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Increased Neurite Orientation-Dispersion and Density in the TgCRND8 Mouse Model of Amyloidosis: Inverse Relation with Functional Connectome Clustering and Modulation by Interleukin-6

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 accurately monitor or predict disease course. In the present study we used high-field diffusion magnetic resonance imaging (dMRI) to determine how Aβ and inflammatory interleukin-6 (IL6), alone or in combination, affect 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 Tesla. Images were processed using the free water elimination method and the neurite orientation dispersion and density imaging (NODDI) model. DTI and NODDI processing in TgCRND8 mice revealed a microstructure pattern consistent with reduced white matter integrity along with an increase in density and geometric complexity of axonal and dendritic processes. This included reduced FA, mean diffusivity (MD), and free water (FW), and increased ‘neurite’ density (NDI) and orientation dispersion (ODI). IL6 produced a ‘protective-like’ effect on FA in TgCRND8 mice, although there were minimal microstructure changes in these mice compared IL6 expressing nTg mice. In addition, we found that NDI and ODI had an inverse relationship with the functional connectome clustering coefficient, which was affected by Aβ and IL6. The relationship between NODDI and graph theory metrics suggests that increasing the density and orientation dispersion of neurites may relate to diminished functional network organization in the brain.