Evaluation of aquaporins in the cerebrospinal fluid in patients with idiopathic normal pressure hydrocephalus

Abstract

Brain aquaporin 1 (AQP1) and AQP4 are involved in cerebrospinal fluid (CSF) homeostasis and might participate in the origin of hydrocephalus. Studies have shown alterations of perivascular AQP4 expression in idiopathic normal pressure hydrocephalus (iNPH) and Alzheimer’s disease (AD). Due to the overlapping of clinical signs between iNPH and certain neurological conditions, mainly AD, specific biomarkers might improve the diagnostic accuracy for iNPH. The goal of the present study was to analyze and quantify the presence of AQP1 and AQP4 in the CSF of patients with iNPH and AD to determine whether these proteins can be used as biomarkers of iNPH. We examined AQP1 and AQP4 protein levels in the CSF of 179 participants (88 women) classified into 5 groups: possible iNPH (81 participants), hydrocephalus associated with other neurological disorders (13 participants), AD (41 participants), non-AD dementia (32 participants) and healthy controls (12 participants). We recorded each participant’s demographic and clinical variables and indicated, when available in the clinical history, the record of cardiovascular and respiratory complications. An ELISA showed virtually no AQP content in the CSF. Information on the vascular risk factors (available for 61 patients) confirmed some type of vascular risk factor in 86% of the patients with possible iNPH and 58% of the patients with AD. In conclusion, the ELISA analysis showed insufficient sensitivity to detect the presence of AQP1 and AQP4 in CSF, ruling out the possible use of these proteins as biomarkers for diagnosing iNPH.

Aquaporin-4 cerebrospinal fluid levels are higher in neurodegenerative dementia: looking at glymphatic system dysregulation

“…However, the hypothesis of higher concentrations of AQP4 in CSF of people suffering from neurodegenerative disease seems more conceivable. A recent study, published in October 2021, considered an overall population of 179 individuals consisting of 81 idiopathic normal pressure hydrocephalus (iNPH), 41 AD, and 32 non-AD dementia [ 24 ]. The study argued that in these last two groups, the levels of AQP4 concentrations were undetectable in the CSF, with a mean (± standard deviation) of 0.009 ± 0.01 ng/mL for the AD patients, and 0.007 ± 0.007 ng/mL for not-AD patients with dementia, but also for the other clinical conditions examined similar negative results were obtained.…”

“…Future perspectives also include the description of normal values for this protein, since there are very few studies which focused on this task [22][23][24], and, consequently, the definition of a pathological threshold, in order to consider AQP4 the same as other proteins, such as Aβ, tau, and P-tau, which are currently utilised. Another interesting potentiality is employing AQP4 levels for prospective, cohort studies.…”

Association between enlarged perivascular spaces and cerebrospinal fluid aquaporin-4 and tau levels: report from a memory clinic

“…Another limitation is the lack of a standardized methodology for the measurement of AQP4. Given both the presence of some data arguing against the detectability of AQP4 in the CSF ( Hiraldo-González et al, 2021 ) and the absence of confirmatory data from other groups, we cannot draw definitive conclusions on the inter-laboratory reproducibility of AQP4 dosage. However, the consistency of the results between our two studies, which analyzed two completely different cohorts of patients, provides reassuring evidence of reliability.…”

The pathogenesis of idiopathic normal pressure hydrocephalus based on the understanding of AQP1 and AQP4

“…However, detecting AQPs in CSF as biomarkers for identifying iNPH and separating these individuals from those with Alzheimer's disease is impossible, according to recent studies, at least given the detection levels afforded by commercial ELISA kits. AQP1 and AQP4 shedding into the CSF does not appear to occur in any of these illnesses, at least not at measurable quantities by ELISA (Hiraldo-González et al, 2021 ). A potentially useful method is to provide quantitative CSF samples during aspiration tests (de Laurentis et al, 2020 ).…”