(3):335-44.

6. Ruppert K et al. MRM 2004;51:676-687.

Figures

Figure 1. Correlation between alveolar septal wall thickness and the xenon ADC average for the entire lung.



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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