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

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