Neurite orientation dispersion and density imaging reveals white matter and hippocampal microstructure changes produced by Interleukin-6 in the TgCRND8 mouse model of amyloidosis
Open accessAbstract
Extracellular β-amyloid (Aβ) plaque deposits and inflammatory immune activation are thought to alter various aspects of tissue microstructure, such as extracellular free water, fractional anisotropy and diffusivity, as well as the density and geometric arrangement of axonal processes. Quantifying these microstructural changes in Alzheimer's disease and related neurodegenerative dementias could serve to monitor or predict disease course. In the present study we used high-field diffusion magnetic resonance imaging (dMRI) to investigate the effects of Aβ and inflammatory interleukin-6 (IL6), alone or in combination, on in vivo tissue microstructure in the TgCRND8 mouse model of Alzheimer's-type Aβ deposition. TgCRND8 and non-transgenic (nTg) mice expressing brain-targeted IL6 or enhanced glial fibrillary protein (EGFP controls) were scanned at 8 months of age using a 2-shell, 54-gradient direction dMRI sequence at 11.1 T. Images were processed using the diffusion tensor imaging (DTI) model or the neurite orientation dispersion and density imaging (NODDI) model. DTI and NODDI processing in TgCRND8 mice revealed a microstructure pattern in white matter (WM) and hippocampus consistent with radial and longitudinal diffusivity deficits along with an increase in density and geometric complexity of axonal and dendritic processes. This included reduced FA, mean, axial and radial diffusivity, and increased orientation dispersion (ODI) and intracellular volume fraction (ICVF) measured in WM and hippocampus. IL6 produced a 'protective-like' effect on WM FA in TgCRND8 mice, observed as an increased FA that counteracted a reduction in FA observed with endogenous Aβ production and accumulation. In addition, we found that ICVF and ODI had an inverse relationship with the functional connectome clustering coefficient. The relationship between NODDI and graph theory metrics suggests that currently unknown microstructure alterations in WM and hippocampus are associated with diminished functional network organization in the brain.
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NODDI provides enhanced sensitivity and specific metrics for detecting Alzheimer's disease-associated microstructural changes.
“In contrast, NODDI provides enhanced sensitivity and specific metrics for detecting AD‐associated microstructural changes. 31 , 32 , 33”
From Apolipoprotein ε4 exacerbates white matter impairment in a mouse model of Aβ amyloidosis by decreasing actively myelinating oligodendrocytes (2025) · cites this paper as [33]
The Introduction (page not available in our copy) says NODDI provides metrics of axonal and dendritic dispersion and density and reports changes in young-onset Alzheimer’s disease. The Discussion reports changes in those metrics in an amyloidosis mouse model. These passages support the specific-metrics and detection portions of the claim, but do not establish enhanced sensitivity relative to another method. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn another mouse model of Alzheimer's disease, greater NDI and ODI than controls were observed in WM and hippocampus.
“Similarly, in another mouse model of Alzheimer's disease, greater NDI and ODI than controls were observed in WM and hippocampus (Colon-Perez et al., 2019).”
From NODDI in clinical research (2020) · cites this paper as Colon-Perez et al., 2019
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“Similarly, in another mouse model of Alzheimer’s disease, greater NDI and ODI than controls were observed in WM and hippocampus (Colon-Perez et al., 2019).”
BackgroundFebo, M., Pérez, P. D., Ceballos‐Diaz, C., Colón-Pérez, L. M., Zeng, H., Ofori, E., Golde, T. E., Vaillancourt, D. E., & Chakrabarty, P. (2020) · Brain Structure and Function · doi:10.1007/s00429-019-02017-1 · Cited by 54 · see citing works
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Interaction of amyloid and tau on cortical microstructure in cognitively unimpaired adults
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Neuroimaging of mouse models of Alzheimer’s disease
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Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis
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Microglia show differential transcriptomic response to Aβ peptide aggregates ex vivo and in vivo
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Self-citationScanning ultrasound-mediated memory and functional improvements do not require amyloid-β reduction
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Network analysis of neuroimaging in mice
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Colón-Pérez, L. M., Turner, S. M., Lubke, K. N., Pompilus, M., Febo, M., & Burke, S. N. (2019) · eNeuro · doi:10.1523/eneuro.0047-19.2019 · Cited by 21 · see citing works
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Pursuit of precision medicine: Systems biology approaches in Alzheimer's disease mouse models
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The future of neuroimaging and gut-brain axis research for substance use disorders
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Connectomic analysis of Alzheimer’s disease using percolation theory
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Self-citationBrain Network Modularity and Resilience Signaled by Betweenness Centrality Percolation Spiking
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Effects of Body Mass Index on Brain Structures in the Elderly: Longitudinal Analyses
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Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis
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“…such as neurite orientation dispersion and density imaging (NODDI), have been used to profile neurite density indexes (NDI) and orientation dispersion indexes (ODI) (Wang et al., 2019) in the mouse models of Aβ amyloidosis (Colon-Perez et al., 2019) and tau pathology (Colgan et al., 2016).”
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Association of C-reactive protein with brain micro- and macro-structure among older adult men
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- Authors
- Colon-Perez, L. M., Ibanez, K. R., Suarez, M., Torroella, K., Acuna, K., Ofori, E., Levites, Y., Vaillancourt, D. E., Golde, T. E., Chakrabarty, P., & Febo, M.
- Affiliations
- University of Florida (US)
- University of Florida Health (US)
- Corresponding author
- Chakrabarty, Paramita
- Febo, Marcelo
- ORCID
- Venue
- NeuroImage
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 202
- Pages
- 116138
- ISSN
- 1053-8119 (ISSN-L)
- PMC
- PMC6894485
- OpenAlex
- W2971088730
- Cited by
- 41
- References
- 90
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 7 · 2023: 3 · 2022: 10 · 2021: 9 · 2020: 5 · 2019: 1
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- NeuroImage (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- NODDI, interleukin-6, Alzheimer's disease, amyloidosis, white matter microstructure, hippocampus, intracellular volume fraction, orientation dispersion index, fractional anisotropy, diffusion tensor imaging, graph theory, neuroinflammation, brain microstructure
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Hippocampus, Mice, Transgenic, Nerve Net, Interleukin-6, Amyloid beta-Peptides, Neurites, Mice, Diffusion Tensor Imaging, White Matter, ErbB Receptors
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