Neurochemical and cognitive changes precede structural abnormalities in the TgF344-AD rat model

Abstract

Alzheimer's disease is a progressive neurodegenerative disorder with a decades-long pre-symptomatic phase, substantiating the need for prodromal biomarker development and early intervention. To deconstruct the processes underlying disease progression and identify potential biomarkers, we used neuroimaging techniques with high translational potential to human clinical studies in the TgF344-AD rat model which recapitulates the full spectrum of Alzheimer's neuropathology (progressive amyloid deposition, tauopathy, frank neuronal loss, gliosis, and cognitive dysfunction). We employed longitudinal MRI and magnetic resonance spectroscopy in conjunction with behavioural testing to characterize multiple facets of disease pathology in male and female TgF344-AD rats (n = 26, 14M/12F) relative to wildtype littermates (n = 24, 12M/12F). Testing was performed at 4, 10, 16, and 18 months, covering much of the adult rat lifespan and multiple stages of disease progression. The TgF344-AD model demonstrated impaired spatial reference memory in the Barnes Maze by 4 months of age, followed by neurochemical abnormalities in the hippocampus by 10 months and major structural changes by 16 months. Specifically, TgF344-AD rats displayed increased total choline and lactate, and decreased total creatine, taurine, and N-acetylaspartate to myo-inositol ratio, dentate gyrus hypertrophy, and atrophy in the hippocampus, hypothalamus, and nucleus accumbens. Overall, these findings support the use of MRI and magnetic resonance spectroscopy for the development of non-invasive biomarkers of disease progression, clarify the timing of pathological feature presentation in this model, and contribute to the validation of the TgF344-AD rat as a highly relevant model for pre-clinical Alzheimer's disease research.