Development of a Multimodal MRI Study to Characterize Morpho-Functional Features in Rodent Models of Alzheimer's Disease

Tolomeo, Daniele (2019). Development of a Multimodal MRI Study to Characterize Morpho-Functional Features in Rodent Models of Alzheimer's Disease. PhD thesis The Open University.

Abstract

Alzheimer’s Disease (AD) is the most common form of dementia, recognized by the World Health Organization as a global public health priority. It is a complex pathology characterized by the accumulation of the Amyloid-β (Aβ) peptide as extracellular plaques and of the intracellullar neuro fibrillary tangles (NFT) alongside with different events, such as chronic neuroinflammation and astrogliosis. None of the existing biomarkers is simultaneously specific for the pathology and sensitive to its progression. Metabolic and functional alterations are the earliest events described in the AD pathological cascade but shared with other form of dementia, while specific structural alterations occurs in a later stage of the disease. The use of transgenic models could simplify the development of new imaging biomarkers that would enable early diagnosis and making new treatments more effective. The objective of this work was to develop a multi-modal panel of magnetic resonance imaging (MRI) techniques and automated analysis pipelines, characterized by a high translational impact, in order to investigate the metabolic, functional and structural alterations in the brains of AD transgenic models. Results obtained in the APP23 transgenic mouse show that chemical exchange saturation transfer (CEST) imaging can be used to detect alterations in the brain uptake of the glucose analogue 2-deoxy-d-glucose (2DG) with a better resolution than PET and without the need of radioactive tracers. Moreover, a longitudinal study highlighted that significant structural and metabolic alterations can be found only in a late stage of the pathology. Furthermore, an advanced pipeline for the analysis of the rodent brain functional connectivity has been developed. This thesis demonstrates that the advantage to the experimental design adopted is simplifying longitudinal studies of the same animal cohort. The translation of the analysis pipelines adopted in human studies enables more powerful results and reduces the number of animals involved in research.

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