Pathophysiological Mechanisms Underlying Idiopathic Normal Pressure Hydrocephalus: A Review of Recent Insights

Abstract

The pathophysiologic mechanisms underpinning idiopathic normal pressure hydrocephalus (iNPH), a clinically diagnosed dementia-causing disorder, continue to be explored. An increasing body of evidence implicates multiple systems in the pathogenesis of this condition, though a unifying causative etiology remains elusive. Increased knowledge of the aberrations involved has shed light on the iNPH phenotype and has helped to guide prognostication for treatment with cerebrospinal fluid diversion. In this review, we highlight the central role of the cerebrovasculature in pathogenesis, from hydrocephalus formation to cerebral blood flow derangements, blood-brain barrier breakdown, and glymphatic pathway dysfunction. We offer potential avenues for increasing our understanding of how this disease occurs.

Molecular Signatures of Normal Pressure Hydrocephalus: A Large-scale Proteomic Analysis of Cerebrospinal Fluid

“…Impairment in this system could lead to inadequate drainage of neuronal markers from ISF, contributing to their decreased presence in CSF and reflecting broader neurodegenerative changes within the central nervous system (CNS) (Figure 4). This hypothesis is supported by imaging studies indicating reduced glymphatic activity in iNPH and aligns with observed synaptic and neuronal marker downregulation 6,40,43,44 .…”

The impact of neurocognitive and psychiatric disorders on the risk of idiopathic normal pressure hydrocephalus: A bidirectional Mendelian randomization study

“…As to iNPH, the glymphatic system, a crucial delicate regulator of CSF balance, is known to participate in dementia in iNPH individuals (Tan et al., 2021 ; Ringstad et al., 2017 ). Studies have shown that restricted arterial pulsatility impairs the glymphatic system, leading to CSF retention and reflux to the ventricles (Bonney et al., 2022 ). Recognized as an integral component of brain clearance (Reeves et al., 2020 ), the glymphatic system's reduced flow fails to eliminate metabolic wastes, including accumulated inflammatory cytokines like ILs and TNFα in the cerebral nerve system, which could contribute to dementia.…”

Cerebrospinal fluid shunt surgery reduces the risk of developing dementia and Alzheimer’s disease in patients with idiopathic normal pressure hydrocephalus: a nationwide population-based propensity-weighted cohort study

“…The enlarged cerebral ventricles due to excess CSF in iNPH may damage the brain, leading to neurodegenerative diseases [ 7 ]. In addition, impaired vascular compliance in iNPH may trigger a cascade of events that lead to irreversible dementia [ 3 ]. Furthermore, the accumulation of amyloid due to CSF circulatory dysfunction and failure in iNPH may substantially increase the risk of AD [ 19 ].…”

“…Idiopathic normal-pressure hydrocephalus (iNPH) is a potentially treatable neurological disorder among the elderly population; it is characterized clinically by dilated cerebral ventricles and the triad of gait disturbance, urinary incontinence, and cognitive deficit without any recognized cause [ 1 – 3 ] The incidence of iNPH ranges from 10 per 100,000 to 22 per 100,000 overall, with 1.30% among those aged ≥ 65 years and 5.9% among those aged ≥ 80 years [ 4 , 5 ]. Although the pathogenesis of iNPH remains largely unclear, communicating hydrocephalus resulting from an excess accumulation of cerebrospinal fluid (CSF) due to an imbalance between its formation and removal is generally believed to initiate a vicious cycle of neurological damages in iNPH [ 3 ]. Guidelines recommend CSF shunt implantation, including ventriculoperitoneal and lumboperitoneal shunts, as treatment for improving motor (gait disturbance and urinary incontinence) and cognitive disabilities among iNPH patients [ 6 , 7 ].…”