Heller, Carolin;
(2025)
Developing novel biomarkers of frontotemporal dementia.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Clinical trials for genetic frontotemporal dementia (FTD) are ongoing, yet many early phase studies have failed due to ineffective pre-selected clinical or surrogate endpoints. Unlike other neurodegenerative diseases, FTD lacks well-established biomarkers for diagnosis, staging, and disease progression, partly due to its heterogeneous nature. FTD can be sporadic or genetic, involve multiple proteinopathies, and present with varied clinical phenotypes, including motor symptoms, language problems, and personality changes. This thesis focuses on exploring dynamic fluid biomarkers in samples from the Genetic Frontotemporal Initiative (GENFI), the largest natural history study of genetic FTD in Europe and Canada. The GENFI Biobank, which I helped establish, forms centralised storage of biosamples collected using standardised GENFI protocols. These samples were used to explore biomarkers at baseline visits, but also investigate longitudinal changes in glial fibrillary acidic protein (GFAP) and neurofilament light chain protein (NfL). My research has helped to identify NfL as a disease staging marker, and GFAP as a promising biomarker to track disease progression, specifically in GRN-associated FTD. Therefore, these biomarkers will be useful in disease-modifying therapeutic trials, to identify the right time to administer treatment, track efficacy, and serve as surrogate clinical endpoints. Additionally, I will also explore novel biomarkers of FTD: cytokines from the vascular endothelial growth factor family in the cerebrospinal fluid of both sporadic and genetic FTD participants. Finally, I will examine the neurotrophin receptor p75 extracellular domain in a more distant sample type, urine, to see whether these samples collected as part of GENFI may be useful matrices to identify novel biomarkers, that have yet to be explored in FTD. These findings aim to impact future clinical trials to expedite access to therapeutic intervention for patients suffering from this devastating disease.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Developing novel biomarkers of frontotemporal dementia |
| Language: | English |
| Additional information: | Copyright © The Author 2025. 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 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 |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10210920 |
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