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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 111

system, consequently building-up of brain metabolic wasters, favoring dementia development [14,15] .
Therefore, it is always a challenge to discriminate iNPH and AD diseases in clinical practice.

The glymphatic system facilitates cerebral metabolite and brain fluid clearance during sleep via glia-
supported perivascular channels. This system facilitates efflux of cerebrospinal and interstitial fluid via
the perivascular spaces to the meningeal and cervical lymphatic vessels, assisting the draining/clearing
of metabolic wastes from the central nervous. The glymphatic flux is proposed to be driven by cardiac-
[16]
induced arterial pulsation , and may be possibly manipulated through change of intracranial pressure
[17]
pulsatility with our cardiac-gated device . Most interestingly, the action of glymphatic flux is predominant
[18]
during sleep , and up to 90% of iNPH patients are associated with obstructive sleep apnea, a common
[19]
sleep disorder . Blockage of the airway in obstructive sleep apnea causes increased awakenings and
[20]
decreased quality of sleep, resulting in glymphatic dysfunction and increased cerebral Ab aggregation .
Patients with obstructive sleep apnea encounter reduced oxygen intake due to intermittent airway
obstruction. Excessive breathing against a closed airway induces negative intrathoracic pressure, sufficient
[19]
to cause atrial distortion and reduced venous return to the heart and ultimately affect arterial pulsation,
resulting in dysfunction of glymphatic flux.

Many studies have shown impaired glymphatic function in both iNPH and AD. Furthermore, iNPH
and AD patients share multiple clinical and pathologic features such as Ab deposition, cerebrovascular
inflammation, impaired localization of perivascular astrocyte aquaporin-4 (AQP4), and sleep
[15]
disturbances . Therefore, it is a diagnostic challenge in daily practice for iNPH and AD. Although
many biomarkers have been investigated for their discrimination, amyloid-b 42 (Ab ), total-tau (t-tau),
42
and phosphorylated tau (p-tau) are the most robust candidate markers to discriminate iNPH from AD
patients . Ab is lower in both iNPH and AD patients compared with healthy control, and Ab does
[1,2]
42
42
not separate iNPH and AD. Tau protein is a microtubule-associated protein and is a marker for neuronal
degeneration . The levels of t-tau and p-tau are higher in AD patients compared with iNPH patients and
[21]
controls, whereas the levels of t-tau and p-tau are within normal range in iNPH patients. The combination
of these biomarkers, i.e., the reduced Ab with concomitant normal or reduced t-tau and p-tau levels
42
in iNPH coupled with reduced Ab with concomitant increased both t-tau and p-tau levels in AD,
42
may significantly improve the accuracy of differential diagnosis between AD and iNPH patients . The
[22]
mechanism of lower Ab level in iNPH patients is unknown. However, the reduced production of Ab
42
42
due to a decline in brain metabolism in the periventricular zone in iNPH patients [23,24] and interstitial
[15]
Ab deposition due to impaired glymphatic function may be possible reasons . Meanwhile, the low
concentrations of CSF t-tau and p-tau do not support the major cortical degenerative process in iNPH [24,25] ,
whereas, in AD patients, the core pathological changes are the accumulation of abnormally folded beta-
amyloid and tau proteins in the plaques and neuronal tangles , and the progressive deposition of amyloid
[26]
plaques lowers Ab level. Moreover, concurrent axonal degenerations and neurofibrillary tangle formation
42
[27]
further increase t-tau and p-tau CSF levels in AD patients . The representative information and main
biomarkers for assisting differential diagnosis of iNPH and AD are summarized in the attached Table 1.
NEURODEGENERATION AND DEMYELINATION
The disturbance of CSF circulation could lead to a potentially hostile milieu for cerebral structures,
especially periventricular areas and subcortical structures, and could result in vascular lesions, destruction
of periventricular white matter, and subsequent neurodegeneration and demyelination [28-30] . Such
pathological changes could be estimated with the examination of CSF contents, such as neurofilament
light chains (NFL), myelin basic protein (MBP), and leucine-rich-α2-glycoprotein (LRG) [31-33] . NFL is a
cytoskeletal element in nerve axons and dendrites, and therefore could be considered as a biomarker for
axonal damage in patients with iNPH [31,34] . Although some studies did not find difference of CSF NFL