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Page 26 Toscano et al. Neuroimmunol Neuroinflammation 2021;8:14-41 I http://dx.doi.org/10.20517/2347-8659.2020.12

In animal models, increased N-CAM expression has been identified in astrocytes in acutely demyelinated
[178]
[179]
areas and, similarly, in areas damaged by kainic acid . Soluble forms of N-CAM have also been found
to be involved in peripheral nerve myelination and repair, with Schwann cells expressing specific receptors
for the molecule [177] . Both soluble and membrane-bound forms of this molecule exist, with different and
[180]
little known expression and specific functions, and N-CAM belongs to the immunoglobulin superfamily .
Normal CSF values of soluble N-CAM range between 460 and 1,060 ng/mL . Among several neurological
[177]
diseases, CSF levels were found to be reduced in MS patients, who showed a mean value of 250 ± 107 ng/mL,
compared with healthy controls (mean value of 412 ± 109), with similar findings when comparing patients
affected by Alzheimer’s disease and meningitis with controls, regardless of age and gender [180] . Moreover,
PPMS patients exhibited lower levels compared with RRMS ones [181] . These data confirmed the results of a
previous study showing lower soluble N-CAM concentrations in non-acute phase MS patients compared
with controls and acute-phase MS patients [182] . In the last group, indeed, increased CSF N-CAM levels
were noted, gradually increasing in the first week after relapse and correlating well with the remission of
symptoms [183] . Moreover, comparing acute-phase patients who underwent steroid treatment with those who
did not, significantly greater values were recorded in the first group [183] . However, steroid treatment does
not determine an increase in N-CAM levels in itself, and this finding was not reported in non-acute phase
MS patients who were treated [183] .

Among DMDs, NTZ and mitoxantrone proved to significantly increase N-CAM levels in MS patients,
while fingolimod did not [181] .

Considering the evidence of lower N-CAM levels in PPMS compared to RRMS [181] , in RRMS compared to
CIS, and in polyneuropathy compared to Guillain-Barré syndrome [180] , this molecule is actually considered
mainly as an indicator of scarce repair capability more than a marker of severe neuronal damage [180] .
However, it is not currently used in clinical practice and needs further validation [1,184] .

Chitinase-3-like-1
Chitinase-3-like-1 (CHI3L1) (or YKL-40) belongs to the family of chitinases, enzymes that catalyze the
cleavage of chitin by hydrolysis. Its biological role in humans has not been definitely clarified, despite many
proofs of its involvement in several processes exist, such as tissue remodeling, angiogenesis, tumorigenesis
and inflammation [185] . Belonging to the same family, chitotriosidase is known to be associated with several
diseases, including infectious and inflammatory ones [186] .

Though it is not a specific marker for MS, CSF CHI3L1 levels have been found to be increased in RRMS
and NMO patients compared with controls, including healthy people, patients suffering from other
inflammatory diseases and SPMS patients [185,187,188] . Conversely, serum CHI3L1 levels were not significantly
different between groups in the aforementioned studies [185,187] . Elevated levels of CHI3L1 were also detected
in both PPMS and SPMS compared with healthy controls [189] . Patients who fulfilled diagnostic criteria for
active progressive MS or showed elevated levels of MMP-9 and CXCL13 also had higher concentrations of
CHI3L1 [189] . However, as a diagnostic biomarker, CHI3L1 needs further replication in additional cohorts .
[3]

Particular attention has been given to the prognostic role of this molecule, whose CSF concentration has
proved to be an independent predictor for the risk of conversion to clinically definite MS in CIS [187,190-192] ,
[32]
but not in RIS . In a study by Comabella and coworkers, CSF CHI3L1 levels additionally correlated
with shorter latency time of conversion and with disability progression during follow-up and radiological
disease activity [190] .

In a large multicenter study involving 813 patients with CIS, the aforementioned results were confirmed.
Not only CSF CHI3L1 concentration was associated with the risk of conversion to clinically definite MS,