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Page 30 Toscano et al. Neuroimmunol Neuroinflammation 2021;8:14-41 I http://dx.doi.org/10.20517/2347-8659.2020.12

study by Ferraro and coworkers, the identification of CSF IgM OCB in CIS patients was predictive of
the occurrence of another relapse within a year [253] . Results from a blinded multicenter study involving
52 neurological patients and 13 centers confirmed the reproducibility of the test [254] . However, further
confirmatory studies in additional cohorts are needed, and IgM OCB detection currently has an
[3]
intermediate level of evidence as a predictive biomarker for CIS conversion .

The presence of CSF IgM OCB has been also associated with a severe disease course in RRMS patients,
while it seems to be less frequent among PPMS compared with RRMS ones [255] . Strong evidence of its value
as a prognostic biomarker for RRMS exists [3,249] , so its potential clinical implementation has to be evaluated.

Finally, there is little evidence for the possible interactions between DMDs and CSF IgM OCB. The
response to IFN-β treatment in RRMS seems to be reduced in patients exhibiting CSF lipid-specific IgM
OCB, who showed a minor reduction in relapse rate and a higher probability of achieving greater EDSS
values [256] .

NTZ has proved to reduce serum IgM and IgG levels after 2 years of treatment in a time-dependent
manner [257] . In a study by Villar and coworkers, NTZ determined a decrease in CSF IgM OCB in patients
with no active disease, with complete disappearance in 70% of them, while no effects were reported in
those with active disease [258] .

Glial fibrillary acidic protein
Glial fibrillary acidic protein (GFAP) is highly expressed in the cytoskeleton of astrocytes, and it belongs
[259]
to the family of intermediate filaments, which are highly cell type specific . Since GFAP is upregulated
in astroglial cell activation (astrogliosis), occurring in many inflammatory and non-inflammatory
diseases [167,259-261] , it has been explored as a biomarker for MS. Particularly, reactive astrocytes proved to
be actively involved in neurodegenerative diseases, probably losing their protective role and developing
neurotoxic functions [262-264] . The glial scar itself, which physically protects a damaged area, may also
physically obstruct remyelination [264] . Finally, A1 astrocytes were found in MS lesions, as in EAE models
where they were associated with neuronal and oligodendrocytic death [262] . On the basis of these remarks,
an association between GFAP and disability in MS has been investigated. Elevated CSF GFAP levels were
found in MS patients compared with controls [265-267] , showing higher concentrations in patients with EDSS
greater than 6.5 compared with those with minor disability [266] . In a study by Högel and coworkers, serum
levels of GFAP proved to be associated with a greater EDSS score as well, but also with longer disease
duration and progressive course [268] . On this issue, positive correlations have been found between CSF
GFAP and disease duration, likewise between serum GFAP and disease severity, in a cohort of 93 PPMS
patients [264] . In a study by Axelsson and coworkers, the increased levels of GFAP in MS patients were
predictive for disability resulting 8-10 years later, confirming the association of this molecule with disability
and progression in MS patients [267] . A similar result was obtained in a more recent longitudinal study
involving 301 patients with CIS/MS with a mean follow-up time of 11 years, showing a correlation between
GFAP levels and an early progression in the EDSS score [234] . However, further studies are needed to confirm
its role as a prognostic biomarker for MS.

Evidence of an association between GFAP and high disease activity also exists, showing correlation with
MRI parameters such as infratentorial chronic lesion load and the intensity of Gd+ in both CIS and RRMS
patients [269] . Effectively, there is evidence that GFAP may increase in CSF and serum soon after (4-24 h)
traumatic brain injuries, as a marker of acute lesion [261] . Due to its high cell type specificity and good
correlation with neuronal degeneration, GFAP is currently considered a potential prognostic biomarker for
progression .
[4]