Decoding the CSF Proteomic Signature of Idiopathic Normal Pressure Hydrocephalus: A Systematic Review

Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible neurological disorder characterized by gait disturbance, cognitive impairment, and urinary incontinence; however, its diagnosis and prediction of shunt responsiveness remain challenging. This systematic review aimed to synthesize current evidence on cerebrospinal fluid (CSF) proteomic biomarkers in iNPH and to identify molecular patterns with diagnostic and prognostic relevance. A PRISMA-guided search of PubMed, Web of Science, and Google Scholar identified 14 eligible studies comprising 1171 iNPH patients. Proteomic analyses revealed substantial heterogeneity in study design and detected proteins; however, consistent patterns emerged. iNPH is associated with upregulation of inflammatory and extracellular matrix-related proteins and relative downregulation of synaptic and neuronal markers. Neurodegenerative proteins, including amyloid-β, tau, and neurofilament light chain, demonstrated value in differentiating iNPH from comorbid neurodegenerative diseases and in predicting response to ventriculoperitoneal shunting (VPS). These findings support a multifactorial model of iNPH involving impaired glymphatic clearance, neuroinflammation, blood-brain barrier dysfunction, and mechanical axonal stress. Multidimensional biomarker profiles, rather than single proteins, appear to provide the greatest clinical utility, highlighting the need for standardized proteomic panels and integrative predictive models. However, given the substantial heterogeneity of the included studies and the predominantly exploratory nature of current proteomic evidence, the identified proteins should be interpreted as candidate biomarkers rather than clinically validated diagnostic or prognostic tools. Multidimensional biomarker profiles appear biologically plausible and may offer greater explanatory value than single proteins, but their clinical utility requires validation in standardized prospective cohorts. The authors therefore propose a conceptual iNPH proteomic "Vulnerability Model" integrating CSF biomarkers to reflect the balance between reversible and irreversible pathology; this is currently a hypothetical model that requires rigorous statistical and clinical validation through large-scale prospective cohort studies before it can fulfill its potential for improving patient stratification and prediction of postoperative outcomes.