Multiple Sclerosis Journal - October 2017 - 1454

713344
research-article2017

MSJ0010.1177/1352458517713344Multiple Sclerosis JournalR Kapoor

MULTIPLE
SCLEROSIS
JOURNAL

MSJ

Controversies in Multiple Sclerosis

Advanced MRI measures like DTI or fMRI
should be outcome measures in future clinical
trials - YES

Multiple Sclerosis Journal
2017, Vol. 23(11) 1454-1455
DOI: 10.1177/
https://doi.org/10.1177/1352458517713344
1352458517713344
https://doi.org/10.1177/1352458517713344
© The Author(s), 2017.
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Raj Kapoor
Neuroprotection and repair are two of the biggest
unmet therapeutic needs in people with progressive
multiple sclerosis (MS). Despite recent positive trials
of ocrelizumab and siponimod, the process of drug
discovery for these needs remains painfully slow and
difficult. This contrasts with the situation in relapsing
MS, where there is an efficient pathway for discovering drugs to prevent relapse: the effects of candidate
drugs on what has emerged as the dominant underlying pathology (inflammation) can be assessed with an
magnetic resonance imaging (MRI) biomarker (lesion
activity), which also correlates with meaningful clinical outcome (relapse).1
The situation is more complicated in progressive MS
because there are numerous mechanisms which contribute to neurodegeneration,2 and meaningful disability outcomes are still under discussion.3 Increasingly
sophisticated computational and phenotypic screens
are likely to generate drug candidates acting on some
of these mechanisms, including compartmentalized
and innate immunity, energy failure, ionic imbalances
and aspects of glial biology.2 Comparison with relapsing MS suggests that drug development would be
accelerated with rational pipelines that include biomarkers which are selected to measure the effects of
drugs on specific injury and repair mechanisms.
For now, neurodegeneration is generally assessed
using MRI techniques to measure atrophy, which integrates the end-stage consequences of diverse injury
mechanisms. However, atrophy is affected by tissue
hydration and by a complex interplay between volumes in multiple cellular compartments, limiting its
sensitivity and responsiveness, as well as the interpretation of volume changes shortly after treatment is
started. Furthermore, neural injury is likely to continue long after its cause is inhibited, leading to a
therapeutic lag which could delay any response of
atrophy to treatment by several years.4 It remains to
be seen whether these issues also place limits on more
refined techniques for tissue microstructure and cellular integrity such as magnetization transfer ratio
(MTR) and optical coherence tomography (OCT),
1454

which are outcomes in repair and progression trials
reporting in the intermediate future. However, even
with further technical refinements, measurements of
tissue structure alone may not be sufficiently specific
to enable shorter and smaller proof of concept trials in
progressive disease.
Tissue fluid biomarkers for injury mechanisms offer
greater pathological specificity and include nitric
oxide metabolites, chemokines associated with
intrathecal B lymphocyte activity, and neurofilaments
released by damaged axons. However, validation of
these biomarkers has proved difficult, and they usually need to be measured in the spinal fluid.

Correspondence to:
R Kapoor
The Queen Square Multiple
Sclerosis Centre, National
Hospital for Neurology and
Neurosurgery, Queen Square,
London WC1N 3BG, UK.
r.kapoor@nhs.net
Raj Kapoor
The Queen Square Multiple
Sclerosis Centre, National
Hospital for Neurology and
Neurosurgery, London, UK

Positron emission tomography (PET) offers highly
sensitive and specific information about tissue cellularity and metabolism. PET radioligands are available
for dissecting tissue metabolism, for myelin and neurons,5 and for activated microglia.6 Despite its attractions for dissecting mechanisms in early stage proof of
concept studies, however, wider implementation of
PET as an outcome in clinical trials, especially multicentre studies, is likely to be limited by its expense and
restricted availability, and by associated practical difficulties for establishing the validity of its outcomes.
OCT techniques are advancing rapidly, and in addition to providing sensitive measurements of neuronal
and axonal compartments, they have the potential to
study aspects of retinal metabolism. Despite correlations with central nervous system (CNS) outcomes,
however, acceptance of OCT outcomes may be limited by the ongoing debate about the extent to which
results in the visual system can be related to processes
in the wider CNS.
These limitations suggest that MRI techniques are
likely to provide the most practical approach for
developing biomarkers for drug pipelines in the
intermediate future. The main attraction of MRI
remains its ability to resolve structure, and MTR and
diffusion-based methods including tractography take
this further than conventional imaging. However,
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