Diffusion MRI detects early brain microstructure abnormalities in 2-month-old 3×Tg-AD mice
Open accessAbstract
The 3×Tg‐AD mouse is one of the most studied animal models of Alzheimer's disease (AD), and develops both amyloid beta deposits and neurofibrillary tangles in a temporal and spatial pattern that is similar to human AD pathology. Additionally, abnormal myelination patterns with changes in oligodendrocyte and myelin marker expression are reported to be an early pathological feature in this model. Only few diffusion MRI (dMRI) studies have investigated white matter abnormalities in 3×Tg‐AD mice, with inconsistent results. Thus, the goal of this study was to investigate the sensitivity of dMRI to capture brain microstructural alterations in 2‐month‐old 3×Tg‐AD mice. In the fimbria, the fractional anisotropy (FA), kurtosis fractional anisotropy (KFA), and radial kurtosis (K┴) were found to be significantly lower in 3×Tg‐AD mice than in controls, while the mean diffusivity (MD) and radial diffusivity (D┴) were found to be elevated. In the fornix, K┴ was lower for 3×Tg‐AD mice; in the dorsal hippocampus MD and D┴ were elevated, as were FA, MD, and D┴ in the ventral hippocampus. These results indicate, for the first time, dMRI changes associated with myelin abnormalities in young 3×Tg‐AD mice, before they develop AD pathology. Morphological quantification of myelin basic protein immunoreactivity in the fimbria was significantly lower in the 3×Tg‐AD mice compared with the age‐matched controls. Our results demonstrate that dMRI is able to detect widespread, significant early brain morphological abnormalities in 2‐month‐old 3×Tg‐AD mice.
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Previously, the authors showed that dMRI detects early myelin abnormalities in the hippocampus, fimbria and fornix of 2-month-old 3xTg-AD mice.
“Previously, we have shown that dMRI is able to detect the early myelin abnormalities described in this AD mouse, particularly in the hippocampus, fimbria and fornix of 2-month-old 3xTg-AD mice [15].”
From Brain microstructure abnormalities in the 3xTg-AD mouse – A diffusion MRI and morphology correlation study (2022) · cites this paper as [15]
The Abstract reports dMRI differences in the hippocampus, fimbria and fornix of 2-month-old 3xTg-AD mice and associates them with myelin abnormalities. The Discussion reports a myelin measurement in the fimbria but says further work is needed to establish a direct correlation between dMRI and morphological findings; it does not establish that dMRI specifically detected myelin abnormalities in all three regions. (LLM, conf=0.83)
Experimental — accuracy not yet measuredSimilar DTI changes have been reported in other regions such as the fimbria, basal forebrain, external capsule, and internal capsule, characterized by decreased fractional anisotropy and axial diffusion and increased radial diffusion.
“Similar DTI changes have also been reported in other regions such as the fimbria, basal forebrain, external capsule, and internal capsule, characterized by decreased fractional anisotropy (FA) and axial diffusion (AxD) and increased radial diffusion (RD) (Falangola et al., 2020; Falangola et al., 2021; Ni, 2021; 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 Falangola et al., 2020
The Results (page unavailable) report decreased FA and increased radial diffusivity in the fimbria of 2-month-old 3×Tg-AD mice. They report decreased axial diffusivity in the corpus callosum, not the fimbria, and only kurtosis-metric decreases in the internal and external capsules. The reported results do not address the basal forebrain, so this source does not support the claimed pattern across all four named regions. (LLM, conf=0.90)
Experimental — accuracy not yet measuredDTI 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 Falangola et al., 2020
The Introduction describes diffusion MRI (dMRI) as a powerful, widely used noninvasive tool for detecting AD-associated white-matter changes. It identifies DTI as one dMRI technique, but the broad statement is about dMRI, not DTI specifically; the study primarily uses DKI and diffusion-tensor measures. (LLM, conf=0.85)
Experimental — accuracy not yet measured
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Self-citationUltrashort echo time magnetization transfer imaging of myelin in APP knock-in mice
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Cristillo, V., Merati, T., Tolassi, C., Rondina, A., Bettonagli, V., Galli, A., Volonghi, I., Bianchi, M., Arici, D., Trasciatti, C., et al. (2026) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2026.579113
- Authors
- Falangola, M. F., Nie, X., Ward, R., McKinnon, E. T., Dhiman, S., Nietert, P. J., Helpern, J. A., & Jensen, J. H.
- Affiliations
- Medical University of South Carolina (US)
- Corresponding author
- Falangola, Maria Fatima
- ORCID
- Venue
- NMR in Biomedicine
- Publisher
- Wiley
- Published
- 2020-06-17
- Volume
- 33
- Issue
- 9
- Pages
- e4346-e4346
- ISSN
- 0952-3480 (ISSN-L)
- 1099-1492
- PMC
- PMC7683375
- OpenAlex
- W3036225878
- Cited by
- 22
- References
- 59
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 6 · 2022: 3 · 2021: 3
- FWCI
- 1.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- NMR in Biomedicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (1RF1AG057602‐01)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- 3xTg-AD mice, Alzheimer's disease, diffusion MRI, white matter microstructure, myelin abnormalities, myelination, fractional anisotropy, kurtosis, radial diffusivity, mean diffusivity, fimbria, fornix, hippocampus, myelin basic protein
- MeSH terms
- Alzheimer Disease, Animals, Brain, Male, Mice, Transgenic, Anisotropy, Diffusion Magnetic Resonance Imaging
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