Woollacott, Ione Olivia Clara;
(2021)
Neuroinflammation in frontotemporal dementia.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Frontotemporal dementia (FTD) is a clinically and pathologically diverse disease with few reliable biomarkers and no effective treatments. Increasing evidence suggests that chronic neuroinflammation and microglial dysfunction contribute to disease, particularly in genetic FTD due to progranulin (GRN) mutations. This thesis examines the clinical, histological and fluid biomarker evidence of immune dysregulation and neuroinflammation in FTD, with a focus on microglia. Assessment of systemic autoimmune diseases in individuals with genetic FTD demonstrates that non-thyroid autoimmune diseases are more prevalent in GRN mutation carriers than controls. Exploration of the histopathological correlates of MRI white matter hyperintensities (WMH) in a patient with FTD due to a GRN mutation links severe WMH in the frontal lobes to extensive white matter demyelination and microglial dystrophy. Immunohistochemical assessment of microglia in frontal and temporal post-mortem brain tissue from individuals with different sporadic and genetic subtypes of frontotemporal lobar degeneration (FTLD), Alzheimer’s disease (AD) and controls demonstrates regional differences in microglial burden, activation and dystrophy, which vary by microglial phenotype, pathological subtype and disease mechanism. Measurement of levels of glia-derived biomarkers (sTREM2, YKL-40 and chitotriosidase) in cerebrospinal fluid (CSF) of individuals with sporadic and genetic FTD and controls shows that levels are elevated in certain subgroups, particularly in those with GRN mutations, or likely underlying AD rather than FTLD. Investigation of these biomarkers in CSF of presymptomatic mutation carriers (PMC) and symptomatic individuals with genetic FTD reveals raised chitotriosidase levels in GRN and MAPT mutation carriers with FTD, with elevation several years before expected onset in GRN PMC. In conclusion, this thesis provides multimodal evidence of dysregulated neuroinflammation in FTD and highlights the role of microglial dysfunction and senescence in the pathogenesis of FTLD, particularly in GRN mutation carriers. Further investigation of these processes may guide therapeutic and biomarker approaches for use in future clinical trials.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Neuroinflammation in frontotemporal dementia |
| Event: | UCL (University College London) |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. 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 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/10122281 |
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