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INTRODUCTION
In the framework of neurological diseases, the need for objective and measurable indicators of the
underlying pathological processes is more and more pressing. Therefore, the search for biological markers,
or biomarkers, is a continuously expanding field, and a large number of molecules have been explored so
[1]
far; but only a few have been validated, and even fewer are currently used in clinical practice .
Indeed, the assessment of the clinical validity and utility of a biomarker requires a multistage process,
which has been proposed as a five-phase procedure going from preclinical exploratory studies (phase 1)
to clinical assay development (phase 2), retrospective studies (phase 3), prospective diagnostic accuracy
[2]
studies (phase 4), and disease burden reduction studies (phase 5) . Moreover, the level of evidence relies
on the number of supporting studies and patients included while exploring the independence of the results
[3]
in independent cohorts .
With effective therapeutic strategies in neurodegenerative diseases still lacking, biomarkers would allow
us to define the start time of degeneration and make an early diagnosis, to monitor the disease course and
[4]
predict the prognosis, but also to identify potential therapeutic targets .

In the context of inflammatory diseases, biomarkers would be useful to specifically define the involved
actors of the immune response and potential therapeutic targets, and also to better understand the
[5]
etiopathogenesis and to monitor disease activity and treatment response .

Multiple sclerosis (MS) is a challenging disease, since it is now clear that both inflammatory and
degenerative components occur since early phases . Although the introduction of the first approved
[6]
[7,8]
medications for progressive MS (PMS) is a recent achievement , therapeutic options are actually
limited in progressive phases. The majority of currently available disease-modifying drugs (DMDs)
target inflammation, and therapeutic efforts are mainly focused on early phases of the disease, with the
purpose of influencing long-term evolution . It is for this reason that the concept of “no evidence of
[9]
disease activity” (NEDA) has been introduced as the main therapeutic goal to achieve in patients with MS.
Extensively used in clinical trials to define and compare the efficacy of DMDs, the concept of NEDA is
still evolving, integrating an increasing number of measures able to define the absence of disease activity.
Even though the achievement of this goal is the main one in a clinical real-life setting while monitoring
patients under treatment as well, long-term studies are needed to provide evidence of its utility in clinical
practice . Currently, NEDA-3 is mainly used in clinical trials and considered the aim of therapeutic
[10]
strategies in clinical practice, consisting in the absence of relapses, magnetic resonance imaging (MRI)
[11]
activity and sustained disability worsening during follow-up . Indeed, the increasingly prominent role
of MRI and recent advances in technology have led to the inclusion of the measurement of brain volume
loss in NEDA (NEDA-4), which may further evolve with the inclusion of biomarkers (NEDA-5) . In this
[12]
respect, the role of neurofilament light chain (NF-L) as a marker of disease activity, correlating with long-
[11]
term prognosis seems to be promising . The availability of biological markers reflecting such a disease
heterogeneity would definitely help us to better understand its complexity and would be an instrument of
unquestionable value.

According to the functional classification provided by the FDA-NIH Biomarker Working Group, such
molecules can be categorized in susceptibility, diagnostic, monitoring, prognostic, safety and response
[13]
biomarkers [Table 1].

Susceptibility biomarkers would be useful to detect among asymptomatic individuals those at risk of
[13]
developing MS, potentially including genetic investigation in first-degree relatives of MS patients .