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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 115

suggests the possibility that the increased NGF levels could represent an increased cerebral regeneration
after shunting.

Vascular endothelial growth factor plays roles in many cerebral physiological and pathological
modifications, and its level in CSF is respondent to ischemic condition involved in different neurological
disorders [59,71-73] . Our group demonstrated that the CSF levels of vascular endothelial growth factor in iNPH
[74]
patients have circadian variations and exercise induced increasing . The higher concentration of vascular
endothelial growth factor level in CSF is associated with less response to shunting and worse clinical
outcome, suggesting a possible concurrent ischemic or vascular injury in iNPH patients [73,75] .

Glial fibrillary acidic protein is a marker for gliosis [34,76] . In iNPH patients, the CSF level of glial fibrillary
[38]
acidic protein was increased when compared with controls, and correlated with disease progression . The
increased glial fibrillary acidic protein level in CSF suggests an irreversible damage to astrocytes, since glial
fibrillary acidic protein is not secreted by astrocytes.

All of these markers suggest the involvement of vascular risk factors and consequent subcortical white
matter lesions in the development of iNPH; however, further studies are needed to explore their predictive
value in clinical application.

OTHER BIOMARKERS AND METHODOLOGICAL IMPACT ON CSF BIOMARKER DETECTION
The level of prostaglandin D synthase was found to be significantly lower in iNPH patients compared with
[77]
controls and other dementia patients, such as Lewy body dementia, vascular dementia, and AD . This
enzyme is secreted into CSF by the leptomeninges and the trabecular cells of the arachnoid membrane. The
authors speculated that the decreased level of prostaglandin D synthase was probably due to a degenerative
change of the arachnoid membrane in iNPH patients.

Finally, the methodology of CSF biomarker detection may also affect the ability to reliably evaluate
[78]
biological biomarkers for the differentiation and prognosis of cognitive impairment diseases . Many
factors may affect the reliability and sensitivity of biomarker detection, for example, the systematic
difference between different assays, different pre-analytical protocol for sample preparation and storage,
analytical variability of measurement procedures, etc. [79,80] . When interpreting measurement results, these
factors should be considered. In addition, some biomarkers exhibit periodic concentration patterns.
Therefore, the most appropriate time for sample collection must also be considered when designing a
[79]
protocol .

CONCLUSION
The overlap of neuroimaging and symptomatic manifestations leads to diagnostic confusion between
iNPH and other neurodegeneration diseases, such as AD and subcortical ischemic vascular disease.
Despite the absence of definite pathological hallmarks, the biomarkers altered in CSF might serve as
targets for diagnosis and therapeutic intervention. Furthermore, the biomarkers in CSF could reflect the
adjacent cerebral pathophysiological status, therefore are potentially useful to provide insight into the
pathological changes in the brain milieu and underling pathogenesis. Although many CSF biomarkers
have been analyzed in iNPH patients, the significant findings include the reduced Ab with concomitant
42
normal or reduced t-tau and p-tau levels in iNPH coupled with reduced Ab with concomitant increased
42
both t-tau and p-tau levels in AD. This characteristic alteration may significantly improve the accuracy
of differential diagnosis between AD and iNPH patients. Other biomarkers may lack specification in
differential diagnosis, but the definite changes may mirror the underlying pathogenesis mechanisms, such
as demyelination, neurodegeneration, and neuroinflammation, and provide valuable information to further
explore the pathogenesis mechanisms and optical therapeutic manipulations.