Systems biology prioritizes drug candidates for an interferon-response-high monocyte state in idiopathic normal pressure hydrocephalus
6 affiliations
- 1DGIST InnoCORE Initiative, Multiscale Brain Digital Twin Convergence (BDT) Research Group, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea
- 2Department of Neurosurgery, Kyungpook National University School of Medicine, Daegu, Republic of Korea
- 3Finance School of Business Administration, Kyungpook National University, Daegu, Republic of Korea
- 4Department of Neurology, Kyungpook National University School of Medicine, Daegu, Republic of Korea
- 5Department of Industrial Engineering, Konkuk University, Seoul, Republic of Korea
- 6Department of Robotics and Mechatronics Engineering, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea
Abstract
BackgroundIdiopathic 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.MethodsWe 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.ResultsThe 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.ConclusionThis 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.
Related
- Accuracy of CSF tap test and lumbar infusion test in predicting shunt response in idiopathic normal pressure hydrocephalus: a systematic review and meta-analysis
- Parkinsonism in Idiopathic Normal Pressure Hydrocephalus or Hydrocephalic Presentation in Parkinson's Disease: A Report of Three Cases
- Patient‐Informed Biomechanical Modeling Reveals Mechanical Mechanism of Brain Damage in Idiopathic Normal Pressure Hydrocephalus
- Altered hippocampal morphology and its association with gait impairment in idiopathic normal-pressure hydrocephalus
- Cerebrospinal fluid surfactant protein-G in neurodegenerative dementia: A comparative study with idiopathic normal-pressure hydrocephalus.
BibTeX
@article{haque2026systems,
title = {{Systems biology prioritizes drug candidates for an interferon-response-high monocyte state in idiopathic normal pressure hydrocephalus}},
author = {Md. Masudul Haque and Md. Masudul Haque and Jongwan Bae and Irin Sultana Nila and Irin Sultana Nila and Kyunghun Kang and Janghyeok Yoon and Sohee Kim and Ki-Su Park},
journal = {Frontiers in Aging Neuroscience},
year = {2026},
month = oct,
doi = {10.3389/fnagi.2026.1971059},
url = {https://doi.org/10.3389/fnagi.2026.1971059},
note = {CC BY},
}
RIS
TY - JOUR
TI - Systems biology prioritizes drug candidates for an interferon-response-high monocyte state in idiopathic normal pressure hydrocephalus
AU - Md. Masudul Haque
AU - Md. Masudul Haque
AU - Jongwan Bae
AU - Irin Sultana Nila
AU - Irin Sultana Nila
AU - Kyunghun Kang
AU - Janghyeok Yoon
AU - Sohee Kim
AU - Ki-Su Park
PY - 2026
DA - 2026/10/23
JO - Frontiers in Aging Neuroscience
DO - 10.3389/fnagi.2026.1971059
UR - https://doi.org/10.3389/fnagi.2026.1971059
AB - BackgroundIdiopathic 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.MethodsWe 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.ResultsThe 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.ConclusionThis 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.
SN - 1663-4365
ER -