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Title: The fluid biomarker and genetic determinants of phenotype and survival in progressive supranuclear palsy
Author: Jabbari, Edwin
ISNI:       0000 0004 9353 3593
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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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.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available