Fig. 3.

Applications of fluid biomarkers in the clinical management of multiple sclerosis. Upper Panel: schematic representation of the multiple sclerosis (MS) clinical course and underlying events. The vertical axis depicts the level of clinical disability, while the horizontal axis represents time. The “sea level” corresponds to the threshold of clinical detection. Green lines represent episodes of acute focal inflammation in the central nervous system (CNS). Acute inflammation can manifest as asymptomatic (below the clinical threshold) or symptomatic (above the clinical threshold). During the preclinical phase of the disease, asymptomatic acute inflammations occur. The first episode of acute inflammation crossing the clinical threshold represents the clinical onset of the disease. Over time, clinical relapses may be followed by incomplete recovery. In parallel with recurring events of acute focal inflammation in the CNS, since the early phase of the disease a “smouldering” pathological process of persistent low-grade inflammation occur (red line), eventually leading to clinically detectable continuous worsening of disability. Lower Panel: MS biomarkers and their potential role in different disease phases. Biomarkers within bars with a solid black frame are those currently used on a large scale in clinical practice. Abbreviations. CHI3L1: chitinase-3-like protein 1. CHIT1: chitinase 1. CIS: clinically isolated syndrome. CNS: central nervous system. CSF: cerebrospinal fluid. CXCL13: chemokine (C-X-C motif) ligand 13. DMT: disease-modifying treatment. FLC: free light chain. GFAP: glial fibrillary acidic protein. NfL: neurofilament light chain. sTREM2: soluble triggering receptor expressed on myeloid cells 2.