Towards Measures for Translation

: An Exploration of Neurophysiological Biomarkers of Disability in Multiple Sclerosis

Abstract

Multiple Sclerosis is the most common acquired cause of neurodegeneration and disability in young adults. Despite recent therapeutic advances in control of the initial inflammatory component, the progressive neurodegenerative aspect remains almost completely untreatable whilst conferring the greatest burden of disability, cognitive dysfunction and misery. Reliance on the current clinical measurement tools accepted by the Food & Drug Administration and European Medicines Authority has and will continue to prove prohibitive to rapid, sensitive and smaller scale clinical research in Progressive MS cohorts. We have sought to explore the utility of neurophysiological techniques to provide surrogate biomarkers which may predict meaningful clinical endpoints in Progressive Multiple Sclerosis; and which may therefore satisfy regulatory criteria for trial outcome measures and potentially enable an acceleration of translational therapeutic research. The central clinical outcomes of interest herein are disease related physical disability and cognitive dysfunction. We demonstrated that Multi-modality Evoked Potential batteries have a consistently meaningful correlation with ratings of physical disability amongst patients with a primary progressive phenotype and explored the nature and utility of this relationship longitudinally over an interval of three years. The relative superiority over conventional neuroimaging metrics derived from MRI was also assessed and reasons for such considered. The lack of association of long tract neurophysiological abnormality with Multiple Sclerosis related cognitive impairment identified herein prompted pursuit of alternate methods to index this disabling and complex problem. A composite psychometric outcome metric to quantify disease related cognitive impairment was derived against which outcomes from cognitive evoked potential and electroencephalographic connectivity analyses from a typical Multiple Sclerosis patient cohort were compared. The findings of such stimulated a reconsideration of the pathophysiological substrate underpinning cognitive impairment in Multiple Sclerosis and the development of a conceptual framework based on ‘disintegration’ rather than the contemporary model of ‘disconnection’. Empirical support for the emerging model was pursued in a final pilot study and plans for future endeavours in pursuit of the team objectives have been developed and are outlined herein.

Date of Award	7 May 2019
Original language	English
Awarding Institution	University of Bristol
Supervisor	David A Cottrell (Supervisor) & Alan L Whone (Supervisor)