Structural and functional pulmonary magnetic resonance imaging

By Aditya Daftary, MBBS
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Dr. Daftary is a second-year Resident in Radiology at Yale University Medical Center, New Haven, CT. He graduated from Dr. D.Y. Patil Medical College, Bombay University, India in 1998. Since then, he has completed a Nuclear Medicine Residency at Yale. He plans to begin a Fellowship in Musculoskeletal Imaging following completion of his residency.

There are 2 major components of lung function, ventilation and perfusion, which are traditionally evaluated with a combination of chest radiography, computed tomography (CT), ventilation-perfusion scintigraphy (VQ), and spirometry. Magnetic resonance imaging (MRI) has been used for imaging both structure and function in many other parts of the body. The purpose of this article is to review the technical aspects and briefly describe the role of pulmonary MRI in clinical imaging.

The growth of pulmonary MRI has been limited by at least 3 obstacles: 1) inflated normal lungs consist of approximately 20% water and 80% air, leading to low proton-density and MR signals; 2) macroscopic (cardiac and respiratory) and microscopic (blood perfusion and thermal diffusion) motion limits the resolution of images obtained by using longer conventional spin and gradient-echo sequences; and 3) the differing diamagnetic properties of air and water result in an inhomogeneous magnetic field. These latter 2 factors decrease the T2* to approximately 2 msec, and, collectively, all three make imaging challenging. Nevertheless, technical advances have largely overcome these obstacles.

MRI techniques for pulmonary imaging include perfusion imaging, with and without contrast agents; structural vascular imaging with MR pulmonary angiography (MRA); time-of-flight (TOF) imaging; and ventilation imaging using hyperpolarized gases, oxygen or sulfur hexafluoride (SF 6 ).

Perfusion imaging

There are 2 major techniques for MR perfusion imaging: First-pass contrast agent techniques and arterial spin labeling (ASL) techniques.

First-pass contrast agent technique

Two-dimensional (2D) T1-weighted ultrashort repetition time (TR) (approximately 6 msec) and echo time (TE) MRI with contrast agent forms the basis of pulmonary perfusion imaging. A short TE (approximately 1.3 to 1.4 msec) is necessary to overcome the inhomogeneous magnetic susceptibility of the lung, which becomes more evident with longer TEs. Three-dimensional (3D) techniques have been used to obtain datasets of the entire pulmonary tree within seconds. Images are obtained after the administration of a low dose of contrast (5 mL); the pulmonary arterial tree distal to the subsegmental branches followed by a gradual diffuse increase in signal intensity in the pulmonary parenchyma is seen (Figure 1). 1

Arterial spin labeling

In ASL techniques, saturation, spatial, or adiabatic inversion pulses are applied to water molecules outside the imaging field, and their signal is imaged as they enter the field. 3 The small signal differences between ASL and control images are detected on a difference image. This reflects tissue perfusion and forms the basis of echoplanar imaging signal targeting with alternating frequency (EPISTAR) (Figure 2). 4

The spin-labeling pulse is applied at the level of the pulmonary arteries, and imaging is performed over the lungs. Continuous arterial spin labeling (CASL) techniques establish a steady state of spin labeling, allowing for steady-state acquisitions with respiratory triggering. Pulsed arterial spin labeling (PASL) techniques result in intermittent spin labeling, and so steady-state acquisitions are not entirely possible. Imaging using PASL techniques requires the use of breath-holding and cardiac gating. 6

Spin-labeling techniques are inherently sensitive to changes in both perfusion as well as blood volume, and high-resolution perfusion maps of the lungs can be obtained. They obviate the need for exogenous contrast agent administration and have the advantage of providing perfusion quantification, because temporal image degradation seen with MRA is not seen. 7 ASL perfusion maps, however, are not entirely accurate, as water molecules are labeled outside the imaging slice, and there is signal loss during the transit time between labeling and imaging. The signal loss cannot be accurately quantified due to different vascular paths, which vary transit times unpredictably.

Pulmonary vascular imaging

Pulmonary MR angiography

Gadolinium chelate paramagnetic agents are used for pulmonary MRA. Gadolinium shortens the T1 relaxation time allowing the use of fast 3D gra-dient-echo sequences, which have very short TE and TR. Gadolinium increases the vessel-to-background contrast-to-noise ratios and mitigates flow artifacts. It also has the advantage of causing fewer adverse reactions compared with iodinated contrast agents used in CT angiography. 8

The MRA sequence should be a rapid T1-weighted sequence with small voxel size, which covers the vascular system under consideration. Three-dimensional gradient-recalled echo (GRE) sequences with rapid radiofrequency (RF) pulses are ideal for this. Short TR and TE sequences are used (TR <2 msec, TE <1 msec); however, it has not been possible to entirely implement this on existing clinical systems. Rapid imaging sequences allow for quick serial data acquisition, which can be used in perfusion imaging (Figure 1).

K-space phase ordering methods have also improved image quality. Centric k-space ordering methods acquire essential data for image interpretation at the beginning of the acquisition as opposed to conventional methods, which place this data in the middle of the acquisition; thus reducing motion artifacts. 9 Gadolinium-enhanced pulmonary MRA provides excellent depiction of pulmonary perfusion, but results in venous enhancement that limits the use of this technique in assessing dynamic aspects of perfusion.

Time-of-flight imaging

Two-dimensional and 3D TOF techniques have also been used to image pulmonary vasculature. 10 These methods depend on blood flow to produce contrast between vessels and surrounding tissues, and have been used to evaluate the vasculature (Figure 3). 10 The techniques are limited by longer than optimal TR and TE, which lead to increased image degradation from motion and air-tissue interfaces and are now seldom used.

Ventilation imaging

Hyperpolarized gas imaging

Inert gases, such as helium 3 (He-3) and xenon 129 (Xe-129), can be polarized by using high-intensity laser illumination. The resulting polarization produces an MRI signal that is far greater than the signal produced by proton MRI. Broadband MRI systems (such as those used for spectroscopy) and special RF coils are used for imaging hyperpolarized gases. The nuclear magnetic moments (µ) for He-3 and Xe-129 are lower than those of hydrogen 1 (H-1), and resonant frequencies of 48.7 MHz and 17.6 MHz, respectively, are used for them at 1.5T, as opposed to 63.9 MHz for H-1. 12,13 Since there is no recoverable polarization, multiple short TR sequences are applied to obtain complete images of the lungs in a single breath-hold while conserving the magnetization available from the gas. 13

Briefly, there are 2 major methods of hyperpolarization: 1) optical pumping and spin exchange, in which rubidium atoms are polarized by using a circularly polarized laser light and the polarization is transferred to either He-3 or Xe-129 by a process called collisional spin exchange (Figure 4); and 2) metastability exchange, in which a layer of metastable He-3 atoms is created by laser illumination and adjacent He-3 atoms are polarized by collisional spin exchange. 14 The differences between He-3 and Xe-129 are summarized in Table 1. Due to the numerous differences between hyperpolarized gas imaging and conventional proton MR, there are different conditions for imaging them (Table 2). 14

There are 4 approaches to hyperpolarized gas imaging: static, dynamic, diffusion, and intrapulmonary oxygen (O 2 ) imaging.

Static imaging- Short TR and TE sequences with initial low flip angle and 10-mm section thickness are adequate for imaging the lungs in a single breath-hold of 10 to 20 seconds. Normally ventilated lungs show homogeneous distribution of signal. Areas that have poor or absent ventilation, such as areas of airway destruction or obstruction, do not show signal. Signal is also not obtained from areas that have increased oxygen concentration, which hastens gas depolarization. Static imaging is limited in providing information about areas of air trapping, which is useful in evaluating chronic obstructive pulmonary disease (COPD) (Figure 5). 15

Dynamic imaging- The key to dynamic ventilation pulmonary imaging is balancing temporal and spatial resolution while conserving the fixed magnetization available from the inhaled hyperpolarized gas. Low flip angle gradient-echo sequences allow for inspiratory and expiratory imaging but have limited spatial and temporal resolution as more RF pulses are required and only a single line of k-space is filled per excitation. 15 Echoplanar imaging (EPI) sequences require fewer RF pulses and have excellent temporal resolution. However, their spatial resolution is limited to about 5 mm due to the high diffusion coefficient and relatively short T2* of these gases at 1.5T. Interleaved spiral pulse sequences are preferred as they represent a compromise between conventional gradient-echo imaging and EPI by limiting the number of RF pulses and motion artifact (Figure 6). 17

Diffusion imaging- Hyperpolarized gases, particularly He-3, have a diffusion coefficient larger than water and have displacements of up to a few millimeters in unrestricted spaces during the TE used in gradient-echo sequences for lung imaging. In more confined distal airways, displacements are smaller, resulting in a lower apparent diffusion coefficient (ADC) measured by MRI. Normal lungs show relatively uniform diffusion values with a low mean ADC, while patients with emphysema have increased and inhomogeneous ADC values. 19 Diffusion imaging provides us with the opportunity to indirectly study lung microstructure (Figure 7).

Intrapulmonary oxygen concentration imaging- Hyperpolarized gases have a greater rate of depolarization in the presence of molecular oxy-gen. 20 The primary mechanisms of loss of hyperpolarization are the application of RF pulses and the presence of molecular oxygen. Intrapulmonary oxygen concentration can be determined from the rate of magnetization decay in successive images obtained by varying the RF pulse flip angle or interimage delay time. At present, these factors cannot be varied during a single breath-hold, hence there are difficulties in reproducing lung position in successive breath-holds. 21

Oxygen imaging

Oxygen is a weakly paramagnetic agent that affects the magnetic properties of the lung primarily due to its large surface area of distribution. Oxygen shortens T1 with an increase in its concentration in the air spaces and blood vessels. Alternately breathing room air (20% oxygen) and 100% oxygen results induces T1 shortening and a 20% to 30% signal change, which can be detected with inversion recovery or multiple inversion recovery (MIR) sequences. Average images during room air and 100% oxygen inhalation are subtracted to obtain qualitative oxygen enhanced ventilation maps. This method is also a means to study gas exchange from alveoli to the pulmonary vasculature (Figure 8). 22,23

Sulfur hexafluoride imaging

Sulfur hexafluoride (SF 6 ) has low blood solubility and high density and has been used to study gas distribution in the lung. The most abundant isotope of fluorine ( 19 F), 25 SF 6 has a spin of - 1 ⁄2 and is seen with MRI: SF 6 can be imaged at equilibrium with repeated RF pulses. 25 This method has not been used in humans as yet (Figure 9). The techniques for pulmonary MRI are summarized in Figure 10.

Clinical applications

Perfusion and vascular imaging

Mediastinal veins-- Thrombo-occlusive disease of the thoracic veins accounts for significant morbidity in patients with in-dwelling catheters, coagulopathies, and underlying malignancies. The veins can be imaged without contrast using 2D and 3D TOF methods, which are limited by long acquisition times and associated artifacts. 26 Better images are obtained by using intravenous gadolinium either directly with first-pass imaging after injection into the affected extremity 27 or indirectly after injection into the antecubital vein of the nonaffected extremity and imaging during equilib-rium. 28 The latter method requires larger quantities of contrast but overcomes the difficulty of injecting into a swollen extremity. MR venography has been found to be extremely sensitive and specific for the evaluation of central thoracic veins with the advantage of imaging a larger field-of-view for a more comprehensive overview of the veins. 10,28

Pulmonary vasculature

Pulmonary hypertension is characterized by increased pulmonary artery pressure, which may be idiopathic or secondary to congenital heart disease, coagulopathies, COPD, and so forth. It has been noted that patients with severe pulmonary hypertension who are imaged with axial dual spin-echo MRI with cardiac gating have increased signal in the pulmonary arteries, and the signal in the right pulmonary artery correlates directly with vascular resistance. 29 Dilated central pulmonary arteries with attenuated peripheral vessels and loss of the normal systolic-diastolic distension and collapse of the right pulmonary artery are also seen on MRI. 29

MRA is excellent for evaluating structural vascular abnormalities. Contrast-enhanced MRA has been used to image vasculitides, such as Takayasu's arteritis and Behçet's disease, that are characterized by pulmonary arterial aneurysms and vascular malformations that may affect the pulmonary arteries. If thrombosed, these malformations may be missed at conventional angiography. 30 Pulmonary arteriovenous malformations in conditions, such as hereditary hemorrhagic telangiectasia, are also seen using gadolinium-enhanced MRA. They are poorly seen on spin-echo images due to flow-related signal void, but are clearly seen on breath-hold cine gradient-echo images (Figure 11). 1,30 MR has also been useful in characterizing rare pulmonary arterial diseases, such as sarcoma and dissection. 30 Congenital conditions, such as total and partial anomalous pulmonary venous connection are seen in 96% to 100% of the time on MRA. 30

Pulmonary embolism

Pulmonary embolism remains an underdiagnosed and potentially fatal disease that accounts for approximately 50,000 deaths per year. 31 Multiple imaging methods, including ventilation perfusion scintigraphy, CT pulmonary angiography, and conventional pulmonary angiography, have been used to diagnose this, each with known limitations. MRI provides the advantage of imaging pulmonary emboli without ionizing radiation and providing ventilatory information. 23,32 Initial studies with spin-echo MRI showed thrombi as low or intermediate signal areas, which are mimicked by slow-flow states. Gradient-echo imaging techniques are more sensitive to flow and have fewer slow-flow artifacts. Three-dimensional gadolini-um-enhanced pulmonary MRA with perfusion imaging is most sensitive, and detailed pulmonary vascular anatomy, including subsegmental vessels and perfusion patterns, can be seen (Figure 12). 32 Ventilation imaging with 100% oxygen and perfusion imaging with ASL have been used as a noninvasive approach to ventilation-perfusion imaging (Figure 8). 22,23

Ventilation imaging

Static imaging

Excellent resolution of the pulmonary air spaces is now possible with the use of single breath-hold hyperpolarized gas MRI. These images are representative of the ventilation pattern in the lungs of healthy subjects imaged when positioned supine; there is preferential ventilation posteriorly with scattered ventilation defects (>2 cm diameter) from dependent atelectasis (Figure 5). 15

Smoking is known to cause chronic inflammation, resulting in significant airway damage. The changes affect the smaller respiratory bronchioles at first and may not produce significant changes in the mean forced expiratory volume in the first second (FEV 1 ). Asymptomatic smokers with normal FEV 1 have been found to have more ventilation defects than healthy nonsmokers, showing that hyperpolarized gas MRI is extremely sensitive in detecting early airway disease. 33

Mucous plugging, chronic infection, and bronchial wall thickening are the hallmarks of cystic fibrosis. These lead to bronchiectasis and impaired ventilation of distal air spaces. In studies performed on patients with cystic fibrosis, images obtained after inhalation of hyperpolarized gas show far more defects than expected from the morphologic abnormalities seen on proton-density images. Thus, MRI with hyperpolarized gases may have utility in the early detection of changes and monitoring disease progression (Figure 5). 34

Asthma is characterized by hypersensitivity of the airways, which causes airway inflammation and reversible obstruction. Hyperpolarized gas MRI is extremely sensitive to these changes and can detect areas of abnormal ventilation even in asymptomatic patients. Resolution of the areas of obstruction after bronchodilator therapy has been documented (Figure 5). 35

Chronic rejection of lung transplants is manifested by bronchiolitis obliterans, a slow process that may be asymptomatic and undetected by CT. Ventilation studies using hyperpolarized gas MRI have shown multiple filling defects in these patients and performed better than ventilation perfusion scintigraphy. 36 Early detection of this process may facilitate prompt treatment and prolonged transplant survival.

More recently, various sequences have been used to study models of lung inflammation. These authors have postulated a correlation between the various components of inflammation and changes in the appearance of the MRI signal. 37,38

Dynamic imaging

Studies with dynamic imaging of hyperpolarized gases have shown that functional ventilation can be directly assessed. There is rapid wash-in, wash-out, and uniform distribution of the gas in healthy subjects. Smokers with centrilobular emphysema show nonuniform distribution of the gas initially, which becomes uniform with rebreathing and shows air trapping in abnormal areas during expiration wash-out. 17 This overcomes the limitation of static imaging, which is unable to detect air trapping. Dynamic imaging has also been used in the evaluation of cystic fibrosis, interstitial pulmonary fibrosis, and lung transplants (Figure 6).

Diffusion imaging

Healthy volunteers show homogeneous diffusion and ADCs with relatively low variation. Patients with emphysema have inhomogeneous diffusion with centrilobular distribution and heterogeneous ADC values with greater variation. Diffusion changes correlate well with pulmonary function tests (Figure 7). 19

In the developing human lung, alveolar number remains stable from approximately 8 years of age, and subsequent lung growth is due to enlargement of the alveoli. Recent diffusion studies confirm this finding by showing an increase in mean ADCs of older patients, but no significant change in the air space variability. 39 Pulmonary diffusion imaging is a novel approach to imaging lung microstructure in vivo and may help detect developmental lung abnormalities.

Intrapulmonary oxygen concentration imaging

Intrapulmonary oxygen concentration can be quantified based on the rate of decay of the T1 signal of hyperpolarized gas. The initial oxygen concentration in the lung also correlates well with the rate of magnetization decay. Because changes in ventilation and perfusion affect the oxygen concentration in the lungs, this is a novel, noninvasive approach to imaging pulmonary oxygenation. 21

Conclusion

Novel imaging techniques have helped overcome obstacles to pulmonary MRI, and we now have reliable, reproducible methods for structural and functional imaging of the lungs. While MRI has been found to be extremely sensitive in early detection of ventilation changes, the treatment implications of these findings are not completely understood, and this is likely to be the greatest obstacle to incorporating pulmonary MRI into clinical imaging.

Acknowledgment

The author thanks Dr. Jeffrey Weinreb for his guidance in writing this paper.

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Structural and functional pulmonary magnetic resonance imaging.  Appl Radiol. 

January 20, 2005
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