Table 1:
Summary of diagnostic and prognostic features of select emerging biomarkers in MS.
| Biomarker | Compartment | Diagnosis/Classification | Disease Activity/Prognosis |
|---|---|---|---|
| Neuroglial Proteins | |||
| NfL | CSF, serum, plasma. Good correlation. | CSF & Serum: ↑ in RMS & PMS vs. HC75–78; ↑↓ in PMS vs. RMS (conflicting results) 89,176 | Serum: ↑ CIS or RIS that converts to MS80–83; ↓ with DMT in RMS or PMS80,84,177; ↑ disease activity in RMS75,76,80,84–86; ↑ risk of new MRI lesions 76,80,84,86; ↑ risk of brain / spinal cord atrophy85 |
| GFAP | CSF, serum, plasma. Good correlation104 | Serum: ↑ in active RMS vs. NIND & HC 74,104,110; ↑↓ in PMS vs. RMS (conflicting results) 78,104,108,111; ↑ in NMOSD vs. MS or HC 74 | Serum: ↑ risk of worsening EDSS107,109,111; ↑ lesion progression on MRI104,107,111 |
| CHI3L1/YKL-40 | CSF. CSF levels do not correlate with serum | CSF: ↑ in RMS vs. HC; ↑ in PMS vs. RMS & SPMS 101 | CSF: ↑CIS that converts to MS; ↑ likelihood of disability progression; ↓ with DMT; ↑ risk of new MRI lesions 83,95–100 |
| Parvalbumin | CSF | CSF: ↑ PMS vs. HC113 | CSF: ↑ increased cortical lesion number; ↑ cortical thinning; ↑ cognitive impairment113 |
| BDNF | Serum, plasma | Serum and plasma: ↓ in MS compared to HC178,179 | Serum: ↓ increased MRI lesions180 |
| Osteopontin | CSF, serum. Some correlation between CSF and serum | CSF and serum: ↑ in PMS & RMS vs. NIND & HC181 Serum: ↑ in RMS vs. CIS & SPMS181 |
CSF: ↑ in active MS vs. stable MS182; ↑ risk of brain atrophy181,183 |
| Neurogranin | CSF | CSF: conflicting results, no difference or ↓ in MS vs. HC184,185 | CSF: ↑ in MS with enhancing lesions vs. MS without enhancing lesions185 |
| NSE | Serum, plasma, CSF. Good correlation between sources | CSF: ↓ in CIS vs. HC186; CSF and plasma: no change between RMS & PMS vs. HC187,188 |
Serum and plasma: conflicting results, no change or negative correlation with EDSS and MSSS187–189 |
| KIF5A | CSF | CSF: ↑ in PMS vs. RMS, NIND, HC190 | CSF: ↑ in RMS correlates with worsened EDSS, MSSS and ARMSSS at 2 year follow up190 |
| Cytokines and Chemokines | |||
| TNFα | Serum, CSF | CSF & serum: ↑ MS vs. healthy control 191,192; CSF: ↑ RMC > PMS > HC193 | |
| IL-4 | Serum, CSF | Serum and CSF: Conflicting results. Large meta-analysis shows no difference in MS vs. HC191 | |
| IL-6 | Serum, CSF | Serum and CSF: Conflicting results. Large meta-analysis shows no difference in MS vs. HC191 | Serum: ↓ with DMT191 |
| IL-8 (CXCL8) | Serum, CSF. Serum does not correlate with CSF194 | Serum: ↑↓ MS vs. healthy control191,194 (conflicting results) CSF: ↑ RMS & PMS vs. healthy control193,194 |
|
| IL-10 | Serum, CSF | CSF: ↑ in RMS & PMS vs. HC193 | Serum: ↑ CIS that converts to MS or NMOSD195; ↑ with DMT (IFN-b1a)196; ↑ in MS remission compared to relapse197; ↓ increased risk of relapse in pediatric MS198 |
| CCL11 (Eotxain-1) | Plasma, CSF | CSF & plasma: ↑ SPMS vs. RMS199 | CSF & plasma: ↑ longer duration of disease199 |
| IL-12p40 | Serum, plasma, CSF | CSF, plasma, serum: ↑ MS vs. healthy control191,199 & NIND CSF: ↑ in CIS vs. HC166 |
|
| CXCL13 | CSF. Serum does not correlate with CSF 128,137 | CSF: ↑RMS and PMS vs. NIND & OIND122–127 | CSF: ↑CIS that convert to MS129–131; ↑ disease activity in RMS124,127–129
CSF>Serum: ↓ with DMT 127,132,133 Serum: Predict response to fingolimod134 |
| IL-17A | Serum, CSF | Serum: ↑ MS vs. healthy control191,200; CSF: Large meta-analysis with nearly-significant ↑ in MS vs. HC191. ↑ RMS > PMS > HC196 | Serum: ↓ with DMT (IFN-b1a)196 |
| IL-23 | Serum | Serum: ↑ MS vs. healthy control191 | |
| IL-27 | Serum, CSF | Serum: Large meta-analysis shows no difference in MS vs. HC191. CSF: ↑ in RMS vs. HC193,201 | |
| IL-33 | Plasma | Plasma: non-significant ↑ RMS vs. HC202,203 | Plasma: ↑ decreased lesions number; ↓ with DMT (IFN-b1a)203 |
| IL-36 | Serum | Serum: ↑ RMS vs. HC204 | |
| IL-37 | Serum | Serum: ↑ RMS vs. HC205 | Serum: ↑ with DMT (fingolimod)206; ↑ during MS relapse; ↑ increased EDSS206 |
| IL-38 | Serum | Serum: ↑ in newly diagnosed MS compared to treated207 | |
| Endothelial Cell-Related Proteins | |||
| Endothelian-1 | Plasma | Plasma: RMS or PMS vs. HC208 | CSF: ↑ increased risk of poor visual recovery from optic neuritis209; increased in active vs. stable MS210 |
| Endothelian-3 | Plasma, CSF | Plasma: ↑ MS vs. HC211 | Plasma: ↑ MS disease duration |
| VEGF (total) | Serum | Serum: ↑ RMS vs. HC212 | Serum: ↑ shortened duration between first and second relapses212 |
| VEGF-A | mRNA, CSF | CSF: ↑ in RMS & PMS vs. HC193 | mRNA (from serum monocytes): ↓ in SPMS vs. RMS213 |
| TGF-α / VEGF-β (ratio) | Serum | Serum: ↑ in CIS vs. RMS214 | Serum: ↓ stable RMS vs. HC; ↑ active RMS vs. HC; ↓ increased EDSS214 |
| sNCAM | CSF | CSF: ↓ in MS vs. HC; ↓ in SPMS > RMS > CIS215–218 | CSF: ↑ after natalizumab or mitoxantrone; ↓ after fingolimod treatment216; ↓ increased EDSS215 |
| VCAM1 | Serum, CSF | Serum and CSF: ↑ in active RMS & PMS vs. HC219 | Serum and CSF: ↑ during MS relapse vs. remission219 Serum: ↑ decreased number of MRI lesions. ↑ with DMT (IFNB-1b)220 |
| Mitochondria and Autophagy-Related Proteins | |||
| Parkin | Serum, CSF | Serum and CSF: ↑ in RMS & PMS vs. HC221–223 | Serum and CSF: ↑ in MS with enhancing lesions vs. MS without enhancing lesions224 |
| ATG5 | Serum, CSF | Serum and CSF: ↑ in RMS vs. HC222,223 | Serum and CSF: ↑ in MS with enhancing lesions vs. MS without enhancing lesions224 |
| ANT1 | Serum, CSF | Serum and CSF: ↓ in RMS vs. HC222,223 | |
| Other | |||
| Kynurenine | Serum, CSF | CSF: ↓ in remission RMS vs. HC225; ↑ in relapsing RMS vs. HC226
Serum: ↑ in active RMS vs. HC and PMS226–228 |
|
| CCN3 | Plasma, CSF. Good correlation between sources229 | Plasma: ↑ in PMS vs. RMS229 | |
| Vitamin D | Serum | Serum: ↑ lower risk of developing MS152,230; ↓ neonatal vitamin D increased risk of developing MS231; ↑ lower degree of brain atrophy; ↑ less clinical progression at 5 year232,233; ↓ increased relapse risk232 | |
Up (↑) and down (↓) arrows designate increase or decrease of the biomarker collected from the designated compartment(s). Correlations are statistically significant except where otherwise noted; topics with conflicting results are reported with up/down (↑↓) arrow.
Abbreviations: CSF = cerebrospinal fluid; MS = multiple sclerosis; RMS = relapsing multiple sclerosis; PMS = progressive multiple sclerosis; SPMS = secondarily progressive multiple sclerosis; CIS = clinically isolated syndrome; RIS = radiologically isolated syndrome; HC = healthy control; NIND = non-inflammatory neurologic disorder; EDSS = expanded disability status scale; NMOSD = neuromyelitis optica spectrum disorder; DMT = disease modifying therapy; NfL = neurofilament light chain; GFAP = glial fibrillary acidic protein; CHI3L1 = chitinase-3-like protein 1; BDNF = brain derived neurotrophic factor; NSE = neuron specific enolase; KIF5A = Kinesin family member 5A protein; VEGF = vascular endothelial growth factor; sNCAM = soluble neural cell adhesion molecule; VCAM = vascular cell adhesion molecule; ATG5 = autophagy related 5 protein; ANT1 = adenine nucleoside translocator 1; CCN3 = cellular communication network factor 3