Quantitative microglia morphological features correlate with diffusion MRI in 2-month-old 3xTg-AD mice

Microglia (Mo) morphologies are closely related to their functional state and have a central role in the maintenance of brain homeostasis. It is well known that inflammation contributes to neurodegeneration at later stages of Alzheimer's Disease, but it is not clear which role Mo -mediated inflammation may play earlier in the disease pathogenesis. We have previously reported that diffusion MRI (dMRI) is able to detect early myelin abnormalities present in 2-month-old 3xTg-AD (TG) mice; since Mo actively participate in regulating myelination, the goal of this study was to assess quantitatively Mo morphological characteristics and its association with dMRI metrics patterns in 2-month-old 3xTg-AD mice. Our results show that, even at this young age (2-month-old), TG mice have statistically significantly more Mo cells, which are overall smaller and more complex, compared with age matched normal control mice (NC). Our results also confirm that myelin basic protein is reduced in TG mice, particularly in fimbria (Fi) and cortex. Additionally, Mo morphological characteristics, in both groups, correlate with several dMRI metrics, depending on the brain region examined. For example, the increase in Mo number correlated with higher radial diffusivity (D & BOTTOM;) (r = 0.59, p = 0.008), lower fractional anisotropy (FA) (r =-0.47, p = 0.03), and lower kurtosis fractional anisotropy (KFA) (r =-0.55, p = 0.01) in the CC. Furthermore, smaller Mo cells correlate with higher axial diffusivity (D||) in the HV (r = 0.49, p = 0.03) and Sub (r = 0.57, p = 0.01). Our findings demonstrate, for the first time, that Mo proliferation/activation are a common and widespread feature in 2-month-old 3xTg-AD mice and suggest that dMRI measures are sensitive to these Mo alterations, which are associated in this model with myelin dysfunction and microstructural integrity abnormalities.