Postmortem Validation of Quantitative MRI for White Matter Hyperintensities in Alzheimer's Disease

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Abstract

White matter hyperintensities (WMH) are frequently observed on MRI in aging and Alzheimers disease (AD), yet their microstructural pathology remains poorly characterized. Conventional MRI sequences provide limited information to describe the tissue abnormalities underlying WMH, while histopathology--the gold standard--can only be applied postmortem. Quantitative MRI (qMRI) offers promising non-invasive alternatives to postmortem histopathology, but lacks histological validation of these metrics in AD. In this study, we examined the relationship between MRI metrics and histopathology in postmortem brain scans from eight donors with AD from the South Texas Alzheimers Disease Research Center. Regions of interest are delineated by aligning MRI-identified WMH in the brain donor scans with postmortem histological sections. Histopathological features, including myelin integrity, tissue vacuolation, and gliosis, are quantified within these regions using machine learning. We report the correlations between these histopathological measures and two qMRI metrics: T2 and absolute myelin water signal (aMWS) maps, as well as conventional T1w/T2w MRI. The results derived from aMWS and T2 mapping indicate a strong association between WMH, myelin loss, and increased tissue vacuolation. Bland-Altman analyses indicated that T2 mapping showed more consistent agreement with histopathology, whereas the derived aMWS demonstrated signs of systematic bias. T1w/T2w values exhibited weaker associations with histological alterations. Additionally, we observed distinct patterns of gliosis in periventricular and subcortical WMH. Our study presents one of the first histopathological validations of qMRI in AD, confirming that aMWS and T2 mapping are robust, non-invasive biomarkers that offer promising ways to monitor white matter pathology in neurodegenerative disorders.

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