Automated Net Water Uptake Quantification in Ischemic Stroke: Validation Against Manual Measurement in the AcT Trial

Background: Net Water Uptake (NWU) is a non-contrast CT (NCCT) biomarker of early cerebral edema in ischemic stroke, calculated from attenuation differences between ischemic and contralateral non-ischemic brain regions. Manual NWU quantification is labor-intensive and prone to inter-operator variability, limiting clinical uptake and research scalability. We developed and internally validated a fully automated NWU evaluation pipeline. Methods: We analyzed 24-hour follow-up NCCT scans from the AcT (Alteplase compared to Tenecteplase) trial. Infarcts were automatically obtained by segmentation framework based on a synchronous image-label diffusion probability model. The images and extracted infarcts were registered to the standard MNI152 space, allowing us to mirror the infarct onto the contralateral hemisphere symmetrically, regardless of size or tilt angle. Subsequently, the mirrored region was inversely transformed to return to its original space. Voxels outside the range of 20-80 Hounsfield Units (HU) were excluded to remove non-parenchymal tissue. Automated NWU was computed as the percentage difference in mean HU between infarct and mirrored contralateral regions. The agreement with manually determined NWU was evaluated using Pearson correlation, mean absolute error (MAE), and Bland-Altman analysis. Results: Of 1,327 patients in the trial, 298 (22.5%) met predefined imaging-quality criteria for the manual validation analysis, including well-aligned raw NCCT scans in the axial plane and clear parenchymal infarct segmentations. Automated 24-hour NWU showed excellent agreement with manual measurements (r = 0.99). Mean absolute error was 0.18% (95% CI: 0.01-0.46). Bland-Altman analysis demonstrated minimal bias (0.09%) and satisfactory limits of agreement (-4.05% to +4.24%). Ninety-nine percent of cases fell within {+/-}5% of the manually determined value. Conclusions: Our automated mirrored segmentation pipeline enables accurate and reproducible NWU quantification from routine 24-hour NCCT scans, matching expert manual measurements with minimal bias.