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Development of Translational Imaging Biomarkers in Mouse Models of Huntington's Disease

Riggall, Laura Jane; (2021) Development of Translational Imaging Biomarkers in Mouse Models of Huntington's Disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Huntington’s disease (HD) is a genetic neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene that results in movement disorders and cognitive and psychiatric decline. To better track disease onset and progression, biomarkers that precede irreversible structural changes are needed. Alterations in metabolic processes detectable using magnetic resonance imaging (MRI) and other MR approaches may provide such biomarkers but need characterisation in HD mouse models to improve their clinical translatability. The aim of this thesis was to develop imaging biomarkers in transgenic R6/2 and knock-in zQ175 mice, two commonly used HD mouse models. To undertake the most comprehensive time-course analyses of metabolite concentrations in these models so far, proton magnetic resonance spectroscopy (1H-MRS) was acquired in selected brain regions throughout disease progression. Significant metabolic alterations were observed in zQ175 and R6/2 mice, with fluctuations at early disease stages. These changes suggested diminished neuronal integrity and reactive gliosis, which were confirmed using histology. Brain regions also exhibited specific metabolic profiles, many of said profiles being observed across both mouse models (albeit with some discrepancies). Chemical Exchange Saturation Transfer (CEST), which ought to overcome the limited sensitivity of 1H-MRS, was also acquired. However, we show CEST is not sensitive to HD pathology and do not recommend it for biomarker development in HD. Lastly, we acquired diffusion-weighted MRS (DW-MRS) in zQ175 mice to assess the diffusion of metabolites confined to cell-specific compartments. We found no changes in metabolite diffusion properties, but given the experimental nature of the protocol we used, DW-MRS needs further investigation in the context of HD. Overall, we have moved the field of HD forward by evaluating in detail the metabolic consequences of the disease in two mouse models that are widely used to investigate HD pathogenesis and evaluate therapeutic targets.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Development of Translational Imaging Biomarkers in Mouse Models of Huntington's Disease
Event: UCL (University College London)
Language: English
Additional information: Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Med Phys and Biomedical Eng
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10127829
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