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Molecular determinants of axonal loss in the multiple sclerosis spinal cord

19 May 2023

A molecular-level study of MS progression by looking at symptoms present in the spinal cord, to investigate ways to identify, diagnose and treat the condition.

MS Research is supporting an exciting project from the Nuffield Department of Clinical Neurosciences at the University of Oxford. The one-year laboratory study, Molecular Determinants of Axonal Loss in the Multiple Sclerosis Spinal Cord, looks at deeply characterised spinal cord samples, which show signs of progressive pathological features including inflammation, demyelination and nerve fibre degeneration. The study is led by Professor Gabriele De Luca with PhD researcher Alex Waldman and incoming PhD student and Research Assistant, Aimee Avery.

Basis for the Research

While most people with MS initially experience symptoms that wax and wane (i.e. relapsing-remitting MS), many people will enter the progressive phase after about 15 years. The progressive phase disproportionately impacts the spinal cord and is associated with the accumulation of irreversible disability, such as loss of mobility.

Permanent damage to the spinal cord is hypothesised to be caused by a triad of causes including:

1) long-standing inflammation,

2) loss of nerve fibre insulation (or demyelination)

3) degeneration of nerve fibres themselves.

However, molecular biomarkers (e.g. biological indicators taken from say samples of tissue, blood or DNA) of these causes have remained elusive.

As a result, the research community is currently unable to identify people with MS at the greatest risk of progressing to severe disease (e.g. SPMS or PPMS). Further, we do not have effective therapies that prevent ongoing progressive inflammation, demyelination, and degeneration.

Methods & Scope

To address these limitations, the researchers are studying deeply characterised spinal cord material that show signs of the above progressive pathological symptoms. This is done through histological (studying cells and tissues under a microscope) and antibody-based immunohistochemistry (the use of antibodies to check for antigens in a tissue sample).

There is substantial biological variation between people with MS who display similar levels of disability in the clinic. According to the researchers, the use of ‘insensitive analysis methods’ have so far frustrated the medical research community’s ability to reliably detect and reproduce the underpinnings of MS progression. The researchers have therefore generated detailed quantitative information about many pathological variables relevant to MS, such as inflammation, demyelination, and degeneration.

“To do this”, says Alex, “we are using histological [studying cells and tissues under a microscope] and antibody-based immunohistochemistry [the use of antibodies to check for antigens in a tissue sample]. We have generated detailed quantitative information about pathological variables relevant to MS, and we will use this information to select cases to study using advanced single-cell and spatial gene expression methods.”

These advanced gene mapping techniques form a ‘pathologically-informed’ approach, by which the study selects relevant cases based on the pathological criteria to compare varying levels of MS progression. This allows the researchers to control for biological variation (i.e. study differences in MS progression across individuals to better understand differences in symptom presentation) which is often seen in studies of people living with MS.

Aims of the Study

“We hope to identify potential molecular biomarkers”, says Alex. That is using DNA, RNA, protein etc benchmarks to test disease progression, “of MS spinal cord pathology [spinal evidence of disease progression] to cast light onto the possible reasons behind disease progression”. Ultimately the researchers hope these can be used to clinically monitor the prediction and diagnosis of MS and/or be targeted for developing effective therapies.

MS Research will provide periodical updates on this study as and when we are able. We are very excited about the potential of this research to benefit the MS community and wish the researchers the best of luck in seeking such positive outcomes.

 

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