Diffusion MRI detects early brain microstructure abnormalities in 2-month-old 3xTg-AD mice

The 3xTg-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 3xTg-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 3xTg-AD mice. In the fimbria, the fractional anisotropy (FA), kurtosis fractional anisotropy (KFA), and radial kurtosis (K-& x2534;) were found to be significantly lower in 3xTg-AD mice than in controls, while the mean diffusivity (MD) and radial diffusivity (D-& x2534;) were found to be elevated. In the fornix,K(& x2534;)was lower for 3xTg-AD mice; in the dorsal hippocampus MD andD(& x2534;)were elevated, as were FA, MD, andD(& x2534;)in the ventral hippocampus. These results indicate, for the first time, dMRI changes associated with myelin abnormalities in young 3xTg-AD mice, before they develop AD pathology. Morphological quantification of myelin basic protein immunoreactivity in the fimbria was significantly lower in the 3xTg-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 3xTg-AD mice.