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The development of new, sensitive and precise measurements of lung function are critical for a better understanding of the structure-function paradigm that exists in the lung in both the normal and disease states.1,2 Currently, the gold standard method for evaluating lung function is spirometry. Specifically FEV1, measuring airflow limitation, is influenced by both regions of functional impairment and anatomical changes in the lung tissue microstructure and airway calibre. Thus, FEV1 is a good indicator of disease presence, but cannot provide any information on the contribution of underlying structural impairments or ventilation abnormalities that contribute to airflow obstruction. Furthermore, it does not give any indicator of the regional burden of disease, which is important for disease classification and guiding interventions and treatments. Therefore, when airflow limitation is detected further examination is often required. Chest x-rays are most commonly used for subsequent evaluation, but provide extremely limited quantitative information. CT is often the imaging modality of choice for high resolution pulmonary imaging.3 Using CT, it is possible to evaluate the lung microstructure by way of lung attenuation measurements3-6 and to evaluate the airways through measurements of the airway wall7-10, but the relationship these structural measurements have with lung function is often not clear. Moreover, CT is associated with significant increase in radiation exposure compared to chest x-ray, and because of the high radiation dose, serial CT exams over short time frames and longitudinal studies are not practical or safe even in elderly subjects. Thus, using clinically available imaging tools, lung structure can be probed without any information on the functional impact of structural abnormalities observed. Nuclear medicine techniques could fill this functional imaging gap, but they too are associated with radiation dose, suffer from poor resolution, and deposition of tracer particles in the central airways.11,12 Given that loss of lung function often occurs regionally within the lung, and may be associated with changes in lung microstructure, airway remodelling, or both, an ideal imaging tool would allow for quantitative

measurements of functional impairments in both cross-sectional and longitudinal studies, in conjunction with measurements of underlying lung structure.2

It is in this context that we embarked on developing quantitative measurements of lung function derived from hyperpolarized 3He MR images. In this thesis we evaluated 3He MRI measurements of lung function in cross-sectional and longitudinal studies of healthy volunteers and subjects with smoking-related lung disease. In regard to these measurements, we tested the following hypotheses: 1) metrics for quantifying 3He MR ventilation images have high short- term reproducibility 2) changes in lung function occurring with normal healthy aging can be detected using measurements of functional 3He MR images, 3) functional and structural 3He MRI measurements of COPD subjects, taken together, can be used to stratify disease, and, 4) radiation-induced lung injury results in long-term changes in lung function that can be measured using 3He MRI.

In Chapter 2, the same-day and seven-day reproducibility of VDV was evaluated from 3He MR images acquired at 3.0T. Twenty-four age-matched subjects were imaged with 3He MRI twice within 7 ± 2 minutes and again 7 ± 2 days later. Same-day and seven-day reproducibility were evaluated using ICC, CCC and linear regression. Same-day VDV was highly reproducible for all subjects (ICC = 0.97, CCC = 0.98, r2 = 0.94), while seven-day VDV was significantly lower (p<0.01, ICC = 0.74, CCC = 0.75, r2 = 0.58). Over the seven day time period there were no significant differences in FEV1 and FEV1/FVC. ADC, derived from diffusion-weighted 3He MRI, was also evaluated for reproducibility over the same time period. ADC was not significantly different at the seven minute or seven day time mark, and was found to be highly reproducible at both time points (same-day r2 = 0.93, seven-day r2 = 0.96). This is the first study to report the reproducibility of VDV, and more importantly, the first to report on the reproducibility of any method for quantifying ventilation defects with 3He MRI. Additionally, this is the first study to report on the reproducibility of 3He MRI evaluated at 3.0T. Overall, in Chapter 2 we demonstrate that 3He MRI VDV has high short-term reproducibility, and therefore has potential as a non-invasive quantitative marker of lung function for use in clinical trials

evaluating new treatments, as well as in longitudinal and cross-sectional research studies of smoking-related lung disease.

In Chapter 3, 3He MRI VDV was measured in a group of young healthy volunteers (mean age = 44), and another group of elderly healthy volunteers (mean age = 67). Images were acquired twice in one day, and again one week later to evaluate the inter-scan VDV variability. Images were scored and analyzed by four trained observers to assess the inter-observer variability of VDV. No ventilation defects were observed in the younger subjects, while in the older subject group, six of eight subjects had ventilation defects, with a mean VDV = 52 ± 34 cm3. Same-day and seven-day COVs were 1.8% and 5.3% respectively, while the inter-observer COV ranged from 10-12%. Overall, this study demonstrates that there are ventilation defects present in healthy elderly adults that are quantifiable using VDV, and that these age-related changes in lung function are highly reproducible over short time periods. Smoking-related lung disease, specifically COPD, tends to occur in elderly individuals, and thus it will be important in future studies quantifying lung function using 3He MRI to differentiate between 3He MRI VDV likely related to age alone, and volumes likely related to both age and COPD in this elderly diseased population.

In Chapter 4, functional and structural 3He MRI measurements were captured and used to stratify subjects with COPD according to the proportional contribution of these measurements to the overall sum of disease. Twenty former smokers with mainly stage II and stage III COPD were imaged using 3He MRI at a single time-point. Based on the relative contribution of normalized ADC and VDP, there was evidence of a predominant measurement in seven of the twenty subjects, three having mainly ventilation defects and four having mainly emphysema. Additionally, those with a predominant measurement had less overall disease, suggesting that mainly ventilation defects or tissue destruction develop early in the disease, with both being present at later stages. This was the first study to explore the potential of 3He MRI derived measurements to stratify subjects with COPD, and results suggest that 35% of subjects had a single predominant measurement – which is in agreement with previously published CT data.9 Further studies with increased sample size should be performed to evaluate 3He MRI based

measurements as a tool for phenotyping COPD. With further validation, 3He MRI VDP and ADC phenotypes may allow for identification and selection of COPD subjects based on their baseline 3He MRI-derived phenotype for clinical studies. Potential new treatments could then be evaluated in a specific 3He MRI phenotype, and specific underlying changes in lung function and structure evaluated.

In Chapter 5, 3He MRI derived measurements of lung function were used for the longitudinal evaluation of subjects with a clinical diagnosis of radiation-induced lung injury. Static ventilation and diffusion-weighted MR images were acquired 35 ± 12 weeks after radiation therapy began and again 22.0 ± 0.8 weeks later. At baseline, PVV was significantly lower (p<0.05) in the ipsilateral diseased lung. In four subjects returning for follow-up evaluation significant differences in both PVV and ADC were reported. 3He MRI PVV increased by 16% ± 6% (p<0.05), and 3He ADC increased by 0.02 ± 0.01 cm2/s (p<0.01). Hyperpolarized 3He MRI was well tolerated in all subjects with moderate to severe RILI. Functional improvements and microstructural changes were observed in the contralateral lung, while the ipsilateral lung remained stable, suggesting that functional compensatory changes may have occurred in the contralateral lung due to ipsilateral radiation-induced lung injury. These findings highlight the sensitivity of 3He MRI VDV to changes in lung function, and for the first time provide evidence of functional changes in the fibrotic stage of RILI. Specifically, this is the first report to suggest that the lung has the ability to compensate for a severe, local functional injury by increasing its functional capacity in other regions.

In Appendix A current methods for analyzing static ventilation images found in the 3He MRI literatre were described along with their limitations. Specific needs for 3He MRI ventilation analysis were addressed, and most importantly methods needed for quantitative comparative analysis of 3He MR ventilation images acquired from the same subject at multiple time-points were described. Requirements for image analysis include registration, signal normalization, and image subtraction for regional difference analysis. Development of these quantitative tools will further establish the potential of 3He ventilation image-derived measurements as sensitive markers of regional lung function that can be used as an analysis tool in clinical trials.

Appendix B described a case study of a single subject imaged pre- and post-Airway Bypass (AB). The subject was imaged over a four year time-period; at baseline, two years later, and again six and twelve months following AB. In the two years between baseline and first follow- up visit, there was a decrease in VDP that corresponded to a visually apparent worsening on the 3_{He MR images. Following the AB procedure VDV and VDP improved, which corresponded to} a self-reported improvement according to the mMRC scale, along with an improvement in cycle ergometry test time. Although the subject reported feeling better and visually apparent changes in ventilation were observed and quantified, there were minimal change in PFTs. While this is the only subject in the Broncus AB study to have 3He MRI data, quantitative 3He ventilation results following therapeutic intervention showed an improvement, were reflective of the improvement in dyspnea scores (while PFTs did not show any change), and therefore highlight the potential of this technique as a sensitive measure of lung function in clinical trials.

Here in Chapter 6 the conclusions that can be drawn from the studies presented in this thesis are addressed, as well as the limitations of these studies and possible future work that will expand on the work presented in Chapters 2-5. The conclusions of this thesis are addressed in section 6.2, the limitations of the current studies and solutions are presented in section 6.3, and possible future studies are detailed in section 6.4.