Assessment of complementary white matter microstructural changes and grey matter atrophy in a preclinical model of Alzheimer’s disease
Abstract
Alzheimer's disease (AD) has been associated with amyloid and tau pathology, as well as neurodegeneration. Beyond these hallmark features, white matter microstructural abnormalities have been observed using MRI. The objective of this study was to assess grey matter atrophy and white matter microstructural changes in a preclinical mouse model of AD (3xTg-AD) using voxel-based morphometry (VBM) and free-water (FW) diffusion tensor imaging (FW-DTI). Compared to controls, lower grey matter density was observed in the 3xTg-AD model, corresponding to the small clusters in the caudate-putamen, hypothalamus, and cortex. DTI-based fractional anisotropy (FA) was decreased in the 3xTg model, while the FW index was increased. Notably, the largest clusters for both FW-FA and FW index were in the fimbria, with other regions including the anterior commissure, corpus callosum, forebrain septum, and internal capsule. Additionally, the presence of amyloid and tau in the 3xTg model was confirmed with histopathology, with significantly higher levels observed across many regions of the brain. Taken together, these results are consistent with subtle neurodegenerative and white matter microstructural changes in the 3xTg-AD model that manifest as increased FW, decreased FW-FA, and decreased grey matter density.
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Age-related brain atrophy and myelin loss are observed on advanced high-field MRI in the 3×Tg-AD model.
“Alongside the progression of AD pathology, age-related brain atrophy and myelin loss are observed on advanced high-field MRI (Ni, 2021; Jullienne et al., 2022; Bergamino et al., 2023).”
From Multimodal MRI combined with RNA sequencing reveals pathological signatures in the 9-month-old 3×Tg-AD mouse brain (2026) · cites this paper as Bergamino et al., 2023
DTI is a powerful noninvasive method widely used for detecting brain microstructural abnormalities associated with Alzheimer's disease.
“DTI is a powerful noninvasive method widely used for detecting brain microstructural abnormalities associated with AD (Kantarci et al., 2017; Falangola et al., 2020; Bergamino et al., 2023).”
From Multimodal MRI combined with RNA sequencing reveals pathological signatures in the 9-month-old 3×Tg-AD mouse brain (2026) · cites this paper as Bergamino et al., 2023
Previous DTI studies have demonstrated WM integrity impairment in various types of AD mouse models.
“Previous DTI studies have demonstrated WM integrity impairment in various types of AD mouse models (Qin et al., 2013; Massalimova et al., 2020; Bergamino et al., 2023).”
From Multimodal MRI combined with RNA sequencing reveals pathological signatures in the 9-month-old 3×Tg-AD mouse brain (2026) · cites this paper as Bergamino et al., 2023
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Li, Y., Tang, Z., Yao, M., Ran, Y., & Qiu, Z. (2026) · Neural Regeneration Research · doi:10.4103/nrr.nrr-d-25-00006
- Authors
- Bergamino, M., Nelson, M. R., Numani, A., Scarpelli, M., Healey, D., Fuentes, A., Turner, G., & Stokes, A. M.
- Affiliations
- Barrow Neurological Institute (US)
- Corresponding author
- Stokes, Ashley M.
- Venue
- Magnetic Resonance Imaging
- Publisher
- Elsevier BV
- Published
- 2023-09
- Volume
- 101
- Pages
- 57-66
- ISSN
- 0730-725X (ISSN-L)
- OpenAlex
- W4362672585
- Cited by
- 4
- References
- 14
- Citations by year
- 2026: 1 · 2025: 3
- FWCI
- 0.71
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Magnetic Resonance Imaging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Arizona Alzheimer’s Consortium
- Barrow Neurological Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Keywords
- Alzheimer's disease, 3xTg-AD mice, white matter microstructure, gray matter atrophy, fractional anisotropy, amyloid pathology, tau pathology, neurodegeneration, fimbria, caudate-putamen, hypothalamus, voxel-based morphometry
- MeSH terms
- Alzheimer Disease, Animals, Atrophy, Brain, Mice, Diffusion Tensor Imaging, White Matter, Gray Matter
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