General Limitations

One major limitation of the studies presented in this thesis is the lack of data collected from other imaging modalities in conjunction with 3He MRI, specifically CT data that could have been used for validation purposes. CT has largely been used both clinically and as a research tool for quantifying attenuation, related to the lung parenchyma3-6, and airway wall dimensions.7-10 Although a limited number of studies have compared ADC measured from diffusion-weighted 3_{He MRI to attenuation on CT}17_{, to date there has not been a direct comparison of} 3_{He ventilation} defect measurements to airway wall dimensions. It is hypothesized that 3He MRI VDV in subjects with COPD is the result of underlying airways disease, and therefore measurements of

airway dimension on CT would provide important complimentary information on airway structure leading to the ventilation defects that could be used to test this hypothesis. In relation to the work presented in Chapter 4 regarding the classification of COPD based on 3He MRI measurements, similar work has been done by Nakano and co-workers using CT9, and a direct comparison of these two techniques in the same COPD subject group would provide further insight into the surrogate measures of underlying emphysema and airways disease captured by these respective imaging modalities. Additionally, the registration of 3He MRI to CT data in Chapter 5 could have potentially been used to correlate regions of ventilation defect with areas of fibrosis on CT, providing a direct link to the etiology of these regions of signal void on 3He MRI. Furthermore, in all studies presented here, registration of 3He MRI with CT images would allow for a breakdown of ventilation defect analysis by lobe. In Chapter 2, the measurement of lobar VDV could be evaluated for reproducibility, which would have the potential to further solidify 3_{He MRI as a highly reproducible technique for evaluating regional pulmonary ventilation.} Overall, CT data collected in conjunction with 3He MRI would aid in validating 3He MRI measurements against more established CT images, and potentially provide some explanation as to the underlying structural abnormalities that result in diminished ventilation. Finally, nuclear medicine techniques would have been valuable for cross-comparison purposes, especially in Chapter 5, where blood flow measurements would have provided important complimentary information to the ventilation results. We hypothesize in Chapter 5 that the increase in PVV in the contralateral lung may be due to a compensatory increase in ventilation due to the diminished ventilation in the ipsilateral lung. Measurements of blood flow from PET would show whether this ventilation improvement translates to a true improvement in contralateral lung function due to a corresponding improvement in blood flow, or whether the increase in ventilation is not mirrored by an increase in blood flow, simply resulting in a ventilation-perfusion mismatch in the contralateral lung.

The second overall limitation is that the etiology of ventilation defects is currently unknown. While we hypothesize that VDV is reflective of underlying airways disease in subjects with COPD, closing volumes in healthy elderly subjects and radiation fibrosis in subjects with RILI, to date there is no direct evidence to affirm these hypotheses. There is also the possibility that

ventilation defects occur in COPD due to bullous disease, representing structural changes in lung parenchyma rather than the hypothesized changes in lung airway structure, or a combination of the two. Without knowing the underlying cause of the ventilation defect, it is difficult to determine whether 3He MRI is truly sensitive to underlying changes in airway structure that may be associated with aging, COPD or fibrosis. Therefore, histological data is necessary to ascertain the direct cause of ventilation defects observed and measured using 3He MRI. Given that this is a potentially difficult task to accomplish in humans, a secondary method of validation would be through multi-modality imaging studies. High resolution CT can provide structural information regarding both airway dimensions and lung parenchyma, and thus could be used in conjunction with 3He MRI to correlate ventilation defects to regions of inflamed, thickened airways, bullae, or fibrosis.

Finally, one major limitation of all studies presented here is the limited translation of this technique for more widespread research investigating lung diseases in both the research setting and for use in guiding therapy or as an endpoint in clinical trials. There is an extremely limited supply of helium-318,19, and therefore further follow-up studies stemming from the studies presented here may not be possible. It has been pointed out in previous paragraphs that increased sample sizes are needed in future studies to expand on the promising results of these small studies, which will likely not be possible given the current gas supply. Therefore, validation of this technique may not be necessary, but rather these studies should be reproduced, perhaps on a larger scale, with 129Xe, which is set to replace 3He as the noble gas contrast agent for hyperpolarized gas MRI.20-22 Thus, previous solutions for limitations addressed in the previous paragraphs would be better suited using 129Xe, which is likely to have increased translational value in the clinical research setting.