Abstract
129Xe MRI provides rapid, sensitive, non-invasive, high spatial resolution and simultaneous measurements of pulmonary ventilation, tissue microstructure and gas exchange, and is poised for routine clinical assessments in patients with chronic lung disease http://bit.ly/2PKkFcU
Introduction
Computed tomography (CT) of the chest is the imaging modality of choice for the non-invasive, quantitative evaluation of chronic lung diseases, because thoracic CT protocols are nearly ubiquitously available and provide rapid, high-resolution images of the airway, and parenchymal structure and anatomy. Pulmonary magnetic resonance imaging (MRI) has not been used clinically, mainly because of complexity (pulmonary MRI signal decays rapidly), cost and because conventional MRI is dependent on proton density (hydrogen atoms in tissue), which is exceptionally low (around 0.1 g·cm−3) in the healthy lung, because it mainly comprises air rather than tissue or being water-filled [1, 2]. Using conventional MRI methods, the lungs mainly appear as dark, signal-deficient voids and the pulmonary MRI signal is further degraded because of the millions of lung air-tissue interfaces that cause local magnetic field distortions, and respiratory and cardiac motion. While anatomical proton MRI of the lung is now developing rapidly to overcome these technical limitations, it still does not provide information beyond that of a low-dose CT, so there is a drive towards functional MRI. One of these approaches involves the use of inhaled gas contrast agents, primarily hyperpolarised (or magnetised) helium-3 (3He) and xenon-129 (129Xe), both of which provide a way to rapidly (<10 s) and directly visualise inhaled gas distribution with high spatial resolution (∼3 mm x, y and z planes). Pulmonary functional MRI is also possible using inhaled fluorinated gas [3], oxygen-enhanced techniques [4] and free-breathing proton methods [5, 6]; however, hyperpolarised inhaled gas MRI has been the most widely used and described. Because inhaled contrast gases have different resonant frequencies than hydrogen protons as used for conventional MRI, these methods inherently have no background signal and excellent contrast.
While inhalation of hyperpolarised gases to measure pulmonary function was originally discovered using 129Xe [7], the field was dominated by 3He MRI until recently, because of superior 3He MRI image quality with low volume (<500 mL) inhaled doses. However, the limited worldwide supply of 3He [8] has driven the field back to 129Xe gas, because it is naturally abundant and turnkey polarisation technologies have significantly advanced [9–11]. 129Xe also has modest solubility in biological tissues and resonates at different frequencies when dissolved in different tissues, so it provides novel alveolar tissue and capillary blood information. Here, we provide an overview of the key concepts and methods for 129Xe MRI, and discuss the current state-of-the-art and how 129Xe MRI may be applied in the future.
How does 129Xe MRI work?
129Xe MRI is dependent on equipment that polarises 129Xe atoms, to effectively increase the nuclear polarisation by approximately 100 000 times. Commercial (Polarean Inc., Durham, NC, USA; Xemed LLC, Durham, NH, USA) and custom-built [10, 11] polariser systems operate via spin-exchange optical pumping [12] whereby circularly polarised light bombards a glass cell housing rubidium and 129Xe. The circularly polarised light is absorbed by rubidium and subsequent collisions between polarised rubidium and 129Xe transfer angular momentum to 129Xe and increase its nuclear-spin polarisation. Typically, isotopically enriched 129Xe (∼86% by volume) is used to further increase the fraction of 129Xe atoms that are polarised in a given volume. 129Xe flows through the glass cell at a constant rate and the hyperpolarised 129Xe is frozen as it leaves the cell and remains frozen until the desired amount is accumulated, upon which it is thawed and dispensed into a bag for patient inhalation. The 129Xe flow rate through the cell can be adjusted to accumulate the desired 129Xe dose within a desired time frame. 129Xe doses vary from 250 mL up to 1.0 L [13], and doses are typically diluted up to 1.0 L using medical-grade nitrogen (N2) or helium-4. 129Xe hyperpolariser equipment is typically located in a small room adjacent to the MRI suite, within close proximity to deliver the polarised gas to the patient as quickly as possible.
129Xe MRI is feasible on both 1.5 T and 3.0 T field strength scanners. To acquire the signal, however, a radiofrequency coil is fitted around the patient's chest and this is specifically tuned to the resonance frequency of 129Xe. There are a number of different 129Xe coils; however, as shown in figure 1, the most common are quadrature rigid birdcage or flexible vests (Clinical MR Solutions, Brookfield, WI, USA; RAPID Biomedical, Rimpar, Germany). Rigid birdcage coils provide more homogeneous MRI signal throughout the lungs (i.e. no artefactual differences in MRI signal that are unrelated to anatomy) and increased signal-to-noise, but they have patient size limitations; flexible vest coils can accommodate a larger range of patient sizes but may require additional image corrections after MRI acquisition [14] to account for signal differences caused by the way the patient and coil interact. Additional receive array-coils may be placed on the patient's chest inside the rigid or flexible design coils, and this improves signal-to-noise ratios and accelerates acquisition times, which enables very short breath-hold scans (∼5 s). Figure 1a shows 129Xe MRI equipment including hyperpolariser, gas delivery bag and radiofrequency coils, and patient set-up in MRI scanner.
129Xe MRI is primarily performed under breath-hold conditions, though dynamic multi-breath protocols have also been applied [15]. While laying supine, patients are coached to inhale the gas mixture from passive end expiration or functional residual capacity and hold their breath while the image is acquired, which may take from 5 to 16 s. Pulmonary 129Xe MRI acquisitions may include static ventilation, diffusion-weighted or dissolved-phase methods. Static ventilation images are the most commonly reported 129Xe MRI acquisition and this provides regional maps of pulmonary gas distribution. A conventional proton (1H) image is also typically acquired in the same scanning session and at the same lung volume so that the anatomical and functional images may be co-registered to distinguish the edges of the thoracic cavity during image analysis and segmentation. Figure 1b shows a 129Xe gas static ventilation coronal image (cyan) and corresponding anatomical proton image (greyscale), and the two co-registered demonstrating a regional ventilation map. A corresponding CT slice is also shown in figure 1 as well as the three-dimensional segmented airway tree (yellow), which may be co-registered to the ventilation map to demonstrate structure–function relationships.
Diffusion-weighted 129Xe MRI methods may also be employed and these estimate the self-diffusion of 129Xe gas within the terminal airways and their restriction within the airspaces on a voxel-wise basis [16], which provides an excellent surrogate measurement of alveolar and terminal bronchiole enlargement.
129Xe has a large, loosely bound electron cloud, making it sensitive to its surroundings and soluble in biological tissue; once dissolved in biological tissues, 129Xe exhibits a different resonance frequency. Thus, 129Xe MRI can also provide in vivo measurements of pulmonary gas exchange [17, 18]. The so-called dissolved-state refers to 129Xe dissolved in the alveolar membrane and in red blood cells. 129Xe that has diffused into biological tissues experiences a different chemical environment and this is reflected via a shift in the 129Xe resonance frequency (chemical shift) from gaseous 129Xe, as shown in figure 1b. In the same manner, there is also a difference in the resonance frequency between 129Xe in the tissue and 129Xe in the blood, which enables simultaneous, independent imaging of these three states or compartments: 1) gas, 2) tissue barrier plus plasma, and 3) red blood cell. The gas state reflects the inhaled gas and has the largest measurable signal. 129Xe dissolved in the tissue barrier and blood plasma have indistinguishable chemical shifts and combine for the second largest measurable signal with a ∼197 ppm shift from gaseous 129Xe [19]. 129Xe dissolved in red blood cells exhibits an additional ∼20 ppm shift beyond the tissue-plasma signal and makes up the smallest, measurable 129Xe signal [19]; moreover, the red blood cell signal is oxygen-dependent and may undergo another measurable ∼5 ppm shift based on blood oxygenation [20]. Tuning the scanner allows acquisition of images of all three compartments, and acquisition protocols have been developed to simultaneously acquire quantitative images from all three compartments within a single breath-hold [18].
Current state-of-the-art
129Xe MRI methods have an excellent safety profile in patients with respiratory disease [21, 22], including asthma [23–25], COPD [16, 26–29], cystic fibrosis [30–32], pulmonary vascular disease [33], idiopathic pulmonary fibrosis [34, 35], lung cancer [36] and lymphangioleiomyomatosis [37].
In healthy volunteers, 29Xe gas distribution is typically highly homogeneous and gas signal fills the entire lung whereas in patients with lung disease such as in figure 1, focal MRI signal voids or ventilation defects and patchy gas distribution are often observed. Ventilation defects are commonly quantified as the ventilation defect percent (VDP) [38]: the volume of ventilation defects normalised to the thoracic cavity volume. In a similar manner, using diffusion-weighted MRI, the apparent diffusion coefficient (ADC), a measure of airspace enlargement, may be estimated. 129Xe ADC is low in healthy participants and increases with increasing airspace size and the extent of emphysema [16, 26]. Diffusion-weighted MRI may also be used to generate morphological airspace measurements [39, 40], for example mean linear intercept analogous to histology. Normalised biomarkers of the ratio of 129Xe dissolved in the tissue barrier and red blood cells [18] have been shown to be particularly relevant in pulmonary fibrosis. A unique feature of 129Xe MRI is that it provides a way to regionally quantify gas exchange [17, 41] in regions of the lung that are ventilated and models have been developed to extract subcomponents of gas exchange and structural measurements [42–44].
At the current time, 129Xe MRI is approved for clinical use in the UK and clinical approval is pending in the USA.
How is 129Xe MRI likely to be used in the future?
The infrastructure needed to enable 129Xe MRI is available in ∼12 respiratory imaging sites worldwide using a wide variety of different scanners, polarisers and coils. Whilst technical developments will enable faster 129Xe polarisation times and larger volumes of polarised gas, multicentre clinical trials are now poised to demonstrate the inter- and intra-site reproducibility of 129Xe MRI biomarkers so that clinical trials of new treatments and interventions using MRI may be powered. A comprehensive 129Xe examination (including localiser scan, anatomical scan, ventilation, diffusion-weighted, perfusion and gas exchange scans) in a patient may be easily performed within 15 min, often with patients inside the MRI bore for approximately 5 min and this is certainly compatible with current clinical imaging workflows.
Highly sensitive 129Xe MRI VDP promises therapy studies utilising smaller sample sizes to evaluate response to therapy. The broad array of 129Xe MRI biomarkers may provide endpoints for clinical trials of novel treatments for asthma, COPD, cystic fibrosis and especially pulmonary fibrosis. The spatially resolved functional information provided by 129Xe MRI may perhaps guide placement of endobronchial valves, which are currently guided using structural information from CT. Moreover, 129Xe MRI may provide a way to generate quantitative pathological evidence for treatment responses, for example following bronchial thermoplasty [45, 46] or novel biological treatments for asthma [47], where patients experience improved quality of life and reduced exacerbation frequency, often in the absence of improvements in forced expiratory volume in 1 s. Another valuable application of 129Xe MRI may be in the prediction of pulmonary exacerbations, which has been demonstrated using 3He MRI [48, 49]. Because 129Xe MRI appears to be more sensitive to ventilation abnormalities [23, 26], it is expected to also predict or explain pulmonary exacerbations of COPD, cystic fibrosis and asthma.
It remains difficult to predict response to treatment in many respiratory diseases, which is becoming increasingly important as novel, expensive therapies continue to be developed. Imaging phenotypes are widely recognised in COPD and pulmonary fibrosis, and the combination of available 129Xe MRI biomarkers may provide novel phenotypes to support regulatory and treatment decisions. Moreover, 129Xe MRI provides a regional map of lung structure-function that can be likened to a fingerprint or “lung-print”, to support individualised therapy decisions or n=1 studies in individual patients.
129Xe MRI is particularly invaluable for longitudinal monitoring of disease progression, disease phenotypes and/or treatment response (in and outside of clinical trials) because it poses no radiation burden on patients. The lack of ionising radiation is particularly needed for examinations in vulnerable populations, such as children with chronic lung disease.
In summary, 129Xe MRI provides rapid, sensitive, non-invasive and simultaneous measurements of pulmonary ventilation, lung tissue microstructure as well as diffusion within the alveolus and into the alveolar tissue and red blood cells, providing new opportunities to more deeply investigate lung diseases and unravel enigmas in respiratory medicine.
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Footnotes
Conflict of interest: R.L. Eddy has nothing to disclose.
Conflict of interest: G. Parraga has nothing to disclose.
- Received October 10, 2019.
- Accepted October 24, 2019.
- Copyright ©ERS 2020