Study Specific Limitations

Pulmonary ventilation defects in older never-smokers (Chapter 2)

In Chapter 2, we sought to better understand the physiological consequences and potential relevance of 3He MRI ventilation defects in older never-smokers. We did not acquire CT images which limited our understanding of age-related airway changes and their relationship to ventilation defects. Our results, therefore, could not be directly compared to more established CT measurements, such as the percentage of low attenuation pixels as a measurement of the extent of senile emphysema or WA% as a measurement of airway wall thickness. A direct comparison of CT and hyperpolarized 3He MRI measurements in the same subjects would allow for a better understanding of the etiology of the ventilation defects observed in older never-smokers.

Another limitation of this study was that subjects were classified by viewing the gray-scale images, while the patients were still in the scanner. In two cases, once the ventilation images were co-registered to the anatomical 1_{H images, offline, previously classified}

ventilation defects could be directly related to anatomical bony structures and were unlikely to be ventilation abnormalities. As a result, the two subjects, who were classified at the scanner as having ventilation defects did not appear to have these once a full analysis was completed. Ideally, all subjects should have undergone deep inspiration and salbutamol administration and image analysis should have been used to evaluate bronchodilator response.

Finally, 129Xe and UTE MRI were not acquired in the older never-smokers. The high cost of 3He gas has restricted translation of this imaging method beyond specialized MRI centres. As previously discussed, this shortage is forcing the noble gas MRI community to transition to 129Xe gas, a less expensive and more readily available contrast agent, and non-contrast enhanced methods such as UTE MRI. One can hypothesize that ventilation defects may be more prominent and obvious using 129Xe MRI since previous work has shown the increased sensitivity of 129Xe gas compared to 3He gas in OLD.14,15 One can also hypothesize that UTE MR signal-intensity measurements would be lower in older individuals than younger individuals due to increased resting lung volumes in older

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subjects. Regardless, future studies should aim to image older never-smokers using 129Xe and UTE MRI to better understand the age-related changes in these imaging measurements.

Ultra-short echo-time pulmonary MRI: evaluation and reproducibility in COPD subjects with and without bronchiectasis (Chapter 3)

In the study presented in Chapter 3, a reproducible UTE MRI method was developed and an understanding of the physiological determinants of UTE signal-intensity in patients with COPD was determined. First, we acquired single slice images rather than whole-lung images. This limited our understanding of this measurement in the anterior and posterior regions of the lung.

Second, it is important to note that the impact of effective transverse decay time T2* on

signal-intensity at different lung volumes was ignored in healthy volunteers for two reasons: 1) in human lungs, T2* variability was significantly smaller than other factors

affecting signal-intensity across different lung volumes 2) the echo-time of 0.05ms was significantly smaller than the parenchymal T2* (0.5-0.8ms), which minimized T2*

weighting. Also, unlike CT, MRI signal-intensity is influenced by hardware factors such as the positioning of the RF coils, which introduce inter-scan variability. While we corrected for absolute signal intensity quantification by normalizing acquired images to the liver, this is influenced by the precision of liver measurements. In this regard, we note that the liver has minimal motion during the image acquisition and is relatively homogeneous despite inter-subject signal variability.

Finally, we acknowledge that the histopathological relationship between UTE MRI signal- intensity and CT radio-density measurements has not yet been established. The quantification of emphysema using CT uses different threshold type analyses has been compared and validated with histology, yet this has not been undertaken with parenchymal MRI signal intensity. The comparison of mean MRI signal-intensity to CT RA950 and

HU15 is likely a conservative estimate of any direct relationships. For this reason, the

comparison of MRI-derived SI15 with CT-derived HU15 is likely a better estimate of the

direct relationships of MRI signal-intensity and CT radio-density measurements.

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In Chapter 4 we developed a whole lung breath-hold UTE MRI protocol and evaluated asthmatics and healthy volunteers. There was a significant age difference between healthy volunteers and asthmatics which may have biased our results.

Another limitation of this study was that CT was not acquired at full expiration. Chest CT at full expiration allows for the evaluation of gas-trapping. The extent of the gas-trapping can be evaluated using a threshold type measurements (i.e. the relative area under -856HU, RA856).16 Unfortunately, this threshold is only appropriate when CT is acquired at a lung

volume of full expiration and this limited our understanding of regional gas-trapping. Consequently, the mean whole lung radio-density was used for direct comparison with mean whole lung signal-intensity. It should be noted that not only does the mean measurement not capture the extent of low signal-intensity, but the lack of expiratory CT limits our understanding of regional gas-trapping and our ability to ascertain the etiology of CT lucency. Although we can comment on the relationship of UTE signal-intensity and CT radio-density, it is difficult to conclude that the signal-intensity at full expiration was reflective of regional gas-trapping. We can conclude, however, that signal-intensity at full expiration and dynamic proton-density measurements are related to pulmonary function test measurements of gas-trapping such as residual volume and the ratio of residual volume to total lung capacity. It is also important to note that UTE signal-intensity measurements were related to hyperpolarized noble gas ventilation defects. Previous studies have demonstrated the relationship of CT lucency and 3He MRI which suggest the relationship between gas-trapping and ventilation defects in asthma.17

Finally, for three asthmatics, only 129Xe MRI was performed, which based on previous work, would be expected to be greater than 3_{He VDP.}14 _{Importantly, however, when these}

data were removed from the analysis, the correlations with VDP were not significantly different. It should also be noted that three subjects underwent the methacholine challenge. Although there were significant differences in signal-intensity at full expiration, caution must be taken when extrapolating these results to a larger sample size.

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