Table 1.
Comprehensive list and strength of evidence for molecular biomarkers in multiple sclerosis
| Exploratory biomarkers | Validated biomarkers | Clinically useful biomarkers |
|---|---|---|
| Cytokines (D, DA, IFN-β-R, GA-R) | Anti-EBNA (P, D, DA) | Anti-NZ (NZ-R) |
| Adhesion molecules (D, DA, IFN-β-R, NZ-R) | KFLC (D) | NAbs (IFN-β-R) |
| Chemokines and receptors (D, DA, IFN-β-R) | IGM OB (D, DA, IFN-β-R, NZ-R) | IgG OB (D) |
| MMPs and inhibitors (D, DA, IFN-β-R) | NCAM1 (D, DA) | IgG index (D) |
| Proteomics (D, DA, IFN-β-R) | NO metabolites (D, DA) | Anti-AQP4 (D) |
| Cystatin C (D) | MMP9 (D, DA, IFN-β-R) | Anti-JC virus (NZ-R) |
| microRNA (D, DA, GA-R) | MBP (D, DA) | Anti-VZV (F-R) |
| C31/C4b (D, DA) | MMP9 (D, DA, IFN-β-R) | |
| sCD146 (DA) | MBP (D, DA) | |
| sCD14 (D, DA) | SPP1 (D, DA) | |
| sHLA I and sHLA II (D, DA, IFN-β-R) | CXCL13 (D, DA) | |
| sHLA-G (D) | GFAP (D, DA) | |
| sNogo-A (D, DA) | BDNF (D, DA, IFN-β-R, GA-R) | |
| Anti-Nogo-A (D, DA) | KCNJ10 (D) | |
| Anti-MBP (D, DA) | MRZ reaction (D, DA) | |
| Anti-MOG (D, DA) | CHI3L1 (D, DA, NZ-R) | |
| Anti-HHV6 (DA) | Complement factor H (DA) | |
| Anti-proteasome (D) | Type I IFNs (DA, IFN-β-R) | |
| Anti-CD46 and anti-CD59 (DA) | GPC5 (IFN-β-R) | |
| Lipocalin 2 (DA) | HLA-DRB1*04:01, HLA-DRB*04:08 (IFN-β-R) | |
| VEGFA (DA) | IL-17 (D, DA) | |
| AMCase and Chit (D,DA) | BAFF (D, DA, IFN-β-R) | |
| Fetuin-A (D, DA, NZ-R) | TNF, IL-12, IL-23 (D, DA) | |
| APRIL (DA) | GWAS genes (P, D) | |
| CSF cells (D, DA) | NEFH (DA) | |
| S/GPL (P, D) | NEFL (D, DA, NZ-R) | |
| HMGB1 (D) | 25(OH) vit D (P, D, DA, IFN-β-R) | |
| TOB1 (D) | CD56bright NK cells (DC-R, IFN-β-R) | |
| S100B and ferritin (D, DA) | ||
| Isoprostanes (P, D, DA) | ||
| Oxysterols (D, DA) | ||
| Pentosidine (D, DA) | ||
| Tau (D, DA) | ||
| 14-3-3 (D, DA) | ||
| NAA and NSE (D, DA) | ||
| Anti-TUb and b-TUb (D, DA) | ||
| Anti-NEFL (DA) | ||
| Neurotrophic factor (D, DA) | ||
| Tregs (DA) | ||
| KCNK5 (D, DA) | ||
| FGF2 and PDGF-AA (DA) | ||
| gMS classifier 1 (D, DA) | ||
| Myeloid MVs (D, DA) | ||
| sAPP, Aβ peptides (D, DA) | ||
| Apoptosis-related molecules (D, DA, IFN-β-R) | ||
| Cosignaling molecules (DA, IFN-β-R) | ||
| GWAS genes (IFN-β-R) | ||
| Candidate genes (IFN-β-R, GA-R) | ||
| CIITA (IFN-β-R) | ||
| APLA (IFN-β-R) | ||
| IL-17F (IFN-β-R) | ||
| ABCB1, ABCG2 (MT-R) | ||
| IL-21 (AL-R) |
Data based on Comabella and Montalban (2014).
Biomarkers can be grouped into the categories of exploratory biomarkers (any biomarker proposed as a candidate for the disease or identified in discovery hypothesis-free studies using so-called omics technologies), validated biomarkers (biomarkers for which there is stronger evidence about their association with the disease), and clinically useful biomarkers (biomarkers routinely tested in clinical settings). The type of biomarker is indicated in parentheses.
P, Predictive biomarker; D, diagnostic biomarker; DA, disease activity biomarker; AL-R, alemtuzumab-response biomarker; DC-R, daclizumab-response biomarker; F-R, fingolimod-response biomarker; GA-R, glatiramer-acetate-response biomarker; IFN-β-R, interferon β response biomarker; MT-R, mitoxantrone-response biomarker; NZ-R, natalizumab-response biomarker; MMP, matrix metalloprotease; C3/C4b, complement components C3 and C4b; sCD146, soluble CD146; sCD14, soluble CD14; sHLA, soluble human leukocyte antigen; sHLA-G, soluble HLA-G; sNogo-A, soluble Nogo-A; anti-Nogo-A; anti-Nogo-A antibodies; anti-MBP, anti-myelin basic protein; anti-MOG, anti-myelin oligodendrocyte protein; anti-HHV-6, anti-human herpesvirus 6; VEGFA, vascular endothelial growth factor A; AMCase, acid mammalian chitinase; Chit, chitinase 1 (chitotriosidase); TNFSF13 (also known as APRIL), tumor necrosis factor (ligand) superfamily, member 13; S/GPL, sulphatide and glycosphingolipid antibody titers; HMGB1, high mobility group box 1; TOB1, transducer of ERRB2 1; NAA, N-acetyl aspartic acid; NSE, neuron-specific enolase; anti-TUb, anti-tubulin antibodies; β-TUb, β-tubulin isoforms II and III; anti-NEFL, anti-neurofilament light chain antibodies; Tregs, T-regulatory cells; KCNK5, potassium channel subfamily K member 5; FGF2, fibroblast growth factor 2; PDGF-AA, platelet-derived growth factor-AA; gMS classifier 1, anti-Glc(αl,4)Glc(α) IgM antibodies; myeloid MVs, myeloid microvesicles; sAPP, soluble amyloid precursor protein; Aβ peptide, amyloid β peptide; GWAS, genome-wide association study; CIITA, class II transactivator; APLA, antiphospholipid antibodies; ABCB1, ATP-binding cassette, subfamily B, member 1; ABCG2, ATP-binding cassette, subfamily G, member 2; anti-EBNA, antibodies against Epstein–Barr virus nuclear antigens; KFLC, κ-free light chain; OB, oligoclonal bands; NCAM1, neural cell adhesion molecule 1; NO metabolites, nitric oxide and its metabolites, nitrates, and nitrites; SPP1 (also known as osteopontin), secreted phosphoprotein 1; CXCL, CXC ligand 1; GFAP, glial fibrillary acidic protein; BDNF, brain-derived neurotrophic factor; KCNJ10 (also known as KIR4.1), potassium inwardly rectifying channel, subfamily J, member 10; MRZ reaction, intrathecal humoral immune response against measles, rubella, and varicella zoster virus; CHI3L1, chitinase-3-like protein 1; GPC5, glypican-5; BAFF, B-cell activating factor; TNF, tumor necrosis factor; NEFH, human neurofi lament heavy chain; NEFL, human neurofilament light chain; 25(OH) vit D, 25-hydroxyvitamin D; CD56bright NK cells, CD56bright natural killer cells; anti-NZ, anti-natalizumab antibodies; NAbs, neutralizing antibodies; anti-AQP4, anti-aquaporin 4 antibody; anti-JC virus, antibodies against JC virus; anti-VZV, anti-varicella zoster virus antibodies.