Transcript 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
Inflammation
Infection
Mucus
obstruction

•
•
•
•
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 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 image linked with
the proton MR image
3He
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
FEV1= 61%
PVV=34%
VDP= 55%
Follow Up
FEV1= 58%
PVV= 45%
VDP= 51%
Patient 003
Baseline
FEV1=82%
PVV= 96%
VDP= 16%
Follow Up
FEV1=79%
PVV= 95%
VDP= 18%
Patient 007
Baseline
FEV1=79%
PVV= 91%
VDP= 12%
Follow Up
FEV1=75%
PVV= 73%
VDP= 25%
Measurement Reproducibility
Scan
(n=8)
Rescan
(n=8)
Scan-Rescan
difference (p)
FEV1 (%pred) (±SD)
75.38(7)
71.50(10)
0.08241
FVC (%pred) (±SD)
87.75(8)
84.625(6)
0.03760*
2.514 (1)
2.94(1)
0.1512
31.91(17)
34.99(14)
0.1580
Spirometry
Plethysmography
RV (mL) † (±SD)
3He
Ventilation MRI
VDP (%) (±SD)
*difference
rescan values are
significant (p < 0.05) 0.9359
PVV (%) between
(±SD) scan and
75.81(29)
75.19(22)
†(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
Baseline
Follow Up
70
60
r = -0.8896
60
50
40
VDP %
VDP %
r = -0.9519
50
40
30
30
20
20
10
10
0
0
61
66
71
76
81
54
59
% FEV1 predicted
64
69
74
79
% FEV1 predicted
Strong negative correlation for both baseline and follow up data
%FEV1 = VDP %
Linear Correlation:
Relationship between FVC and VDP
Baseline
Follow Up
60
60
r = -0.7374
r = -0.2437
50
50
40
VDP %
VDP %
40
30
30
20
20
10
10
0
0
75
80
85
77
90
FVC %
•
79
81
83
85
87
FVC %
moderately strong negative
correlation
FVC % = VDP %
weak negative correlation
•
89
Linear Correlation:
Relationship between RV and VDP
Baseline
Follow Up
60
60
r = 0.971
50
40
40
VDP %
VDP %
r = 0.5309
50
30
20
30
20
10
10
0
98
118
138
158
178
198
218
0
109
Residual Volume (RV) mL
•Strong
159
209
259
Residual Volume (RV) mL
positive correlation
•Moderate
RV α VDP %
positive correlation
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
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, 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