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Page 114 Zhang et al. Neuroimmunol Neuroinflammation 2020;7:109-19 I http://dx.doi.org/10.20517/2347-8659.2019.018

Cerebral metabolism changes may occur in iNPH patients. iNPH patients were also reported to
have altered levels of lactate, an end product of anaerobic glycolysis underlying a presence of chronic
ischemia [58,59] . Free-radical peroxidation could result in cellular dysfunction and may therefore be
implicated in the pathogenesis of iNPH and dementia. A study showed that the levels of free-radical
[60]
peroxidation products significantly increased in iNPH patients . The authors implied that peroxidation of
cytoplasmic membranes might be involved in the development of cognitive dysfunction in iNPH.

BLOOD-BRAIN BARRIER CHANGE AND BIOMARKERS RESPONDING TO CEREBRAL AND

VASCULAR INSULTING IN INPH
Blood-brain barrier is a physically powerful gateway that strictly monitors and controls the interchange
[61]
of substances between central nervous system and blood flow . Its function is strictly dependent on
the integrity of microvascular endothelium and thus affected by many pathophysiological risk factors,
including vascular/hemodynamic changes, inflammation, etc., and in turn affects the homeostasis of
[62]
central nervous system . The “CSF/blood albumin ratio” represents a reliable index of blood-brain barrier
function. Blood-brain barrier impairment was reported in different neurodegenerative diseases, including
[63]
AD and cerebral vascular disease . Nowadays, it has been scarcely evaluated in iNPH patients, but
available reports indicate a substantial preservation of the blood-brain barrier [22,36] .

Vascular risk factor may be a component of subcortical neuropathology in the development of iNPH .
[2]
As key components, cerebral white matter lesions and hypertension were reported to be related to the
pathophysiology of iNPH [64-66] . White matter lesions, involved in different cognitive processes and/or
clinical outcomes, are associated with small vessel disease and white matter ischemia. The association
between iNPH and white matter lesions indicates the involvement of microvascular disturbances in the
white matter and in the pathological processes of iNPH. In addition, hypertension increases the risk of
iNPH through the mechanisms of involved small vessel diseases, including hypertension induced endothelial
damage and resultant extravasation of blood products into white matter, impaired blood flow with reduced
metabolism, and direct mechanical effect on ventricular size [66,67] . Therefore, identifications of vascular
related risk factors may improve diagnostic accuracy and address the underlying pathology regarding the
development of iNPH, and ultimately provide suitable intervention for iNPH management. Overall, the
dynamic and morphological alterations in subcortical structure of iNPH brain could be resulted from white
matter lesions, hypertension related vascular lesions, destruction of periventricular white matter axons and
[28]
gliosis, and impaired CSF circulation . Such pathological alterations could affect CSF protein contents
and biomarkers in CSF could mirror the underlying pathologic alterations. As markers of subcortical
[1]
damage, at least three proteins have been measured in iNPH patients, including NFL, LRG, and MBP . The
functions and clinical application of these proteins are discussed above. In summary, NFL is a cytoskeletal
protein for maintenance of axonal architecture and is considered as a marker for neuronal morphological
integrity . Although it has also been assessed as a biomarker for inflammatory and neurodegenerative
[31]
diseases, it has been observed that ventricular NFL levels in iNPH patients directly correlate with more
extensive altered signals in periventricular white matter in brain MRI . LRG is an astrocytic protein and
[1]
is increased in CSF of iNPH patients, suggesting a potential biomarker for iNPH, but it also changes with
[68]
aging and non-specific inflammation . MBP is an oligodendroglial structural protein of myelin. Its CSF
levels are increased in iNPH patients and other cerebrovascular and neurodegenerative diseases, indicating
the damage of periventricular white matter [1,32] .

In addition, nerve growth factor (NGF) play an important role in neuro-regeneration in response to brain
injury and age-related atrophy. NGF is scarcely detectable in innervated tissues, but denervation of cerebral
[69]
tissue could lead to the production of NGF and become measurable in the target tissues . The CSF level of
[70]
NGF was found to be significantly higher in hydrocephalus patients compared with the controls , which