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Zhang et al. Neuroimmunol Neuroinflammation 2020;7:109-19 I http://dx.doi.org/10.20517/2347-8659.2019.018 Page 113

one of the causes of neurodegeneration, therefore its level in CSF could be an anticipated marker for early
diagnosis of iNPH and other dementia diseases [33,43] .

Taking together, all these markers allow tracking the integrity of periventricular and subcortical structures.
Although they are not disease specific, their changes in CSF directly reflect cerebral damage, and they may
be useful indicators in comparative analyses between iNPH and other neurodegenerative diseases.

NEUROINFLAMMATION
Cytokines mediate inflammatory response and often correlate with neurodegeneration in neurological
diseases. The profile of CSF cytokines provides access to explore the pathogenic mechanisms of different
[44]
neurological diseases and therapeutic approaches . Abundant CSF cytokines have been investigated in
iNPH patients, but a more definite profile still needs to be clarified [32,36] .

Tumor-necrosis factor (TNF-α) is a cytokine of inflammatory mediator and its level in CSF is significantly
high in iNPH patients [45,46] . Most interestingly, the CSF level of TNF-α returned to the control level in the
patients with shunt improvement. Because of its short half-life, the increased CSF TNF-α may be caused
by increased production rather than the accumulation due to CSF stagnation, which suggests that TNF-α
in CSF might be used as a candidate marker for the evaluation of demyelination and disease progression in
iNPH patients. More studies are needed for validation.

Transforming growth factor b1(TGF-b1), one of the three cytokines in the TGF family, plays a role in cell
differentiation and tissue modification during brain development. It could be released from microglia and
astrocytes in response to cerebral insult to initiate neuroinflammation and neurodegeneration through the
induction of fibrosis, vascular hypertrophy, accumulation of extracellular matrix components, and neuronal
apoptosis [47-49] . TGF-b level was found to be higher in iNPH patients than controls, and was considered to
[49]
be a reliable index of cerebral damage in iNPH .
Other increased inflammatory biomarkers measured in iNPH patients include IL-1b and IL-6 (pro-
inflammatory cytokines), IL-10 (anti-inflammatory cytokine), tissue factor pathway inhibitor 2 (TFPI-2),
chitinase-3-like protein-1 (YKL-40), and monocyte chemoattractant protein (MCP-1) [50-52] . However, as
similar changes are also observed in AD and Parkinson’s disease, these changes only reflect an underlying
neuroinflammatory processes of pro-inflammatory reaction (IL-1b and IL-6) and compensatory anti-
inflammatory reaction (IL-10), rather than disease-specific indicators [44,51,52] . TFPI-2 is involved in
inflammatory process by recruiting astrocytes and microglia to the injury site . YKL-40 is then released
[50]
from astrocyte and/or microglia in response to neuroinflammation. The increased CSF YKL-40 levels seem
to be correlated with cognitive decline and therefore to predict progression of dementia . However, more
[53]
studies are deserved on the clinical use of this novel promising neuroinflammation biomarker [35,48] .

NEUROPEPTIDES AND CEREBRAL METABOLITES
Neuropeptides, including somatostatin, vasoactive intestinal peptide, neuropeptide Y, and delta-sleep
inducing peptide, have been evaluated by various groups [10,54,55] . Decreased CSF somatostatin levels
suggest damage to the hypothalamus and the cortical neurons that normally have high concentrations of
[54]
somatostatin . Higher level of somatostatin correlates with better visual memory and mental condition
[10]
in iNPH patients, proposing that somatostatin may have a modulatory role in cognition . Vasoactive
intestinal peptide is a potent vasodilator and therefore may play a role in chronic ischemia, and the CSF
level is usually higher in iNPH patients with cerebrovascular disease [55-57] . Delta-sleep inducing peptide is a
nine-amino acid peptide with a role in sleep-wakefulness regulation. iNPH patients with lower delta-sleep
inducing peptide level show worse psychomotor performance . Several studies also reported reduced
[56]
levels of neuropeptide Y in iNPH patients [54-56] .