Hyperpolarized Helium-3 MRI of Cystic Fibrosis
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
Infection
Mucus obstruction
Inflammation
Cystic Fibrosis: Median Survival Age
Canadian Cystic Fibrosis Patient Data Registry, 2002.
Study Motivation•Deve
lopment 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
Current Measurement Tools 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 3He 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)
3He
hyperpolarized ventilation contrast agent
generation of high signal intensity in airspaces
Hyperpolarized 3He Magnetic Resonance Imaging (MRI)
3He MR image3He MR image linked with the proton MR image
Study Objective
Evaluate 3He 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 3He MRI measurements
2) Through examination of the relationship between 3He MRI derived measurements and standard measurements of lung function
Standard Measurements of Lung Function
FEV1: forced expiratory volume in 1 second
The volume of air exhaled in the 1st 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 FEV1 > 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
TCV VDV 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 007Baseline
Follow Up
FEV1=75%PVV= 73%VDP= 25%
FEV1=79%PVV= 91%VDP= 12%
Measurement ReproducibilityScan (n=8)
Rescan (n=8)
Scan-Rescan difference (p)
Spirometry
FEV1 (%pred) (±SD) 75.38(7) 71.50(10) 0.08241
FVC (%pred) (±SD) 87.75(8) 84.625(6) 0.03760*
Plethysmography
RV (mL) † (±SD) 2.514 (1) 2.94(1) 0.1512
3He Ventilation MRI
VDP (%) (±SD) 31.91(17) 34.99(14) 0.1580
PVV (%) (±SD) 75.81(29) 75.19(22) 0.9359*difference between scan and rescan values are significant (p < 0.05)†(n=6)
Discussion: Measurement Reproducibility
Scan and 7 ± 2 day rescan 3He MRI measurements (VDP, PVV) were highly reproducible
Spirometry measures at scan and 7 ± 2 rescan :• FEV1(%pred) measurements were reproducible
• FVC (%pred) measurements were not reproducible• RV measurements were reproducible
Linear Correlation: Relationship between FEV1 and VDP
Strong negative correlation for both baseline and follow up data
%FEV1 = VDP %
Baseline Follow Up
61 66 71 76 810
10
20
30
40
50
60R² = 0.79129713735014
% FEV1 predicted
VD
P %
54 59 64 69 74 790
10
20
30
40
50
60
R² = 0.90616701078823
% FEV1 predicted
VD
P %
Linear Correlation:Relationship between FVC and VDP
• weak negative correlation • moderately strong negative correlation
Baseline Follow Up
75 77 79 81 83 85 87 890
10
20
30
40
50
60
R² = 0.0593892692887126
FVC %
VD
P %
77 79 81 83 85 87 890
10
20
30
40
50
60
R² = 0.543805822151801
FVC %V
DP
%
FVC % = VDP %
Linear Correlation:Relationship between RV and VDP
•Strong positive correlation •Moderate positive correlation
Baseline Follow Up
98 118 138 158 178 198 2180
10
20
30
40
50
60
R² = 0.635507431761782
Residual Volume (RV) mL
VD
P %
109 129 149 169 189 209 229 249 2690
10
20
30
40
50
60
R² = 0.281948927833642
Residual Volume (RV) mL
VD
P %
RV α VDP %
Discussion: Ventilation Measurements
VDP was associated with FEV1, FVC and RV suggesting that VDP is sensitive to the level of bronchial obstruction, pulmonary hyperinflation and gas trapping
VDP was negatively correlated with FEV1%pred signifying that in CF, an increase in ventilation defects is accompanied by decreased FEV1%pred
Thus there are noteworthy associations between the 3He MRI and lung function measurements
Conclusion
This study demonstrates the potential for 3He 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
ScientistImaging Research Laboratories
Hassaan AhmedBSc
References
(1) Hodson, Margaret E., Duncan M. Geddes, and Andrew Bush. Cystic Fibrosis. 3rd ed. London: Hodder
Arnold, 2007. 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): 2483-490. Print.
(3) "Lung Function Testing." All about Spirometry. Web. 20 Mar. 2010.
<http://www.spirxpert.com/indices7.htm>.
(4) "Magnetic Resonance Imaging of the Lung in Cystic Fibrosis." Proc Am Thorac Soc 4 (2007): 321-27. Print.
Questions