Lifespan diffusion MRI reveals structural abnormalities in the 5xFAD model of Alzheimer’s Disease

Abstract

AbstractBackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium has been established to develop the next generation of Alzheimer’s disease (AD) models based on human genomic findings. As new models are developed, phenotypic data are compared to established models, including the 5xFAD mouse model. We undertook measurements of diffusion metrics to characterize the temporal alterations in brain structure in male and female 5xFAD mice, including connectivity analysis between the hippocampus and infralimbic prefrontal cortex (PFC).Method5xFAD mice were compared to age‐matched littermates (C57BL/6J, WT) at 4, 8, and 12 months (mo). Mice underwent high resolution diffusion tensor imaging (DTI) magnetic resonance imaging (MRI) at 9.4T (5 B0, 30 directions b=3000 mm2/sec) to assess regional white and gray matter. Regional tissue features were extracted from fractional anisotropy (FA), radial (RD), axial (AxD) and mean diffusivity (MD) parametric maps. Tractography was performed based on the AMBMC mouse atlas. 18F‐AV45 PET was performed in a separate cohort at 4, 6, and 12mo to quantitate amyloid β (Aβ) load.ResultElevated FA within hippocampal CA1 was first observed in 5xFAD males at 8mo, but at 12mo 5xFAD females had increased FA in bilateral CA1 compared to WT mice. Connectivity between CA1 and PFC found 12mo 5xFAD females had significantly increased RD along the tract with concomitant increases in MD and AxD. AV45‐PET uptake was increased at 6mo (∼20%) and remained elevated at 12mo (∼25%) in the PFC in male and female 5xFAD compared to WT. In the hippocampus there was a ∼20% increase in AV45 binding at 6mo, that then declines by 12mo in 5xFAD mice.ConclusionPhenotyping of mouse models using DTI identifies altered brain connectivity and regional tissue modifications that may be indicative of increasing Aβ deposition. These data support that increasing Aβ deposition results in altered DTI metrics and connectivity using clinically relevant imaging modalities.