Diffusion MRI alterations coincide with memory deficits in a novel hAβKI mouse model of Alzheimer’s Disease

Abstract

BackgroundThe Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium is developing the next generation of Alzheimer’s disease (AD) models based on human genomic and imaging data. Recently, MODEL‐AD has generated a new human Aβ Knock‐In (hAβKI) mouse. These mice exhibit age‐dependent cognitive and synaptic impairments. Preclinical neuroimaging was performed, specifically diffusion MRI (dMRI) to investigate brain‐wide structural alterations in conjunction with connectomic analyses across the hAβKI mouse lifespan.MethodhAβKI and WT mice were compared at 4, 12, and 18 months (mo) of age. Two cohorts were generated for: 1) behavior and long‐term potentiation (LTP), and 2) high resolution diffusion tensor imaging at 9.4T (30 directions b=3000 mm2/sec) to assess regional white and gray matter changes. Regional tissue features based on the AMBMC atlas were extracted from fractional anisotropy (FA), radial (RD), axial (AxD) and mean diffusivity (MD) parametric maps.ResultSignificant impairments in hippocampal LTP were observed in male hAβKI mice at 4mo of age relative to WT but not at 12 or 18mo. In contrast, in female hAβKI mice, LTP impairments were observed only at 12 and 18mo relative to WT. dMRI heatmaps of MD highlighted regional differences between sexes across time and genotype, with MD progressively decreasing with time. Male hAβKI mice had progressive changes within the brain with advancing age whereas the largest changes in females was at 12mo of age. AxD in 18mo male hAβKI mice was increased in 4 of 7 white matter regions but not in female hAβKI mice compared to WT.ConclusionIn summary, using the newly developed hAβKI mouse model of AD, we identified progressive altered regional dMRI tissue metrics. The hippocampal CA1 region appeared to be particularly vulnerable, findings consistent with observed impairments in LTP and behavior. MRI of new mouse models is a powerful tool to investigate tissue level modifications to brain structure and function to inform human disease.