Jabbari, Edwin;
(2020)
The fluid biomarker and genetic determinants of phenotype and survival in progressive supranuclear palsy.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Progressive supranuclear palsy (PSP) is a neurodegenerative disorder and common cause of atypical parkinsonism (APS), with an estimated prevalence of 5-7 per 100,000. The pathology of PSP is centred on the microtubule associated protein tau, encoded by MAPT. Richardson’s syndrome (PSP-RS) is the classical clinical phenotype related to PSP pathology. Recently, variant clinical phenotypes related to PSP pathology have been operationalised in the 2017 Movement Disorder Society diagnostic criteria. Early and accurate clinical diagnosis of PSP is challenging as there is heterogeneity within PSP and significant clinical overlap with other neurodegenerative conditions including Parkinson’s disease (PD) and frontotemporal dementia. Fluid biomarker studies have identified that levels of CSF and plasma neurofilament light chain (NF-L) are able to differentiate PSP-RS from PD and controls but are unable to differentiate PSP from other causes of APS. Case-control genome-wide association studies using pathologically confirmed PSP cases have identified risk loci at MAPT, MOBP, STX6 and EIF2AK3. In addition, studying the progression of neurodegenerative disorders is central to discovering determinants of disease progression and assessing the effects of therapeutic interventions. During this PhD I have: 1) Used baseline data from the PROSPECT study to highlight distinct clinical trajectory, cognitive, neuroimaging and fluid biomarker profiles of different PSP subtypes. 2) Used baseline CSF and plasma NF-L to predict survival in PSP, and used proximity extension assay to discover novel diagnostic biomarkers of APS. 3) Defined early onset PSP and characterised its genetic and clinico-pathological profile. 4) Discovered the TRIM11/17 locus as a genetic determinant of PSP phenotype, and the LRRK2 locus as a genetic determinant of survival in PSP.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The fluid biomarker and genetic determinants of phenotype and survival in progressive supranuclear palsy |
| 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 > Clinical and Movement Neurosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10104891 |
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