Next generation biomarkers to understand early multiple sclerosis

Martin, Sarah-Jane (2021) Next generation biomarkers to understand early multiple sclerosis. PhD thesis, University of Glasgow.

Abstract

Multiple sclerosis (MS) is increasingly treatable. However, highly efficacious treatments carry serious potential risks. Treatment decisions must therefore weigh up the risk of treatment with the risk of irreversible disability. Current prognostic tools do not fully capture the scope of the pathology of MS, particularly axonal loss (an important substrate of disability). As a result, the identification of individuals at greatest risk of poor prognosis is suboptimal, and treatment decisions can be difficult and inconsistent. There is therefore an unmet need for a clinical tool or biomarker which can be employed early in the disease to identify those at greatest risk of future disability. New technologies and techniques have the potential to address this unmet need but require careful analysis in large cohorts. The aim of this work was to establish a large cohort of relapsing remitting MS patients at the point of diagnosis and whilst treatment naïve, and then to explore the potential role of next-generation biomarkers in early relapsing remitting multiple sclerosis.

We focused on fluid biomarkers reflective of axonal damage, and in particular neurofilament (NfL). We evaluated the role of CSF NfL in MS subtypes through systematic review and meta-analysis and concluded that NfL has utility as a biomarker of acute disease activity. We then employed a single molecule array (Simoa) to demonstrate NfL can be measured in blood, and that blood NfL levels correlate with CSF NfL levels.

The extent to which demyelination drives axonal loss in MS is unknown. We combined analysis of blood NfL levels with advanced magnetic resonance imaging (MRI) techniques of myelin integrity- the MRI g-ratio, to examine, in vivo, the relationship between myelin integrity and axonal damage. The MRI g-ratio was higher (suggesting loss of myelin integrity) in MS lesions compared with normal appearing white matter, but varied between individuals. We showed an association between lesion volume, lesion MRI g-ratio, and blood NfL levels. This demonstrates how blood-based biomarkers can be combined with advanced imaging biomarkers to gain insights into clinically relevant biology of disease.

Finally, we asked whether the additional measurement of other brain proteins, such as glial fibrillary acidic protein (GFAP), could provide further insights into disease biology and clinical outcomes. Longterm follow-up of the Future MS cohort will identify whether the biomarker trends found in this work continue to be relevant in the identification of patients at the greatest risk of poor prognosis from relapsing remitting multiple sclerosis.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Multiple sclerosis, neurofilament, biomarkers.
• Subjects: Q Science > QP Physiology; R Medicine > R Medicine (General); R Medicine > RZ Other systems of medicine
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Funder's Name: Anne Rowling Clinic for Regenerative Medicine, University of Edinburgh, UNSPECIFIED
• Supervisor's Name: Hunt, Professor David, Overell, Dr. James and Willison, Professor Hugh
• Date of Award: 2021
• Depositing User: Dr Sarah-Jane Martin
• Unique ID: glathesis:2021-82065
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 29 Mar 2021 11:11
• Last Modified: 29 Mar 2021 11:18
• URI: https://theses.gla.ac.uk/id/eprint/82065

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