Pulmonary xenon-129 MRI: new opportunities to unravel enigmas in respiratory medicine

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.

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FIGURE 1

Xenon-129 magnetic resonance imaging (MRI) infrastructure requirements and image acquisition. a) ¹²⁹Xe hyperpolariser, gas delivery bag, radiofrequency coils (flexible vest and rigid birdcage), and patient set-up for MRI. b) ¹²⁹Xe gas (cyan), anatomical proton (¹H), and computed tomography (CT) airway (yellow) images co-registered, with ¹²⁹Xe gas, tissue plus plasma and red blood cell (RBC) spectrum.

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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