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Review Article
Protein biomarkers in multiple sclerosis
Jun-Soon Kim
DOI : https://doi.org/10.47936/encephalitis.2022.00101

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Encephalitis > Volume 3(2); 2023 > Article


Kim: Protein biomarkers in multiple sclerosis

Review Article



encephalitis 2023;3(2):54-63.

Published online: April 4, 2023

DOI: https://doi.org/10.47936/encephalitis.2022.00101






PROTEIN BIOMARKERS IN MULTIPLE SCLEROSIS

Jun-Soon Kim1,2

1Department of Neurology, Seoul National University Bundang Hospital, Seongnam,
Korea

2Department of Neurology, Seoul National University College of Medicine, Seoul,
Korea

Correspondence: Jun-Soon Kim Department of Neurology, Seoul National University
Bundang Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea
E-mail: bigai300@gmail.com



Received October 15, 2022       Accepted January 18, 2023

Copyright © 2023 Korean Encephalitis and Neuroinflammation Society

This is an Open Access article distributed under the terms of the Creative
Commons Attribution Non-Commercial License
(http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted
non-commercial use, distribution, and reproduction in any medium, provided the
original work is properly cited.



ABSTRACT

This review aimed to elucidate protein biomarkers in body fluids, such as blood
and cerebrospinal fluid (CSF), to identify those that may be used for early
diagnosis of multiple sclerosis (MS), prediction of disease activity, and
monitoring of treatment response among MS patients. The potential biomarkers
elucidated in this review include neurofilament proteins (NFs), glial fibrillary
acidic protein (GFAP), leptin, brain-derived neurotrophic factor (BDNF),
chitinase-3-like protein 1 (CHI3L1), C-X-C motif chemokine 13 (CXCL13), and
osteopontin (OPN), with each biomarker playing a different role in MS. GFAP,
leptin, and CHI3L1 levels were increased in MS patient groups compared to the
control group. NFs are the most studied proteins in the MS field, and
significant correlations with disease activity, future progression, and
treatment outcomes are evident. GFAP CSF level shows a different pattern by MS
subtype. Increased concentration of CHI3L1 in the blood/CSF of clinically
isolated syndrome (CIS) is an independent predictive factor of conversion to
definite MS. BDNF may be affected by chronic progression of MS. CHI3L1 has
potential as a biomarker for early diagnosis of MS and prediction of disability
progression, while CXCL13 has potential as a biomarker of prognosis of CIS and
reflects MS disease activity. OPN was an indicator of disease severity. A
periodic detailed patient evaluation should be performed for MS patients, and
broadly and easily accessible biomarkers with higher sensitivity and specificity
in clinical settings should be identified.



Keywords: Biomarkers, Cerebrospinal fluid, Intermediate filaments, Multiple
sclerosis

Go to :



INTRODUCTION

Multiple sclerosis (MS) is a common autoimmune demyelinating disease that can
affect the entire central nervous system. Most patients develop a ‘relapsing’
form, while some develop a ‘secondary relapsing progressive form,’ wherein the
overall neurological function steadily deteriorates with repeated relapses
[1,2]. Because the burden of acute phase treatment due to relapse and functional
impairment due to progressive neurodegeneration are social/medical economic
burdens, including a long-term decline in quality of life, early diagnosis and
treatment of MS have been consistently studied [3,4]. According to long-term
pathophysiology studies, an autoimmune-mediated inflammatory response involving
B cells and T cells is the main pathological phenomenon of MS [5,6]. Hence,
various therapeutics have been introduced, from interferon-beta (IFN-β)
injections over the past several decades to recent high-efficacy drugs (e.g.,
cladribine, alemtuzumab, and natalizumab) [7]. Moreover, many published study
results elucidated the need to identify high-risk MS patient groups at an early
stage of disease onset and to actively start treatment to avoid long-term
progression. In fact, the McDonald’s diagnostic criteria, which are widely used
internationally, are being revised to increase the efficiency of early diagnosis
[8]. Accordingly, although studies on biomarkers that can be used for ‘early
diagnosis/prediction of disease activity/monitoring of treatment response’ are
limited, there have been recent attempts to maximize the efficiency of the
process from diagnosis to treatment. Therefore, this review focuses on protein
biomarkers in body fluids, including blood and cerebrospinal fluid (CSF), among
the recently published results of biomarker studies.
Go to :



MAIN SUBJECTS


NEUROFILAMENT PROTEINS

Neurofilament proteins (NFs) are responsible for maintaining cytoskeletal
integrity throughout the nervous system and are composed of neurofilament light
chain (NfL), neurofilament medium chain, neurofilament heavy chain, and
alpha-internexin [9]. NF levels can increase in pathophysiological situations,
leading to axonal nerve injury, and they are the most extensively studied
biomarker candidates in a wide variety of neurological diseases, including MS.
Among the various NFs, NfL has shown the highest efficacy as a biomarker, as
NfLs are released into the CSF either by damage to the cell membrane or by
active secretion through multivesicular bodies [10]. Then, some NfLs enter the
blood through the glymphatic system or periarterial drainage [11]. The NfL
levels in the blood and CSF had a significant correlation regardless of
measurement platform [12]. Physiologically, neurodegeneration occurs with aging,
and as the blood-brain barrier integrity is disrupted, lower-than-normal
concentrations of NfL can be detected in normal body fluids [13]. However, in
various pathological conditions, including MS, its level is more likely to
increase. Since NfL is the most studied substance as a biomarker of MS, we aim
to describe it in terms of its role in diagnosis, disease activity, and
therapeutic monitoring (Table 1 [14-37]).

TABLE 1

Summary of representative studies with NfL chain as a biomarker of MS

Subtype (No.) Body fluid Assay method Finding Reference Diagnostic marker  RIS
(75) CSF ELISA High NfL levels (cut-off value, 619 ng/L) were associated with a
significantly shorter time to MS (p = 0.017) [14]  CIS (adults, 88; children,
65) CSF ELISA Increased NfL levels were associated with a shorter time to CDMS
diagnosis (pediatric: HR, 3.7; p = 0.007 / adult: HR, 2.1; p = 0.032) [15]  CIS
(222) Serum ECL Converters to MS showed higher NfL baseline levels compared to
non-converters (median, 30.2 pg/mL vs. 9.7 pg/mL; p < 0.001) [16]  CIS (32) CSF
ELISA Converters to MS showed higher NfL baseline levels compared to
non-converters (median, 812.5 pg/mL vs. 329.5 pg/mL; p = 0.002) [17]  MS (MS,
60; control, 60) Serum Simoa NfL levels of MS patients were higher compared with
matched controls in samples drawn a median of 6 years before clinical onset
(median, 16.7 pg/mL vs. 15.2 pg/mL; p = 0.04), and a within-person increase was
associated with higher MS risk (rate ratio ≥ 5 pg/mL increase, 7.50; 95% CI,
1.72–32.80; p = 0.007) [18]  MS (67) Serum Simoa Those with baseline NfL levels
less than 7.62 pg/mL were 4.3 times less likely to develop an EDSS score ≥ 4 (p
= 0.001) [19] Disease activity  Past relapse (RRMS, 47) CSF ELISA Baseline NfL
levels correlated with the number of relapses occurring in the previous six (R =
0.565, p < 0.001) and 12 months (R = 0.758, p < 0.001) [20]  Future relapse
(RRMS, 607) Serum Simoa High baseline NfL levels (above the 80th percentile)
could predict relapse in the short-term (60 days) (OR, 1.98; 95% CI, 1.12–3.37;
p = 0.015) and long-term (1 year) (OR, 1.67; 95% CI, 1.27–2.18; p < 0.001) [21]
 T1-enhancing lesion on brain MRI (RRMS, 34) CSF ELISA NfL levels were higher in
patients with T1-enhancing lesions in brain MRI compared to those without
lesions (median, 3,970.5 pg/mL vs. 1,530.0 pg/mL; p < 0.001) [22]  T1-enhancing
lesion on brain MRI (RRMS, 85) Serum Simoa Patients with T1-enhancing lesions
had significantly higher serum NfL levels than patients without MRI disease
activity (mean difference, 12.6 pg/mL; p < 0.01) [23]  T1-enhancing lesion on
brain MRI (RRMS, 42) Serum ELISA 10-fold higher NfL baseline levels were
associated with 2.9-fold more frequent enhancing lesions over time (95% CI,
2.2–3.8; p < 0.001). A 10-fold increase in NfL over time was associated with a
4.7-fold increase in number of new enhancing lesions (95% CI, 3.3–6.9; p <
0.001) [24]  T2-weighted lesions on brain MRI (RRMS, 52) CSF Simoa Patients with
CSF NfL above the cut-off (807.5 pg/mL) 1 year after treatment had a relative
risk of 5.0 for relapse and/or new T2-weighted lesions on MRI (p < 0.001) during
the first year of treatment [25]  T2-weighted lesions on brain MRI (RRMS, 142)
Serum ELISA Serum NfL levels were associated with number of contrast-enhancing
and T2 lesions on brain MRI (beta coefficient = 3.00 and 0.75, respectively;
both p < 0.001) [26] Therapeutics monitoring  Glatiramer acetate (RRMS, 20) &
INF-β (RRMS, 12) Serum Simoa NfL levels remained high in nonresponders with
clinical relapse, whereas NfL decreased significantly during follow-up (24
months) in patients with a relapse-free course [27]  DMF (RRMS, 52; HC, 23;
placebo, 52) CSF Simoa RRMS patients had higher NfL levels at baseline compared
to HC (mean, 2,368 pg/mL vs. 417 pg/mL; p < 0.001), and 72% of samples showed a
reduction to levels comparable to HCs after 1 year of treatment [25]  DMF (DMF,
27; placebo, 27) CSF ELISA Mean change in CSF NfL level did not differ between
groups (mean difference, 99 ng/L; 95% CI, –292 to 491; p = 0.61) [28]
 Fingolimod (RRMS, 36) CSF ELISA Fingolimod proved effective in decreasing NfL
levels in RRMS (–326 pg/mL, 83.3% with reduction, p = 0.002), and the NfL levels
one year after treatment were higher in patients with relapse during the study
vs. those without (mean, 1,448 pg/mL vs. 384 pg/mL; p = 0.014) [29]  Natalizumab
(RRMS, 96) Serum Simoa In the second year after natalizumab treatment, patients
who later developed PML had significantly higher NfL levels than non-developers
(mean, 10.1 vs. 7.1 pg/mL; p = 0.03) [30]  Natalizumab (RRMS, 92) CSF ELISA
Significant decrease in NfL levels after 12 months of Tx (3-fold reduction: from
a mean value of 1,300–400 ng/L; p < 0.001) [31]  Natalizumab (SPMS, 748) Serum
Simoa NfL concentrations at weeks 48 and 96 were significantly lower in
natalizumab versus placebo participants (ratio, 0.84; 95% CI, 0.79–0.89; p <
0.001 and ratio, 0.80; 95% CI, 0.7–0.85; p < 0.001, respectively) [32]
 Alemtuzumab (RRMS, 354) Serum Simoa Alemtuzumab reduced serum NfL levels
significantly (baseline, 31.7 pg/mL; year 2, 13.2 pg/mL), which was sustained at
long-term follow-up (year 7, 12.7 pg/mL) [33]  Alemtuzumab (RRMS, 15) Serum
Simoa Low NfL levels (< 8 pg/mL) correlated with stable disease status, whereas
increased NfL levels (> 20 fold) showed an association with T2 lesion
progression and development of new T1-enhancing lesions [34]  Cladribine
(progressive MS, 2) CSF ELISA NfL levels were significantly reduced 1 year after
treatment (73% and 80%) [35]  Siponimod (SPMS, 525) Serum Simoa SPMS patients
revealed decreased (–5.7%) NfL levels 21 months after treatment, while the
placebo group showed increased NfL levels (+9.2%) [36]  Ofatumumab (RRMS, 936)
Serum Simoa In ASCLEPIOS I, NfL levels were lower in the ofatumumab group than
in the teriflunomide group by 27% at month 12 and by 23% at month 24. In
ASCLEPIOS II, the corresponding differences were 26% and 24% [37]

NfL, neurofilament light chain; MS, multiple sclerosis; RIS, radiologically
isolated syndrome; CSF, cerebrospinal fluid; ELISA, enzyme-linked immunosorbent
assay; CIS, clinically isolated syndrome; CDMS, clinically definite multiple
sclerosis; HR, hazard ratio; ECL, electrochemiluminescence immunoassay; EDSS,
Expanded Disability Status Scale; RRMS, relapsing-remitting multiple sclerosis;
OR, odds ratio; MRI, magnetic resonance imaging; INF, interferon; HC, healthy
control; DMF, dimethyl fumarate; Tx, treatment; SPMS, secondary progressive
multiple sclerosis.



DIAGNOSIS

Since NfL levels have been shown to increase not only in MS but also in other
inflammatory nervous diseases, it would not be appropriate to use only NfL for
diagnosis of MS [38,39]. However, in MS research, efforts are being made to
shorten the time from onset of symptoms to diagnosis of MS. Hence, studies have
been conducted on the use of NfL for the purpose of early discovery of patients
who transition from clinically isolated syndrome (CIS) or radiologically
isolated syndrome (RIS) to clinically definite MS (CDMS).
Recently, when CSF NfL levels were measured in RIS patients, patients who later
converted to CDMS showed higher levels than those who did not [14]. A
prospective study in adult and pediatric CIS patients in a Dutch cohort also
showed that the higher the CSF NfL level, the higher the risk of later
conversion to relapsing-remitting MS (RRMS) [15]. Moreover, a 15-year
longitudinal follow-up study predicted future transition to secondary
progressive MS (SPMS) with a very high level of accuracy (93.3% sensitivity,
46.1% specificity) depending on the baseline serum NfL level (> 7.62 pg/mL)
[19]. Various studies have reported that increase in CSF or serum NfL levels
helps predict later conversion to MS in patients at a first demyelinating event.

DISEASE ACTIVITY

Evaluating disease activity reflects the severity of an acute attack at a
certain point in time; however, it is also useful to predict long-term prognosis
and changes in advance during follow-up. When evaluating disease activity in
terms of relapse activity, which is the most commonly used clinical indicator, a
high baseline serum NfL level was associated not only with past relapse activity
[20] but also with future relapse [21]. Studies showed that the direction of
dynamic change is critical, in addition to the concentration measured
unilaterally. There was a case report wherein, after measuring baseline CSF NfL
levels in RRMS patients, follow-up measurements were performed after 6 and 28
weeks; the patient experienced clinical relapse at 15 weeks, and the CSF NfL
level measured at 6 weeks was three times higher than baseline [40]. In
addition, a study elucidated that some relapsed patients with highly active MS
treated with alemtuzumab showed serum NfL level increase at 5 months before
clinical onset [34]. Referring to the above findings, from the perspective of
“predicting” long-term disease activity, regular follow-up evaluation of NfL
levels is essential.
Many associations with findings related to brain magnetic resonance imaging
(MRI) have been studied and are used as indicators to evaluate the activity of
important diseases in clinical practice and clinical trials. Exploring
T1-enhancing lesions, CSF NfL assessment showed that high baseline NfL level was
associated with many baseline T1-enhancing lesions [22] and high possibility of
future T1-enhancing lesions [17]. Similarly, a close correlation between
baseline serum NfL levels and baseline T1-enhancing lesions/future T1-enhancing
lesions has been reported [23,26], and an increase in serum NfL levels (not
baseline serum levels) was associated with new T1-enhancing lesions [24,34].
Similar results have been reported for T2 lesions. Baseline NfL CSF and serum
levels can predict the overall T2 lesion burden and the occurrence of new T2
lesions in the future [25,26]. However, some studies have shown that serum NfL
levels are unrelated to T1-enhancing lesions or T2 lesion burden [24,41]. In
interpreting this result, it is necessary to consider the limited possibility of
conventional MRI because high NfL levels are significantly associated with
decreased fractional anisotropy and increased diffusivity (for the entire
normal-appearing white matter [NAWM]; ρ = –0.49, p = 0.005) when measuring the
diffusion tensor index in NAWM in 79 MS patients [42]. Although there is no
routine T1 or T2 lesion, a study [42] showed the possibility of determining the
progress of overall diffuse white matter damage through NfL level measurement.

THERAPEUTIC RESPONSE MONITORING

As various MS therapeutics are developed and utilized clinically, one of the
most critical issues is appropriately verifying the effectiveness of
therapeutics. A practically used method is to assess whether a patient has a
clinical relapse or to follow up with MRI annually to monitor the presence of
newly developed lesions. However, the medical cost may not be the only dilemma,
as disease activity may not necessarily be revealed as a change in the image.
Accordingly, there has been an expectation that NfL measurement can be used as
an auxiliary indicator to reflect subclinical disease activity, and studies on
this have been conducted recently.
Exploring drugs that are usually selected as first-line agents in Korea, in 32
RRMS patients treated with glatiramer acetate or IFN-β, NfL levels were
decreased in those who responded to treatment, whereas those with increased
levels showed lesions on MRI and frequent clinical relapses [27]. With dimethyl
fumarate, baseline NfL levels in both the CSF and serum were high in
treatment-naïve RRMS patients; however, after 1 year of treatment, these levels
in treatment-naïve RRMS patients were the same as those of the healthy control
group, and CSF NfL levels were more sensitive in reflecting clinical relapse or
MRI activity than were blood NfL levels [25]. However, when the same drug was
used to analyze CSF NfL levels in primary progressive MS (PPMS) patients, no
significant difference was found in the levels at baseline or after follow-up
compared with those of the placebo group [28].
After administration of fingolimod, CSF NfL level in RRMS patients decreased and
was correlated with the relapse rate [29]. Interestingly, CSF NfL level was
significantly decreased when using fingolimod as first-line treatment [43] but
was unchanged when treatment was switched to fingolimod after using natalizumab
[44]. This finding demonstrates the use of NfL to provide information on the
efficacy of therapeutic agents and to simply monitor the treatment response.
Natalizumab is one of the most frequently prescribed high-efficiency drugs, and
CSF NfL level decreased significantly after 12 months of administration in RRMS
patients [45]. The CSF NfL level was stable when the disease activity was
stable, but it increased rapidly upon relapse [46]. When prescribing natalizumab
in clinical practice, one of the critical considerations is the risk of
progressive multifocal leukoencephalopathy (PML). When following up with
patients prescribed natalizumab, serum NfL levels decreased with stabilization
of the disease after initial administration, and results obtained in the second
year showed higher serum NfL levels in the group of patients who developed PML
than in the group of patients who did not develop PML [30]. This is a valuable
finding because serum NfL levels can be used as an adjuvant to determine the
risk of PML in John Cunningham virus (+) patients and when deciding to stop
natalizumab treatment.
An alemtuzumab-related study identified significantly lower serum NfL levels
after administration in RRMS patients after 2 years, and this effect was
maintained until the 7th year [33]. In addition, when using alemtuzumab in
highly active MS patients (n = 15), there was no sign of relapse or new lesion
on brain imaging in a small cohort of patients with low serum NfL levels after
administration, whereas increase in serum NfL levels was associated with
increase in T2 lesion burden and occurrence of new T1-enhancing lesions on brain
MRI [34]. In a study comparing alemtuzumab with dimethyl fumarate, fingolimod,
natalizumab, teriflunomide, and rituximab, treatment with alemtuzumab showed the
lowest plasma NfL levels and the most significant decrease in NfL levels
compared to baseline [47], and NfL levels are believed to reflect clinical drug
efficacy.
In addition, cladribine [35], which was recently introduced in Korea, and
siponimod [36] and ofatumumab [37], which have not yet been introduced,
decreased CSF or serum NfL levels according to RRMS or progressive MS types,
indicating NfL levels as a possible indicator reflecting treatment response in
progressive MS.

OTHERS

As MS progresses, overall brain atrophy progresses, which indicates overall
deterioration of the patient’s long-term neurological function. Hence, studies
to predict future brain atrophy are being conducted. Several studies have shown
a correlation between higher CSF NfL levels and severe brain atrophy [48], some
have shown an association with gray matter (GM) atrophy [49], and another showed
correlation with thalamus and nucleus accumbens volumes rather than overall
brain volume [50]. In addition, a study showed that the baseline level of serum
NfL and the degree of increase during follow-up could predict future brain
volume changes [24].
In diagnosing and treating patients with MS, interest in systemic symptoms that
can affect the quality of life of patients, as well as clinical relapse in the
form of actual focal neurological deficit, is increasing. In the case of
fatigue, the most representative MS symptom, a study of CIS and RRMS patients (n
= 38) showed no significant association between serum NfL levels and fatigue
[51]. However, since another study showed a correlation between baseline serum
NfL levels and baseline quality of life measured using the Multiple Sclerosis
Quality of Life-54 questionnaire [52], further studies are needed.


GLIAL FIBRILLARY ACIDIC PROTEIN

Glial fibrillary acidic protein (GFAP) is a type III intermediate filament
protein expressed in the GFAP gene located on chromosome 17 and is found in
large amount in the cytoplasm of mature astrocytes in the central nervous
system. Although it plays various roles, the most important is to maintain the
cytoskeleton of astrocytes and provide mechanical tension [53]. CSF GFAP level
was increased in conjunction with astrocytosis that occurs in brain trauma,
toxic damage, and various genetic diseases. Similarly, CSF GFAP level was
increased in MS patients compared with healthy controls. According to the most
recently published meta-analysis [54], a mean difference of 0.62 (95% confidence
interval [CI], 0.56–0.88; p < 0.001) in CSF GFAP level was reported between the
RRMS patient group and healthy control group, and a very large mean difference
of 103.83 (95% CI, 68.09–139.57; p < 0.001) was reported between the remission
and relapse periods within the RRMS group. Although CSF GFAP level was
significantly lower in the progressive MS patient group than in the RRMS patient
group, no difference was noted between the SPMS and PPMS groups. Additionally,
CSF GFAP level has been positively correlated with duration of disease (ρ = 0.3,
p = 0.014), reflecting the phenomenon of astrogliosis alongside disease
progression [55].
Few studies have measured GFAP level in the blood compared with CSF. Patients
with PPMS showed higher blood but not CSF GFAP level than patients with RRMS (p
< 0.05), and blood GFAP level was correlated with disease severity (ρ = 0.5, p <
0.001) [56]. However, since the literature on this topic is limited, follow-up
studies with a larger cohort are needed to clarify the role of blood GFAP level.
In summary, the pattern of GFAP CSF level differs by MS subtype, which is
expected to aid in early classification of PPMS and RRMS. In particular, it may
be a helpful biomarker for determining disease severity and progression.


LEPTIN

Leptin is a protein consisting of 167 amino acids expressed by the ob gene and
is mainly produced in adipocytes, enterocytes, T-lymphocytes, and bone marrow
cells. It has been shown to have a wide range of effects on angiogenesis, wound
healing, energy balance, and fat storage by acting through type I cytokine
receptors [57]. In addition to its role in immune system regulation, leptin is
gaining attention in the field of autoimmune diseases, including MS. Mechanisms
acting on the immune system have been reported to promote the proliferation of
autoreactive T cells, inhibit the proliferation of T-reg cells, and promote the
secretion of proinflammatory cytokines [58,59]. Some studies have shown
conflicting results for circulating leptin level in MS patients. However, the
largest recently published meta-analysis (including 645 MS patients and 586
controls from nine studies) showed that MS patients had significantly higher
blood leptin level than individuals in the control group (standardized mean
difference [SMD], 0.70; 95% CI, 0.24–1.15) [60]. A follow-up study showing that
overweight young adults (20 years old) had a greater than two-fold higher risk
of developing MS supports this finding [61]; however, some studies have reported
contradictory results depending on sex/age. For example, in a Swedish
biobank-based study, the higher the blood leptin level in men, the higher the MS
risk (odds ratio [OR], 1.4; 95% CI, 1.0–2.0; p = 0.04), but the higher was the
leptin level in women in their 30s, the lower was the risk of MS (OR, 0.74; 95%
CI, 0.54–1.0; p = 0.05) [62]. A study in Kuwait, where the prevalence of obesity
is high, reported that leptin level was significantly lower in MS patients than
in individuals in the control group [63].
The diverse study results may be attributed to limitations such as small sample
sizes, a heterogeneous mixture of factors known to affect leptin level (age,
sex, smoking status, body mass index, and treatment status including steroids),
and inconsistent sampling timing (fasting vs. non-fasting). The use of leptin as
a valuable biomarker in MS depends on the results of subsequent studies
controlling the various confounding factors.


BRAIN-DERIVED NEUROTROPHIC FACTOR

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family,
with splicing pattern depending on the type of stimulation, and approximately 30
types of messenger RNA transcripts are produced. BDNF is widely expressed in the
central nervous system and plays a vital role in neuronal development and
long-term potentiation of synapses by regulating survival, growth,
differentiation, and death of neurons and various types of cells through the
receptors TrkB and p75 [64,65]. BDNF in MS has been associated with the
single-nucleotide polymorphism (SNP) rs6265, with alteration in some domain
structures of BDNF by substituting methionine for valine at codon 66 (Val66Met).
This change attenuated BDNF release and receptor binding [66]. Controversial
results have been reported regarding the association between this genetic
variation and MS. While studies have reported that the Val66Met polymorphism
results in more severe GM atrophy in the brain than that of Val/Val carriers
(mean GM volume, 812.92 mL vs. 846.42 mL; p = 0.005) [67], some studies have
shown low BDNF expression in Val66Met carriers, with a protective effect on
cognitive decline (p = 0.027) [68]. These differing results led to the
hypothesis that the polymorphism itself is not essential compared to the
direction of “epigenetic regulation” (i.e., the methylation status of the BDNF
gene). This hypothesis was supported by a recently reported study in an Italian
cohort [69]. According to that study, disease severity and presence of the
rs6265 SNP were unrelated, and the lower the methylation ratio of the BDNF gene,
the higher the severity of the disease and the faster the progression. This is
probably because the more active is the disease and the stronger the
inflammation, the greater the demethylation of BDNF as a defense mechanism and
the greater BDNF translation, maximally suppressing inflammation. The expression
of BDNF and its receptors in or near MS plaques is increased in the brain
pathology tissues of patients with MS, but it decreases in older chronic plaques
[70].
Regarding studies of BDNF level at various stages of MS, some studies showed
slightly elevated BDNF level in the serum of patients with relapse [71].
However, compared with that of the control group, BDNF level was decreased in MS
patients (mean, 60.7 ng/mL vs. 23.9 ng/mL; p = 0.013) [72]. This suggests a
possible effect of chronic progression of MS by reducing the overall capacity of
the nerve repair mechanism due to decreased levels of neurotrophic factors, such
as BDNF, in the long-lasting chronic inflammatory phase.


CHITINASE-3-LIKE PROTEIN 1

Chitinase-3-like protein 1 (CHI3L1) is a glycoprotein secreted from various
types of cells, including macrophages, astrocytes, smooth muscle cells, and
chondrocytes, and plays an essential role in various inflammatory responses,
tissue damage, fibrosis, and extracellular tissue remodeling [73]. In the
central nervous system, most CHI3L1 is secreted by astrocytes, activated
microglia, and macrophages at sites of inflammatory lesions and reactive gliosis
[74]. Many studies have measured the concentration of CHI3L1 in the CSF and
blood in patients with MS, with similar results. A recent meta-analysis of 486
patients with MS and 228 healthy controls identified significantly higher CHI3L1
level in the CSF of MS patients compared to a healthy control group (SMD, 0.964;
95% CI, 0.795–1.133; p < 0.001) [75]. Furthermore, CIS patients had higher
CHI3L1 level than the healthy control group, and increased concentration of
CHI3L1 in the blood/CSF of CIS patients was an independent predictive factor of
conversion to definite MS (hazard ratio, 1.6; p = 3.7 × 10–6) and rapid
disability development (p = 1.8 × 10–10) [76]. In another study, the higher the
CHI3L1 level, the higher the number of T2 and Gd+ contrast-enhancing lesions on
brain MRI [77]. Furthermore, CSF CHI3L1 level was reduced when natalizumab or
fingolimod was administered in patients with RRMS [44,78] and in those who
responded to treatment with IFN-β (p = 0.013) [79].
Although no significant difference was observed among MS subtypes, CHI3L1 showed
potential as a biomarker for early diagnosis of MS and prediction of disability
progression. This conclusion requires validation in a larger sample size
including patients with homogeneous disease phenotypes.


C-X-C MOTIF CHEMOKINE 13

C-X-C motif chemokine 13 (CXCL13) is a chemokine and the most potent B-cell
chemoattractant, which is a ligand protein of the B-cell receptor CXCR5 [80]. It
is responsible for organization of B cells in the lymphoid follicle and is
involved in formation of ectopic meningeal B-cell follicles in the central
nervous system, which is very important for forming intrathecal autoimmunity in
MS [81]. Since B-lymphocytes are one of the most critical factors in development
and progression of MS, CXCL13 has received attention as a candidate early
biomarker for MS.
The CSF CXCL13 level has been reported to be associated with CSF pleocytosis and
immunoglobulin G (IgG) oligoclonal band (OCB)-positive findings in CIS patients,
and high CXCL13 level increased the risk of conversion to CDMS [82]. In RRMS
patients, IgG index, CSF white blood cell count, and degree of cerebral cortical
atrophy were significantly correlated with CSF CXCL13 level [83] and with
disease activity and levels of other biomarkers (NfL and CHI3L1) in progressive
MS [84,85]. In addition, when the CXCL13 index ([CSFCXCL13 / serumCXCL13)] /
[CSFalb / serumalb]) was introduced, it showed better accuracy than OCB in
predicting future disease activity (CXCL13 index: sensitivity/specificity,
91%/64%; OCB: sensitivity/specificity, 81%/30%) [86].
Among patients on high-efficacy disease-modifying therapies, CSF CXCL13 level
was increased in some of those who were stable without clinical/imaging relapse
(RRMS, 39%; progressive MS, 50%) [87]. This finding suggests that CXCL13 can be
used to assess disease activity more sensitively than can clinical indicators or
MRI.
Studies have also reported CXCL13 as a marker of response to MS treatment, with
levels of both CXCL13 and CCL19 chemokines being significantly reduced in the
CSF after rituximab administration and after natalizumab or methylprednisolone
treatment [88,89]. It was also reported that baseline serum CXCL13 level before
administration of fingolimod was significantly lower in the group that responded
to fingolimod than in the group that did not (mean level of responders vs.
nonresponders, 58.25 pg/mL vs. 127.2 pg/mL; p = 0.009). This suggests that serum
CXCL13 level indicates treatment response to fingolimod [90].
In summary, CXCL13 has potential as a biomarker of prognosis of CIS and reflects
disease activity in MS. Furthermore, after validation in larger cohorts, CXCL13
is expected to be used as a biomarker related to treatment response
(particularly for B-cell-depleting agents).


OSTEOPONTIN

Osteopontin (OPN) is an extracellular matrix glycoprotein, a substance secreted
by many cell types in different tissues. It is involved in various physiological
functions, such as bone remodeling, wound healing, and immune cell activation.
In the immune response, it promotes interleukin (IL)-1b, IL-12, and IL-17
production and inhibits IL-10 expression, contributing to transformation of the
overall cytokine balance into a proinflammatory state [91]. Because OPN is
widely expressed in both the neurons and glia of the brain, it has attracted
attention in neuroinflammatory diseases, including MS.
A recent meta-analysis (including 27 previous studies) showed that, regardless
of MS subtype, OPN level in MS patients was significantly increased in both the
CSF (SMD, 0.65; 95% CI, 0.28–1.01; p < 0.01) and blood (SMD, 0.61; 95% CI,
0.34–0.87; p < 0.01) compared with that in the control group. In addition, RRMS
had the highest level among MS subtypes, followed by PPMS, CIS, and SPMS in that
order [92]. Another study has shown that CSF OPN level increased during the
acute phase of the disease and decreased after the acute phase, indicating it
may as an indicator of disease activity [93]. However, in the meta-analysis, no
significant difference was noted in CSF OPN level between MS patients and other
inflammatory nervous system disease groups (p = 0.079), hindering clinical use
as a diagnostic marker of MS. Nevertheless, decrease of an indicator reflecting
disease severity or CSF OPN level after natalizumab administration in
progressive MS (–65 ng/mL; 95% CI, –34 to –96; p < 0.001) [89] indicates the
possibility of its use as a marker to evaluate the effect of treatment.
Go to :



CONCLUSION

With the development of various therapeutic agents for MS within the past 20
years, the relapse rate has significantly decreased compared with that of the
past, and it has become possible to reduce damage caused by MS to the nervous
system. However, since MS has a heterogeneous phenotype and complex
pathophysiology, it requires ‘treatment and control’ for the remaining lifetime.
A periodic detailed patient evaluation should be performed, and it is essential
to have a system to detect subclinical disease activity and respond in advance.
In addition to the biomarker proteins mentioned in this review article, there is
need for broadly and easily accessible biomarkers with higher sensitivity and
specificity. Furthermore, valuable study results are expected in the future, not
only in the field of proteins but also for genomic markers, including microRNAs.
Go to :



NOTES

Conflicts of Interest

No potential conflict of interest relevant to this article was reported.

Go to :






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ORCID iDs

Jun-Soon Kim
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