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Clinical Research

Asthma

Investigating the causes of ventilation defects may provide insights into the spectrum of obstructive mechanisms underlying the heterogeneity of asthma. We are applying hyperpolarized (HP) gas MRI in conjunction with CT to advance the understanding of asthma. Regions of the lung that are poorly ventilated due to airway obstruction ("ventilation defects") are characteristic of asthma, but the manifestation of local obstructive mechanisms associated with these defects is not well understood. Using CT to spatially locate ventilation defects observed on HP MRI enables targeted sampling of airways leading to ventilation defects (and to well-ventilated control sites) in order to assess the pathophysiological changes associated with localized airway obstruction.


Figure: An airway tree derived from CT is combined with an HP MRI image with a prominent ventilation defect selected as target site for sampling, illustrating how the two modalities viewed in conjunction facilitate the anatomical location of defects and the study of structure-function relationships in the progression of disease.

Ventilation Defects

HP gas MRI has been used extensively in research for evaluating ventilation and defect in obstructive pulmonary disease. A semiautomated quantification method has been developed, validated and used at our site to establish the ventilation defect percent (VDP). This measure of whole lung or regional defect burden is being developed as a functional biomarker of obstructive disease. The figure below shows typical examples of axial mid-lung 3He images for different subjects with defect outlines color-coded by lobes. The lobar segmentation was done using multidetector computed tomography (MDCT).


Figure: Examples of detected ventilation defect boundaries in lobes (RUL-green, RML-yellow, RLL-cyan, LUL-magenta, LLL-red) for four subjects.

A better understanding of these phenomena may help researchers refine models of disease phenotypes, evaluate response to therapies, and predict severe clinical outcomes of this widespread and costly disease.

The Pulmonary and Metabolic Imaging Center also supports fundamental investigations of lung physiology in basic research and pre-clinical models. Many of our MRI tools for imaging regional structure and function can be applied with equal facility to pre-clinical and clinical studies helping to translate findings in controlled pre-clinical experiments.

Idiopathic Pulmonary Fibrosis (IPF)

In this project including both Duke University and our site at University of Wisconsin—Madison, we seek to establish a comprehensive, non-invasive, sensitive and quantitative MR-based exam to evaluate pulmonary gas exchange impairment and show therapy response early. The objective of this grant is to refine and disseminate MR-based imaging of gas exchange, perfusion and proton anatomy and identify regions of reversible disease and response to treatment. Our team is making excellent progress towards meeting our specific aims, which are:

  1. Establish a Comprehensive, Quantitative Structure/Function MRI Protocol for IPF at 2 Centers
  2. Identify Regional Early-Stage Disease By Combining Gd Perfusion and 129Xe Exchange MRI
  3. Use Structure/Function MRI to Monitor Progression and Response to Therapy in IPF

Our primary focus in on developing structure/function MRI to monitor progression and response to Therapy in IPF. Associations between lung parenchymal structure and areas of abnormal xenon gas uptake are evident (figure below). The next phase of image fusion will combine similar measures of lung perfusion with both xenon and UTE MRI of lung structure to explore structure-function mismatches as possible biomarkers of progression.


Figure: Ultrashort echo time (UTE) MRI of lung structure fused with MR spectroscopic 129Xe of Tissue and RBC compartments in a patient with idiopathic pulmonary fibrosis. Arrow indicates obvious region of diffusion block co-incident with ground class opacity. Note other such regions of abnormal gas exchange throughout the lungs.

More information about this study can be found here.

One element of this study is ventilation imaging. The following figure shows how MRI images of xenon ventilation (top rows) can be quantified into four ventilation levels. The lowest ventilation level (red in the middle rows of the figure) indicates ventilation defects. The fraction of the lung volume at the lowest ventilation level is referred to as the VDP (see above). Regions of low, medium, and high ventilation are shown as orange, green, and blue in the middle rows, and from these regions the corresponding low-, medium-, and high-ventilation percentages (LVP, MVP, and HVP) can be computed. The bottom rows show maps of heterogeneity score, which is calculated as the regional signal coefficient of variation in the ventilated lung volume. The dark cool colors in the heterogeneity map reflect the regions with high homogeneity. The global measures of VDP, LVP, MVP, HVP and heterogeneity score for this IPF subject are 20.0%, 34.5%, 41.2%, 4.3% and 0.31 respectively.


Figure: (a) MRI images pulmonary ventilation distribution of hyperpolarized xenon-129; (b) four ventilation levels computed from the images (a); (c) maps of local ventilation heterogeneity.

Xenon is soluble in both the lung tissues and red blood cells, and these two compartments can be distinguished from each other (and from gaseous phase xenon) because of their unique chemical shifts. In the figure below, we demonstrate results using this technique in a healthy normal volunteer and a patient diagnosed with fibrotic lung disease, specifically IPF. The density of xenon in the lung tissue relative to the density of gas in the airspaces (top row) is elevated in IPF, possibly indicative of thickened alveolar walls due to fibrotic processes. The proportion of xenon in the airspaces that transfers to the blood (middle row) is generally reduced with IPF. Regions of very low red blood cell signal (colored red) tend to coincide with obvious regions of fibrosis, visible in the ultrashort echo time (UTE) proton MRI depicting pulmonary structure (bottom row).

Pediatric Lung Disease

A special focus is placed on developing better tools for characterizing pediatric lung diseases using imaging. Conventional pulmonary function tests are inadequate for the assessment of mild lung disease, especially in CF and bronchopulmonary dysplasia (BPD), where X-ray CT and chest radiography have played an increasing role despite their use of ionizing radiation. Currently, non-invasive assessments of underlying structural and functional changes in pediatric lung diseases are not easily performed without using X-ray or radionuclide-based imaging methods that have limited sensitivity and spatial resolution.

Specific advances in pulmonary MRI by our group include variations on ultrashort echo time (UTE) MRI, which has provided markedly improved water proton signal from parenchymal and airway structures not previously detectable with MRI. Related fast imaging techniques have enabled functional imaging of perfusion, dynamics of ventilation in childhood asthma with single bolus delivery of hyperpolarized 3He or 129Xe gas and multiple breath oxygen-enhanced MRI during free breathing. Hyperpolarized 129Xe MRI is also under study to detect abnormalities of gas exchange in IPF, while oxygen-enhanced MRI with whole chest coverage and isotropic resolution is being applied to study ventilation abnormalities in both asthma and CF.



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