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Development of biofluid biomarkers for Huntington’s disease

Byrne, Lauren Mary; (2020) Development of biofluid biomarkers for Huntington’s disease. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Though no treatments can currently prevent onset or slow progression of Huntington’s disease (HD), many huntingtin-lowering drug candidates targeting the root cause of HD are in the development pipeline. This brings much hope that disease-modifying treatments for HD will be a reality. However, success of potential candidates may be hindered by a lack of sensitive tools to measure biological efficacy over short intervals. Decades of attempts to develop robust biofluid biomarkers of HD progression has yielded little success or replication of results. Cerebrospinal fluid (CSF), fluid that bathes the brain and is enriched for brain-specific proteins, is a plausible target for uncovering neuropathologically relevant markers of HD. However, a lack of standardisation of collection protocols, biological rationale and technological sensitivity has hampered the progress of CSF biomarkers within the field of HD. At the core of this thesis lies the HD-CSF study – a single-site CSF collection study, with a standardised protocol designed to generate high-quality CSF and blood with matched clinical and phenotypic data. It is the first CSF collection prospectively designed for longitudinal sampling and having matching MRI data. Mutant huntingtin protein (mHTT) can be quantified in CSF and has been identified as having high potential as a biomarker of HD progression. Further, the interpretation of drug-induced lowering of mHTT in the CNS relies upon elucidation of the natural history of CSF mHTT in HD gene carriers. Neurofilament light (NfL) has emerged as a promising marker of neuronal damage that can be measured in CSF and blood. This thesis includes the first reports of blood NfL in HD, head to head comparison of NfL and mHTT, and assessment of longitudinal alterations in mHTT and NfL, in addition to proposed biomarkers of specific pathogenic pathways. The work in this thesis will have significant implications for the use of NfL and mHTT as pharmacodynamic markers of HD.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Development of biofluid biomarkers for Huntington’s disease
Event: UCL (University College London)
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/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
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases
URI: https://discovery.ucl.ac.uk/id/eprint/10097682
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