Sarah Svenningsen University of Western Ontario Medical Biophysics April. 6, 2010

Cystic Fibrosis  CF is a lethal, autosomal recessive, disease resulting from mutations in the cystic fibrosis transmembrane regulator (CFTR) gene (1)  Mutations in the CFTR gene interfere with epithelial ion transport  Primarily affecting organs of epithelial origin; lungs, pancreas, intestines, and reproductive tract (1)  Children and young adults are predominantly affected  Death is mainly the result of respiratory failure, a consequence of progressive lung damage resulting from lung inflammation and infection (1)

CF: Pathophysiology of Lung Disease CFTR gene defect defective ion transport defective airway surface liquid impaired mucociliary clearance CF lung disease

CF: Lung Disease  Multiple Inter-related Clinical Symptoms including: Bronchiectasis Pulmonary Hyperinflation Air Trapping Ventilation Abnormalities

Cystic Fibrosis: Median Survival Age Canadian Cystic Fibrosis Patient Data Registry, 2002.

Study Motivation Development of a wide array of treatments aimed at different targets in CF pathway Numerous clinical trials for CF treatments Urgent need for precise, practical and sensitive clinical endpoint measures to evaluate treatments

 Pulmonary function tests (PFT): Global measurement of disease  Limitation: 1)PFT provide no regional information about lung function and/or structure (4) 2) insensitive to small changes in severity (4)  X-ray & X-ray CT: high resolution CT is the current ‘gold standard’ for depicting lung changes in CF (2)  Limitation: 1) radiation exposure

Hyperpolarized 3 He magnetic resonance imaging: a new imaging modality that allows for the visualization of lung structure and function at high resolution  With a low physical density of protons there is low signal intensity naturally generated in the lungs (3) 3 He hyperpolarized ventilation contrast agent generation of high signal intensity in airspaces

Hyperpolarized 3 He Magnetic Resonance Imaging (MRI) 3 He MR image 3 He MR image linked with the proton MR image

Study Objective  Evaluate 3 He MRI measurements as possible intermediate endpoints in adult CF patients. This objective will be met by: 1) Assessment of the short term (7-day) reproducibility of 3 He MRI measurements 2) Through examination of the relationship between 3 He MRI derived measurements and standard measurements of lung function

Standard Measurements of Lung Function  FEV 1 : forced expiratory volume in 1 second The volume of air exhaled in the 1 st second of forced expiration (3)  FVC: forced vital capacity The volume of air that can be forcibly blown out after full inspiration (3)  RV: residual volume The volume of air present in the lungs at the end of exhalation (3)

Study Design: 8 Adult CF Subjects  Between 21 and 41 years of age  FEV 1 > 50% predicted  MRI was performed on a whole body 3.0 Tesla Excite 12.0 MRI system

Image Analysis: Ventilation Measurements Image analysis was performed slice by slice Ventilation volumes (VV), ventilation defect volumes (VDV), and thoracic cavity volumes (TCV) were manually segmented TCVVDV VV

Patient 001 Baseline Follow Up FEV1= 61% PVV=34% VDP= 55% FEV1= 58% PVV= 45% VDP= 51%

Patient 003 Baseline Follow Up FEV1=79% PVV= 95% VDP= 18% FEV1=82% PVV= 96% VDP= 16%

Patient 007 Baseline Follow Up FEV1=75% PVV= 73% VDP= 25% FEV1=79% PVV= 91% VDP= 12%

Measurement Reproducibility Scan (n=8) Rescan (n=8) Scan-Rescan difference (p) Spirometry FEV 1 (%pred) (±SD)75.38(7)71.50(10) FVC (%pred) (±SD)87.75(8)84.625(6) * Plethysmography RV (mL) † (±SD)2.514 (1)2.94(1) He Ventilation MRI VDP (%) (±SD) 31.91(17)34.99(14) PVV (%) (±SD) 75.81(29)75.19(22) *difference between scan and rescan values are significant (p < 0.05) †(n=6)

Discussion: Measurement Reproducibility  Scan and 7 ± 2 day rescan 3 He MRI measurements (VDP, PVV) were highly reproducible  Spirometry measures at scan and 7 ± 2 rescan : FEV 1 (%pred) measurements were reproducible FVC (%pred) measurements were not reproducible RV measurements were reproducible

Linear Correlation: Relationship between FEV 1 and VDP Strong negative correlation for both baseline and follow up data %FEV 1 = VDP % BaselineFollow Up

Linear Correlation: Relationship between FVC and VDP weak negative correlation moderately strong negative correlation BaselineFollow Up FVC % = VDP %

Linear Correlation: Relationship between RV and VDP Strong positive correlation Moderate positive correlation BaselineFollow Up RV α VDP %

Discussion: Ventilation Measurements  VDP was associated with FEV 1, FVC and RV suggesting that VDP is sensitive to the level of bronchial obstruction, pulmonary hyperinflation and gas trapping  VDP was negatively correlated with FEV 1 % pred signifying that in CF, an increase in ventilation defects is accompanied by decreased FEV 1 % pred  Thus there are noteworthy associations between the 3 He MRI and lung function measurements

Conclusion  This study demonstrates the potential for 3 He MRI phenotypes as clinical endpoints in adult cystic fibrosis patients  Providing an accurate evaluation of disease progression and/or the effect of longitudinal treatment while providing regional information of the lung

Acknowledgements  Grace Parraga, PhD Scientist Imaging Research Laboratories  Hassaan Ahmed BSc

References (1) Hodson, Margaret E., Duncan M. Geddes, and Andrew Bush. Cystic Fibrosis. 3rd ed. London: Hodder Arnold, Print. (2) "Hyperpolarized 3helium Magnetic Resonance Ventilation Imaging of the Lung in Cystic Fibrosis: Comparison with High Resolution CT and Spirometry." Eur Radiol 16 (2006): Print. (3) "Lung Function Testing." All about Spirometry. Web. 20 Mar (4) "Magnetic Resonance Imaging of the Lung in Cystic Fibrosis." Proc Am Thorac Soc 4 (2007): Print.

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