Hyperpolarized3 He Magnetic Resonance Imaging of Chronic Obstructive Pulmonary Disease

Rationale and Objectives

We assessed subjects with stage II and stage III chronic obstructive pulmonary disease (COPD) and age-matched healthy volunteers at a single center using 3 He magnetic resonance imaging (MRI) at 3.0 T. Measurements of the 3 He apparent diffusion coefficient (ADC) and center coronal slice 3 He ventilation defect volume (VDV) were examined for same-day and 7-day reproducibility as well as subgroup comparisons.

Materials and Methods

Twenty-four subjects who provided written informed consent (15 males; mean age 67 ±7 years) with stage II ( n = 9), stage III COPD ( n = 7), and age-matched healthy volunteers ( n = 8) were enrolled based on their age and pulmonary function test results. All subjects underwent plethysmography, spirometry, and MRI at 3.0 T. The time frame between scans was 7 ± 2 minutes (same-day rescan) and again 7 ± 2 days later (7-day rescan). 3 He ADC and VDV reproducibility was evaluated using linear regression, intraclass correlation coefficients (ICC) and Lin’s concordance correlation coefficients (CCC).

Results

ADC reproducibility was high for same-day rescan ( r 2 = 0.934) and 7-day rescan ( r 2 = 0.960, ICC and CCC of 0.96 and 0.98, respectively). Same-day rescan VDV reproducibility evaluated using the ICC and CCC (0.97 and 0.98, respectively) as well as linear regression ( r 2 = 0.941) was also high, but VDV 7-day rescan reproducibility was lower and significantly different ( r 2 = 0.576, P < .001, ICC 0.74, CCC 0.75, P < .01).

Conclusions

Hyperpolarized 3 He MRI was well-tolerated in subjects with stage II and stage III COPD. Seven-day repeated scanning was highly reproducible for ADC and moderately reproducible for VDV.

Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and continues to increase in incidence, morbidity and mortality rates, and direct and indirect costs ( ). The increasing prevalence and economic burden related to COPD is motivating the assessment of new ways to provide earlier diagnosis, better patient risk assessment, and improved patient monitoring of disease progression and treatment. Although both pulmonary function tests and high-resolution computed tomography have been well-established as noninvasive diagnostic tools and biomarkers in clinical studies of COPD, some of the limitations of these approaches are driving the development of new imaging tools that are sensitive to disease changes, provide regional information, and have the appropriate specificity and precision for use in clinical research.

Hyperpolarized 3 He magnetic resonance imaging (MRI) has emerged as a radiologic research method for the evaluation of the regional distribution of anatomic and functional lung changes associated with COPD ( ). In particular, the measurement of the 3 He apparent diffusion coefficient (ADC) ( ) has been exploited to probe the lung microstructure in patients with COPD ( ) and in ex vivo explanted lungs ( ). Same-day scanning reproducibility has also been assessed ( ). Increases in ADC are consistent with expected increases in acinar size because of destruction of alveoli accompanying emphysema ( ) have been shown to correlate with histologic measurements of disease ( ) and also have been shown to correlate positively with age ( ). Parenchymal focal ventilation defects in 3 He images also appear to be sensitive to lung ventilation changes that accompany COPD ( ). The 3 He ventilation defect score correlates with both age ( ) and disease status, providing radiologists and respirologists with a new measurement tool for clinical studies of the spatial and temporal changes in the lung that accompany COPD. The percent ventilation volume ( ) as well as ADC measurements ( ) derived from 3 He images have been shown to be altered in otherwise asymptomatic smokers with normal pulmonary function values, suggesting that these measures are sensitive to early lung changes in smokers. Finally, safety and tolerability have been shown to be excellent across a variety of healthy and respiratory compromised patients ( ).

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Materials and methods

Study Subjects

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Study Assessments

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Safety Monitoring and Hyperpolarized 3 He Administration

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Imaging

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Image Analysis

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Statistical Analysis

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Results

Study Subjects

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Table 1

Subject Demographics

Healthy Volunteers ( n = 8) Stage II COPD ( n = 9) Stage III COPD( n = 7) Age (y) (range) 67 (6) (58–74) 68 (6) (59–74) 67 (8) (52–75) Males 5 4 6 Body mass index (range) 27 (4) (24–35) 28 (5) (21–38) 27 (4) (22–34) FEV 1 % ⁎ 106 (19) 63 (8) 42 (7) FEV 1 /FVC% 77 (5) 54 (11) 38 (10) IC% ⁎ 111 (16) 99 (18) 78 (17) RV% ⁎ 97 (10) 142 (20) 188 (55) FRC% ⁎ 95 (14) 116 (14) 152 (37) TLC% ⁎ 104 (19) 108 (9) 115 (23)

FEV 1 : forced expiratory volume in 1 second; FVC: forced vital capacity; FRC: functional residual capacity; IC: inspiratory capacity; LC: total lung capacity.

Data are presented as mean (± standard deviation).

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3 He MRI Measurements

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Table 2

Same Day and 7-day Rescan ADC and VDV Measurements

Healthy Volunteers ( n = 8) Stage II COPD ( n = 9) Stage III COPD ( n = 7) Whole lung mean ADC (±SD) cm 2 /s Scan 0.27 (0.02) 0.38 (0.09) 0.44 (0.09) Same-day rescan 0.26 (0.02) 0.36 (0.09) 0.42 (0.09) ⁎ 7-day rescan 0.26 (0.02) † 0.39 (0.08) ‡ 0.43 (0.09) Whole-lung ADC SD (±SD) cm 2 /s Scan 0.18 (0.03) 0.24 (0.07) 0.24 (0.04) Same-day rescan 0.19 (0.05) 0.22 (0.08) 0.24 (0.04) ⁎ 7-day rescan 0.16 (0.02) † 0.25 (0.08) ‡ 0.24 (0.04) Center slice mean ADC (±SD) cm 2 /s Scan 0.26 (0.02) 0.38 (0.10) 0.47 (0.10) Same-day rescan 0.25 (0.03) 0.36 (0.09) 0.46 (0.11) ⁎ 7-day rescan 0.24 (0.02) † 0.39 (0.10) ‡ 0.46 (0.10) Center slice ADC SD (±SD) cm 2 /s Scan 0.15 (0.03) 0.19 (0.06) 0.26 (0.07) Same-day rescan 0.14 (0.04) 0.15 (0.03) 0.24 (0.06) ⁎ 7-day rescan 0.12 (0.03) † 0.19 (0.04) ‡ 0.29 (0.15) Center slice ventilation defect volume (±SD) cm 3 Scan 80 (30) 70 (40) 220 (160) Same-day rescan 70 (30) 80 (50) 220 (150) ⁎ 7-day rescan 70 (30) † 110 (70) ‡ 220 (110)

ADC: apparent diffusion coefficient; COPD: chronic obstructive pulmonary disease; SD: standard deviation; VDV: ventilation defect volume.

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3 He Measurement Reproducibility

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Table 3

Scan–Rescan Reproducibility

Healthy Volunteers ( n = 8) Stage II COPD ( n = 9) Stage III COPD ( n = 7) All Subjects ( n = 24) ICC CCC ICC CCC ICC CCC ICC CCC Center slice mean ADC (cm 2 /s) Same-day rescan 0.83 0.85 0.91 0.91 0.98 0.93 0.96 0.96 7-day rescan 0.17 0.24 0.97 0.96 0.99 0.98 0.98 0.98 Center slice VDV (cm 3 ) Same-day rescan 0.91 0.90 0.94 0.94 0.96 0.96 0.97 0.98 7-day rescan 0.56 0.57 0.59 0.62 0.63 0.58 0.74 0.75 FEV 1 (% predicted) Same-day spirometry 0.98 0.98 0.97 0.97 0.94 0.94 0.99 0.99 7-day spirometry 0.99 0.99 0.94 0.94 0.97 0.96 0.99 0.99

ADC: apparent diffusion coefficient; CCC: Lin’s concordance correlation coefficient; COPD: chronic obstructive pulmonary disease; FEV 1 : forced expiratory volume in 1 second; ICC: intraclass correlation coefficient; VDV: ventilation defect volume.

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Table 4

3 He ADC and VDV Sample Size Calculations

Healthy Volunteers ( n = 8) Stage II COPD ( n = 9) Stage III COPD ( n = 7) ADC (center slice) 7-day ( n ) 7 8 7 Mean (BL and 7-day cm 2 /s) 0.25 0.39 0.47 Difference (SD diff ) cm 2 /s 0.02 0.01 0.01 Sample size 1%/5%/10% change (n) 975/39/10 100/4/1 69/3/1 VDV (center slice) 7-day ( n ) 7 8 7 Mean (BL and 7-day) cm 3 73 92 220 SD diff cm 3 17 35 93 Sample size 5%/10% change ( n ) 331/83 882/220 1,089/272

ADC: apparent diffusion coefficient; BL: baseline; COPD: chronic obstructive pulmonary disease; VDV: ventilation defect volume.

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Discussion

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Conclusions

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Acknowledgment

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References

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Hyperpolarized3 He Magnetic Resonance Imaging of Chronic Obstructive Pulmonary Disease

Rationale and Objectives

Materials and Methods

Results

Conclusions

Materials and methods

Study Subjects

Study Assessments

Safety Monitoring and Hyperpolarized 3 He Administration

Imaging

Image Analysis

Statistical Analysis

Results

Study Subjects

3 He MRI Measurements

3 He Measurement Reproducibility

Discussion

Conclusions

Acknowledgment

References

Further Reading

Abstracts of Funded National Institutes of Health Grants

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