Visual Outcome Measures of Remyelination and Neuroprotection in Multiple Sclerosis

One of the most tractable ways to delay, prevent or reverse multiple sclerosis (MS) disability progression is by harnessing therapies capable of enhancing endogenous remyelination. Recent trials of remyelination-promoting drugs have marked the beginning of a new phase in the development of treatments capable of repairing MS damage (Green et al., 2017, Cadavid et al., 2019, Cadavid et al., 2017, Brown et al., 2021). However, the optimum method to measure remyelination in people is unknown, presenting a risk of missing a clinically important effect in clinical trials of remyelination. The visual pathway has been identified as a promising target for the assessment of myelin and axon health. This is because it is often involved in the course of MS, recovery from inflammatory demyelination in the visual pathway is often incomplete, and multiple non-invasive, inexpensive measures that can be readily used for functional and structural assessment of the visual pathway already exist. These include visual evoked potentials (VEP), optical coherence tomography (OCT), visual acuity and colour vision. It remains unclear which visual outcome measure, if any, is best suited for assessment of remyelination and neuroprotection for use in MS research and clinical trials of remyelination. During my PhD, I collected VEP, OCT, visual acuity, colour vision, oculometry, and blood biomarker measures on approximately 180 people with MS and 30 healthy volunteers across three clinical studies. My findings suggest that there is no single visual outcome measure that should be used in isolation for MS clinical research and trials of MS remyelination. Rather, a combination of visual outcome measures should be used, to build a comprehensive picture of myelin and axonal health. VEP, both full-field (FF-VEP) and multi-focal (MF-VEP), was found to be a highly valid and reproducible measure of myelin and axon status, capable of identifying visual pathway demyelination and neurodegeneration in MS and correlating with other structural and clinical function measures of the visual pathway. Although useful in providing a more precise evaluation of the full visual field that is less affected by macular overrepresentation and phase-cancellation, MF-VEP was particularly taxing in terms of fatigue, comfort, and difficulty. Additionally, MF-VEP took investigators the longest to conduct. The decision to include MF-VEP as an outcome measure in remyelinating trials might therefore ultimately come down to overall patient burden when considering all other trial procedures involved. A noted additional challenge to the use of VEP (both FF- and MF-) across multi-centre studies is the reproducibility of data as conducted by different investigators. OCT was also found to be a highly valid and reproducible structural measure of axonal integrity and correlated with functional measures of visual integrity such as VEP as well as clinical measures of visual performance such as colour vision and acuity. Because of its ease of use, and reproducibility, it is an optimal measure for the assessment of neuroaxonal integrity in MS participants. In the context of remyelinating-promoting trials, OCT is best reserved to ensure there is adequate axon scaffolding for remyelination to occur, rather than to demonstrate a direct remyelinating treatment effect in short-duration trials. Visual acuity and colour vision were both sensitive to identifying visual pathway involvement as a result of MS pathophysiology. Both visual performance measures correlated with functional and structural measures of VEP and OCT. Although colour vision as assessed via the Cambridge Colour Test (CCT) was considered to be amongst the most difficult assessments to be completed by our participant population, ease of use of both tools by part of the clinical investigator, and ease of interpretation of outputs renders both of these measures useful in the context of clinical trials of remyelination. With regards to more novel measures of remyelination, our findings suggest that saccadic latency as measured via oculometry, may be a relevant outcome measure for the assessment of afferent and efferent visual pathway involvement in MS. However, this measure was associated with a less positive patient experience given the comfort and time required to conduct. Finally, serum neurofilament light chain (NfL), global fibrillary acidic protein (GFAP) and Tau blood biomarkers were not responsive indicators of treatment efficacy in the Cambridge Centre for Myelin Repair study One (CCMR-One), a Phase IIa randomised, controlled trial assessing bexarotene as a remyelinating drug. These particular blood biomarkers may be better suited for longer-duration trials. When correlated to VEP, only NfL was suggestive of a potential remyelinating-induced neuroprotective effect as driven by bexarotene. Whilst this gives us confidence in biomarkers of neurodegeneration, a blood biomarker that is both sensitive and specific to remyelination is still needed. Overall, we established visual outcome measures to be clinically useful, reliable, and reproducible measures reflective of MS demyelination and axonal degeneration. Further longitudinal analysis of these measures in MS will enable a more comprehensive understanding of the influences driving heterogeneity in remyelination capacity. Paving the way for a more personalised treatment approach in MS.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2025

Author dc:creator

• Riboni Verri, Gioia

Advisor dc:contributor.advisor

• Coles, Alasdair

• Multiple Sclerosis
• Neuroprotection
• Remyelination
• Visual Outcome Measures

Licence

• https://www.repository.cam.ac.uk/bitstreams/f1359ab6-1bb7-451b-919f-624ef07d11ba/download
• http://purl.org/NET/rdflicense/allrightsreserved

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.118989

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/385325