Abstract
Phosphorylated tau (pTau) is a defining pathology in Alzheimer's disease. Establishing how pTau is reflected in magnetic resonance imaging (MRI) is important because MRI is scalable, repeatable, and noninvasive, making it a practical modality for tracking pathology burden over space and time. However, it remains unclear whether an MRI signature of pTau exists, and whether such a signature could enable accurate voxelwise detection of tau concentration. We investigate whether tau-related tissue injury has a unique signature based on tissue microenvironments in diffusion-relaxation space, and whether this signature can be validated against histological ground truth.
Using ex vivo human cortical tissue (14 postmortem slices; internal cohort, n=8; independent external cohort, n=6), we reconstructed voxelwise T1-MD and T2-MD joint distributions and co-registered them with histology-derived pTau measurements. We compared three representation strategies: divergence descriptors, principal component analysis (PCA), and transport-based morphometry followed by PCA (TBM-PCA). Model performance was evaluated using 5-fold cross-validation and Bayesian hyperparameter optimization.
We report that pTau-related structure is present in MRI, as captured by divergence analysis in native space. PCA provides reasonable performance, while TBM-PCA yields the overall best results and improves linear model generalization. In the internal cohort, random forest with TBM-PCA achieved an R2 of 0.883 for T1-MD regression, binary accuracy of 92.6% and three-class accuracy of 89.3% on unseen data. In the external cohort, classification remained comparatively stable, and predicted maps retained spatial localization of pTau-enriched regions.
Taken together, we present a proof-of-concept that the signature of pTau can be accurately detected on multidimensional MRI. These data indicate that multidimensional MRI distributions carry histology-linked pTau signal, and that this signal is recovered more effectively when distributional structure is modeled rather than reduced to variance-only embeddings. Looking ahead, this framework could help enable scalable, radiation-free MRI markers of tau pathology for longitudinal monitoring, biologically grounded staging, and treatment-response tracking as disease-modifying therapies expand.
Committee Chair
Shinjini Kundu
Committee Members
Joseph A. O’Sullivan, Jinsong Zhang
Degree
Master of Science (MS)
Author's Department
Electrical & Systems Engineering
Document Type
Thesis
Date of Award
Spring 5-2026
Language
English (en)
Author's ORCID
https://orcid.org/0009-0002-4307-6331
Recommended Citation
Zhang, Hongyi, "Multidimensional MRI Maps Histology-Defined Phosphorylated Tau Burden in Alzheimer’s Disease" (2026). McKelvey School of Engineering Theses & Dissertations. 1356.
https://openscholarship.wustl.edu/eng_etds/1356