CSF Aquaporin-4 in Idiopathic Normal Pressure Hydrocephalus: Potential as a Biomarker for Shunt Response and Glymphatic Function

Background Aquaporin-4 (AQP4) is crucial for brain fluid regulation and glymphatic system function. Idiopathic normal pressure hydrocephalus (INPH), characterized by impaired CSF flow, is often treated with shunt surgery. This study investigated AQP4 levels in INPH patients to explore its role in pathophysiology and potential as a biomarker for shunt response. Methods CSF samples from 233 INPH patients and 29 controls were analysed. AQP4 levels were compared between preoperative patients and controls, before and after shunt surgery (110 patients), and between shunt responders and non-responders (204 patients). A bead-based assay was used to measure AQP4, and outcomes were assessed by postoperative changes in maximum gait velocity. Results Preoperative AQP4 levels were lower in INPH patients (1177 ± 259 AU) than in controls (1351 ± 279 AU, p = 0.003), but the difference did not persist after adjustment for confounders (p = 0.87). Postoperatively, AQP4 levels increased (1714 ± 473 vs 1186 ± 269 AU, p < 0.001), with a modest correlation between AQP4 increase and gait improvement (rₛ = 0.22, p = 0.022). Compared with non-responders, shunt responders (130 patients) had lower preoperative AQP4 levels (1144 ± 250 vs. 1238 ± 273 AU, p = 0.016) Conclusions INPH patients presented AQP4 levels comparable to those of controls. The postoperative increase in AQP4 may result from altered CSF dynamics induced by the shunt; however, the underlying mechanism remains unclear, underscoring the need for further studies to clarify this relationship. Notably, lower preoperative AQP4 levels in shunt responders suggest a potential predictive role.