Multiple Sclerosis Journal - October 2017 - 1444

Multiple Sclerosis Journal 23(11)
Table 1. Other potential neurodegenerative biomarkers in MS.
Name

Biology

Animal data

Blood

CSF

14-3-3

14-3-3 proteins is
released into the CSF
following cellular
disruption
Amyloid aggregates
impair synaptic
plasticity
Involved in synaptic
plasticity, neuronal
survival and
differentiation
Reflects astrogliosis

14-3-3 deficiency leads to
more severe chronic EAE3

Not evaluated

↑ In MS and correlates with IgG
index.4 Detected in those with
more severe disease5

Hexameric amyloid fibrils
attenuate EAE6

↑ Amyloid A
protein in MS7

↓ Amyloid beta (1-42) in MS with
cognitive impairment8

Modulated by exercise in
EAE with ↑ BDNF and ↓
demyelination9

↑ Serum BDNF
in progressive MS
after exercise10,11

The early activation of
astroglial cells in EAE is
connected with ↑ GFAP15
Not evaluated

Not useful16

↑ BDNF in MS, particularly
OCB + MS,12,13 But ↓ BDNF in
RRMS improved by Glatiramer
acetate therapy14
↑ GFAP in SPMS than RRMS and
correlates with disability17-20

Amyloid

BDNF

GFAP

Microtubules
(actin and
tubulin)

Structural
cytoskeletal
components of
neurons

Nogo-A

Inhibitor of neurite
outgrowth

↓ Acute phase EAE, ↑ chronic
phase23

↑ Serum
autoantibody
response to Nogo-A
in MS, especially
RRMS24

VEGF

Proangiogenic
factor but also a
neurotrophic factor in
the CNS

Overexpression of VEGF
exacerbates inflammatory
response in EAE.27 However,
blocking VEGF receptor
worsens motor neurone loss in
the spinal cord28

↓ mRNA expression
in MS, but greater
in RRMS than in
remission/SPMS29

Not detectable21

↑ Actin, tubulin in progressive
disease compared to RRMS, ↑
higher EDSS scores.21 ↑ β-Tub III
in progressive MS, ↑ β-Tub II in
RRMS22
Soluble Nogo-A (−25 kDa)
felt specific for MS.25 But
later demonstrated in all CSF
but stronger in MS (possibly
immunoglobulin light chains).26
↑ Intrathecal anti-Nogo-A
antibodies in RRMS compared to
progressive MS24
MS CSF induces an angiogenic
response,30,31 ↓ mRNA expression
in PBMC from SPMS32

MS: multiple sclerosis; CSF: cerebrospinal fluid; EAE: encephalomyelitis; IgG: immunoglobulin G; BDNF: brain-derived neurotrophic factor; OCB:
oligoclonal bands; RRMS: relapsing-remitting multiple sclerosis; GFAP: glial fibrillary acidic protein; SPMS: secondary progressive multiple sclerosis; EDSS:
Expanded Disability Status Scale; VEGF: vascular endothelial growth factor; CNS: central nervous system.

Temporal sequence. CSF NfL reach their peak
levels approximately 3 weeks after relapse onset,36,55
although levels appear to remain high even after a
relapse (within 3 months), suggesting continued axonal degeneration; presumably Wallerian degeneration of axons distal to the MS lesion.56 In a mouse
model of MS, chronic relapsing experimental allergic
encephalomyelitis (EAE), there is release of NfH
into the blood compartment during both relapses
and remissions, indicating a constant disease process
which starts soon after the initial acute event.16
Biological gradient. There is an association with
both disease severity and future disability. High CSF
NfH levels at diagnosis can predict clinically relevant
disease progression at 15-year follow-up, both by
EDSS progression and MRI brain atrophy,57,58 In
the short term, even serum levels of NfH have been
1444

correlated with poor walking times, with patients
having elevated NfH taking nearly twice as long to
complete the test as those with no detectable levels.16
Equally, high NfL levels have been associated with
poorer prognosis,59 and as an independent prognostic
biomarker for the conversion to clinically definite
MS.18
There is also an observed treatment effect. The
highly active anti-inflammatory treatment natalizumab evokes an almost threefold reduction in CSF
NfL levels,47 and this effect is also demonstrated by
fingolimod when switching from first-line therapies.60
Less efficacious first-line agents are less likely to
reduce NfL levels than second-line therapies.40 CSF
NfH levels also appear to respond to natalizumab
treatment, albeit to a lesser extent,61 suggesting differences in axonal protection by anti-inflammatory
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