Systemic inflammation and disease progression in Multiple Sclerosis

Abstract

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterised by immune-mediated demyelination and neurodegeneration causing neurological and physical disability. The mechanisms leading to disease progression are not fully understood.
Here it is hypothesised that systemic inflammation is associated with disease progression in MS. With this in mind, the aims of this thesis were to (1) develop a method to measure systemic inflammation longitudinally, (2) relate systemic inflammation to brain atrophy rates in MS, and (3) relate systemic inflammation to disability progression in MS. Since extracellular haemoglobin has been associated with progression in MS, a novel mechanism linking systemic inflammation and erythrocyte fragility is explored.
In this thesis, my initial focus is on method development. Firstly, I show that monitoring urinary neopterin to creatinine ratio (UNCR) using ultra-performance liquid chromatography - mass spectrometry (UPLC-MS) is a useful and robust method of measuring systemic inflammation. Secondly, I show that remote physical activity monitoring can be used to track disability progression in people with progressive MS.
Employing these methods, I then proceed to address the primary hypothesis in individuals with progressive MS. I find that background systemic inflammation, as measured by UNCR, and cognitive function are linked and that the magnitude of the host immune response to both symptomatic and unknown systemic inflammatory events correlates with brain atrophy rate in persons with annual brain atrophy of less than 0.4%. However, the clinical significance of this appears
vi
minor and there is no role for systemic inflammation in overall disability progression.
In a prospective study I demonstrate that in vitro erythrocyte fragility is linked to systemic inflammation as measured by UNCR. Using UK Biobank data, I confirm an association between reticulocyte count and C-reactive protein in health and disease. Finally, I provide evidence supporting causation of haemolysis by systemic inflammation in a preclinical animal model.
In summary, neurodegeneration in individuals with progressive MS may be impacted by both symptomatic and unknown, or asymptomatic, systemic inflammatory events. Further work is required to establish the importance of erythrocyte fragility in MS disease pathology and progression.

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Identifiers

ORCID for Charlotte Stuart: orcid.org/0000-0002-5779-5487

ORCID for Ian Galea: orcid.org/0000-0002-1268-5102

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