Brain microstructure abnormalities in the 3xTg-AD mouse - A diffusion MRI and morphology correlation study

The widely studied triple transgenic (3xTg-AD) mouse provides a robust model of Alzheimer's disease (AD) with region dependent patterns of progressive amyloid-β (Aß) and tau pathology. Using diffusion MRI (dMRI), we investigated the sensitivity of dMRI measures in capturing AD pathology associated microstructure alterations in older 3xTg-AD mice, and the degree to which dMRI changes correlate with measurements of Aβ and tau pathology. 3xTg-AD and normal control (NC) mice, 15 to 21 months of age, were used in this study. In vivo dMRI data were acquired for the generation of diffusion tensor (DT) and diffusional kurtosis (DK) measures within the hippocampus and fimbria (Fi). For these same brain regions, Aβ and tau pathology were quantified by morphological analysis of Aß1-42 and AT8 immunoreactivity. Two-tailed, two-sample t-tests were performed to assess group differences in each brain region of interest (ROI), with the Benjamini-Hochberg false discovery rate (FDR) method being applied to adjust for multiple comparisons. Spearman correlation coefficients were calculated to investigate associations between diffusion and morphological measures. Our results revealed, depending on the brain region, DT and DK measures were able to detect group differences. In the dorsal hippocampus (HD), fractional anisotropy (FA) was significantly higher in the 3xTg-AD mice compared with NC mice. In the subiculum (SUB), FA, axial diffusivity (D_||) and radial kurtosis (K_┴) were significantly higher in 3xTg-AD mice compared with NC mice. Morphological quantification of Aß1-42 and AT8 immunoreactivity showed elevated Aß and tau in the Fi, ventral hippocampus (HV) and SUB of 3xTg-AD mice. The presence of Aβ and tau was significantly correlated with several DT and DK measures, particularly in the SUB, where an increase in tau correlated with an increase in mean kurtosis (MK) and K_┴. This work demonstrates significant dMRI differences between older 3xTg-AD and NC mice in the hippocampus and Fi. Significant correlations were found between dMRI and morphological measures of Aβ and tau pathology. These results support the potential of dMRI-derived parameters as biomarkers of AD pathology. Since the imaging methods employed here are easily translatable to clinical MRI, our results are also relevant for human AD patients.