Diagnostic and Predictive CSF Biomarkers in Idiopathic Normal Pressure Hydrocephalus (iNPH): A Systematic Review

Abstract

Idiopathic normal pressure hydrocephalus (iNPH) is a progressive disorder clinically characterized by Hakim’s triad: gait disturbance, cognitive impairment, and urinary incontinence. iNPH treatment consists of neurosurgical implantation of a ventriculoperitoneal CSF diversion, whose outcome depends on an early and correct diagnosis. Currently, there is no specific diagnostic test to perform preoperatively. Still, the combination of neurological examination, gait analysis, neurocognitive evaluation, and the tap test is useful to suggest when surgery is indicated. Our systematic review aims to identify diagnostic and outcome predictor CSF biomarkers (BM) in iNPH. The present systematic review was conducted following PRISMA 2020 guidelines. PubMed, Scopus, and the Cochrane Library databases were first consulted in April 2025 and updated in May 2026. Studies were selected using the terms “idiopathic normal pressure hydrocephalus” and “CSF biomarkers” under Medical Subject Headings (MeSH) as inclusion criteria. The eligibility of a record was defined according to the study title and abstract. The QUADAS-2, QUIPS, ROBINS-I V2, and RobVis tools were used to assess the risk of bias. Ninety-nine records were included in this systematic review. Amyloid proteins (Aβ40-42), followed by tau (τT, τP−181) and neuroinflammatory proteins were the most frequently CSF BM analyzed in patients with iNPH. ELISA was the most used method to measure BM in CSF samples. Forty-seven records investigated the potential diagnostic role of CSF BM; comparisons were frequently made among iNPH, Alzheimer’s disease (AD), and healthy control CSF samples. Regarding outcome prediction, 28 records examined CSF BM, with heterogeneous comparisons such as lumbar versus ventricular CSF or shunted versus non-shunted iNPH CSF samples, including healthy controls and iNPH. Seven records proposed both the diagnostic and predictive role of some CSF biomarkers, especially for tau proteins and Aβ42. On the other hand, 17 records concluded that neither a diagnostic nor a predictive role could be proposed for the CSF BM they analyzed. However, these records increased knowledge about an iNPH CSF pattern. Collecting and analyzing CSF samples from iNPH patients can be advantageous in differential diagnosis with other similar neurodegenerative disorders, especially AD, and therefore a predictor of neurosurgical outcomes. Combined biomarker panels should be integrated in standardized protocols, measuring: Aβ42, Aβ42/Aβ40, p-tau, total tau, ADAβ42/p-tau, L-PGDS, NFL and NRGN.