Multidimensional diffusion MRI reveals heterogeneous microstructural remodeling associated with amyloid pathology
- 1National Institutes of Health
Abstract
Alzheimer's disease (AD) pathology involves amyloid deposition, reactive gliosis, and localized tissue alterations that coexist within the same brain regions, creating heterogeneous microstructural environments within individual imaging voxels. Conventional diffusion MRI averages these environments into aggregate measures, potentially obscuring their distinct contributions. Frequency-dependent multidimensional MRI ({omega}MD-MRI) resolves distributions of water components with different diffusion length scales, anisotropies, and relaxation properties, providing sensitivity to microstructural restriction, heterogeneity, and shape-size correlations within a voxel. Whether these measurements reveal microstructural complexity associated with AD pathology remains unclear. Here, we performed {omega}MD-MRI on ex vivo brain specimens from approximately 8-month-old 5xFAD and wild-type mice and interpreted the imaging findings alongside complementary histology. {omega}MD-MRI revealed widespread but spatially nonuniform differences between 5xFAD and wild-type brains. Measurements sensitive to microstructural restriction, heterogeneity, and shape-size correlations consistently indicated greater microstructural heterogeneity in 5xFAD brains, with the most prominent differences in the hippocampal formation and major cerebral white matter tracts. Complementary qualitative histology demonstrated extensive amyloid deposition and glial activation in affected regions, while overall cytoarchitecture and myelin organization remained largely preserved. Thus, the {omega}MD-MRI abnormalities occurred in tissue characterized by multiple coexisting pathological and relatively preserved microstructural environments rather than widespread structural degeneration. These findings demonstrate that {omega}MD-MRI can reveal the spatial and microstructural heterogeneity associated with amyloid pathology and provide a more comprehensive characterization of AD-related tissue alterations.
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BibTeX
@misc{or2026multidimensional,
title = {{Multidimensional diffusion MRI reveals heterogeneous microstructural remodeling associated with amyloid pathology}},
author = {P. S. K. Or and M. Yon and O. Narvaez and V. Sitnikova and T. Malm and M. Bouhrara and A. Sierra and D. Topgaard and D. Benjamini},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.26.747377},
url = {https://www.biorxiv.org/content/10.64898/2026.08.26.747377v1},
note = {CC0},
}
RIS
TY - UNPB
TI - Multidimensional diffusion MRI reveals heterogeneous microstructural remodeling associated with amyloid pathology
AU - P. S. K. Or
AU - M. Yon
AU - O. Narvaez
AU - V. Sitnikova
AU - T. Malm
AU - M. Bouhrara
AU - A. Sierra
AU - D. Topgaard
AU - D. Benjamini
PY - 2026
DA - 2026/08/26
PB - bioRxiv
DO - 10.64898/2026.08.26.747377
UR - https://www.biorxiv.org/content/10.64898/2026.08.26.747377v1
AB - Alzheimer's disease (AD) pathology involves amyloid deposition, reactive gliosis, and localized tissue alterations that coexist within the same brain regions, creating heterogeneous microstructural environments within individual imaging voxels. Conventional diffusion MRI averages these environments into aggregate measures, potentially obscuring their distinct contributions. Frequency-dependent multidimensional MRI ({omega}MD-MRI) resolves distributions of water components with different diffusion length scales, anisotropies, and relaxation properties, providing sensitivity to microstructural restriction, heterogeneity, and shape-size correlations within a voxel. Whether these measurements reveal microstructural complexity associated with AD pathology remains unclear. Here, we performed {omega}MD-MRI on ex vivo brain specimens from approximately 8-month-old 5xFAD and wild-type mice and interpreted the imaging findings alongside complementary histology. {omega}MD-MRI revealed widespread but spatially nonuniform differences between 5xFAD and wild-type brains. Measurements sensitive to microstructural restriction, heterogeneity, and shape-size correlations consistently indicated greater microstructural heterogeneity in 5xFAD brains, with the most prominent differences in the hippocampal formation and major cerebral white matter tracts. Complementary qualitative histology demonstrated extensive amyloid deposition and glial activation in affected regions, while overall cytoarchitecture and myelin organization remained largely preserved. Thus, the {omega}MD-MRI abnormalities occurred in tissue characterized by multiple coexisting pathological and relatively preserved microstructural environments rather than widespread structural degeneration. These findings demonstrate that {omega}MD-MRI can reveal the spatial and microstructural heterogeneity associated with amyloid pathology and provide a more comprehensive characterization of AD-related tissue alterations.
ER -