Multiple Sclerosis Journal - October 2017 - 1446

Multiple Sclerosis Journal 23(11)
N-Acetylaspartate
Biological plausibility. N-acetylaspartate (NAA) is
an amino acid, highly expressed in neurons, oligodendrocytes and myelin that actively transfer water
molecules extracellularly against a concentration
gradient.89 It is a marker of functional integrity of
neuronal metabolism.90 NAA levels could reflect
either neuronal or oligodendrocyte damage.91
Strength and specificity of association. NAA has
been found to be reduced in MS compared to controls and it may be a marker of disease burden.43,92
Reduced NAA does not appear to be specific for MS
and has also been described in Parkinson's disease,
amyotrophic lateral sclerosis, Alzheimer's disease
and traumatic brain injury.37
Consistency of findings. A reduction in NAA in
MS is not a consistent finding, and this may have
something to do with the stage of MS studied or the
disease controls used.43,44,93 However, when modelled in combination with neurofilaments, NAA
could predict disability by EDSS and MSSS scores.44
Temporal sequence of association. Again like its
axonal counterparts, changes in NAA are more apparent in chronic disease than in early disease.43 SPMS
patients have lower CSF levels of NAA than RRMS
and CIS patients.43,92
Biological gradient. High MRI lesion loads, black
hole lesion load and a decrease in brain volume are
directly correlated with a reduction in CSF NAA
levels.92 Clinically, there is a negative correlation
between NAA and EDSS.43,92,94 There is, however,
little data on a treatment effect on NAA levels.16
Chitinase and chitinase-like proteins
Biological plausibility. Chitinase proteins (particularly chitinase 1/chitotriosidase (CHIT1), chitinase
3-like 1 (CHI3L1) and chitinase 3-like 2 (CHI3L2))
are expressed by astrocytes and microglial cells in
reaction to pro-inflammatory conditions.95,96 CHI3L1
was the first to be discovered as a potential biomarker
through an unbiased proteomic screen of MS CSF.97
Strength and specificity of association. Chitinases
predict prognosis in early MS. The most recent evidence indicates that CHI3L2 performs better than
CHI3L1 and predicts the development of MS after the
first demyelinating episode,98 although in the earlier
work, CHI3L1 was mostly studied and a similar predictive capability was demonstrated.99,100 CHI3L2
moreover correlates with other biomarkers of tissue
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damage (NfL, myelin basic protein (MBP), OPN),
suggesting that it may be upregulated in relation with
cellular damage.98 CHI3L1 has been noted not to
be specific for MS and is commonly increased in disorders where there is a possibility of active inflammation, neuromyelitis optica (NMO), HIV, stroke and
Alzheimer's disease.96,97,101-103 CHIT1 was found to
correlate with MBP and could be a biomarker of
demyelination or phagocytic activity.98 It was also
more likely to be elevated in those with mononuclear
cells and evidence of intrathecal IgG synthesis in their
CSF than in those without these findings.104
Consistency of findings. Overall, all of the studies are
mostly concordant. Correale et al.,101 however, did
not find serum CHI3L1 levels particularly useful, noting no difference between MS and other inflammatory disorders, and healthy controls. Hinsinger et al.105
noted that CSF CHI3L2 levels were lower in progressive MS than in RRMS, unlike CHI3L1 levels.
Temporal sequence of association. There is a trend
for CSF and serum CHI3L1 to increase with disease
progression, from CIS, through to RRMS and progressive MS (although this is cross-sectional sampling only): a relationship which is less clear with
CHI3L2.105
Biological gradient. Measuring chitinases at the first
demyelinating event will help identify those with a
poorer prognosis.100 Novakova et al.60 demonstrate
that CHI3L1 and CHIT1 reduced after escalation
in therapy to fingolimod from first-line therapies,
but was essentially unchanged in those who were
previously on natalizumab. In a separate proteomic
analysis, natalizumab treatment for 1 year was demonstrated to reduce CSF CHI3L1 levels, suggesting
that neurodegeneration-related protein CHI3L1 can
be modulated by natalizumab.106
Osteopontin
Biological plausibility. Osteopontin (OPN) is a proinflammatory cytokine found in many tissues and
body fluids, involved in inflammation, bone mineralization, tissue repair, tumour cell biology, atherosclerosis and renal disease.107,108 Its main function is
to regulate cytokines, boosting interferon-gamma
(IFN-g), interleukin-12 (IL-12) and decreasing interleukin-10 (IL-10) levels. As such, OPN targets
T cells and polarizes toward a T helper type-1 (Th1)
immune response.109 It may also regulate T helper
type-17 (Th17) autoimmune response.110 OPN was
initially implicated as a candidate biomarker for disease activity after demonstration of its upregulation
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Table of Contents for the Digital Edition of Multiple Sclerosis Journal - October 2017
