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Page 110 Zhang et al. Neuroimmunol Neuroinflammation 2020;7:109-19 I http://dx.doi.org/10.20517/2347-8659.2019.018

INTRODUCTION
Idiopathic normal pressure hydrocephalus (iNPH) is one of the disabling neurological disorders whose
potential treatability is significantly impacted by the timeliness of unequivocal diagnosis. iNPH is
characterized by ventriculomegaly that is caused by an imbalance between cerebrospinal fluid (CSF)
production and absorption. The characteristic triad symptoms of dementia, gait disturbance, and urinary
[1,2]
incontinence are thought to be caused by a disruption of CSF dynamics . Therefore, the triad symptoms
[3]
of iNPH could be surgically treatable with a diversion of CSF into peritoneal cavity or heart . However,
the diagnostic workup of iNPH can be a challenge due to neuroimaging and symptomatic overlaps with
other neurological disorders, such as Alzheimer’s disease (AD) and subcortical ischemic vascular disease,
especially at early stage. Moreover, although the cognitive decline could be proceeded by these diseases,
they are not equally responsive to the treatment of CSF shunting. Therefore, further effort to improve the
diagnosis of iNPH would benefit the current imaging and symptomatic diagnostic criteria. Increasing
studies indicate that the pathogenesis of iNPH involves multiple mechanisms, including abnormalities of
brain development, brain extracellular matrix, synaptic function, blood flow, and cerebral metabolism,
which could result in protein content changes in CSF. On the other hand, impaired CSF absorption could
lead to a pathological flow of CSF into the periventricular tissues to initiate a cascade of pathological
[4]
processes such as edema and consequent neuronal degenerative changes . Therefore, measurements
of different biomarkers in CSF may reflect the underlying neuropathological changes of the brain and
could play an important role in revealing the possible etiological mechanisms. Furthermore, its detection
may facilitate the timeliness and accuracy of iNPH diagnosis, and thus becomes potentially useful for
therapeutic selection and treatment response monitoring. In addition, the biomarkers could help to
differentiate iNPH from other neurological disorders, which might mimic iNPH symptomatology but
[5,6]
show unsatisfactory outcomes after shunting . Despite a growing interest, the CSF biomarker profile
in iNPH has not yet been identified definitively. In this review, we summarize the main findings of CSF
biomarkers regarding iNPH and outline a rough CSF profile in order to assist iNPH diagnosis and provide
adequate treatment. It is notable that, due to the etiological complexity of iNPH, most biomarkers might
lack specificity for iNPH diagnosis and are possibly coincidental, confounding with other overlapping
neurological diseases. In addition, in comparison with a cortical brain biopsy or neuropsychological
testing, biomarkers may also have limitations in distinguishing iNPH from comorbid iNPH plus AD , as
[7]
well as in predicting clinical cognitive outcome post shunting [6,8,9] . However, a combination of more than
one biomarker may enhance the predictive value and provide more viable and accurate solutions. Ideally,
the dynamic changes of biomarker measured before and after surgical diversion of CSF would supply useful
clinical information for the diagnosis and assistance in monitoring disease progression. The biomarkers
could be categorized as AD discrimination, neurodegeneration and demyelination, neuroinflammation,
neuropeptides and cerebral metabolites, and as biomarkers in response to cerebral and vascular insulting,
among others [1,2,10,11] .

BIOMARKERS FOR AD DISCRIMINATION
Dementia in iNPH is potentially reversible if adequately treated. However, it often resembles the clinical
[12]
appearance of patients with AD, such as memory decline, as well as attention and executive impairment .
Urinary incontinence and gait disturbance may also occur in both diseases due to disturbed subcortical
network caused by vascular pathology. Moreover, ventricular enlargement may have been observed in
[13]
AD patients as a result of cerebral atrophy rather than CSF circulation impairment . Furthermore, the
pathological examination of cortical brain biopsies performed during placement of CSF shunts revealed AD
neurodegenerative changes in 24% of iNPH patients, suggesting a high comorbidity of both diseases. Thus,
[6,8]
cortical brain biopsy may provide a valuable predictive way for outcome evaluation . However, cortical
brain biopsy is not always available or appropriate in some cases. Moreover, both iNPH and AD diseases
may manifest sleep disturbances, which correlate with dysfunction of the glia-lymphatic (glymphatic)