Verber, Nick (2021) Biochemical biomarkers of disease in a deeply-phenotyped cohort of patients with motor neuron disease. PhD thesis, University of Sheffield.
Abstract
Background Motor neuron disease is a fatal, neurodegenerative condition in which patients suffer progressive weakness due to loss of motor neurons. Biomarker research deepens disease understanding through exploration of pathophysiological mechanisms which, in turn, highlights targets for novel therapies. Aims and objectives a) To recruit patients with motor neuron disease and control subjects, collate clinical information and collect biosamples. This will form a comprehensive database of well- phenotyped patient information and biosamples for analysis. b) To explore the concentrations of 3-nitrotyrosine in cerebrospinal fluid (CSF) and serum across the subject cohorts. A sensitive biomarker of oxidative stress will be of use in experimental medicine studies aimed at reducing this mechanism of nerve injury. c) To explore the inflammatory milieu present in serum and CSF using multiplex enzyme-linked immunosorbent assays (ELISAs). d) To develop Raman spectroscopy as a tool to analyse biofluid samples. Results The AMBRoSIA study proved to be a successful recruitment method, with a high proportion of subjects donating the full complement of clinical information and biosamples. 3- nitrotyrosine was not reliably detected in these samples. Neurofilament light chain emerged as a consistently useful biomarker in terms of differentiating patients from controls and clinical correlations. Provisional analyses yielded several inflammatory biomarkers that were differentially expressed; many of these did not survive conservative statistical corrections or repeated experimentation, however. Plasma monocyte chemoattractant protein-1 (MCP-1), interferon-gamma (IFN-γ) and CSF tyrosine-protein kinase receptor (TIE-2) were differentially expressed, and serum amyloid-A (SAA) inversely correlated with disease severity. Raman spectroscopy was moderately successful in demonstrating the ability to differentiate between subject groups. Conclusions This body of work supports systematic patient recruitment and collection of clinical data and biosamples to identify biomarkers. electrochemiluminescent-ELISA is a sensitive and capable multiplex platform for analysis of biofluids. Raman spectroscopy is a promising technique and further development is required. Additional multi-centre recruitment and sample testing is still required for the development and validation of biomarkers in motor neuron disease.
Metadata
Supervisors: | Shaw, Pamela and Alix, James and Collins, Mark |
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Awarding institution: | University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield) |
Identification Number/EthosID: | uk.bl.ethos.852136 |
Depositing User: | Dr Nick Verber |
Date Deposited: | 08 Apr 2022 14:43 |
Last Modified: | 01 Jun 2022 09:54 |
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