Abstract
INTRODUCTION: Neuroinflammation in the context of idiopathic normal pressure hydrocephalus (iNPH) is poorly studied. Currently, no single objective test can reliably predict outcomes after shunt surgery. The aim was to investigate whether neuroinflammatory proteins in cerebrospinal fluid (CSF) are associated with the characteristic symptoms of iNPH and whether they can predict outcome after shunting. METHODS: Neuroinflammatory proteins were analyzed from preoperative CSF using proximity extension assay (PEA). In total, 92 proteins were analyzed from 74 patients with iNPH referred to shunt surgery at a single center, with follow-up at the same hospital. Symptoms were assessed before surgery and at follow-up (primarily 12 months post-surgery), graded with the Swedish iNPH scale. Associations between protein levels and preoperative symptoms, as well as outcome, were analyzed using linear regression models adjusted for age and sex; outcome models were additionally adjusted for baseline symptom level. Benjamini-Hochberg with a false discovery rate (FDR) of 5% was used to control for multiple analyses. RESULTS: Of the 92 analyzed proteins, 60 had detectable values greater than 50% and were included in the analyses. No associations between preoperative symptom severity and levels of inflammatory proteins remained statistically significant after correction for multiple comparisons (FDR 5%). After adjustment, CST5 showed a significant negative association with postoperative improvement in balance and continence domains (b = -34, q = 0.017 and b = -35, q = 0.026, respectively) but not for outcome in the total iNPH scale. A general trend was observed where higher levels of inflammatory proteins were linked to less favourable outcomes, although these did not remain statistically significant after correction. CONCLUSION: CST5 emerged as the only protein significantly associated with postoperative improvement after shunt surgery, suggesting a potential role in iNPH pathophysiology. Furthermore, no associations were observed between preoperative symptom severity and levels of inflammatory CSF proteins. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12987-025-00751-9.