Imaging lung function in mice using SPECT/CT and per-voxel analysis.

Chronic lung disease is a major worldwide health concern but better tools are required to understand the underlying pathologies. Ventilation/perfusion (V/Q) single photon emission computed tomography (SPECT) with per-voxel analysis allows for non-invasive measurement of regional lung function. A clinically adapted V/Q methodology was used in healthy mice to investigate V/Q relationships. Twelve week-old mice were imaged to describe normal lung function while 36 week-old mice were imaged to determine how age affects V/Q. Mice were ventilated with Technegas™ and injected with (99m)Tc-macroaggregated albumin to trace ventilation and perfusion, respectively. For both processes, SPECT and CT images were acquired, co-registered, and quantitatively analyzed. On a per-voxel basis, ventilation and perfusion were moderately correlated (R = 0.58±0.03) in 12 week old animals and a mean log(V/Q) ratio of -0.07±0.01 and standard deviation of 0.36±0.02 were found, defining the extent of V/Q matching. In contrast, 36 week old animals had significantly increased levels of V/Q mismatching throughout the periphery of the lung. Measures of V/Q were consistent across healthy animals and differences were observed with age demonstrating the capability of this technique in quantifying lung function. Per-voxel analysis and the ability to non-invasively assess lung function will aid in the investigation of chronic lung disease models and drug efficacy studies

Representative CT and SPECT slice images in axial, coronal, and sagittal planes.

<p>The animal shown was chosen based on average mean and standard deviation values for the data set. <b>CT</b> refers to the ventilation-associated CT. <b>Label</b> refers to the lung segmentation seen as a black overlay on the CT. <b>Vent</b> and <b>Perf</b> refer to V and Q images with the colour scale increasing from red through yellow to white for both. <b>Log(V/Q)</b> refers to the final calculated data and the colour bar indicates the values seen in the associated log(V/Q) images.</p

Distribution and measures of log(V/Q) data.

<p><b>A</b> Average volume-standardized distribution of log(V/Q) values measured in percentage of total lung volume. Dashed lines indicate average ±2 standard deviations from the average mean. Values over arrows represent average±SEM percentage of lung volume beyond ±2 standard deviations, including log(V/Q) ±∞ values. <b>B</b> Descriptive analysis of log(V/Q) distribution central tendency and variation within the lung, calculated without ±∞ values. <b>C</b> Percentage of total lung volume with log(V/Q) mismatching. Mismatching is defined as values greater or less than 2 average standard deviations from the average mean. −∞ and +∞ refer to voxels where V = 0 and Q = 0, respectively. Box plots describe the data for all 12w.o. animals in terms of the median, interquartile range, and minimum/maximum values.</p

Simplified representation of the methodology used in image acquisition and processing to provide the final V/Q data sets.

<p>Simplified representation of the methodology used in image acquisition and processing to provide the final V/Q data sets.</p

Comparison of group characteristics between 12 week old and 36 week old mice.

*<p>p<0.05, **p<0.01, ***p<0.001 by two-tailed t-test against 12 w.o. animals.</p

Lung segmentation used in the V/Q analysis.

<p><b>A</b> Representative lung segmentation used in V/Q co-registration and analysis, with CT orthoslices for reference. <b>B</b> Average volume-standardized CT densitometry of ungated images in Hounsfield units (HU) depicting the distribution of densities within the label.</p

Regionalization of V/Q mismatching.

<p><b>A</b> Representative axial log(V/Q) slices depicting changes with age in the apex, middle, and base of the lung. The colour scale represents 2 average standard deviations from the average mean of 12w.o. animals. <b>B</b> Regional analysis of averaged log(V/Q) standard deviation values in the apex, middle, and base of the lung as well as inner and outer regions. *p<0.05, **p<0.01 by two-tailed t-test between 12 and 36w.o. groups. <b>†</b>p<0.05 apex vs. base, <b>‡</b>p<0.05 middle vs. base by one-way ANOVA with Tukey post-hoc. <b>§</b>p<0.05 by two-tailed t-test between inner and outer regions.</p