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Bozzetti et al. Neuroimmunol Neuroinflammation 2021;8:1-13 I http://dx.doi.org/10.20517/2347-8659.2020.26 Page 9

target aquaporin-4, an integral membrane protein of astrocytes and ependymal cells of CNS, and have
[6]
pathogenic potential . As a consequence, soluble GFAP, which reflects astrocytic damage, has been
[86]
proposed as a useful disease-severity marker in subjects with AQP4-Abs related NMOSD . In addition,
subjects positive for both AQP4-Abs or MOG-Abs show an increase in CSF myelin basic protein in
[87]
comparison with MS cases, reflecting the concomitant presence of myelin injury . This concept is
supported by the demonstration that the main target in MOG-Abs related conditions is located on the
[88]
surface of myelin sheath and in the plasma membrane of oligodendrocytes .
In this scenario, the possible concomitant increase in biomarkers reflecting axonal damage (i.e., NfL) has
appeared worthy of investigation in the scientific community. A possible implication of axonal damage
[87]
in patients with NMOSD was first suggested by Wang et al. , who demonstrated an increase in CSF
NfH and NfL in this disorder. However, this study did not explore serum NfL levels and also did not
distinguish patients according to antibody status, which might influence tissue damage according to the
specific target site. We recently analyzed serum NfL levels in patients with NMOSD and related disorders,
and when comparing AQP4-Abs-positive, MOG-Abs-positive and seronegative patients, we observed
increased serum NfL levels in patients with AQP4-Abs and MOG-Abs . In particular, we detected higher
[89]
NfL levels in AQP4-Abs-positive subjects, possibly reflecting the prominent axonal damage consequent
to astrocytic and cellular injury, and consequently explaining the severe clinical phenotype/evolution
usually described in these subjects. On the other hand, we also detected relatively increased levels of NfL
in MOG-Abs-positive patients, suggesting the concomitant presence of axonal damage in this disorder
[89]
and potentially explaining the long-term disability observed in some MOG-Abs-positive cases . We then
replicated these observations focusing on 38 MOG-Abs-positive patients and assessing serum and CSF
NfL concentration according to clinical/paraclinical characteristics to investigate NfL as a biomarker of
disease severity in this condition . We confirmed previous observations on the increase in serum NfL
[90]
levels in patients with MOG-Abs compared with healthy controls, providing more data on the concomitant
presence of axonal damage in this disorder. In addition, when analyzing both serum and CSF samples, we
observed a significant correlation between NfL levels in paired samples, supporting the analysis of serum
as a reliable and more accessible biological fluid. Even more interestingly, we demonstrated that serum NfL
[90]
values correlated with attack severity and might predict long-term outcome in patients with MOG-Abs .
These observations support the broader use of NfL as an accessible and repeatable biomarker of tissue
damage in MOG-Abs related conditions, where it is essential to improve the prediction of short- and long-
term prognosis. More recently, the analysis of NfL in a group of 33 NMOSD patients (30 seropositive for
AQP4-Abs) reported increased levels in comparison with those detected in healthy controls together with
a significant correlation between serum and CSF values and a significant association between NfL levels
and age. In addition, serum NfL levels were increased during relapses and correlated with EDSS score
but were not influenced by treatment and did not predict relapse occurrence in the subsequent year after
[91]
sampling .Altogether, these observations expand the utility of NfL as a possible disease activity biomarker
also in NMOSD and related conditions.

CONCLUSION
NfL recently emerged as a promising biomarker in the spectrum of demyelinating CNS conditions, in
particular after the development of high-sensitivity techniques, which allow us to measure and monitor
serum levels over time. NfL values allow us to distinguish patients vs. healthy controls, as confirmed by
[92]
a recent meta-analysis examining 10 studies focused on NfL in CSF and 4 studies on NfL in serum . In
addition, NfL levels show a correlation with clinical and radiological disease activity and help to predict
MS conversion in patients with a first demyelinating event. Finally, different studies support their role
in predicting future disability/long-term prognosis and in monitoring therapeutic response, further
supporting their role in clinical practice. Additional evidence is needed to clarify whether CSF/blood
NfL assessment is a prognostic/predictive tool in MS patients independently from currently available