Imaging of lung function using hyperpolarized helium-3 magnetic resonance imaging: Review of current and emerging translational methods and applications

During the past several years there has been extensive development and application of hyperpolarized helium-3 (HP (3)He) magnetic resonance imaging (MRI) in clinical respiratory indications such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, radiation-induced lung injury, and transplantation. This review focuses on the state-of-the-art of HP (3)He MRI and its application to clinical pulmonary research. This is not an overview of the physics of the method, as this topic has been covered previously. We focus here on the potential of this imaging method and its challenges in demonstrating new types of information that has the potential to influence clinical research and decision making in pulmonary medicine. Particular attention is given to functional imaging approaches related to ventilation and diffusion-weighted imaging with applications in chronic obstructive pulmonary disease, cystic fibrosis, asthma, and radiation-induced lung injury. The strengths and challenges of the application of (3)He MRI in these indications are discussed along with a comparison to established and emerging imaging techniques.     

Lung MRI with hyperpolarised gases: current & future clinical perspectives

The use of pulmonary MRI in a clinical setting has historically been limited. Whilst CT remains the gold-standard for structural lung imaging in many clinical indications, technical developments in ultrashort and zero echo time MRI techniques are beginning to help realise non-ionising structural imaging in certain lung disorders. In this invited review, we discuss a complementary technique – hyperpolarised (HP) gas MRI with inhaled ³He and ¹²⁹Xe – a method for functional and microstructural imaging of the lung that has great potential as a clinical tool for early detection and improved understanding of pathophysiology in many lung diseases. HP gas MRI now has the potential to make an impact on clinical management by enabling safe, sensitive monitoring of disease progression and response to therapy. With reference to the significant evidence base gathered over the last two decades, we review HP gas MRI studies in patients with a range of pulmonary disorders, including COPD/emphysema, asthma, cystic fibrosis, and interstitial lung disease. We provide several examples of our experience in Sheffield of using these techniques in a diagnostic clinical setting in challenging adult and paediatric lung diseases.     

Functional imaging of the lungs with gas agents

This review focuses on the state‐of‐the‐art of the three major classes of gas contrast agents used in magnetic resonance imaging (MRI)—hyperpolarized (HP) gas, molecular oxygen, and fluorinated gas—and their application to clinical pulmonary research. During the past several years there has been accelerated development of pulmonary MRI. This has been driven in part by concerns regarding ionizing radiation using multidetector computed tomography (CT). However, MRI also offers capabilities for fast multispectral and functional imaging using gas agents that are not technically feasible with CT. Recent improvements in gradient performance and radial acquisition methods using ultrashort echo time (UTE) have contributed to advances in these functional pulmonary MRI techniques. The relative strengths and weaknesses of the main functional imaging methods and gas agents are compared and applications to measures of ventilation, diffusion, and gas exchange are presented. Functional lung MRI methods using these gas agents are improving our understanding of a wide range of chronic lung diseases, including chronic obstructive pulmonary disease, asthma, and cystic fibrosis in both adults and children. J. Magn. Reson. Imaging 2016;43:295–315.     

Evaluation of structure-function relationships in asthma using multidetector CT and hyperpolarized He-3 MRI

RATIONALE AND OBJECTIVES: Although multiple detector computed tomography (MDCT) and hyperpolarized gas magnetic resonance imaging (HP MRI) have demonstrated ability to detect structural and ventilation abnormalities in asthma, few studies have sought to exploit or cross-validate the regional information provided by these techniques. The purpose of this work is to assess regional disease in asthma by evaluating the association of sites of ventilation defect on HP MRI with other regional markers of airway disease, including air trapping on MDCT and inflammatory markers on bronchoscopy. MATERIALS AND METHODS: Both HP MRI using helium-3 and MDCT were acquired in the same patients. Supervised segmentation of the lung lobes on MRI and MDCT facilitated regional comparisons of ventilation abnormalities in the lung parenchyma. The percentage of spatial overlap was evaluated between regions of ventilation defect on HP MRI and hyperlucency on MDCT to determine associations between obstruction and likely regions of gas trapping. Similarly, lung lobes with high defect volume were compared to lobes with low defect volume for differences in inflammatory cell number and percentage using bronchoscopic assessment. RESULTS: There was significant overlap between sites of ventilation defect on HP MRI and hyperlucency on MDCT suggesting that sites of airway obstruction and air trapping are associated in asthma. The percent (r=0.68; P= .0039) and absolute (r=0.61; P= .0125) number of neutrophils on bronchoalveolar lavage for the sampled lung lobe also directly correlated with increased defect volume. CONCLUSIONS: These results show promise for using image guidance to assess specific regions of ventilation defect or air trapping in heterogeneous obstructive lung diseases such as asthma.     

Hyperpolarised 3He MRI and 81mKr SPECT in chronic obstructive pulmonary disease

Purpose During recent years, magnetic resonance imaging (MRI) using hyperpolarised (HP) ³He gas has emerged as a promising new method for the imaging of lung ventilation. However, systematic comparisons with nuclear medicine techniques have not yet been performed. The aim of this study was to compare ventilation imaging methods in 26 patients with chronic obstructive pulmonary disease (COPD) and nine lung healthy volunteers.Methods HP ³He MRI, ^81mKr single-photon emission computed tomography (SPECT), high-resolution computed tomography (HRCT) and pulmonary function tests were performed. The three scans were scored visually as percentage of non-ventilated/diseased lung, and a computer-based objective measure of the ventilated volume in HP ³He MRI and ^81mKr SPECT and an emphysema index in HRCT were calculated.Results We found a good correlation between HP ³He MRI and ^81mKr SPECT for both visual defect score (r=0.80, p<0.0001) and objective estimate of ventilation (r=0.45, p=0.0157). In addition, both scans were well correlated with reference methods for the diagnosis of emphysema (pulmonary function test and HRCT). The defect scores were largest on ^81mKr SPECT (the score on HP ³He MRI was one-third less than that on ^81mKr SPECT), but the difference was reduced after normalisation for different breathing depths (HP ³He MRI at total lung capacity; ^81mKr SPECT at tidal breathing at functional residual capacity).Conclusion HP ³He MRI provides detailed ventilation distribution images and defect scores are comparable on HP ³He MRI and ^81mKr SPECT. Additionally, new insights into the regional pulmonary microstructure via the apparent diffusion coefficient measurements are provided by HP ³He MRI. HP ³He MRI is a promising new diagnostic tool for the assessment of ventilation distribution.     

Pulmonary CT and MRI phenotypes that help explain chronic pulmonary obstruction disease pathophysiology and outcomes

Pulmonary x‐ray computed tomographic (CT) and magnetic resonance imaging (MRI) research and development has been motivated, in part, by the quest to subphenotype common chronic lung diseases such as chronic obstructive pulmonary disease (COPD). For thoracic CT and MRI, the main COPD research tools, disease biomarkers are being validated that go beyond anatomy and structure to include pulmonary functional measurements such as regional ventilation, perfusion, and inflammation. In addition, there has also been a drive to improve spatial and contrast resolution while at the same time reducing or eliminating radiation exposure. Therefore, this review focuses on our evolving understanding of patient‐relevant and clinically important COPD endpoints and how current and emerging MRI and CT tools and measurements may be exploited for their identification, quantification, and utilization. Since reviews of the imaging physics of pulmonary CT and MRI and reviews of other COPD imaging methods were previously published and well‐summarized, we focus on the current clinical challenges in COPD and the potential of newly emerging MR and CT imaging measurements to address them. Here we summarize MRI and CT imaging methods and their clinical translation for generating reproducible and sensitive measurements of COPD related to pulmonary ventilation and perfusion as well as parenchyma morphology. The key clinical problems in COPD provide an important framework in which pulmonary imaging needs to rapidly move in order to address the staggering burden, costs, as well as the mortality and morbidity associated with COPD. J. MAGN. RESON. IMAGING 2016;43:544–557.     

Morphological and functional imaging in COPD with CT and MRI: present and future

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide. COPD is defined by irreversible airflow obstruction. It is a heterogeneous disease affecting the airways (i.e. chronic bronchitis, airway collapse), the parenchyma (i.e. hyperinflation, air trapping and emphysematous destruction) as well as the vasculature (i.e. hypoxic vasoconstriction, rarefication and pulmonary arterial hypertension) with different severity during the course of the disease. These different aspects of COPD can be best addressed by imaging using a combination of morphological and functional techniques. Three-dimensional high-resolution computed tomography (3D-HRCT) is the technique of choice for morphological imaging of the lung parenchyma and airways. This morphological information is to be accomplished by functional information about perfusion, regional lung mechanics, and ventilation mainly provided by MRI. The comprehensive diagnostic possibilities of CT complemented by MRI will allow for a more sensitive detection, phenotype-driven characterization and dedicated therapy monitoring of COPD as presented in this review.     

Simultaneous measurement of pulmonary partial pressure of oxygen and apparent diffusion coefficient by hyperpolarized 3He MRI

Hyperpolarized ³He (HP ³He) MRI shows promise to assess structural and functional pulmonary parameters in a sensitive, regional, and noninvasive way. Structural HP ³He MRI has applied the apparent diffusion coefficient (ADC) for the detection of disease‐induced lung microstructure changes at the alveolar level, and HP ³He pulmonary partial pressure of oxygen (pO₂) imaging measures the oxygen transfer efficiency between the lung and blood stream. Although both parameters are affected in chronic obstructive pulmonary disease (COPD), a quantitative assessment of the regional correlation of the two parameters has not been reported in the literature. In this work, a single acquisition technique for the simultaneous measurement of ADC and pO₂ is presented. This technique is based on the multiple regression method, in which a general linear estimator is used to retrieve the values of ADC and pO₂ from a series of measurements. The measurement uncertainties are also analytically derived and used to find an optimal measurement scheme. The technique was first tested on a phantom model, and then on an in vivo normal pig experiment. A case study was performed on a COPD patient, which showed that in a region of interest ADC was 29% higher while oxygen depletion rate was 61% lower than the corresponding global average values. Magn Reson Med, 2009. © 2009 Wiley‐Liss, Inc.     

Assessment of the lung microstructure in patients with asthma using hyperpolarized 3He diffusion MRI at two time scales: comparison with healthy subjects and patients with COPD

PURPOSE: To investigate short- and long-time-scale (3)He diffusion in asthma. MATERIALS AND METHODS: A hybrid MRI sequence was developed to obtain co-registered short- and long-time-scale apparent diffusion coefficient (ADC) maps during a single breath-hold. The study groups were: asthma (n = 14); healthy (n = 14); chronic obstructive pulmonary disease (COPD) (n = 9). Correlations were made between mean-ADC and %ADC-abn (abnormal) (%pixels with ADC > mean +2 SD of healthy) at both time scales and spirometry. Sensitivities were determined using receiver operating characteristic (ROC) analysis. RESULTS: For asthmatics, the short- and long-time-scale group-mean ADCs were 0.254 +/- 0.032 cm(2)/s and 0.0237 +/- 0.0055 cm(2)/s, respectively, representing a 9% and 27% (P = 0.038 and P = 0.005) increase compared to the healthy group. The group-mean %ADC-abn were 6.4% +/- 3.7% and 17.5% +/- 14.2%, representing a 107% and 272% (P = 0.004 and P = 0.006) increase. For COPD much greater elevations were observed. %ADC-abn provided better discrimination than mean-ADC between asthmatic and healthy subjects. In asthmatics ADC did not correlate with spirometry. CONCLUSION: With long-time scale (3)He diffusion magnetic resonance imaging (MRI) changes in lung microstructure were detected in asthma that more conspicuous regionally than at the short time scale. The hybrid diffusion method is a novel means of identifying small airway disease.     

Functional imaging of COPD by CT and MRI

This commentary reviews the contribution of imaging by CT and MRI to functional assessment in chronic obstructive pulmonary disease (COPD). CT can help individualize the assessment of COPD by quantifying emphysema, air trapping and airway wall thickening, potentially leading to more specific treatments for these distinct components of COPD. Longitudinal changes in these metrics can help assess progression or improvement. On hyperpolarized gas MRI, the apparent diffusion coefficient of provides an index of airspace enlargement reflecting emphysema. Perfusion imaging and measurement of pulmonary vascular volume on non-contrast CT provide insight into the contribution of pulmonary vascular disease to pulmonary impairment. Functional imaging is particularly valuable in detecting early lung dysfunction in subjects with inhalational exposures.     

Management of COPD: Is there a role for quantitative imaging?

While the recent development of quantitative imaging methods have led to their increased use in the diagnosis and management of many chronic diseases, medical imaging still plays a limited role in the management of chronic obstructive pulmonary disease (COPD). In this review we highlight three pulmonary imaging modalities: computed tomography (CT), magnetic resonance imaging (MRI) and optical coherence tomography (OCT) imaging and the COPD biomarkers that may be helpful for managing COPD patients. We discussed the current role imaging plays in COPD management as well as the potential role quantitative imaging will play by identifying imaging phenotypes to enable more effective COPD management and improved outcomes.     

Combined helium-3/proton magnetic resonance imaging measurement of ventilated lung volumes in smokers compared to never-smokers

PURPOSE: To use a combination of helium-3 (3-He) magnetic resonance imaging (MRI) and proton single-shot fast spin echo (SSFSE) to compare ventilated lung volumes in groups of "healthy" smokers, smokers diagnosed with moderate chronic obstructive pulmonary disease (COPD), and never-smokers. MATERIALS AND METHODS: All study participants were assessed with spirometry prior to imaging. 3-He images were collected during an arrested breath hold, after inhaling a mixture of 200 mL of hyperpolarized 3-He/800 mL of N2. Proton SSFSE images were acquired after inhaling 1 liter of room air. The ventilated volume for each study participant was calculated from the 3-He images, and a ratio was calculated to give a percentage ventilated lung volume. RESULTS: Never-smokers exhibited a 90% mean ventilated volume. The mean ventilated lung volumes for healthy smokers and smokers diagnosed with COPD were 75.2% and 67.6%, respectively. No correlation with spirometry was demonstrated for either of the smoking groups. CONCLUSION: Combined 3-He/Proton SSFSE MRI of the lungs is a noninvasive method, using nonionizing radiation, which demonstrates ventilated airspaces and enables the calculation of ventilated lung volumes. This method appears to be sensitive to early obstructive changes in the lungs of smokers.     

Imaging phenotypes of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide. COPD is defined by irreversible airflow obstruction. It is a heterogeneous disease affecting the airways and/or the parenchyma with different severity during the course of the disease. These different aspects of COPD can be addressed by imaging using a combination of morphological and functional techniques. Computed tomography (CT) is the technique of choice for morphological imaging of the lung parenchyma and airways. This morphological information is to be accomplished by functional information about ventilation and perfusion, mainly provided by magnetic resonance imaging (MRI). The comprehensive diagnostic possibilities of CT complemented by MRI will allow for a more sensitive detection, phenotype-driven characterization, and dedicated therapy monitoring of the disease.     

Demonstration of the heterogeneous distribution of asthma in the lungs using CT and hyperpolarized helium-3 MRI

Asthma is a chronic inflammatory disease that affects both the large and small airways and results in bronchoconstriction, mucous hypersecretion, smooth muscle hypertrophy, and subepithelial fibrosis. To gain insight into the pathophysiology of asthma, chest computed tomography (CT) has been investigated as a noninvasive method to evaluate airway wall thickness of medium and large airways. Hyperpolarized gas MRI can assess the functional alterations of airflow within the lung resulting from the structural changes in the airways. In this article, we review the application of CT-based techniques and hyperpolarized gas MRI to study structural and functional changes in asthma. From the result of studies with CT and hyperpolarized gas MRI, it is becoming apparent that asthma has a regional distribution within the lung, that is, some areas of the lung are more affected than others. Furthermore, there appears to be some persistence to this distribution which may explain the observed patterns of airway remodeling and provide targets for localized therapies such as local application of anti-inflammatory agents or bronchial thermoplasty. Thus, cross sectional imaging in asthma is providing new insights into the pathophysiology of the disease and has the potential to become essential in the guidance of localized treatments.     

Investigation of hyperpolarized 3He magnetic resonance imaging utility in examining human airway diameter behavior in asthma through comparison with high-resolution computed tomography

RATIONALE AND OBJECTIVES: Application of a previously developed model-based algorithm on hyperpolarized (HP) (3)He magnetic resonance (MR) dynamic projection images of phantoms was extended to investigate the utility of HP (3)He MR imaging (MRI) in quantifying airway caliber changes associated with asthma. MATERIALS AND METHODS: Airways of seven volunteers were imaged and measured using HP (3)He MRI and multidetector-row computed tomography (MDCT) before and after a methacholine (MCh) challenge. MDCT data were obtained at functional residual capacity and 1 L above functional residual capacity. RESULTS: Comparison of the resultant data showed that HP (3)He MRI did not match MDCT in measuring the ratios of airway calibers before and after the MCh challenge in 37% to 43% of the airways from the first six generations at the two lung volumes tested. However, MDCT did yield the observation that 49% to 69% of these airways displayed bronchodilation following MCh challenge. CONCLUSION: The current implementation of HP (3)He MRI did not match the MCh-induced postchallenge-to-prechallenge airway caliber ratios as measured with MDCT. Elevated parenchymal tethering due to bronchoconstriction-induced hyperinflation was proposed as a possible explanation for this airway dilation.     

3He MRI in mouse models of asthma.

In the study of asthma, a vital role is played by mouse models, because knockout or transgenic methods can be used to alter disease pathways and identify therapeutic targets that affect lung function. Assessment of lung function in rodents by available methods is insensitive because these techniques lack regional specificity. A more sensitive method for evaluating lung function in human asthma patients uses hyperpolarized (HP) (3)He MRI before and after bronchoconstriction induced by methacholine (MCh). We now report the ability to perform such (3)He imaging of MCh response in mice, where voxels must be approximately 3000 times smaller than in humans and (3)He diffusion becomes an impediment to resolving the airways. We show three-dimensional (3D) images that reveal airway structure down to the fifth branching and visualize ventilation at a resolution of 125 x 125 x 1000 microm(3). Images of ovalbumin (OVA)-sensitized mice acquired after MCh show both airway closure and ventilation loss. To also observe the MCh response in naive mice, we developed a non-slice-selective 2D protocol with 187 x 187 microm(2) resolution that was fast enough to record the MCh response and recovery with 12-s temporal resolution. The extension of (3)He MRI to mouse models should make it a valuable translational tool in asthma research.     

Perfusion abnormalities in pulmonary embolism studied with perfusion MRI and ventilation-perfusion scintigraphy: an intra-modality and inter-modality agreement study

PURPOSE: To compare perfusion magnetic resonance imaging (MRI) and ventilation-perfusion scintigraphy (V-P scan) in the study of perfusion abnormalities in pulmonary embolism (PE) and to compare the PE results to the findings previously reported for pneumonia and chronic obstructive pulmonary disease (COPD), in terms of perfusion abnormalities. MATERIALS AND METHODS: Dynamic contrast-enhanced MR images and V-P scans of 20 patients with PE, 11 patients with acute pneumonia, and 13 patients with exacerbation of COPD were studied. Five categories of perfusion abnormalities within each imaging modality were defined. Intra- and inter-modality agreement (kappa values) in the evaluation of perfusion abnormalities were calculated, based on the two observers of each imaging modality (all blinded to each other and true diagnosis). Finally, three categories of perfusion MRI diagnosis (PE, pneumonia, and COPD) were also defined and the inter-observer agreement (kappa value) was calculated. RESULTS: For PE, the intra-modality agreement (kappa value) in the evaluation of perfusion abnormalities was 0.77 for MRI and 0.65 for V-P scan. The inter-modality agreement varied from 0.52 to 0.57, respectively, and was observer-dependent. For the pooled group of PE, pneumonia, and COPD, the intra-modality agreement of perfusion abnormalities was 0.76 for MRI and 0.65 for V-P scan, and the inter-modality agreement varied from 0.51 to 0.56. The kappa value for inter-observer agreement for MRI diagnosis was 0.92. CONCLUSION: Evaluation of perfusion abnormalities in PE, pneumonia, and COPD using perfusion MRI and V-P scan showed a high intra-modality agreement that was higher than the inter-modality agreement. Further studies are now needed in patients presenting with possible PE to evaluate the sensitivity and specificity of the method.     

Pulmonary hyperpolarized noble gas MRI: Recent advances and perspectives in clinical application

The invention of hyperpolarized (HP) noble gas MRI using helium-3 (³He) or xenon-129 (¹²⁹Xe) has provided a new method to evaluate lung function. Using HP ³He or ¹²⁹Xe for inhalation into the lung air spaces as an MRI contrast agent significantly increases MR signal and makes pulmonary ventilation imaging feasible. This review focuses on important aspects of pulmonary HP noble gas MRI, including the following: (1) functional imaging types, (2) applications for major pulmonary diseases, (3) safety considerations, and (4) future directions. Although it is still challenging to use pulmonary HP noble gas MRI clinically, the technology offers promise for the investigation of the microstructure and function of the lungs.     

Single-scan acquisition of registered hyperpolarized (3)He ventilation and ADC images using a hybrid 2D gradient-echo sequence.

The pulse sequences for hyperpolarized (3)He lung MRI that have made the most clinical impact to date are 1) those that supply regional apparent diffusion coefficient (ADC) measurements, which provide insight into early emphysematous destruction of the alveoli in the lungs, and 2) high-resolution ventilation images that provide regional indicators of airway obstruction in obstructive airway disease, such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease (COPD). In this work a hybrid 2D ADC-ventilation sequence was used with low flip angles to acquire both sets of data in the same breath-hold. The performance of the sequence was investigated in vivo in a healthy subject and a subject with mild emphysema, and compared with conventional 2D gradient-echo (GRE) (3)He ventilation and ADC imaging sequences. Acquisition of the ADC and ventilation images in one breath-hold provides ventilation images with equal or better SNR (approximately 20) and the same spatial resolution (3.75 mm x 3.3 mm in plane) with simultaneous accurate, high-resolution ADC images. The hybrid sequence offers a means of conserving gas by using two-thirds of the (3)He gas needed for separate ADC and ventilation exams, and saves the subject from having to perform an extra breath-hold. The data are inherently spatially and temporally registered, allowing quantitative cross-correlation between high-spatial-resolution ADC and ventilation data.     

The role of hyperpolarized 129xenon in MR imaging of pulmonary function

In the last two decades, functional imaging of the lungs using hyperpolarized noble gases has entered the clinical stage. Both helium (³He) and xenon (¹²⁹Xe) gas have been thoroughly investigated for their ability to assess both the global and regional patterns of lung ventilation. With advances in polarizer technology and the current transition towards the widely available ¹²⁹Xe gas, this method is ready for translation to the clinic. Currently, hyperpolarized (HP) noble gas lung MRI is limited to selected academic institutions; yet, the promising results from initial clinical trials have drawn the attention of the pulmonary medicine community. HP ¹²⁹Xe MRI provides not only 3-dimensional ventilation imaging, but also unique capabilities for probing regional lung physiology. In this review article, we aim to (1) provide a brief overview of current ventilation MR imaging techniques, (2) emphasize the role of HP ¹²⁹Xe MRI within the array of different imaging strategies, (3) discuss the unique imaging possibilities with HP ¹²⁹Xe MRI, and (4) propose clinical applications.