Multiple Sclerosis Journal - October 2017 - 1442

709362
research-article2017

MSJ0010.1177/1352458517709362Multiple Sclerosis JournalN Dubuisson, F Puentes

MULTIPLE
SCLEROSIS
JOURNAL

MSJ

Topical Review

Science is 1% inspiration and 99% biomarkers
Nicolas Dubuisson, Fabiola Puentes, Gavin Giovannoni and Sharmilee Gnanapavan

Abstract: Neurodegeneration plays a key role in multiple sclerosis (MS) contributing to long-term disability in patients. The prognosis is, however, unpredictable coloured by complex disease mechanisms
which can only be clearly appreciated using biomarkers specific to pathobiology of the underlying process. Here, we describe six promising neurodegenerative biomarkers in MS (neurofilament proteins,
neurofilament antibodies, tau, N-acetylaspartate, chitinase and chitinase-like proteins and osteopontin),
critically evaluating the evidence using a modified Bradford Hill criteria.

Multiple Sclerosis Journal
2017, Vol. 23(11) 1442-1452
DOI: 10.1177/
https://doi.org/10.1177/1352458517709362
1352458517709362
https://doi.org/10.1177/1352458517709362
© The Author(s), 2017.
Reprints and permissions:
http://www.sagepub.co.uk/
journalsPermissions.nav

Keywords: Neurodegenerative biomarkers, multiple sclerosis, tau, chitinase and chitinase-like proteins,
neurofilaments, neurofilament antibodies
Date received: 6 January 2017; revised: 16 April 2017; accepted: 20 April 2017
Introduction
Over the last decade, we have learnt that multiple
sclerosis (MS) is both an inflammatory demyelinating disorder and a neurodegenerative one. However,
endeavours to answer precisely what is neurodegeneration in MS have been met with only partial success. The race to reach the finish line has meant that
researchers have had to be more knowledgeable
about the molecular and cellular basis of disease
than ever before. Biomarkers are at the forefront of
scientific discovery, medical diagnosis and treatment, and with this knowledge comes progress.
A field which has greatly benefited from the use of
biomarkers has been cancer research, where biomarkers such as prostate-specific antigen (PSA), for
example, are currently utilized in screening programmes and personalized care.
We are currently standing at the cusp of a biomarker
revolution from the perspective of critical mass,
and also from a technological standpoint with more
resources available to measure physiological and
pathological changes in the human body than ever
before.
In principle, a biomarker is a 'characteristic that is
objectively measured and evaluated as an indicator
of normal biological processes, pathogenic processes
or pharmacological responses to a therapeutic intervention'.1 There needs to be a sensible format for
assessing biomarkers in a critical way. Using a modified version of the Bradford Hill criteria,2 we ask the

1442

question whether there are biomarkers of neurodegeneration that meet the criteria? Namely, is there
sufficient biological plausibility (i.e. a relationship
between the biomarker and effect), strength and
specificity of association, consistency of findings,
temporal sequence (the effect follows the change in
biomarker) and a biological gradient (a proportionate
relationship between the biomarker and effect)?
Biomarkers
Below, we discuss six promising biomarkers of
neurodegeneration in MS (Figure 1). Lesser wellcharacterized biomarkers are detailed in Table 1.

Correspondence to:
S Gnanapavan
Department of Neuroscience
and Trauma, Blizard Institute,
Queen Mary University of
London, London E1 2AT,
UK.
s.gnanapavan@qmul.ac.uk
Nicolas Dubuisson
Fabiola Puentes
Gavin Giovannoni
Sharmilee Gnanapavan
Department of Neuroscience
and Trauma, Blizard Institute,
Queen Mary University of
London, London, UK

Neurofilaments
Biological plausibility. Axonal calibre and functionality are determined by proteins such as microtubules,
neurofilaments, actin and tau protein. Neurofilaments
(Nf) consist of the subunits light chain (neurofilament
light (NfL)): 68-70 kDa, medium chain (neurofilament
medium polypeptide (NfM)): 145-160 kDa and heavy
chain (neurofilament heavy (NfH)): 200-220 kDa.33-35
Axonal damage in MS results in the release of the
neurofilaments.36 Only NfL chain and heavy chain are
stable enough to be measured in immunoassays.37,38
Strength and specificity of association. High cerebrospinal fluid (CSF) NfL correlates with relapse
activity, formation of new and gadolinium-enhancing
magnetic resonance imaging (MRI) lesions39,40 and

journals.sagepub.com/home/msj
https://uk.sagepub.com/en-gb/journals-permissions https://uk.sagepub.com/en-gb/journals-permissions https://journals.sagepub.com/home/msj
Table of Contents for the Digital Edition of Multiple Sclerosis Journal - October 2017
