Dynamics of longitudinal biomarker changes in the Mcgill-R-Thy1-APP rat


      Rat transgenic models of human brain amyloidosis constitute a unique opportunity to explore the impact of amyloid pathology on imaging biomarkers without the bias of tau pathology invariably present in the human brain. Due to its size, the McGill-R-Thy1-APP rat is ideal for multi-modal neuroimaging observations as compared to transgenic mouse. Here, we studied the associations between the rates of structural brain remodeling as a function of the rate of progression of hypometabolism in transgenic rats. We hypothesize regional specific interactions between biomarkers.


      McGill-R-Thy1-APP rat (n=9) and wild type (wt; n=12) had [18F]FDG and structural MRIs scans at 11-month (baseline) and 16-month (follow-up). Structural images were acquired using a Bruker 70/30USR Biospect MRI (FISP; TE/TR: 2.5/5.0ms; FOV: 3.6cm3; isotropic 250um voxels; 8 angles). Voxel-based morphometry was performed to obtain longitudinal deformation maps. [18F]FDG PET images were acquired and analyzed as described previously (3). For both scans, longitudinal difference maps were generated. Global uptake values obtained from these maps were then correlated with structural deformation maps using a voxel-level linear model.


      The olfactory bulb, anterior pituitary lobe, multiple cortical areas, lateral ventricle, and a portion of the hippocampus showed association between [18F]FDG declines and structural shrinkage. The left motor cortex and thalamic nuclei as well as the right primary somatosensory cortex showed dissociation between structural changes (expansion) and [18F]FDG declines.


      McGill-R-Thy1-APP allows for longitudinal biomarker measures without confounding effects of neurofibrillary tangles or cell death. In fact, the present results suggest that brain abnormal amyloid aggregates present in the McGill-R-Thy1-APP rat leads to expansion or shrinkage of grey matter structures and progressive hypometabolism. However these processes occur in synchrony in specific brain regions. These suggest a complex interface between amyloid pathology and pathophysiological mechanisms involved in structural declines in transgenic animals.
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      Figure 1t-stat map of regions that shrink when the metabolism decreases throughout the brain.
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      Figure 2t-stat map of regions that expand when the metabolism decreases throughout the brain.