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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 7

NFL IN PROGRESSIVE MS
PPMS is characterized by progressive neurological decline from disease onset, without experiencing attacks,
and accounts for 15% of MS cases at presentation. SPMS in characterized by progression occurring after a
[1]
RR course and involves about 50% of cases after 15 years . In this context, the potential role of NfL levels
in predicting and quantifying disease progression has been explored. In one of the first studies considering
95 patients with MS and a long-term follow-up (median 14 years, range 8-20), high CSF NfL levels were
[58]
associated with an unfavorable prognosis and with conversion to SPMS . Although divergent CSF NfL
values have been observed in patients with PPMS and SPMS, the authors suggested that NfL is a useful
prognostic biomarker under these conditions [59,60] . However, the absence of correlation between NfL levels
and disease duration or disease severity, measured with EDSS, led to the idea that CSF NfL levels could
[27]
not properly reflect disease severity in PPMS . The slow axonal degeneration occurring in subjects with
PPMS together with the more robust NfL increase in the course of acute axonal damage could explain these
results. Different studies further support this hypothesis. Damasceno et al. analysed CSF NfL values in
[61]
consecutive patients with MS, including 32 subjects with RRMS and 15 with progressive MS, and correlated
NfL values with radiological and clinical variables. Interestingly, NfL levels were significantly increased in
patients with RRMS in association with cortical lesions and relapses, whereas they were not different in
[62]
patients with progressive MS in comparison with healthy controls. Sellebjerg et al. measured CSF NfL
levels in 26 patients with PPMS, 26 with SPMS, and 24 healthy controls and observed higher values in cases
with active progressive MS in comparison with those with inactive progressive MS, thus supporting the
role of NfL in distinguishing active vs. inactive cases. These data further confirm the specific association
between NfL concentration and active disease at sampling, which has a significant impact on axonal
[61]
damage . Partially divergent data emerged according to a recent meta-analysis of case-control studies,
where three times higher CSF NfL levels were observed in 158 patients with progressive MS in comparison
with healthy controls, although significantly lower values were detected in progressive vs. relapsing cases.
NfL values tended to be higher, although not significantly different, in RRMS on remission (229 patients)
[63]
in comparison with patients with progressive MS (158) . In addition to the lower levels measured in cases
with progressive vs. relapsing MS, a correlation between CSF levels of sCD27 (a soluble marker of T-cells)
and NfL values in subjects in progression before and after treatment with natalizumab (17 patients) and
methylprednisolone (23 patients) was reported, suggesting a connection between residual inflammation
[64]
and axonal damage and a role of these biomarkers in monitoring treatment response .

The analysis of serum NfL values in patients with progressive MS further confirmed previous observations
on CSF NfL measurement. In particular, higher values of serum NfL in the presence of disease activity,
defined as a clinical relapse or new gadolinium-enhancing lesions on MRI, were reported in a cohort of 286
[49]
patients with MS, including both RRMS and progressive cases (19 PPMS and 63 SPMS) . In a longitudinal
[9]
study, Disanto et al. examined paired serum and CSF samples of different subjects (CIS n = 48, RIS n =
13, RRMS n = 62, PPMS n = 16, and SPMS n = 3) and confirmed the strong association between CSF and
serum NfL levels and the presence of 42-fold lower values in serum. A more striking association between
NfL values and disability, measured with EDSS, was noted in cases with CIS/RRMS than in those with
PPMS/SPMS, once again reflecting the predominant axonal damage occurring in active cases.

A study including subjects with CIS, RRMS, PPMS, and SPMS detected an association between the
probability of EDSS worsening and the increase in serum NfL values, with serum NfL levels reflecting
future disease progression in terms of brain and cervical spinal cord atrophy. The authors also confirmed
the association between serum NfL levels and spinal cord volume loss in patients with PPMS, even in the
absence of radiological signs of inflammation, thus supporting the correlation between axonal damage
and spinal cord atrophy in the course of disease progression . More recently, Ferraro et al. specifically
[65]
[51]
studied 27 patients with PPMS and 43 with SPMS (mean follow-up of 25 months) and demonstrated
a positive correlation between plasma NfL values and disability assessed with EDSS, together with an