Work

Systems biology prioritizes drug candidates for an interferon-response-high monocyte state in idiopathic normal pressure hydrocephalus

Year: 2026

Type: article

Abstract: Background Idiopathic normal pressure hydrocephalus (iNPH) is an age-associated neurological disorder characterized by gait disturbance, cognitive impairment, and urinary dysfunction. Although cerebrospinal fluid dynamics are central to its pathophysiology, the contribution of peripheral immune alterations remains poorly understood. We characterized an interferon-response-high monocyte state observed in iNPH and evaluated computational compound prioritization. Methods We used a fixed set of marker criteria to characterize the IFN-response-high monocyte state. We then compared monocyte clusters 5 and 0 and used 150 upregulated and 150 downregulated genes to screen compounds in LINCS. We tested whether candidate rankings changed with different state definitions, comparison groups, gene-list sizes, clustering settings, and inclusion of all patients. We also repeated the queries after excluding each donor while retaining the original cell-state labels and compared the results with 100 expression-matched random gene signatures. External blood datasets and paired blood–ventricular CSF samples provided additional context. Results The marker rule classified 3,195 of 22,197 canonical monocytes as IFN-response-high. The cluster contrast identified 1,231 FDR-significant genes. Of 1,376 THP1 compounds, 138 met the operational criteria of normalized connectivity score (NCS) <−0.5 and WTCS FDR <0.05. Rosuvastatin and roflumilast ranked first and 14th in the primary screen and first and 15th in the integrated robustness ranking. Rosuvastatin met the operational criteria in all 11 core analyses; roflumilast did so in 10, returning NCS = 0 at resolution 0.7. Both met the criteria across all nine donor omissions. In exploratory comparisons performed after candidate selection, both observed scores were more negative than those from all 100 sampled expression-matched signatures. The blood-derived program was detectable in ventricular-CSF candidate monocytes, although unequal cell recovery limited inference about compartmental enrichment. Conclusion This study characterizes an interferon-response-high classical-monocyte state observed within an iNPH cohort and nominates compounds with predicted inverse connectivity for experimental testing. Computational support was more consistent for rosuvastatin than for roflumilast. These findings support further investigation of peripheral innate immune states observed in an iNPH cohort and provide experimentally testable hypotheses for therapeutic repurposing.

Source: Frontiers in Aging Neuroscience

DOI: 10.3389/fnagi.2026.1971059