International Journal of

Molecular Sciences

Review
Molecular Biomarkers in Multiple Sclerosis and Its
Related Disorders: A Critical Review
Maryam Gul 1, *, Amirhossein Azari Jafari 2 , Muffaqam Shah 3 ,
Seyyedmohammadsadeq Mirmoeeni 2 , Safee Ullah Haider 4 , Sadia Moinuddin 5
and Ammar Chaudhry 6
1 Precision Rheumatology INC, 2050 South Euclid Street, Anaheim, CA 92802, USA
2 Student Research Committee, School of Medicine, Shahroud University of Medical Sciences,
Shahroud 3614773947, Iran; [email protected] (A.A.J.); [email protected] (S.M.)
3 Deccan College of Medical Sciences, P.O. Kanchanbagh, DMRL ‘X’ Road, Santhosh Nagar,
Hyderabad 500058, Telangana State, India; [email protected]
4 Shaikh Khalifa Bin Zayed Al-Nahyan Medical College, Shaikh Zayed Medical Complex,
Lahore 54000, Pakistan; [email protected]
5 Department of Internal Medicine, San Antonio Regional Medical Center, 999 San Bernardino Rd,
Upland, CA 91786, USA; [email protected]
6 Department of Radiology, City of Hope National Medical Center, 1500 East Duarte Road,
Duarte, CA 91010, USA; [email protected]
* Correspondence: [email protected]; Tel.: +1-(714)-269-6469




Received: 20 May 2020; Accepted: 14 August 2020; Published: 21 August 2020


Abstract: Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system
(CNS) which can lead to severe disability. Several diseases can mimic the clinical manifestations of
MS. This can often lead to a prolonged period that involves numerous tests and investigations before
a definitive diagnosis is reached. As well as the possibility of misdiagnosis. Molecular biomarkers can
play a unique role in this regard. Molecular biomarkers offer a unique view into the CNS disorders.
They help us understand the pathophysiology of disease as well as guiding our diagnostic, therapeutic,
and prognostic approaches in CNS disorders. This review highlights the most prominent molecular
biomarkers found in the literature with respect to MS and its related disorders. Based on numerous
recent clinical and experimental studies, we demonstrate that several molecular biomarkers could
very well aid us in differentiating MS from its related disorders. The implications of this work will
hopefully serve clinicians and researchers alike, who regularly deal with MS and its related disorders.

Keywords: multiple sclerosis; MS; biomarker; molecular; pathophysiology; prognosis; treatment;

mimics; differential diagnosis

1. Multiple Sclerosis (MS)

Multiple sclerosis (MS) is a chronic autoimmune disease affecting the central nervous system (CNS),
caused by genetic and environmental factors. It is characterized by intermittent and recurrent episodes
of inflammation that result in the demyelination and subsequent damage of the underlying axons present
in the brain, optic nerve and spinal cord [1–3]. There are four courses of MS: (a) relapsing–remitting,
(b) primary progressive, (c) secondary progressive and (d) progressive relapsing [3]. There are a
number of illnesses that can mimic the clinical manifestations of MS and this can include several
pathologic processes because they all share a common pathway of demyelination and ensuing damage
to the underlying axons present in the brain, optic nerve and spinal cord [1–4]. Over the years,
the similarity of symptoms has led to numerous instances of neurologic conditions being misdiagnosed
as MS and vice versa [1,3]. The McDonalds criteria established in 2001 aimed to rectify this by setting

Int. J. Mol. Sci. 2020, 21, 6020; doi:10.3390/ijms21176020 www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2020, 21, 6020 2 of 22

guidelines for MS diagnosis [5]. However, because MS is often a diagnosis of exclusion, there is still a
considerable portion of time where patients may take unnecessary medications for other plausible
diseases before a diagnosis is established [1,3,6,7]. With the advent of immunomodulating therapy,
it has become more important to diagnose or even exclude MS more effectively earlier on in the course
of the illness [1,3,6,7]. By being aware and cognizant of the various diseases which mimic MS, this can
empower clinicians and researchers to help deliver accurate counseling and treatment to their patients
for their specific diagnosis [8].

1.1. Biomarkers in Pathophysiology of MS

One of the most prominent biomarkers of MS are miRNAs, which target several protective or
pathogenic signaling pathways, and they have been found to be upregulated or downregulated in MS
patients [9,10]. It is reported that protective miR-199a, pathogenic miR-320, miR-155, miR-142-3p and
miR-142 are increased in MS lesions or peripheral blood mononuclear cells (PBMCs) [9–11]. On the
other hand, miR-219, miR-34a, miR-103, miR-182-5p, miR-124 and miR-15a/b are decreased in the
Cerebrospinal fluid (CSF), Tregs or PBMCs of MS patients [9,10,12–14]. There is a strong correlation
between miRNAs and various manifestations of MS such as cognitive dysfunction and oxidative status,
which can result in depression or fatigue [9–14].
Another oxidative biomarker is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase
2 (Nox2); an enzyme that catalyzes the reduction of oxygen to produce reactive oxygen species,
which plays a role in the pathogenesis of MS [15].
Recent research has suggested that reactive T cells directed against neuronal protein β-synuclein
can invade and destroy the gray matter, which is a hallmark of MS [16]. In addition, a high level of
β-synuclein reactive T cells in the peripheral blood of MS patients indicates that this biomarker has a
key role in provoking T cells in MS [16].

1.2. Biomarkers in Diagnosis of MS

It has been suggested that the levels of specific complement proteins such as C1q, C3d and C5b-9
in the serum and CSF could potentially serve as novel biomarkers to diagnose the various MS subtypes
and determine the disease activity [17]. miRNAs levels such as low miR-219 and high miR-150 in CSF
are novel biomarkers that can distinguish MS from other neurologic conditions [18,19].
Recent studies have also shown that brain-derived neurotrophic factor (BDNF) and soluble
isoform of the interferon-β (IFN-β) receptor (sIFNAR2) levels may serve as useful biomarkers for the
diagnosis of MS [20,21].

1.3. Biomarkers in Treatment and Prognosis of MS

Several studies demonstrate that a vast number of immune modulators or oxidative stress
biomarkers can be used as therapeutic targets and for further studies on MS. The most notable examples
are miR-497-5p, semaphorin-3A, coenzyme Q10, interferon gamma-stimulated dendritic cell exosomes
(IFNγ-DC-Exos), glutathione (GSH) and dimethyl fumarate (DMF) [22–26].
It has been suggested that GSH (the major antioxidant in the brain) can be used for therapeutic
applications as well as to predict and monitor the disease progression [26]. Monitoring disease activity
in MS can be done by the use of total antioxidant status (TAS), high levels of total hydroperoxides and
ceruloplasmin transferrin ratio (Cp:Tf) ratio (strictly related to Fe management) [27,28].
The potential biomarkers which can be used to predict the prognosis of relapsed or progressive
forms of MS, as well as the responsiveness to treatment in patients with MS are SIRT1 (a NAD-dependent
deacetylase sirtuin-1) mRNA, Response gene to complement-32 (RGC-32), Fasl, IL-21, Tau proteins
(proteins that stabilize microtubules), miR-191-5p, miR-128-3p and serum netrin-1 (an axon guidance
protein) [17,21,29–32].
The primary CSF biomarkers which can be used to predict the prognosis of MS are β-amyloid
(Aβ) levels, neurofilament light (NF-L), neurofilament heavy (NF-H), chitinase 3-like-1 (CHI3L1) and
Int. J. Mol. Sci. 2020, 21, 6020 3 of 22

immunoglobulin M (IgM) [33,34]. Elevated levels of lysophosphatidic acid (LPA) in the serum and
CSF of relapsed MS patients can also be used as biomarkers to monitor the disease activity [35].

1.4. Systemic Lupus Erythematosus: Neuropsychiatric SLE

The nervous system is one of the major organs affected in patients with systemic lupus
erythematosus (SLE) [36]. Neuropsychiatric SLE (NPSLE) is a major cause of morbidity and mortality
in patients with SLE and it can be hard to distinguish NPSLE from MS [36].
It is proposed that many autoimmune biomarkers like anti-NR2A antibodies, anti-dsDNA antibody,
SLEDAI, complement levels, anti-ribosomal P antibodies (anti-P) and possibly anti-endothelial cell
antibodies (ECA) have a potential role in the NPSLE pathogenesis [37,38].
A recent study showed that serum brain-derived neurotrophic factor (BDNF) level is a useful
biomarker not only to diagnose NPSLE from other neurological diseases like MS, but also to monitor
the prognosis and response to treatment [39]. In addition, it was found that anti-U1 ribonucleoprotein
(RNP) antibodies (anti-U1RNP Abs) in the CSF could be a useful diagnostic tool for central NPSLE [40].
It is determined that serum anti-dsDNA antibodies can predict the development and prognosis
of NPSLE [41]. Recently, the small colony-stimulating factor-1 receptor (CSF-1R) kinase inhibitor
has been used in experiments on lupus-prone mice. Results showed that it could reduce the NPSLE
manifestations such as depression-like behavioral deficits [42].

1.5. Antiphospholipid Syndrome

Antiphospholipid syndrome (APS, or Hughes syndrome) is a systemic autoantibody-mediated
acquired thrombophilia that is characterized by the presence of antiphospholipid antibodies (APL)
against phospholipid-binding plasma proteins, such as beta-2-glycoprotein I (b2GPI) [43–46]. Because
of its neurological symptoms which include strokes, migraine, memory loss and the common clinical,
laboratory and radiological features; it has the potential to be misdiagnosed with other neurological
diseases especially MS [44–47].
In the pathophysiology aspect, the biomarker b2GPI has been identified as the major
autoantigen of APS, but there are other antibodies that bind to phosphatidylserine, prothrombin
and thrombomodulin [45–48]. The laboratory biomarker tests for the diagnosis and management
of APS are anti-beta-2-glycoprotein I (anti-b2GPI), anti-cardiolipin (ACL) and lupus anticoagulant
(LAC) [45,46,48,49].

1.6. Neuro-Behçet’s Disease

Neuro-Behçet’s disease (NBD) is not very common in the course of Behçet’s disease (BD, a systemic
variable vessel vasculitis), however, it is associated with significant mortality and morbidity [50].
Several biomarkers like interferon-alpha, IL-6 receptor blocking agent (tocilizumab), and anti-TNF
agents are the most preferred options for treatment [50,51]. In a retrospective study, most patients with
NBD exhibited Mediterranean fever (MEFV) gene mutations which can act as a disease modifier in NBD
and it can be targeted with CNS anti-inflammatory treatments especially colchicine [52]. Defensin alpha
1B (DEFA1B) and NOD-like receptor protein 3 (NLRP3) gene expressions increase during NBD attacks
so they can be used as biomarkers to predict disease activity and also as possible targets for future
therapeutic experiments [53].

1.7. Primary Angiitis of the CNS

Primary angiitis of the CNS (PACNS) is an extremely rare disorder resulting in inflammation and
destruction of CNS vessels without any evidence of vasculitis outside the CNS and there is no valuable
biomarker test to diagnose PACNS [54,55].
Recently, the efficacy and safety of a new biomarker mycophenolate mofetil (MMF) for achieving
and maintaining remission of childhood PACNS have been demonstrated [56]. Furthermore, high levels
Int. J. Mol. Sci. 2020, 21, 6020 4 of 22

of a protein biomarker neurofilament light chain (NFL) in the sera (CSF) indicates neuroaxonal damage,
and its predictive value has been shown recently [57].

1.8. Polyarteritis Nodosa

Polyarteritis nodosa (PAN), is a necrotizing vasculitis mainly manifested by peripheral neuropathy
(most frequent and earliest), weight loss, fever, cutaneous lesions, hypertension and cardiac failure [58].
One of the suggested biomarkers in PAN is matrix metalloproteinase-3 (MMP-3) which can be
used in the diagnosis, management and following up on the PAN prognosis [59]. A recent study
demonstrated that high serum lysosomal-associated membrane protein-2 (LAMP-2) could be a useful
biomarker for evaluating the prognosis and the disease activity of PAN [60].

1.9. Antineutrophil Cytoplasmic Antibodies (ANCA)-Associated CNS Vasculitis (AAV)

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV), is a systemic
small-vessel vasculitis by pathogenic ANCA production, consists of granulomatosis with polyangiitis
(GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA) and
Neurologic involvement [61,62].
The ANCA is the main pathogenic biomarker of AAV which targets proteinase 3 (PR3) and
myeloperoxidase (MPO) in the cytoplasm of neutrophils and monocytes [63]. ANCA is also a strong
biomarker for diagnosis and even the monitoring of AVV activity [64].
The treatment goal of AVV is to inhibit the ANCA so it mainly consists of high-dose corticosteroids,
cyclophosphamide or rituximab [65].

1.10. Acute Disseminated Encephalomyelitis (ADEM)

Acute disseminated encephalomyelitis (ADEM) is a monophasic demyelinating disorder of the
CNS with a high incidence in children [66–68].
The elevated cytokines and chemokines (involved in helper T cells, regulatory T cells and B cell
pathways) in CSF suggest the possible role of these biomarkers on the pathogenesis of the ADEM [66,68].
Until recently there was no diagnostic biomarker test to confirm ADEM [68,69]. Moreover,
there are no clinical features or biomarkers that can reliably differentiate ADEM from MS at the first
attack [67,70]. In spite of this, MS can occur after ADEM in up to 17% of cases, which indicates the
importance of differentiating ADEM from MS early on [66]. Several studies have shown that some new
biomarkers like myelin oligodendrocyte glycoprotein (MOG) antibody, serum IgG targeting myelin
basic protein (MBP) and myelin-associated oligodendrocyte basic protein (MOBP) can be used to
diagnose and differentiate ADEM from MS at the first attack [67,69,71,72].

1.11. Neuromyelitis Optica (NMO)

Neuromyelitis Optica (NMO, Devic’s disease) is an idiopathic autoimmune disorder of the
CNS presenting with optic neuritis, transverse myelitis and possibly medullary involvement and
narcolepsy [73,74].
The pathogenesis of NMO can be attributed to the anti-aquaporin 4 (anti-AQP4) antibodies that
cross the blood–brain barrier and damage the astrocyte foot processes. IL-6 may also play a role [73].
IL-6 is produced by the macrophages and dendritic cells and promotes differentiation of T cells into
Th-17 cells. The IL-6 levels in NMO have been found to be higher than those in optic neuritis and
related disorders suggesting a greater role in disease pathogenesis [75].
Immunosuppressants are used for treatment. High dose steroids may be used acutely. In refractory
cases, exchange plasmapheresis [76] and intravenous or subcutaneous tocilizumab, an interleukin-6
antagonist has shown promise [77,78].
Int. J. Mol. Sci. 2020, 21, 6020 5 of 22

1.12. Optic Neuritis

Optic neuritis is a disease most commonly seen in women presenting as pain with extraocular
movements and potentially progressing to partial or complete loss of vision [79]. Optic neuritis usually
resolves within 3–6-week on its own however it may also progress into MS [80].
The pathology is inflammatory damage to the optic nerve and is confirmed by the presence
of anti-myelin oligodendrocyte glycoprotein (anti-MOG) or anti-AQP4 antibodies. It may also be a
manifestation of systemic lupus erythematosus, sarcoidosis or immune-mediated vasculitis [81,82].
Typical optic neuritis is usually self-limited and resolves on its own without any clinical treatment.
The use of steroids may reduce the duration of the disease [83]. However, it is debatable and the
treatment plan should be based on the biomarker [84].

1.13. Vitamin B12 Deficiency

Vitamin B12 (cobalamin) deficiency presents with a range of signs from megaloblastic anemia and
macrocytic anemia to subacute combined degeneration of the spinal cord [85].
If diagnosed early the prognosis is good, however, delayed treatment may lead to permanent
neurological dysfunction [86].
Elevated serum methylmalonic acid and homocysteine levels lead to neuronal damage and can be
detected as biomarkers [87,88]. Holotranscobalamin is used as a biomarker since B12 levels alone may
be misleading [89]. Anti-intrinsic factor antibodies (AIFA) and anti-parietal cell antibodies (APCA) may
also be useful when pernicious anemia is the cause [85]. Intramuscular injections and oral replacement
are used to treat deficiency [90].

1.14. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy
(CADASIL)
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
(CADASIL) is a rare autosomal dominant (AD) disease caused by mutations in the NOTCH3 gene of
chromosome (Chr.) 19p13.2-p13.1 [91]. It affects small vessels of the vascular system causing diffuse
microangiopathy [92,93].
Biomarkers that have shown promising results are the Von Willebrand factor (vWF), endothelial
progenitor cells (EPCs) and circulating progenitor cells (CPCs). The levels of vWF levels were
significantly higher, while EPCs and CPCs levels were reduced [92].
Management is solely pragmatic and no therapies have been able to limit the disease progression.
The biomarkers are not suitable prognostic indicators. Increases in the number of ischemic attacks
worsen the prognosis [94].

1.15. Leber’s Hereditary Optic Neuropathy (LHON)

Leber’s hereditary optic neuropathy (LHON) is a rare mitochondrial disease characterized by
progressive, bilateral and typically painless central vision loss [95,96].
Some promising/experimental biomarkers are low arylsulfatase A levels and elevated CSF/urine
sulfatide levels. These biomarkers are also present in other diseases, hence more research is warranted
in the search for a specific biomarker. Nonetheless, these biomarkers are still useful when formulating
a focused differential diagnosis when presented with the varying signs of a neurodegenerative
disease. [95,97,98].
The current standard of care is therapies with idebenone/quinine analogs, 4-aminopyridine (4-AP),
gene therapy and stem cell therapy [99,100].
The prognosis is generally poor, and most patients will end up legally blind with visual acuity of
20/200 or worse. Biomarker levels do not correlate well with the disease progression [101,102].
Int. J. Mol. Sci. 2020, 21, 6020 6 of 22

1.16. Mitochondrial Encephalomyopathy with Lactic Acidosis and Stroke-like Episodes (MELAS)
Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is a
multiorgan disease with stroke-like episodes, dementia, epilepsy, lactic acidemia, myopathy and
recurrent headaches [103]. The MT-TL1 mutation accounts for most cases [104]
Broad yet unspecific biomarkers mentioned are [104–108]: Varying levels of serum lactate,
CSF lactate/pyruvate ratio, Ventricular lactic acid (LA), creatine kinase (CK), nitric oxide (NO),
N-acetyl-L-aspartate (NAA) and total choline (t-Cho). The most novel one is serum miR-27b-3p.
There is no known cure or consensus on the proper approach for treating MELAS. L-arginine is the
most commonly used/effective agent. Some benefits are noted with CoQ, idebenone, vitamins B/C/E
and levocarnitine. The prognosis is highly variable, and the biomarker levels do not correlate well
with disease progression [103,104,109,110].

1.17. Metachromatic Leukodystrophy (MLD)

Metachromatic leukodystrophy (MLD)is an autosomal recessive (AR) lysosomal storage disease.
It is caused by mutations in the ARSA region on Chr. 22q13.33. This causes a deficiency of the
arylsulfatase-A (ASA) enzyme and the accumulation of sulfatides, leading to demyelination [111].
The most reliable/mentioned biomarkers are low arylsulfatase A levels and elevated CSF/urine
sulfatide levels. These are mentioned numerous times in the literature and warrant a strong suspicion
for MLD [112–115].
There is no treatment available for MLD. Hematopoietic stem cell transplantation (HSCT), gene
therapy and enzyme replacement therapy (ERT) are the options currently in the trial phase [116–118].
Biomarker levels do not correlate well with the disease progression and cannot serve as prognostic
indicators [119].

1.18. Krabbe’s Leukoencephalopathy (KL)

Krabbe’s leukoencephalopathy (KL) is a rare AR disorder with widespread demyelination.
Mutations on Chr. 14q31 cause a deficiency of the β-galactosylcerebrosidase (GALC) enzyme [115,120,
121].
There are elevated blood levels of galactosphingosine (psychosine) and reduced GALC enzyme
activity. Elevated psychosine levels correlate well with disease severity (possible prognostic indicator).
It is specific to confirm the diagnosis, along with clinical manifestations and imaging [120,122–125].
Currently, the only approved treatment for presymptomatic infantile and late-onset patients is
HSCT. The prognosis varies based on how early the diagnosis is made, how quickly HSCT was started
(10%–20% mortality rate associated with HSCT) and the severity of the disease progression [115,125].

1.19. Multiple Sulfatase Deficiency (MSD)

Multiple sulfatase deficiency (MSD) is a rare inherited metabolic disorder caused by a deficiency
in the formylglycine-generating enzyme (FGE), due to mutations in the sulfatase modifying factor 1
(SUMF1) gene on Chr. 3p26.1. Leading to a deficiency in all molecules of the sulfatase enzyme family.
This results in increased sulfated lipids and mucopolysaccharides buildup in various cells leading to
dysfunction [126,127].
The major trends of biomarker levels mentioned are [126–136]: (a) elevation of sulfatides in the
urine; (b) deficiency of sulfatase enzyme activity in the leukocytes; (c) elevation of glycosaminoglycan
(GAG) in the urine and at times plasma (variable).
There is no specific therapy available for MSD, but ERT and gene therapy options are being
explored [127,136]. Prognostic indicators are based on FGE stability and residual enzyme activity. Those
with drastic impairments in both had a worse prognosis, whereas those with residual activity/levels
had a better prognosis.
Int. J. Mol. Sci. 2020, 21, 6020 7 of 22

1.20. Alexander Disease (AxD)

AxD is a rare, progressive and generally fatal neurological disorder. Resulting from dominant
mutations affecting the coding region of GFAP, which encodes for glial fibrillary acidic protein (GFAP).
GFAP is the major intermediate filament protein of astrocytes in the CNS [137].
The biomarker most mentioned was GFAP. The levels were consistently elevated in the CSF,
but only occasionally elevated in the blood [137–141].
Management revolves around supportive care, dealing with various CNS dysfunctions and an
emphasis on genetic counseling [138,141]. Experimental work is being done on using GFAP as a target
for pharmacological agents [141]. GFAP levels do not serve as an accurate prognostic indicator, because
elevated levels do not correlate well with disease severity.

1.21. Adrenoleukodystrophy (ALD)

Adrenoleukodystrophy (ALD) is an X-linked disorder caused by mutations in the ABCD1 gene
which encodes the adrenoleukodystrophy protein (ALDP). A defect in ALDP results in elevated levels
of very-long-chain fatty acids (VLCFAs) and their accumulation in plasma and tissues [142,143].
The biomarkers mentioned are elevated levels of plasma and tissue VLCFAs and elevated levels
of C26:0 lysophosphatidylcholine (C26:0-lyso-PC) [144–147]. Huffnagel et al. found that C26:0-lysoPC
is a better and more accurate biomarker than plasma VLCFA levels [145].
There is no curative treatment available for ALD. HSCT remains the only therapeutic intervention.
There is no treatment for any associated progressive myelopathy. Early diagnosis of males with ALD
by screening at birth allows for the early detection of adrenal insufficiency [144,145].
The levels of the biomarkers mentioned cannot be used as prognostic indicators [144,145]. There is
variability noted in the literature for disease progression [146–148].

1.22. Pelizaeus-Merzbacher Disease (PMD)

Pelizaeus-Merzbacher disease (PMD) is an X-linked disorder caused by mutations in the
proteolipid protein 1 (PLP1) gene on Chr. Xq22, which encodes for PLP1. PLP1 plays an integral
role in compact myelin sheath stabilization [149].
Mierzejewska et al. state that the diagnosis can be confirmed only with molecular analysis of
the genetic mutation/abnormality [150]. A thorough search of the literature did not yield any reliable
evidence of a diagnostic biomarker for PMD. However, some experimental results are being reported.
Takanashi et al. found that on magnetic resonance spectroscopy (MRS), an LCModel revealed increased
total N-acetyl-L-aspartate (tNAA), creatine (Cr), myo-inositol (min), choline (Cho) [151].
There are no effective therapies for PMD. Genetic counseling and supportive care for
disabilities/special needs are the current protocols [149,152,153]. White-matter atrophy serves as
a marker of clinical severity, and a prognostic indicator [152,153].

1.23. Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to

Steroids (CLIPPERS)
The immunopathogenesis of most inflammatory CNS disorders, like Chronic lymphocytic
inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) remains
poorly understood [154]. Hence, there is not a useful diagnostic and prognostic biomarker test as of
yet [154].
CLIPPERS is specified by determining punctate or curvilinear gadolinium-enhancing MRI lesions
that are most noted in the pons [155,156].
Analysis of cerebrospinal fluid can determine mildly elevated protein, pleocytosis and oligoclonal
bands or could be unremarkable. A CLIPPERS display can be connected with antibodies to MOG,
but most cases are seronegative. Intravenous and oral steroids can improve clinical and paraclinical
effects rapidly. Long-term steroid-sparing agents such as azathioprine and mycophenolate have
Int. J. Mol. Sci. 2020, 21, 6020 8 of 22

been used as well, except for immunomodulatory monoclonal antibodies like tocilizumab and
rituximab [155].

1.24. HIV-Related Disorders of the CNS

Chemokines and their receptors tend to play a key role for connection among neurons and
inflammatory cells. Evidence is mounting for the connection between chemokines and their receptors
in the progression of brain damage, including MS and HIV associated dementia. This system is
therefore likely to become a serious goal for the treatment of neurodegenerative diseases. In the
development of demyelinating lesions in MS patients, the RANTES polymorphism would contribute.
In damaged tissues, RANTES is an inflammatory chemokine remarked to respond to pro-inflammatory
cytokines or contact with pathogens. Its main role is the recruitment of effector cells to sites of
inflammation. The data shows a strong association between the severity of dementia and CSF HIV
viral load, suggesting the development of HIV-induced brain damage [157].

1.25. HTLV-1-Associated Myelopathy

The first human retrovirus that was associated with the development of cancer was the human
T-cell lymphotropic virus (HTLV)-1, namely adult T-cell leukemia (ATL), the pathogenesis is still
unknown [158].
HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) can be confirmed by
HTLV-1 antibodies via western blot and/or a positive PCR. The finding of anti-HTLV-1 antibodies
in CSF is necessary for the diagnosis of HAM/TSP. To rule out other diseases similar to HAM/TSP,
like MS, neuroimaging is necessary but is not specific for HAM/TSP. Most treatments in HAM/TSP
attempt to suppress or modulate the immune response or to reduce the HTLV-1 proviral load in
this disorder. Some treatments have discovered that display improves in the progress of HAM/TSP,
like corticosteroids, INF-α, mogamulizumab or monoclonal antibody against IL-2 Rα. Mogamulizumab
is a synthesized anti-CCR4 monoclonal antibody, effectively decreased both the proviral load (PVL)
and inflammatory activity in cells acquired from patients with HAM/TSP. Reduction in the PVL
and spontaneous proliferation is caused by the Monoclonal antibody against IL-2 Rα. Given that
HAM/TSP is characterized by activated T-cells in both the periphery and CNS, studies in HAM/TSP can
give a chance for clarifying the pathogenesis of other neuroinflammatory disorders such as multiple
sclerosis [159].

1.26. Lyme Borreliosis

Lyme borreliosis is a multisystem disease caused by spirochete Borrelia burgdorferi sensu lato [159].
Although B. burgdorferi can be one of the reasons for MS, it does not have a key role in the MS
etiology [160]. Both Lyme borreliosis and MS can mimic lymphoma [160]. Rituximab can be useful for
both MS and lymphoma, whether it could have a good effect on Lyme borreliosis or not [160].
Some investigation has shown that MR imaging results may be valuable for diagnostic workup of
a patient with neuroborreliosis and T2 brain lesion indiscernible from those of MS [159].

1.27. Myelin Oligodendrocyte Glycoprotein IgG-associated Encephalomyelitis (MOG)

Myelin sheaths and oligodendrocytes express a protein that is named MOG. Anti-MOG
antibodies (MOG-IgG) can cause demyelination in vitro and persuade experimental autoimmune
encephalomyelitis. This disease is so rare and the incidence of that in children and adults is low [161].
The studies have shown that the brain lesion distribution criteria could be distinguishable in the
MS patient from MOG-EM, even as early on as the disease onset [162].
Int. J. Mol. Sci. 2020, 21, 6020 9 of 22

1.28. Neurosyphilis
The CNS lesions in MS and syphilis disease are similar in histological appearance. Spirochetes can
be the cause of both MS and syphilis, so the antibiotics could be useful for the treatment of these [162].
The most common characteristic of meningovascular syphilis is the atypical stroke-like presentation
while the contrast-enhancing gammas in later stages may potentially look like MS. Both illnesses
can result in CSF pleocytosis with elevated CSF gamma globulin and the presence of oligoclonal
bands [163]. Even though the fact that neurosyphilis can still be the “great imitator”, the presence or
absence of a serum fluorescent treponemal antibody study (FTA-ABS) should provide essentially 100%
sensitivity for infection with syphilis [163].

1.29. Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) caused by the JC virus (JCV) which is a fatal
demyelinating disease of the CNS, this human polyomavirus can lytically infect and destroy the
oligodendrocytes in immunosuppressed patients [164].
On the whole we can say that the RANTES polymorphism could be involved in the development
of demyelinating lesions in NDLE pathology similarly to what was observed in MS patients, but not in
PML [164].

2. Discussion
This review was written with the intended purpose of highlighting the current state of available
evidence for the vast and growing sum of MS-related disorders. An emphasis was placed on featuring
their associated biomarkers. As indicated in Table 1, we highlighted a wide array of molecular
biomarkers that can aid us in the diagnosis, inform prognosis and act as guidelines for therapeutic
management in MS and its related disorders. (Table 1)
Many of the mentioned biomarkers have strong evidence supporting their current use in the
workup and management of their respective diseases. Despite the multitude of diseases that can
potentially mimic MS, most patients express enough characteristic clinical evidence that in fact, there is
only a limited need for an alternative diagnosis or supplementary testing/investigations.
The use of biomarkers in conjunction with the current standard of imaging modalities, namely
MRI will hopefully allow for a quicker and more accurate diagnosis, as well as precise management
strategies. The implications of this work will hopefully serve clinicians/researchers that are regularly
dealing with MS and its related disorders. Further research is most definitely warranted for those
diseases that have minimal to no biomarkers associated which can be relied upon confidently.
The overall data collated provides an accessory pathway that can be utilized in the management
of MS and the diseases which mimic it. With continued research and work in this field, there is a
possibility that biomarkers can become a routine and indispensable tool in the management of those
diseases which historically did not rely upon such an avenue.
Int. J. Mol. Sci. 2020, 21, 6020 10 of 22

Table 1. Summary of molecular biomarkers in multiple sclerosis and its related disorders (abbreviations are below table).
Biomarkers
Type of Disease Disease References
Pathophysiologic Diagnostic Therapeutic Prognostic
SIRT1
RGC-32
miR-199a Fasl
miR-320 IL-21
miR-155 Tau proteins
complement
miR-142-3p miR-191-5p
proteins:C1q, C3d and miR-497-5p
miR-142 miR-128-3p
C5b-9 semaphorin-3A
miR-219 serum netrin-1
miR-219 coenzyme Q10
MS miR-34a β-amyloid [9–12,14–32,35]
miR-150 IFNγ-DC-Exos
miR-103 NF-L
BDNF GSH
miR-182-5p NF-H
anti-U1RNP Abs DMF
miR-124 CHI3L1
sIFNAR2
miR-15a/b IgM
Nox2 LPA
β-synuclein GSH
TAS
Cp:Tf
anti-NR2A Ab
anti-dsDNA Ab
SLEDAI BDNF BDNF
NPSLE CSF-1R [37–41]
Complement levels anti-U1RNP Abs anti-dsDNA Ab
anti-P Ab
ECA
Autoimmune or inflammatory
anti-b2GPI
APS APL Abs against b2GPI ACL – – [43–46,48,49]
LAC
IFN-α
IL-6 receptor blocker DEFA1B gene
NBD MEFV gene mutations – [50–53]
anti-TNF agents NLRP3 gene
MEFV gene mutations
PACNS NF-L – MMF – [56,57]
ESR
ESR ESR
PAN – MMP-3 [59,60]
MMP-3 MMP-3
LAMP-2
AAV ANCA ANCA inhibit the ANCA ANCA [61–65]
MOG Ab
CSF elevated cytokines
ADEM IgG targeting MBP – – [66–69,71,72]
and chemokines
MOBP
anti-AQP4
NMO anti-AQP4 – – [73]
IL-6
Protein
CLIPPERS pleocytosis - – – [155]
oligoclonal bands
MOG-EM anti-MOG Abs - - - [160]
Int. J. Mol. Sci. 2020, 21, 6020 11 of 22

Table 1. Cont.
Biomarkers
Type of Disease Disease References
Pathophysiologic Diagnostic Therapeutic Prognostic
HIV-related
disorders
– CSF HIV viral load – – [157]
of the
Infectious
CNS
HAM/TSP HTLV-1 Abs – – – [158]
Neurosyphilis – FTA-ABS – – [163]
vWF
CADASIL NOTCH3 gene mutation EPCs – – [92]
CPCs
Arylsulfatase A Arylsulfatase A
LHON – – [95,97,98]
CSF/urine sulfatide CSF/urine sulfatide
Genetic disorders Lactate
CSF lactate/pyruvate ratio
Ventricular LA
MELAS MT-TL1 mutation CK – – [104–108]
NO
NAA
t-Cho
Optic
anti-MOG – – – [81,82]
neuritis
Arylsulfatase A Arylsulfatase A
MLD – – [112–115]
CSF/urine sulfatide CSF/urine sulfatide
Galactosphingosine Galactosphingosine Galactosphingosine
KL – [120,122–125]
(Psychosine) (Psychosine) (Psychosine)
SUMF1 gene mutations Urine sulfatides
FGE deficiency Sulfatase enzyme
demyelinating disorders MSD – FGE levels [126–136]
Sulfated lipids deficiency
Mucopolysaccharides Urine/Plasma GAG
AxD GFAP GFAP – – [137]
VLCFAs
ALD VLCFAs – – [142–147]
C26:0-lyso-PC
tNAA
Cr
PMD PLP1 gene – – [149,151]
min
Cho
Methylmalonic acid
Vitamin Homocysteine
Other disorders B12 – Holotranscobalamin – – [85,87–89]
deficiency AIFA
APCA
Int. J. Mol. Sci. 2020, 21, 6020 12 of 22

Author Contributions: A.A.J.: Responsible for searching the literature to collate all relevant papers pertaining
to the following diseases: abstract, introduction, multiple sclerosis and its subtypes, neuropsychiatric SLE,
antiphospholipid (Hughes) syndrome, neurosarcoidosis, neuro-Behcet’s disease, primary angiitis of the
CNS, polyarteritis nodosa, antineutrophil cytoplasmic antibodies, (ANCA)-associated CNS vasculitis and,
acute disseminated encephalomyelitis. Then drafted the critical review for the above-mentioned diseases.
Revised and edited the overall manuscript with the other co-authors critically and has given approval for
the final version to be submitted. M.S.: Responsible for searching the literature to collate all relevant papers
pertaining to the following diseases: migraine, cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy, Leber’s hereditary optic neuropathy, mitochondrial encephalomyopathy with
lactic acidosis and stroke-like episodes, metachromatic leukodystrophy, Krabbe’s leukoencephalopathy, multiple
sulfatase deficiency, Alexander disease, adrenoleukodystrophy and Pelizaeus–Merzbacher disease. A critical
review was done, along with drafting the manuscript for the above-mentioned sections, as well as part of the
discussion/conclusion. Revised and edited the overall manuscript with the other co-authors critically for important
intellectual content and has given approval for the final version to be submitted. S.M. (Seyyedmohammadsadeq
Mirmoeeni): Responsible for collecting literature relevant to the related disorders including chronic lymphocytic
inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), HIV-related disorders of
the CNS, HTLV-1-associated myelopathy, Lyme borreliosis, myelin oligodendrocyte glycoprotein IgG-associated
encephalomyelitis, neurosyphilis and progressive multifocal leukoencephalopathy. Then drafted, revised and
edited the critical review for the above-mentioned diseases, completed a part of the discussion, responsible for
drafting all of Table 1. Has given approval for the final version to be submitted. S.U.H.: Responsible for collecting
literature relevant to the related disorders including neuromyelitis optica, vitamin b12 deficiency and optic neuritis.
Contributed to the original draft writing of the aforementioned papers. Reviewed and edited the final paper along
with co-authors. Has given approval for the final version to be submitted. S.M. (Sadia Moinuddin): Responsible
for the revision of manuscript and the scientific approval. A.C.: Responsible for the revision of manuscript and the
scientific approval. M.G.: As the corresponding author, responsible for article conceptualization and methodology.
Carried out the role of supervision and project administration. As well as conducting a final review and editing
of the overall article. M.G. was responsible for conceptualization and methodology; A.A.J., M.S., S.U.H., S.M.
(Sadia Moinuddin), S.M. (Seyyedmohammadsadeq Mirmoeeni) were responsible for data curation, writing the
original draft in its entirety including formatting assigned diseases in Table 1, as well as a thorough review, then
editing and revising; S.M. (Sadia Moinuddin), S.M. (Seyyedmohammadsadeq Mirmoeeni) was also responsible
for drafting all of Table 1; A.A.J. was responsible for editing/formatting Table 1; M.G. carried out the role of
supervision and project administration, as well as a final review and editing of the overall article. All authors
have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Acknowledgments: This work has not been supported by any funding sources.
Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations
MS Multiple sclerosis
CNS central nervous system
PBMCs peripheral blood mononuclear cells
Nox2 nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2
BDNF brain-derived neurotrophic factor
IFN-β interferon-β
sIFNAR2 soluble isoform of the IFN-β receptor
IFNγ-DC-Exos interferon gamma-stimulated dendritic cell exosomes
GSH glutathione
DMF dimethyl fumarate
Cp:Tf hydroperoxides ceruloplasmin transferrin ratio
H3K9me2 histone H3 lysine 9 dimethylation
RGC-32 response gene to complement-32
SIRT1 a NAD-dependent deacetylase sirtuin-1
NF-L neurofilament light
NF-H neurofilament heavy
CHI3L1 chitinase 3-like-1
IgM immunoglobulin M
LPA lysophosphatidic acid
Int. J. Mol. Sci. 2020, 21, 6020 13 of 22

TAS total antioxidant status

NPSLE neuropsychiatric systemic lupus erythematosus
Ab antibody
ECA anti-endothelial cell antibodies
anti-U1RNP anti-U1 ribonucleoprotein (RNP)
BDNF brain-derived neurotrophic factor
CSF-1R colony-stimulating factor-1 receptor
APS antiphospholipid syndrome
APL antiphospholipid
b2GPI beta-2-glycoprotein I
ACL anti-cardiolipin
LAC lupus anticoagulant
NBD neuro-Behçet’s disease
IFN-α interferon alpha
TNF tumor necrosis factor
MEFV Mediterranean fever
DEFA1B defensin alpha 1B
NLRP3 NOD-like receptor protein 3
PACNS primary angiitis of the CNS
MMF mycophenolate mofetil
PAN polyarteritis nodosa
ESR erythrocyte sedimentation rate
MMP-3 matrix metalloproteinase-3
LAMP-2 lysosomal-associated membrane protein-2
AAV anti-neutrophil cytoplasmic antibody associated vasculitis
ANCA anti-neutrophil cytoplasmic antibody
ADEM acute disseminated encephalomyelitis
CSF cerebrospinal fluid
MOG myelin oligodendrocyte glycoprotein
MBP myelin basic protein
MOBP myelin-associated oligodendrocyte basic protein
NMO neuromyelitis optica
anti-AQP4 anti-aquaporin 4
IL-6 interleukin-6
CLIPPERS chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids
MOG-EM myelin oligodendrocyte glycoprotein IgG-associated encephalomyelitis
HAM HTLV-1 associated myelopathy
TSP tropical spastic paraparesis
FTA-ABS fluorescent treponemal antibody study
CGRP calcitonin gene-related peptide
CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy
vWF Von Willebrand factor
EPCs endothelial progenitor cells
CPCs circulating progenitor cells
LHON Leber’s hereditary optic neuropathy
MELAS mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes
LA lactic acid
CK creatine kinase
NO nitric oxide
NAA N-acetyl-L-aspartate
t-Cho total choline
anti-MOG anti-myelin oligodendrocyte glycoprotein
MLD metachromatic leukodystrophy
KL Krabbe’s leukoencephalopathy
Int. J. Mol. Sci. 2020, 21, 6020 14 of 22

MSD multiple sulfatase deficiency

SUMF1 sulfatase modifying factor 1
FGE formylglycine-generating enzyme
GAG glycosaminoglycan
AxD Alexander disease
GFAP glial fibrillary acidic protein
ALD adrenoleukodystrophy
VLCFAs very-long-chain fatty acids
C26:0-lyso-PC C26:0 lysophosphatidylcholine
PMD Pelizaeus–Merzbacher disease
PLP1 Proteolipid protein 1
tNAA total N-acetyl-L-aspartate
Cr creatine
Min myo-inositol
Cho choline
AIFA anti-intrinsic factor antibodies
APCA anti-parietal cell antibodies

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