Table 1.

Biomarkers in MS.

(A) Diagnostic biomarkers (criteria i, iv, v, and vi)
(1) Genetic-immunogenetic
HLA-DRB1*1501	+++ Risk for MS	See also B, E
DR3 and DR4 haplotypes	++ Risk for MS
HLA-DRB1*04	++ Risk for MS
HLA-DRB1*0401	+ Risk for high familial autoimmunity in MS patients	See also F
HLA-DQ1*0102	+ Risk for MS, in coexistence with HLA-DRB1*1501
HLA-DPB1*0501	+ Risk for opticospinal MS
HLA-DPB1*0301	+ Risk for opticospinal MS
IL2RA and IL7RA polymorphisms	+ Risk for MS
EVI5, CD58, KIAA0350, and RPL5 polymorphisms	+/− Risk for MS
(2) Laboratorial
OCB IgG	+++ But with low specificity	See also E
KFLC	+++ But with low specificity	See also E
MRZ reaction	+++ Higher specificity than OCB IgG	See also E, F
Anti BRRF2, anti EBNA-1	++	See also B, C
Anti MBP 48–70 and 85–170	+	See also B, E
Anti MBP 43–68 and 146–170	+ Differential diagnosis with OND's	See also B, E
MBP/MOG conformational epitopes antibodies	+ But low specificity	See also B, E, F
VEGF-A	+ Lower CSF levels in all disease forms, but low specificity	See also D, E
Vitamin D	+++ Lower levels, higher risk for MS	See also C, F
TRECs	+ Lower serum levels in all disease forms, but low specificity	See also B
CSF levels of lipocalin 2	+ Higher CSF levels in MS, but low specificity	See also F
AR	+++ Differential diagnosis of MS and NMO	See also C, E
NO and NO metabolites	+ Higher CSF and serum levels in MS, but low specificity	See also C, E
NF-L	++ Higher CSF levels in MS patients	See also C, F
NAA	+++ Differential diagnosis of RRMS and NMO	See also D, E
GFAP	+++ Differential diagnosis of MS and NMO	See also C, E
S100B	+ Differential diagnosis of MS and NMO	See also C, E
Nogo-A	++ For MS forms with prominent neurodegenerative element	See also D
(3) Imaging
Contrast-enhanced T1 lesions	+++	See also C
Hyperintense T2-weighted lesions	+++	See also C, D, E
Corpus callosum DTI abnormalities	++ Early diagnostic biomarker	See also E
MRS findings (glutamate/choline)	+++	See also C, D, E
PET	++ But still experimental
EPs  Motor EPs  VEMPs	+++ +++ Spinal cord syndrome at presentation +++ Brainstem dysfunction	See also C, D, E
SSR	++ Autonomic dysfunction assessment in MS patients	See also E
(B) Biomarkers of phenotypical expression (criteria ii, iv, v, and vi)
(1) Genetic-immunogenetic
HLA-DRB1*1501	+++ Early disease onset	See also A, E
HLA-DRB1*1501	+ Risk for cognitive decline
HLA-DRB1*01	++ Protection against malignant disease form
ApoE ε4	++ Greater risk for mental disorders
(2) Laboratorial
OCB IgM against myelin lipids	+/− Aggressive disease course	See also E
EBV antibodies	+ Early disease onset	See also A, C
Anti-MBP	+++ ADEM-like onset in childhood MS	See also A, E
Anti-MOG	+++ Childhood MS, ADEM, isolated optic neuritis, anti-AQP4 (−) NMO	See also A, E, F
rMOG index	+++ Progressive disease forms
IL-6 serum levels	+++ Age at onset	See also C
TRECs	++ Lower levels PPMS	See also A
Amyloid-β (1–42)	++ Lower levels, higher risk for mental disorders
(3) Imaging
UCCA atrophy	+++ Progressive disease forms	See also E
NAGM DTI abnormalities	+++ Progressive disease forms
(C) Biomarkers of demyelination-neuroinflammation-relapse (criteria i, ii, iii, iv, v, and vi)
(1) Genetic-immunogenetic
TOB1	+++ Underexpression, higher Th1 and Th17 percentage	See also E
(2) Laboratorial
EBV antibodies	+ Higher inflammatory activity	See also A, B
CXCL13	++ Mobilizes B-cells, T-helper cells
CXCL12	+/− Neuroprotection against inflammation in EAE/ experimental
IFN-γ/TNF-a	+++ Th1 immune response
IL-1 levels imbalance	+ Triggering factor for neuroinflammation
IL-6	+++ B-cell and T-cell immunity link, Th17 immune response triggering factor ++ Correlation with relapse frequency in female MS patients	See also B
IL-10 −592 position polymorphisms	++ Regulation of CNS autoimmunity
IL-15	++ BBB disruption, enhanced CD8(+) T cytotoxicity
IL-33	+ Increase in IFN-γ and IL-17 in mice EAE
sICAM-1	++ Higher levels, higher inflammatory activity +++ Higher levels in NMO than MS—marker of BBB disruption	See also F
sVCAM-1	+++ Higher levels in NMO than MS—marker of BBB disruption	See also F
Laminin 411	++ TH-17 enhancement
α4 Integrin	++ Correlation with gadolinium-enhanced lesions during CIS	See also E, F
Osteopontin	++ Serum and CSF elevation during relapse
Fetuin-A	+++ Overexpression in active demyelinating lesions	See also F
Vitamin D	+++ High levels, anti-inflammatory role—lower radiological disease activity	See also A, F
CSF mature B-cells/plasma-blasts	++ Bigger accumulation, higher inflammatory activity
CXCR3	++ Helps T-cells to enter the brain
CX(3)CR1	++ CD4(+)CD28(−) cytotoxic cells biomarker
CSF CCR2(+)CCR5(+) T cells	+++ Increase during MS relapse—osteopontin enhancement
CD56 Bright NK	++ Remission phase
AR	+++ Biomarker of BBB disruption	See also A, E
MMP-9	++ Higher CSF levels during relapse
Ninjurin-1	++ Upregulation in active demyelinating lesions
MBP and fragments	+++ Higher CSF levels during relapse	See also F
αB-Crystalline	+++ Over-expression in active demyelinating lesions
NO and metabolites	++	See also A, E
7-Ketocholesterol	++
Glutamate	+++ Higher levels in active demyelinating lesions
Cystine/glutamate antiporter	+ Over-expression in active demyelinating lesions
NF-L	+++ Higher CSF levels, especially the 3rd week after relapse onset	See also A, F
GFAP	++ Higher levels during relapse	See also A, E
S100B	+/− Higher CSF levels during MS/NMO relapse	See also A, E
N-CAM	+ CSF elevation at remission onset
BDNF	++ Lower levels inhibit demyelination and axonal loss	See also D, E, F
(3) Imaging
Contrast-enhanced T1 lesions	+++ Active lesions	See also A
Hyperintense T2-weighted lesions	++ Combination of different mechanisms	See also A, D, E
MTR decrease	+ Demyelination and axonal loss combined	See also D
DTI abnormalities	++ Combination of different mechanisms	See also D, E
MRS findings (especially changes in glutamate and choline)	+++ Active lesions	See also A, D, E
DTS	++ Promising but still experimental	See also D
EP's delayed conduction	++ Demyelination biomarker	See also A, D, E
(D) Biomarkers of axonal loss-neurodegeneration (criteria i, iv, v, and vi)
(1) Laboratorial
VEGF-A	++ Lower levels, higher risk for neurodegeneration	See also A, E
14-3-3	+/− Axonal loss
NAA	+++ Axonal loss	See also A, E
BDNF	++ Lower levels inhibit demyelination and axonal loss	See also C, E, F
Nogo-A	+++ Higher CSF levels, failure in axonal repair	See also A
(2) Imaging
RNFL thinning	+++ Axonal loss in the optic nerve	See also E, F
Hyperintense T2-weighted lesions	++ Combination of different mechanisms	See also A, C, E
Black holes	+++ Axonal loss	See also E
MTR decrease	++ Demyelination and axonal loss combined	See also C
DTI abnormalities	++ Combination of different mechanisms	See also C, E
MRS findings (especially NAA)	++	See also A, C, E
DTS	+++ Promising but still not widely accessible	See also C
Visual and motor EPs	++	See also A, C, D
(E) Prognostic biomarkers—biomarkers of disability progression (criteria ii, iv, v, vi, and viii)
(1) Genetic-immunogenetic
HLA-DRB1*1501	+/− Early progression from RRMS to SPMS	See also A, B
HLA-DRB1*1501	+ Worst brain atrophy measures
HLA-DQB1*0301	+ Worst brain atrophy measures
HLA-DQB1*0602	+ Worst whole and gray matter atrophy measures
TOB1	+++ Early conversion from CIS to CDMS	See also C
(2) Laboratorial
OCB IgG	+++ Conversion from CIS to CDMS	See also A
KFLC	+++ Conversion from CIS to CDMS	See also A
OCB IgM	+/− Bad prognostic biomarker	See also B
MRZ reaction	+++ Conversion from CIS to CDMS	See also A, F
Anti-MBP	+/− Conversion from CIS to CDMS	See also A, B
Anti-MOG	+/− Conversion from CIS to CDMS	See also A, B, F
AR	++ Marker of clinical severity in NMO	See also A, C
VEGF-A	++ Lower levels, progression from RRMS to SPMS	See also A, D
NO and NO metabolites	++ Higher CSF levels, longer relapses/higher disability progression rates	See also A, C
NF-H	+++ Higher CSF levels, progressive forms/bad prognostic biomarker
NF-H and tau	+++ Combined high CSF levels, conversion from CIS to CDMS
Tubulin/actin	++ Higher CSF levels, progressive forms/worst disability scores
NAA	+++ Lower CSF levels, progressive forms/worst disability scores	See also A, D
GFAP	++ Higher CSF levels, progressive MS forms/worst disability scores +++ Disability progression in NMO	See also A,C
S100B	+ Disability progression in NMO	See also A,C
BDNF	++ Lower CSF levels in SPMS patients	See also C, D, F
Unblocked α4 integrin	+ Prognostic factor of risk for PML	See also C, F
(3) Imaging
RNFL thinning	+ Correlation with brain atrophy measures and disease progression	See also D, F
Hyperintense T2-weighted lesions	+/−	See also A, C, D
Black holes	+/−	See also D
Whole brain atrophy measures	++ Worsening rates at MS onset, prognostic biomarker of disability after 8 years
Gray matter atrophy measures	+++ Higher worsening rates, progressive forms/early CIS conversion to RRMS
UCCA atrophy	++ Progressive forms, good correlation with EDSS, bad prognostic in RRMS	See also B
DTI abnormalities	+++ Early prognostic biomarker of relapse	See also C, D
Corpus callosum DTI abnormalities	+++ Bad prognostic biomarker	See also A
Spinal cord DTI abnormalities	+++ Good correlation with EDSS scores
Early MRS abnormalities	++ Bad prognostic biomarker	See also A, C, D
Combined EPs	+++ Good prognostic biomarker, especially for benign disease forms	See also A, C, D
SSR	++ Correlation with higher EDSS scores	See also A
(F) Biomarkers of therapeutical response (criteria i, iv, v, vi, and vii)
(1) Genetic-immunogenetic
HLA-DRB1*0401, 0408, 1601	+++ Higher risk for developing neutralizing antibodies against IFN-B	See also A
(2) Laboratorial
MRZ reaction	++ B-cell immunity targeted therapy	See also A, E
Anti-MOG	++ B-cell immunity targeted therapy	See also A, B, E
Fetuin-A	+++ Decreased CSF levels in Natalizumab responders	See also C
MBP	+++ Decrease in CSF levels in methylprednizolone responders	See also C
CSF lipocalin 2	++ Decreased CSF levels in Natalizumab responders	See also A
Unblocked α4 integrin	+++ Therapeutical response to Natalizumab	See also C, E
NF-L	+++ Normalized CSF levels in Natalizumab responders	See also A, C
BDNF	+++ CSF elevation in Glatiramer Acetate responders	See also C, D, E
TRAIL	++ Serum levels good predictors of response in IFN-B
MxA	++ Serum levels good predictors of response in IFN-B
sVCAM	++ CSF alterations in IFN-B responders	See also C
Th17 immune profil	+/− Immune response exacerbation by IFN-B
Vitamin D	+++ Increased levels in IFN-B responders	See also A, C
sICAM-1	+ Lower levels in Cladribine responders	See also C
sE-Selectin	+ Lower levels in Cladribine responders
(3) Imaging
RNFL	+++ Biomarker of therapeutical efficacy for several agents	See also D, E

Classification of biomarkers. +++ very strong correlation, ++ strong correlation, + modest correlation, and +/− controversial correlation. Criteria used for classification., (i) Biological rationale; (ii) clinical rationale; (iii) predictability of disease initiation, reactivation or progression, or of disease differentiation; (iv) sensitivity and specificity; (v) reproducibility; (vi) practicality; (vii) correlation with therapeutical outcome; (viii) correlation with prognosis and disability. Biomarkers of more than one category are indicated in the third column.