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Toscano et al. Neuroimmunol Neuroinflammation 2021;8:14-41 I http://dx.doi.org/10.20517/2347-8659.2020.12 Page 31

CONCLUSION
Research on biological markers is very active and current. At present, there are few molecules available,
considering the hundreds under investigation. But they are continuously increasing due to a greater
knowledge of MS and its underlying physiopathology. For instance, there are no clinically useful disease
activity biomarkers, despite the large number of exploratory molecules described for this functional group.

As for the group of diagnostic biomarkers, previously dominated by IgG OCB analysis, the possibility to
rely on quantitative, less expensive and less time-consuming assessments as a first-line screening, is moving
forward.

[15]
Though it is true that CSF is the most suitable means for getting information about CNS physiopathology ,
it is equally true that much of interest is moving towards serum biomarkers. For quite some time, their
clinical use has been limited by both a greater variability and very low concentrations, a problem overcome
by the introduction of increasingly sophisticated tools (e.g., the detection of serum NF-L levels through
Simoa) [222] . Furthermore, treatment response biomarkers, such as anti-IFN-β and anti-NTZ antibodies,
are mainly determined in serum and have not been included in this review, which is focused on CSF
biomarkers. Despite requiring a more invasive approach, CSF still represents a unique source of data about
[4]
the CNS, enough to have been defined as a “liquid biopsy” of CNS . This is even more true since the
histological analysis of brain tissue cannot be routinely performed and almost any study on new potential
biomarkers has to start from CSF analysis. There is no doubt that we are now able to diagnose and treat
patients in early phases and even wondering about treating asymptomatic patients with only radiological
signs suggestive of the disease. Thinking of how MS diagnosis has been revolutionized by MRI in the last
20 years, it would not be impressive if new and promising biomarkers might lead to a new revolution in MS
in the coming years.

HIGHLIGHTS
1. CSF is a unique source of potential biomarkers for MS, despite requiring a certain invasiveness for its
collection.
2. Only CSF diagnostic biomarkers are currently used in clinical practice, though hundreds of molecules
have been validated as disease activity and prognostic biomarkers.
3. IgG OCB maintain a prominent role as a validated diagnostic biomarker and are considered an
alternative tool to MRI which can substitute for dissemination in time according to the 2017 revision of
McDonald criteria. They also retain a prognostic role for conversion to MS when detected in patients with
CIS.
4. NF-L has proved to be a useful biomarker as indicator of disease activity in MS. The possibility of
measuring NF-L at different time points through serum detection makes it also suitable for the monitoring
of treatment response.
5. KFLC index has proved to be a more sensitive but less specific diagnostic biomarker compared with IgG
OCB, representing a potential first-line assessment in patients with suspected MS and reducing the request
for IgG OCB analysis. It has a role as a prognostic for CIS conversion biomarker as well, but the lack of a
universal cut-off value still represents a limit.
6. IgM OCB show good potential as a prognostic biomarker, since they are associated with an aggressive
disease course, a higher risk of conversion to MS in CIS patients, disability progression and conversion to
SPMS.
7. Several disease activity biomarkers seem promising, though requiring further validation. Increased levels
of NO metabolites, OPN, MBP, MMP-9, N-CAM, CXCL13 and CHI3L1 have been detected in a close
temporal correlation with relapses.