Cerebrospinal-fluid Proteomic Signatures of the SUR1–TRPM4 Pathway are Associated with Secondary Injury and Outcome After Aneurysmal Subarachnoid Hemorrhage
Aurelia Cors1, Shreya Satheesh2, Aditya Kumar3, Thomas Donovan4, Ethan Gaskin4, Semeon Afework3, Joshua Catapano5, Adam Eberle6, Sirin Gandhi3, Jane Hwang3, Kaitlyn Hebig3, Raemier Javelosa3, Erin McNally3, Margaux Miller7, Diana Monge Sanchez3, Nasathapot Namphol3, Anupama Rani3, Felipe Albuquerque3, Andrew Ducruet3, Ashutosh Jadhav3, Michael Lawton3, Patrick Kochanek4, Dhivyaa Rajasundaram4, Ruchira Jha3
1Yale University, 2Arizona State University, 3Barrow Neurological Institute, 4University of Pittsburgh, 5University of Pennsylvania, 6Icahn School of Medicine at Mount Sinai, 7Temple University
Objective:
To identify cerebrospinal-fluid (CSF) biomarkers within the Sulfonylurea-receptor-1(SUR1)—transient-receptor-potential-cation-channel-M-member-4 (TRPM4) pathway associated with secondary brain injury after aneurysmal-subarachnoid hemorrhage (aSAH).
Background:
The SUR1-TRPM4 pathway has been mechanistically implicated with cerebral-edema, vasospasm, and delayed cerebral ischemia (DCI) after aSAH, and represents a promising therapeutic target. However, no clinically available biomarkers currently exist to predict/monitor these secondary injuries.
Design/Methods:
We have previously identified 175 proteins with experimentally proven or high-probability putative upstream/downstream associations with SUR1-TRPM4. We quantified these (SomaScan) in a prospectively enrolled cohort (106 CSF samples: 92 aSAH, 14 control, multiple timepoints/patient). Outcomes included cerebral-edema (via the subarachnoid-hemorrhage-early-brain-edema (SEBES) score on CT), vasospasm (conventional angiography), DCI (CT/MRI), and discharge disposition. T-tests with Benjamini-Hochberg correction identified differentially expressed proteins as an initial screen. Multivariate integrative sparse partial least squares identified the most discriminative proteins and confirmed robustness. Longitudinal associations were tested using linear mixed-models (generalized-estimating-equations), controlling for clinical covariates (age, Hunt-Hess, sex, modified-Fisher).
Results:
5676 proteins were elevated post-aSAH vs controls (all-padj = 0.049-4.9E-56), with ≥10-fold increases in 686 proteins. Twenty-two proteins increased over time (24h-9d post-aSAH; all-padj = 0.048-0.00004), a subset were associated with cerebral-edema, vasospasm and/or DCI. Although some proteins were uniquely associated with cerebral-edema, vasospasm, or DCI. Overlapping associations across these secondary injuries (IL6, IL6R, MIF1, CTNNB1) suggested possible mechanistic convergence around inflammation and BBB integrity. Thirty-five proteins were associated with ≥2% increased odds of death at discharge per-unit increase (all-padj < 10-6) implicating processes involving inflammation, energy/hypoxia metabolism, autophagy, cell-survival, and tight-junctions.
Conclusions:
Key proteins in the SUR1-TRPM4 pathway are quantifiable in post-aSAH CSF and associated with measures of secondary injury. If validated, these may be valuable prognostic and/or predictive biomarkers in aSAH and inform novel/precision-targeted therapies.
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