Pathogenesis and pathophysiology of idiopathic normal pressure hydrocephalus

Abstract

First defined in 1965, idiopathic normal pressure hydrocephalus (iNPH)is a surgically reversible neurological disorder in adults. It is characterized by dementia, gait disturbance, and urinary incontinence (known as Hakim's triad). 1,2 INPH is not a rare clinical entity. The prevalence of iNPH has been estimated to be 10 per 100 000 to 22 per 100 000 overall, with 1.30% in those aged ≥65 years and 5.9% in those aged ≥80 years. 3,4 One of the core features of iNPH is that the cerebrospinal fluid (CSF) pressure of an iNPH patient is within normal ranges. 2 Typical brain imaging of iNPH displays ventriculomegaly, periventricular hyperintensities, wide Sylvian fissures, narrowed subarachnoid space, and cortical sulci at the high convexity. 5 In contrast to the secondary normal pressure hydrocephalus with known etiology, the exact cause of iNPH is unknown. 6 Its specific pathogenesis also remains elusive, although several

Novel therapeutics for hydrocephalus: Insights from animal models

“…The ventricles of these rats remained enlarged, even after the blood pressure was lowered by captopril 89 . Current studies have found that choroid plexus cell death, ependymal injury, impaired glymphatic transport, hemorrhage, and other factors may be involved in the development of hydrocephalus in spontaneously hypertensive rats 17,87,90,91 . Therefore, minocycline is a promising drug for the treatment of hydrocephalus and related tissue damage.…”

“…These substances into the brain parenchyma are collected in the perivenous spaces surrounding the large deep veins and flow into the neck lymphatic system 109 . Some evidence suggests that there may be impaired glymphatic transport in patients with idiopathic normal pressure hydrocephalus (iNPH) and that the abnormal expression of AQP4 may be involved in this damage 91,113–115 . By using magnetic resonance imaging contrast agent as CSF tracer, it was found that there is a significant delay in the tracer clearance stage of iNPH patients 115,116 .…”

“… 89 Current studies have found that choroid plexus cell death, ependymal injury, impaired glymphatic transport, hemorrhage, and other factors may be involved in the development of hydrocephalus in spontaneously hypertensive rats. 17 , 87 , 90 , 91 Therefore, minocycline is a promising drug for the treatment of hydrocephalus and related tissue damage. However, minocycline has some side effects, such as the possibility of inducing lupus erythematosus.…”

“… 109 Some evidence suggests that there may be impaired glymphatic transport in patients with idiopathic normal pressure hydrocephalus (iNPH) and that the abnormal expression of AQP4 may be involved in this damage. 91 , 113 , 114 , 115 By using magnetic resonance imaging contrast agent as CSF tracer, it was found that there is a significant delay in the tracer clearance stage of iNPH patients. 115 , 116 This delayed clearance may be related to the deposition of amyloid‐β peptides (Aβ) in the brain tissues of iNPH patients, but the mechanism remains to be explored.…”

The importance of non-invasive imaging in understanding the glymphatic system in normal pressure hydrocephalus

“…In NPH, glymphatic dysfunction could play a role in worsening the hydrocephalus and symptoms. The low compliance of the brain and high glymphatic resistance leads to more CSF accumulation in the peri-arterial space and subsequently decreased arterial pulsatility [5]. Similar to Alzheimer's disease, this leads to the accumulation of toxic metabolites and worsened cognition [3].…”