Book Description

"Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder that accounts for 60-80% of the 50 million dementia cases worldwide. The most widely accepted risk factor for developing AD is age. The distinction between aging and AD is particularly crucial during the early stages of disease progression since this is when intervention is most likely to be effective. However, there is a lack of biological markers capable of identifying early-stage AD, limiting opportunities for diagnosis and treatment. Comprehensive characterization of aging and disease processes in relevant animal models represents one promising avenue towards developing options for diagnosis and treatment. In particular, longitudinal preclinical studies that employ techniques with high translational potential to clinical studies, such as non-invasive neuroimaging techniques, would enable identification of homologous biomarkers across species. The content of this thesis describes the application of whole-brain MRI and localized MRS to investigate age- and sex-related changes in neurochemistry and neuroanatomy in a commonly used rat model of aging (the Fischer 344 rat), and the subsequent integration of these techniques with behavioural testing in a transgenic rat model developed on a Fischer 344 background to distinguish the effects of aging versus Alzheimer's disease pathology on neuroimaging and cognitive markers. Chapters 1 and 2 provide a general introduction and background information on the current state of knowledge regarding the impact of age and AD pathology on brain structure and tissue chemistry, as well as the neuroimaging and statistical methods used to investigate these neurobiological changes. Chapter 3 presents a published study examining age- and sex-related changes in hippocampal biochemistry in the Fischer 344 rat. Age was associated with prominent differences in metabolites implicated in anaerobic energy metabolism, antioxidant defenses, and neuroprotection, as well as numerous macromolecule changes. Chapter 4 builds upon the previous study of highly localized effects of aging by examining whole-brain volumetric changes associated with age and sex, again in the Fischer 344 rat. This publication identifies age- and sex-related volume changes in regions such as the cortex, hippocampus, cingulum, caudoputamen, and nucleus accumbens, which are implicated in memory and motor control circuits frequently affected by aging and neurodegenerative disease. Chapter 5 incorporates the techniques and knowledge developed in earlier chapters by applying the same neuroimaging techniques in combination with behavioural testing in a transgenic model of Alzheimer's disease developed on a Fischer 344 background, the TgF344-AD rat. The TgF344-AD model demonstrated impaired spatial reference memory by 4 months of age, followed by neurochemical abnormalities by 10 months and major structural changes by 16 months, many of which were similar to findings in human Alzheimer's disease subjects. A mild influence of sex was also seen on neuroimaging and cognitive markers. Finally, Chapter 6 provides a discussion and summary of the relevance of these findings. Altogether, this thesis describes the application of highly translatable neuroimaging techniques to identify multiple neurobiological features influenced by age-, sex-, and pathology throughout the lifespan of two relevant rat models. This thesis therefore provides support for the use of MRI and MRS in rodent models in vivo to develop markers of pathological change which may be used to improve age- and disease-related outcomes in humans"--