A comparative VBM study of longitudinal neuroanatomical changes in AD transgenic mouse models

Purpose/Introduction: Neurodegeneration and signs of atrophy in brain areas such as the hippocampus and entorhinal cortex are typical for Alzheimer’s disease (AD). To various extents, available transgenic (TG) mouse models of AD recapitulate such hallmarks of the disease as amyloid and tangle pathology, cognitive impairment, synaptic and neuronal loss. Less is known, however, about the brain volumetric changes over time in different genetic strains. Voxel-based morphometry (VBM) of structural MRIs is an in vivo method used to study subtle volumetric changes over time in the whole brain longitudinally. Although it has been seldom used in mice, recent developments in automated image analysis algorithms made it a bridgeable gap. Subjects and Methods: In this study, we compared the progression of neurodegeneration in double (TASTPM; amyloid? at 6 m; tangle-) and triple (TAUPS2APP amyloid? ; tangle? ; both at 4 m) TG strains of AD with a longitudinal design. Control (C67/BL6), TG (TASTPM and TAUPS2APP) male and female mice received MRI scan at 4 m, 13 m, and 24 m; (N & 10–20 mice per group). Datapreprocessing was performed with toolkits from the AFNI, FMRIB, and ANTs software libraries; the statistical analysis—in SPM12 and the read-out of anatomical labels—in ITK-snap. Results: The flexible factorial analysis in SPM12 revealed a strong interaction between time and genotype among the 3 groups in the hippocampal formation, entorhinal area, vermis, thalamus, and neostriatum. In paired comparison—‘controls against TASTPM’ a strong interaction between time and genotype was seen in the nucleus accumbens, striatum, thalamus, cerebellum, and olfactory areas. The analogous comparison with TAUPS2APP group showed in triple TG mice this interaction was isolated to the hippocampal formation. Discussion/Conclusion: The present results extend previous evidence obtained from the same database (Micotti et al. 2015; manual tracing) disclosing novel regions of progressive brain atrophy in TASTPM mice (i.e., thalamus, nucleus accumbens, and cerebellum). The effect in the nucleus accumbens corroborated literature about early alterations of mesolimbic dopaminergic systems in Tg2576 TG mice overexpressing the APP695 protein (Nobili et al. 2017), while the alteration in the cerebellum fits previous observation of local AD pathology in early-onset AD patients with PS1 mutation (Larner and Doran 2006). Overall, the present approach was successful to unveil different abnormalities in the brain over time in two common TG strains of AD.