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Toscano et al. Neuroimmunol Neuroinflammation 2021;8:14-41 I http://dx.doi.org/10.20517/2347-8659.2020.12 Page 17

OPN Validated Diagnostic Significantly greater levels in MS patients compared with controls [102,107,108,110]
Disease-activity In RRMS patients, higher levels detected in active disease compared with
stable disease and during relapses compared with remission phases [100-103]
NO Validated Disease-activity Increased levels in body fluids of MS patients, particularly RRMS compare
metabolites with SPMS. Higher values detected during relapses [78,90]
MRZ Validated Diagnostic A humoral response against at least 2 of 3 viruses is detected in 78% of
reaction patients with MS with high specificity [73]
Prognostic for conversion Associated with higher risk of conversion in MS when detected in CIS [69,70]
MS: multiple sclerosis; CIS: clinically isolated syndrome; RIS: radiologically isolated syndrome; MRI: magnetic resonance imaging; OCB:
oligoclonal bands; RRMS: relapsing-remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis; NMO: neuromyelitis
optica; NEDA: no evidence of disease-activity; N-CAM: neuronal cell adhesion molecule; CHI3L1: chitinase-3-like-1; MBP: myelin basic
protein; GFAP: glial fibrillary acidic protein; Gd+: gadolinium-enhancing; MMP-9: matrix metalloproteinase-9; CXCL13: C-X-C motif
ligand 13; NFs: neurofilaments; NF-L: light chains of neurofilaments; NF-H: heavy chains of neurofilaments; OPN: osteopontin; NO: nitric
oxid; MRZ: measles-rubella-varicella; NTZ: natalizumab; RTX: rituximab

Diagnostic biomarkers should be able to confirm the diagnosis of MS, improving diagnostic accuracy
when applied together with clinical and MRI criteria. Thus, they can allow clinicians to exclude other
possible differential diagnoses, including different autoimmune disorders and other neurological diseases.
They should also ideally detect patients with clinically isolated syndrome (CIS) and radiologically isolated
syndrome (RIS) and distinguish between different subtypes of the disease [5,13] .

Monitoring biomarkers play a relevant role in MS, allowing neurologists to serially assess the status of the
[13]
disease . Particularly, disease activity biomarkers may crucially affect therapeutic decisions by detecting
high disease activity and rapid disability worsening in early phases of MS [9,14] . Correlating with clinical
and radiological activity, they may aid in identifying aggressive forms of MS and also provide an indirect
[1]
assessment of low therapeutic response in patients under DMDs .

The definition of prognostic biomarkers as a separate class is slightly more controversial, since a prognostic
impact is recognized in other categories of biomarkers . Indeed, those markers able to predict either
[1]
[13]
the risk of relapses or progression or both would belong to this group . However, this term is usually
attributed to those molecules reflecting axonal damage, astrocyte activation and remyelination, prevailing
[4]
in progressive phases of disease . They would also be important in identifying transitional progressive
[9]
forms of MS, since reliable indicators are not available . Alongside these, many studies have considered
those molecules that are predictive of conversion to clinically definite MS when detected in patients
with CIS as being “prognostic”. To distinguish these “prognostic for conversion” biomarkers from the
aforementioned “prognostic for progression” ones, their role in this review will be discussed as belonging
to the diagnostic category for conceptual similarity.

Finally, the monitoring of treatment response in terms of both efficacy and safety may be very important in
[5]
personalizing therapies and planning switches whenever appropriate and may be of benefit in the use of
[13]
pharmacodynamic/response and safety biomarkers .
However, boundaries are blurred and some markers may exhibit more than one function. Moreover, to
be validated, exploratory molecules have to be reproducible among independent studies, and only easily
detectable and cost-effective ones truly impacting the diagnostic therapeutic processes would be used in
[5]
clinical practice .

For both anatomic and physiological reasons, cerebrospinal fluid (CSF) represents the main source of
[4]
potential biomarkers for MS among body fluids . Indeed, its composition may reflect the impairment of
brain metabolism, the breakdown of the blood-brain barrier (BBB) and many ongoing processes occurring
[15]
in the central nervous system (CNS) with a consequent production of catabolites . However, requiring
less invasiveness and due to blood continuity with CSF, serum samples are being increasingly used and
[1]
explored as a source of biomarkers .