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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 25

An increased expression of MMP-9 in active MS lesions and in active borders of chronic lesions has been
found in some studies employing brain tissue from MS patients [150,151] , confirming previous results and
corroborating MMP-9 as a potentially valid disease activity biomarker.

Some studies have explored the variations of MMPs levels in patients under DMDs. A significant decrease
in serum MMP-9 mRNA in RRMS patients under IFN-β has been noted after a 12-month follow-up by
Galboiz and coworkers [152] and confirmed by other studies [153] . Among these, changes in MMP-9 levels
occurred under IFN-β-treatment in a study by Comabella and coworkers, with a trend of reduction
during the first 3 months and then an increase until reaching baseline values. Worthy of note, a significant
increase in TIMP-1 concentrations occurred in the responder group compared with non-responders [154] .
A possible response to NTZ treatment has also been explored. Balasa and coworkers reported a significant
decrease in serum MMP-9 after 8 months of treatment and a good correlation between the biomarker
and disease activity [155] , but this finding was not confirmed by other studies [156] . In NTZ-treated patients,
decreased baseline levels of MMP-9 were found in patients who developed progressive multifocal
leukoencephalopathy compared with those who did not [157] .

However, additional studies are needed for its validation, providing evidence of its role as a potential
disease activity biomarker for MS.

Myelin basic protein
It has long been known that MBP is a potential disease activity biomarker for MS [158] , since it displays
an acute damage to CNS myelin, despite not being specific for the disease [159] . MBP is a polypeptide
that assures the preservation of myelin structure and membrane compaction [160] . Four human isoforms
are known, one of them prevailing in adult CNS myelin as a polypeptide containing 170 amino acid
residues [161] . MBP contains multiple epitopes, with the ones recognized by monoclonal and polyclonal
antibodies mainly allocated in 80-100 residues [161,162] . MBP-specific effector T lymphocytes have proved to
play an essential role in the pathogenesis of experimental EAE models [163] , which is rather suppressed when
T cells are inhibited by MBP-specific Tregs [164] .

Several studies have found increased CSF levels of MBP in patients with MS, temporally related to
relapses [158,159,165-167] and detectable up to 5-6 weeks later [168] . Accordingly, RRMS patients with disease
activity show higher values than progressive MS and stable patients [165] . CSF MBP concentrations are also
greater when polysymptomatic and severe relapses occur, correlating with EDSS score and MRI activity
and decreasing after corticosteroid treatment [168,169] . Zhou et al. [170] explored the association between MBP
gene variations and MS course in a 5-year prospective study involving 127 patients with CIS, identifying a
risk genotype (CT+TT of rs12959006) for the risk of conversion to MS, disability progression and relapses.
MBP-like material has been found in the urine of MS patients as well, although its concentration fluctuates
and does not seem to be temporally related to acute myelin damage. Conversely, higher values have been
found in SPMS patients and are supposed to be related to disease progression [161] . Considering the role of
MBP in the pathogenesis of MS and its potential role as a therapeutic target, several clinical trials have been
carried out or are currently ongoing to evaluate possible new drugs [171-174] . However, this biomarker has not
been validated and the preliminary results need to be replicated in additional cohorts.

Neuronal cell adhesion molecule
Neuronal cell adhesion molecule (N-CAM) is considered a marker of repair and remyelination [175] and it
[176]
is mainly expressed in the CNS, but its involvement in neoplastic diseases has also been documented .
During the development of the CNS, the polysialylated form of N-CAM is actively involved in myelination,
axonal growth and neural cell migration [177] . It has been found to be expressed by neural precursors of
oligodendrocytes, astrocytes and neurons, supporting the process of myelination in the olfactory bulb in
mouse brain [177] .