Swift, Imogen Joanna;
(2024)
Developing novel fluid biomarkers for progranulin-associated frontotemporal dementia.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Frontotemporal dementia (FTD) is the second most common form of dementia in people under 65, where individuals present with behavioural, language and/or motor symptoms. Around a third to a half of all cases have a genetic component, largely caused by mutations in three key genes: chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) and microtubule-associated protein tau (MAPT). Research conducted in this thesis focused on progranulin-associated FTD (FTDGRN), where individuals have significantly reduced levels of the progranulin protein (PGRN), measurable in biofluids such as plasma and cerebrospinal fluid (CSF). This discovery formed the basis for several clinical trials aiming to treat FTD-GRN by increasing PGRN concentration. However, we currently lack robust and effective outcome measures to evaluate the efficacy of these treatments, including markers in human biofluids. Here, immunoassay and mass spectrometry methods were developed and tested to quantify a range of analytes related to FTD-GRN pathology and across different sample types. Biofluid samples and related data were collected from hundreds of individuals as part of the genetic FTD initiative and in collaboration with other international studies in the FTD prevention initiative. Project findings included significant differences in plasma PGRN concentration across different GRN mutation types and a novel clinical cut-off value established for both plasma and CSF PGRN, based on 3301 and 1346 participants, respectively. Results also showed significant differences between FTD-GRN and controls across several biofluid analytes of interest, including a significantly higher CSF concentration of PGRN-associated protein, prosaposin, in presymptomatic FTD-GRN and reduced CSF concentrations of granulin peptides and granin family member proteins in FTDGRN. These findings further our understanding of the underlying biology of this condition and provide promising biomarkers for use as outcome measures in existing clinical trials as well as potential targets for future therapies.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Developing novel fluid biomarkers for progranulin-associated frontotemporal dementia |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2024. 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 > 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 UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10194355 |
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