Diffusion tensor MRI is sensitive to fibrotic injury in a mouse model of oxalate-induced chronic kidney disease.

Chronic kidney disease (CKD) is characterized by inflammation and fibrosis in the kidney. Renal biopsies and estimated glomerular filtration rate (eGFR) remain the standard of care, but these endpoints have limitations in detecting the stage, progression, and spatial distribution of fibrotic pathology in the kidney. MRI diffusion tensor imaging (DTI) has emerged as a promising noninvasive technology to evaluate renal fibrosis in vivo both in clinical and preclinical studies. However, these imaging studies have not systematically identified fibrosis particularly deeper in the kidney where biopsy sampling is limited, or completed an extensive analysis of whole organ histology, blood biomarkers, and gene expression to evaluate the relative strengths and weaknesses of MRI for evaluating renal fibrosis. In this study, we performed DTI in the sodium oxalate mouse model of CKD. The DTI parameters fractional anisotropy, apparent diffusion coefficient, and axial diffusivity were compared between the control and oxalate groups with region of interest (ROI) analysis to determine changes in the cortex and medulla. In addition, voxel-based analysis (VBA) was implemented to systematically identify local regions of injury over the whole kidney. DTI parameters were found to be significantly different in the medulla by both ROI analysis and VBA, which also spatially matched with collagen III immunohistochemistry (IHC). The DTI parameters in this medullary region exhibited moderate to strong correlations with histology, blood biomarkers, hydroxyproline, and gene expression. Our results thus highlight the sensitivity of DTI to the heterogeneity of renal fibrosis and importance of whole kidney noninvasive imaging.NEW & NOTEWORTHY Chronic kidney disease (CKD) can be characterized by inflammation and fibrosis of the kidney. Although standard of care methods have been limited in scope, safety, and spatial distribution, MRI diffusion tensor imaging (DTI) has emerged as a promising noninvasive technology to evaluate renal fibrosis in vivo. In this study, we performed DTI in an oxalate mouse model of CKD to systematically identify local kidney injury. DTI parameters strongly correlated with histology, blood biomarkers, hydroxyproline, and gene expression.

Preclinical MRI Using Hyperpolarized 129Xe.

Although critical for development of novel therapies, understanding altered lung function in disease models is challenging because the transport and diffusion of gases over short distances, on which proper function relies, is not readily visualized. In this review we summarize progress introducing hyperpolarized 129Xe imaging as a method to follow these processes in vivo. The work is organized in sections highlighting methods to observe the gas replacement effects of breathing (Gas Dynamics during the Breathing Cycle) and gas diffusion throughout the parenchymal airspaces (3). We then describe the spectral signatures indicative of gas dissolution and uptake (4), and how these features can be used to follow the gas as it enters the tissue and capillary bed, is taken up by hemoglobin in the red blood cells (5), re-enters the gas phase prior to exhalation (6), or is carried via the vasculature to other organs and body structures (7). We conclude with a discussion of practical imaging and spectroscopy techniques that deliver quantifiable metrics despite the small size, rapid motion and decay of signal and coherence characteristic of the magnetically inhomogeneous lung in preclinical models (8).

Multireader Determination of Clinically Significant Obstruction Using Hyperpolarized 129Xe-Ventilation MRI.

OBJECTIVE: The objective of our study was to identify the magnitude and distribution of ventilation defect scores (VDSs) derived from hyperpolarized (HP) 129Xe-MRI associated with clinically relevant airway obstruction. MATERIALS AND METHODS: From 2012 to 2015, 76 subjects underwent HP 129Xe-MRI (48 healthy volunteers [mean age ± SD, 54 ± 17 years]; 20 patients with asthma [mean age, 44 ± 20 years]; eight patients with chronic obstructive pulmonary disease [mean age, 67 ± 5 years]). All subjects underwent spirometry 1 day before MRI to establish the presence of airway obstruction (forced expiratory volume in 1 second-to-forced vital capacity ratio [FEV1/FVC] < 70%). Five blinded readers assessed the degree of ventilation impairment and assigned a VDS (range, 0-100%). Interreader agreement was assessed using the Fleiss kappa statistic. Using FEV1/FVC as the reference standard, the optimum VDS threshold for the detection of airway obstruction was estimated using ROC curve analysis with 10-fold cross-validation. RESULTS: Compared with the VDSs in healthy subjects, VDSs in patients with airway obstruction were significantly higher (p < 0.0001) and significantly correlated with disease severity (r = 0.66, p < 0.0001). Ventilation defects in subjects with airway obstruction did not show a location-specific pattern (p = 0.158); however, defects in healthy control subjects were more prevalent in the upper lungs (p = 0.014). ROC curve analysis yielded an optimal threshold of 12.4% ± 6.1% (mean ± SD) for clinically significant VDS. Interreader agreement for 129Xe-MRI was substantial (κ = 0.71). CONCLUSION: This multireader study of a diverse cohort of patients and control subjects suggests a 129Xe-ventilation MRI VDS of 12.4% or greater represents clinically significant obstruction.

Using hyperpolarized 129Xe MRI to quantify regional gas transfer in idiopathic pulmonary fibrosis.

BACKGROUND: Assessing functional impairment, therapeutic response and disease progression in patients with idiopathic pulmonary fibrosis (IPF) continues to be challenging. Hyperpolarized 129Xe MRI can address this gap through its unique capability to image gas transfer three-dimensionally from airspaces to interstitial barrier tissues to red blood cells (RBCs). This must be validated by testing the degree to which it correlates with pulmonary function tests (PFTs) and CT scores, and its spatial distribution reflects known physiology and patterns of disease. METHODS: 13 healthy individuals (33.6±15.7 years) and 12 patients with IPF (66.0±6.4 years) underwent 129Xe MRI to generate three-dimensional quantitative maps depicting the 129Xe ventilation distribution, its uptake in interstitial barrier tissues and its transfer to RBCs. For each map, mean values were correlated with PFTs and CT fibrosis scores, and their patterns were tested for the ability to depict functional gravitational gradients in healthy lung and to detect the known basal and peripheral predominance of disease in IPF. RESULTS: 129Xe MRI depicted functional impairment in patients with IPF, whose mean barrier uptake increased by 188% compared with the healthy reference population. 129Xe MRI metrics correlated poorly and insignificantly with CT fibrosis scores but strongly with PFTs. Barrier uptake and RBC transfer both correlated significantly with diffusing capacity of the lungs for carbon monoxide (r=-0.75, p<0.01 and r=0.72, p<0.01), while their ratio (RBC/barrier) correlated most strongly (r=0.94, p<0.01). RBC transfer exhibited significant anterior-posterior gravitational gradients in healthy volunteers, but not in IPF, where it was significantly impaired in the basal (p=0.02) and subpleural (p<0.01) lung. CONCLUSIONS: Hyperpolarized129Xe MRI is a rapid and well-tolerated exam that provides region-specific quantification of interstitial barrier thickness and RBC transfer efficiency. With further development, it could become a robust tool for measuring disease progression and therapeutic response in patients with IPF, sensitively and non-invasively.

Vagal innervation is required for pulmonary function phenotype in Htr4-/- mice.

Human genome-wide association studies have identified over 50 loci associated with pulmonary function and related phenotypes, yet follow-up studies to determine causal genes or variants are rare. Single nucleotide polymorphisms in serotonin receptor 4 (HTR4) are associated with human pulmonary function in genome-wide association studies and follow-up animal work has demonstrated that Htr4 is causally associated with pulmonary function in mice, although the precise mechanisms were not identified. We sought to elucidate the role of neural innervation and pulmonary architecture in the lung phenotype of Htr4-/- animals. We report here that the Htr4-/- phenotype in mouse is dependent on vagal innervation to the lung. Both ex vivo tracheal ring reactivity and in vivo flexiVent pulmonary functional analyses demonstrate that vagotomy abrogates the Htr4-/- airway hyperresponsiveness phenotype. Hyperpolarized 3He gas magnetic resonance imaging and stereological assessment of wild-type and Htr4-/- mice reveal no observable differences in lung volume, inflation characteristics, or pulmonary microarchitecture. Finally, control of breathing experiments reveal substantive differences in baseline breathing characteristics between mice with/without functional HTR4 in breathing frequency, relaxation time, flow rate, minute volume, time of inspiration and expiration and breathing pauses. These results suggest that HTR4's role in pulmonary function likely relates to neural innervation and control of breathing.

Establishing an accurate gas phase reference frequency to quantify 129 Xe chemical shifts in vivo.

PURPOSE: 129 Xe interacts with biological media to exhibit chemical shifts exceeding 200 ppm that report on physiology and pathology. Extracting this functional information requires shifts to be measured precisely. Historically, shifts have been reported relative to the gas-phase resonance originating from pulmonary airspaces. However, this frequency is not fixed-it is affected by bulk magnetic susceptibility, as well as Xe-N2 , Xe-Xe, and Xe-O2 interactions. In this study, we addressed this by introducing a robust method to determine the 0 ppm 129 Xe reference from in vivo data. METHODS: Respiratory-gated hyperpolarized 129 Xe spectra from the gas- and dissolved-phases were acquired in four mice at 2T from multiple axial slices within the thoracic cavity. Complex spectra were then fitted in the time domain to identify peaks. RESULTS: Gas-phase 129 Xe exhibited two distinct resonances corresponding to 129 Xe in conducting airways (varying from -0.6 ± 0.2 to 1.3 ± 0.3 ppm) and alveoli (relatively stable, at -2.2 ± 0.1 ppm). Dissolved-phase 129 Xe exhibited five reproducible resonances in the thorax at 198.4 ± 0.4, 195.5 ± 0.4, 193.9 ± 0.2, 191.3 ± 0.2, and 190.7 ± 0.3 ppm. CONCLUSION: The alveolar 129 Xe resonance exhibits a stable frequency across all mice. Therefore, it can provide a reliable in vivo reference frequency by which to characterize other spectroscopic shifts. Magn Reson Med 77:1438-1445, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Uncovering a third dissolved-phase 129 Xe resonance in the human lung: Quantifying spectroscopic features in healthy subjects and patients with idiopathic pulmonary fibrosis.

PURPOSE: The purpose of this work was to accurately characterize the spectral properties of hyperpolarized 129 Xe in patients with idiopathic pulmonary fibrosis (IPF) compared to healthy volunteers. METHODS: Subjects underwent hyperpolarized 129 Xe breath-hold spectroscopy, during which 38 dissolved-phase free induction decays (FIDs) were acquired after reaching steady state (echo time/repetition time = 0.875/50 ms; bandwidth = 8.06 kHz; flip angle≈22 °). FIDs were averaged and then decomposed into multiple spectral components using time-domain curve fitting. The resulting amplitudes, frequencies, line widths, and starting phases of each component were compared among groups using a Mann-Whitney-Wilcoxon U test. RESULTS: Three dissolved-phase resonances, consisting of red blood cells (RBCs) and two barrier compartments, were consistently identified in all subjects. In subjects with IPF relative to healthy volunteers, the RBC frequency was 0.70 parts per million (ppm) more negative (P = 0.05), the chemical shift of barrier 2 was 0.6 ppm more negative (P = 0.009), the line widths of both barrier peaks were ∼2 ppm narrower (P < 0.001), and the starting phase of barrier 1 was 20.3 ° higher (P = 0.01). Moreover, the ratio RBC:barriers was reduced by 52.9% in IPF (P < 0.001). CONCLUSIONS: The accurate decomposition of 129 Xe spectra not only has merit for developing a global metric of pulmonary function, but also provides necessary insights to optimize phase-sensitive methods for imaging 129 Xe gas transfer. Magn Reson Med 78:1306-1315, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

3D MRI of impaired hyperpolarized 129Xe uptake in a rat model of pulmonary fibrosis.

A variety of pulmonary pathologies, in particular interstitial lung diseases, are characterized by thickening of the pulmonary blood-gas barrier, and this thickening results in reduced gas exchange. Such diffusive impairment is challenging to quantify spatially, because the distributions of the metabolically relevant gases (CO2 and O2) cannot be detected directly within the lungs. Hyperpolarized (HP) (129)Xe is a promising surrogate for these metabolic gases, because MR spectroscopy and imaging allow gaseous alveolar (129)Xe to be detected separately from (129)Xe dissolved in the red blood cells (RBCs) and the adjacent tissues, which comprise blood plasma and lung interstitium. Because (129)Xe reaches the RBCs by diffusing across the same barrier tissues (blood plasma and interstitium) as O2, barrier thickening will delay (129)Xe transit and, thus, reduce RBC-specific (129)Xe MR signal. Here we have exploited these properties to generate 3D, MR images of (129)Xe uptake by the RBCs in two groups of rats. In the experimental group, unilateral fibrotic injury was generated prior to imaging by instilling bleomycin into one lung. In the control group, a unilateral sham instillation of saline was performed. Uptake of (129)Xe by the RBCs, quantified as the fraction of RBC signal relative to total dissolved (129)Xe signal, was significantly reduced (P = 0.03) in the injured lungs of bleomycin-treated animals. In contrast, no significant difference (P = 0.56) was observed between the saline-treated and untreated lungs of control animals. Together, these results indicate that 3D MRI of HP (129)Xe dissolved in the pulmonary tissues can provide useful biomarkers of impaired diffusive gas exchange resulting from fibrotic thickening.

Quantitative analysis of hyperpolarized 129Xe ventilation imaging in healthy volunteers and subjects with chronic obstructive pulmonary disease.

In this study, hyperpolarized (129) Xe MR ventilation and (1) H anatomical images were obtained from three subject groups: young healthy volunteers (HVs), subjects with chronic obstructive pulmonary disease (COPD) and age-matched controls (AMCs). Ventilation images were quantified by two methods: an expert reader-based ventilation defect score percentage (VDS%) and a semi-automated segmentation-based ventilation defect percentage (VDP). Reader-based values were assigned by two experienced radiologists and resolved by consensus. In the semi-automated analysis, (1) H anatomical images and (129) Xe ventilation images were both segmented following registration to obtain the thoracic cavity volume and ventilated volume, respectively, which were then expressed as a ratio to obtain the VDP. Ventilation images were also characterized by generating signal intensity histograms from voxels within the thoracic cavity volume, and heterogeneity was analyzed using the coefficient of variation (CV). The reader-based VDS% correlated strongly with the semi-automatically generated VDP (r = 0.97, p < 0.0001) and with CV (r = 0.82, p < 0.0001). Both (129) Xe ventilation defect scoring metrics readily separated the three groups from one another and correlated significantly with the forced expiratory volume in 1 s (FEV1 ) (VDS%: r = -0.78, p = 0.0002; VDP: r = -0.79, p = 0.0003; CV: r = -0.66, p = 0.0059) and other pulmonary function tests. In the healthy subject groups (HVs and AMCs), the prevalence of ventilation defects also increased with age (VDS%: r = 0.61, p = 0.0002; VDP: r = 0.63, p = 0.0002). Moreover, ventilation histograms and their associated CVs distinguished between subjects with COPD with similar ventilation defect scores, but visibly different ventilation patterns.

Generalized Linear Binning to Compare Hyperpolarized 129Xe Ventilation Maps Derived from 3D Radial Gas Exchange Versus Dedicated Multislice Gradient Echo MRI.

RATIONALE: Hyperpolarized 129Xe ventilation MRI is typically acquired using multislice fast gradient recalled echo (GRE), but interleaved 3D radial 129Xe gas transfer MRI now provides dissolved-phase and ventilation images from a single breath. To investigate whether these ventilation images provide equivalent quantitative metrics, we introduce generalized linear binning analysis. METHODS: This study included 36 patients who had undergone both multislice GRE ventilation and 3D radial gas exchange imaging. Images were then quantified by linear binning to classify voxels into one of four clusters: ventilation defect percentage (VDP), Low-, Medium- or High-ventilation percentage (LVP, MVP, HVP). For 3D radial images, linear binning thresholds were generalized using a Box-Cox rescaled reference histogram. We compared the cluster populations from the two ventilation acquisitions both numerically and spatially. RESULTS: Interacquisition Bland-Altman limits of agreement for the clusters between 3D radial vs GRE were (-7% to 5%) for VDP, (-10% to 14%) for LVP, and (-8% to 8%) for HVP. While binning maps were qualitatively similar between acquisitions, their spatial overlap was modest for VDP (Dice = 0.5 ± 0.2), and relatively poor for LVP (0.3 ± 0.1) and HVP (0.2 ± 0.1). CONCLUSION: Both acquisitions yield reasonably concordant VDP and qualitatively similar maps. However, poor regional agreement (Dice) suggests that the two acquisitions cannot yet be used interchangeably. However, further improvements in 3D radial resolution and reconciliation of bias field correction may well obviate the need for a dedicated ventilation scan in many cases.

Quantitative 129Xe MRI detects early impairment of gas-exchange in a rat model of pulmonary hypertension.

Hyperpolarized 129Xe magnetic resonance imaging (MRI) is capable of regional mapping of pulmonary gas-exchange and has found application in a wide range of pulmonary disorders in humans and animal model analogs. This study is the first application of 129Xe MRI to the monocrotaline rat model of pulmonary hypertension. Such models of preclinical pulmonary hypertension, a disease of the pulmonary vasculature that results in right heart failure and death, are usually assessed with invasive procedures such as right heart catheterization and histopathology. The work here adapted from protocols from clinical 129Xe MRI to enable preclinical imaging of rat models of pulmonary hypertension on a Bruker 7 T scanner. 129Xe spectroscopy and gas-exchange imaging showed reduced 129Xe uptake by red blood cells early in the progression of the disease, and at a later time point was accompanied by increased uptake by barrier tissues, edema, and ventilation defects-all of which are salient characteristics of the monocrotaline model. Imaging results were validated by H&E histology, which showed evidence of remodeling of arterioles. This proof-of-concept study has demonstrated that hyperpolarized 129Xe MRI has strong potential to be used to non-invasively monitor the progression of pulmonary hypertension in preclinical models and potentially to also assess response to therapy.

Applications of 3D printing in small animal magnetic resonance imaging.

Three-dimensional (3D) printing has significantly impacted the quality, efficiency, and reproducibility of preclinical magnetic resonance imaging. It has vastly expanded the ability to produce MR-compatible parts that readily permit customization of animal handling, achieve consistent positioning of anatomy and RF coils promptly, and accelerate throughput. It permits the rapid and cost-effective creation of parts customized to a specific imaging study, animal species, animal weight, or even one unique animal, not routinely used in preclinical research. We illustrate the power of this technology by describing five preclinical studies and specific solutions enabled by different 3D printing processes and materials. We describe fixtures, assemblies, and devices that were created to ensure the safety of anesthetized lemurs during an MR examination of their brain or to facilitate localized, contrast-enhanced measurements of white blood cell concentration in a mouse model of pancreatitis. We illustrate expansive use of 3D printing to build a customized birdcage coil and components of a ventilator to enable imaging of pulmonary gas exchange in rats using hyperpolarized Xe 129 . Finally, we present applications of 3D printing to create high-quality, dual RF coils to accelerate brain connectivity mapping in mouse brain specimens and to increase the throughput of brain tumor examinations in a mouse model of pituitary adenoma.

A portable ventilator with integrated physiologic monitoring for hyperpolarized 129Xe MRI in rodents.

Hyperpolarized (HP) 129Xe MRI is emerging as a powerful, non-invasive method to image lung function and is beginning to find clinical application across a range of conditions. As clinical implementation progresses, it becomes important to translate back to well-defined animal models, where novel disease signatures can be characterized longitudinally and validated against histology. To date, preclinical 129Xe MRI has been limited to only a few sites worldwide with 2D imaging that is not generally sufficient to fully capture the heterogeneity of lung disease. To address these limitations and facilitate broader dissemination, we report on a compact and portable HP gas ventilator that integrates all the gas-delivery and physiologic monitoring capabilities required for high-resolution 3D hyperpolarized 129Xe imaging. This ventilator is MR- and HP-gas compatible, driven by inexpensive microcontrollers and open source code, and allows for precise control of the tidal volume and breathing cycle in perorally intubated mice and rats. We use the system to demonstrate data acquisition over multiple breath-holds, during which lung motion is suspended to enable high-resolution 3D imaging of gas-phase and dissolved-phase 129Xe in the lungs. We demonstrate the portability and versatility of the ventilator by imaging a mouse model of lung cancer longitudinally at 2 Tesla, and a healthy rat at 7 Tesla. We also report the detection of subtle spectroscopic fluctuations in phase with the heart rate, superimposed onto larger variations stemming from the respiratory cycle. This ventilator was developed to facilitate duplication and gain broad adoption to accelerate preclinical 129Xe MRI research.

Hyperpolarized 129Xenon Magnetic Resonance Imaging to Quantify Regional Ventilation Differences in Mild to Moderate Asthma: A Prospective Comparison Between Semiautomated Ventilation Defect Percentage Calculation and Pulmonary Function Tests.

OBJECTIVES: The aim of this study was to investigate ventilation in mild to moderate asthmatic patients and age-matched controls using hyperpolarized (HP) Xenon magnetic resonance imaging (MRI) and correlate findings with pulmonary function tests (PFTs). MATERIALS AND METHODS: This single-center, Health Insurance Portability and Accountability Act-compliant prospective study was approved by our institutional review board. Thirty subjects (10 young asthmatic patients, 26 ± 6 years; 3 males, 7 females; 10 older asthmatic patients, 64 ± 6 years; 3 males, 7 females; 10 healthy controls) were enrolled. After repeated PFTs 1 week apart, the subjects underwent 2 MRI scans within 10 minutes, inhaling 1-L volumes containing 0.5 to 1 L of Xe. Xe ventilation signal was quantified by linear binning, from which the ventilation defect percentage (VDP) was derived. Differences in VDP among subgroups and variability with age were evaluated using 1-tailed t tests. Correlation of VDP with PFTs was tested using Pearson correlation coefficient. Reproducibility of VDP was assessed using Bland-Altman plots, linear regression (R), intraclass correlation coefficient, and concordance correlation coefficient. RESULTS: Ventilation defect percentage was significantly higher in young asthmatic patients versus young healthy subjects (8.4% ± 3.2% vs 5.6% ± 1.7%, P = 0.031), but not in older asthmatic patients versus age-matched controls (16.8% ± 10.3% vs 11.6% ± 6.6%, P = 0.13). Ventilation defect percentage was found to increase significantly with age (healthy, P = 0.05; asthmatic patients, P = 0.033). Ventilation defect percentage was highly reproducible (R = 0.976; intraclass correlation coefficient, 0.977; concordance correlation coefficient, 0.976) and significantly correlated with FEV1% (r = -0.42, P = 0.025), FEF25%-75% (r = -0.45, P = 0.019), FEV1/FVC (r = -0.71, P < 0.0001), FeNO (r = 0.69, P < 0.0001), and RV/TLC (r = 0.51, P = 0.0067). Bland-Altman analysis showed a bias for VDP of -0.88 ± 1.52 (FEV1%, -0.33 ± 7.18). CONCLUSIONS: Xenon MRI is able to depict airway obstructions in mild to moderate asthma and significantly correlates with PFTs.

Quantitative analysis of hyperpolarized 129 Xe gas transfer MRI.

PURPOSE: Hyperpolarized 129 Xe magnetic resonance imaging (MRI) using Dixon-based decomposition enables single-breath imaging of 129 Xe in the airspaces, interstitial barrier tissues, and red blood cells (RBCs). However, methods to quantitatively visualize information from these images of pulmonary gas transfer are lacking. Here, we introduce a novel method to transform these data into quantitative maps of pulmonary ventilation, and 129 Xe gas transfer to barrier and RBC compartments. METHODS: A total of 13 healthy subjects and 12 idiopathic pulmonary fibrosis (IPF) subjects underwent thoracic 1 H MRI and hyperpolarized 129 Xe MRI with one-point Dixon decomposition to obtain images of 129 Xe in airspaces, barrier and red blood cells (RBCs). 129 Xe images were processed into quantitative binning maps of all three compartments using thresholds based on the mean and standard deviations of distributions derived from the healthy reference cohort. Binning maps were analyzed to derive quantitative measures of ventilation, barrier uptake, and RBC transfer. This method was also used to illustrate different ventilation and gas transfer patterns in a patient with emphysema and one with pulmonary arterial hypertension (PAH). RESULTS: In the healthy reference cohort, the mean normalized signals were 0.51 ± 0.19 for ventilation, 4.9 ± 1.5 x 10-3 for barrier uptake and 2.6 ± 1.0 × 10-3 for RBC (transfer). In IPF patients, ventilation was similarly homogenous to healthy subjects, although shifted toward slightly lower values (0.43 ± 0.19). However, mean barrier uptake in IPF patients was nearly 2× higher than in healthy subjects, with 47% of voxels classified as high, compared to 3% in healthy controls. Moreover, in IPF, RBC transfer was reduced, mainly in the basal lung with 41% of voxels classified as low. In healthy volunteers, only 15% of RBC transfer was classified as low and these voxels were typically in the anterior, gravitationally nondependent lung. CONCLUSIONS: This study demonstrates a straightforward means to generate semiquantitative binning maps depicting 129 Xe ventilation and gas transfer to barrier and RBC compartments. These initial results suggest that the method could be valuable for characterizing both normal physiology and pathophysiology associated with a wide range of pulmonary disorders.

Dose and pulse sequence considerations for hyperpolarized (129)Xe ventilation MRI.

PURPOSE: The aim of this study was to evaluate the effect of hyperpolarized (129)Xe dose on image signal-to-noise ratio (SNR) and ventilation defect conspicuity on both multi-slice gradient echo and isotropic 3D-radially acquired ventilation MRI. MATERIALS AND METHODS: Ten non-smoking older subjects (ages 60.8±7.9years) underwent hyperpolarized (HP) (129)Xe ventilation MRI using both GRE and 3D-radial acquisitions, each tested using a 71ml (high) and 24ml (low) dose equivalent (DE) of fully polarized, fully enriched (129)Xe. For all images SNR and ventilation defect percentage (VDP) were calculated. RESULTS: Normalized SNR (SNRn), obtained by dividing SNR by voxel volume and dose was higher for high-DE GRE acquisitions (SNRn=1.9±0.8ml(-2)) than low-DE GRE scans (SNRn=0.8±0.2ml(-2)). Radially acquired images exhibited a more consistent, albeit lower SNRn (High-DE: SNRn=0.5±0.1ml(-2), low-DE: SNRn=0.5±0.2ml(-2)). VDP was indistinguishable across all scans. CONCLUSIONS: These results suggest that images acquired using the high-DE GRE sequence provided the highest SNRn, which was in agreement with previous reports in the literature. 3D-radial images had lower SNRn, but have advantages for visual display, monitoring magnetization dynamics, and visualizing physiological gradients. By evaluating normalized SNR in the context of dose-equivalent formalism, it should be possible to predict (129)Xe dose requirements and quantify the benefits of more efficient transmit/receive coils, field strengths, and pulse sequences.

Extending semiautomatic ventilation defect analysis for hyperpolarized (129)Xe ventilation MRI.

RATIONALE AND OBJECTIVES: Clinical deployment of hyperpolarized (129)Xe magnetic resonance imaging requires accurate quantification and visualization of the ventilation defect percentage (VDP). Here, we improve the robustness of our previous semiautomated analysis method to reduce operator dependence, correct for B1 inhomogeneity and vascular structures, and extend the analysis to display multiple intensity clusters. MATERIALS AND METHODS: Two segmentation methods were compared-a seeded region-growing method, previously validated by expert reader scoring, and a new linear-binning method that corrects the effects of bias field and vascular structures. The new method removes nearly all operator interventions by rescaling the (129)Xe magnetic resonance images to the 99th percentile of the cumulative distribution and applying fixed thresholds to classify (129)Xe voxels into four clusters: defect, low, medium, and high intensity. The methods were applied to 24 subjects including patients with chronic obstructive pulmonary disease (n = 8), age-matched controls (n = 8), and healthy normal subjects (n = 8). RESULTS: Linear-binning enabled a faster and more reproducible workflow and permitted analysis of an additional 0.25 ± 0.18 L of lung volume by accounting for vasculature. Like region-growing, linear-binning VDP correlated strongly with reader scoring (R(2) = 0.93, P < .0001), but with less systematic bias. Moreover, linear-binning maps clearly depict regions of low and high intensity that may prove useful for phenotyping subjects with chronic obstructive pulmonary disease. CONCLUSIONS: Corrected linear-binning provides a robust means to quantify (129)Xe ventilation images yielding VDP values that are indistinguishable from expert reader scores, while exploiting the entire dynamic range to depict multiple image clusters.

Probing the regional distribution of pulmonary gas exchange through single-breath gas- and dissolved-phase 129Xe MR imaging.

Although some central aspects of pulmonary function (ventilation and perfusion) are known to be heterogeneous, the distribution of diffusive gas exchange remains poorly characterized. A solution is offered by hyperpolarized 129Xe magnetic resonance (MR) imaging, because this gas can be separately detected in the lung's air spaces and dissolved in its tissues. Early dissolved-phase 129Xe images exhibited intensity gradients that favored the dependent lung. To quantitatively corroborate this finding, we developed an interleaved, three-dimensional radial sequence to image the gaseous and dissolved 129Xe distributions in the same breath. These images were normalized and divided to calculate "129Xe gas-transfer" maps. We hypothesized that, for healthy volunteers, 129Xe gas-transfer maps would retain the previously observed posture-dependent gradients. This was tested in nine subjects: when the subjects were supine, 129Xe gas transfer exhibited a posterior-anterior gradient of -2.00 ± 0.74%/cm; when the subjects were prone, the gradient reversed to 1.94 ± 1.14%/cm (P < 0.001). The 129Xe gas-transfer maps also exhibited significant heterogeneity, as measured by the coefficient of variation, that correlated with subject total lung capacity (r = 0.77, P = 0.015). Gas-transfer intensity varied nonmonotonically with slice position and increased in slices proximal to the main pulmonary arteries. Despite substantial heterogeneity, the mean gas transfer for all subjects was 1.00 ± 0.01 while supine and 1.01 ± 0.01 while prone (P = 0.25), indicating good "matching" between gas- and dissolved-phase distributions. This study demonstrates that single-breath gas- and dissolved-phase 129Xe MR imaging yields 129Xe gas-transfer maps that are sensitive to altered gas exchange caused by differences in lung inflation and posture.