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Abstract Details

Cerebrospinal-fluid Proteomic Signatures of the SUR1–TRPM4 Pathway are Associated with Secondary Injury and Outcome After Aneurysmal Subarachnoid Hemorrhage
Cerebrovascular Disease and Interventional Neurology
S10 - Advances in Stroke Imaging and Biomarkers (5:06 PM-5:18 PM)
009

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). 

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. 

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).   

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.  

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. 
Authors/Disclosures
Aurelia Cors
PRESENTER 		An immediate family member of Ms. Cors has received personal compensation in the range of $100,000-$499,999 for serving as a Office Director with US Environmental Protection Agency. An immediate family member of Ms. Cors has received personal compensation in the range of $100,000-$499,999 for serving as a Attorney with US Department of Justice.
Shreya Satheesh, Student Ms. Satheesh has nothing to disclose.
Aditya Kumar, MD (Barrow Neurological Institute) Dr. Kumar has nothing to disclose.
Thomas Donovan, MSc Mr. Donovan has nothing to disclose.
Ethan Gaskin, MS Mr. Gaskin has nothing to disclose.
Semeon Afework Mr. Afework has nothing to disclose.
Joshua Catapano, MD Dr. Catapano has nothing to disclose.
Adam Eberle Mr. Eberle has nothing to disclose.
Sirin Gandhi, MBBS Dr. Gandhi has nothing to disclose.
Jane Hwang Ms. Hwang has nothing to disclose.
Kaitlyn Hebig Ms. Hebig has nothing to disclose.
Raemier Javelosa Ms. Javelosa has nothing to disclose.
Erin McNally, BS Miss McNally has nothing to disclose.
Margaux Miller Ms. Miller has nothing to disclose.
Diana L. Monge Sanchez, MD Dr. Monge Sanchez has received research support from Barrow Neurological Foundation.
NASATHAPOT NAMPHOL, MD Dr. NAMPHOL has nothing to disclose.
Anupama Rani, PhD Dr. Rani has nothing to disclose.
Felipe C. Albuquerque, MD Dr. Albuquerque has nothing to disclose.
Andrew Ducruet, MD Andrew Ducruet, MD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kos. Andrew Ducruet, MD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medtronic. Andrew Ducruet, MD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Phenox. Andrew Ducruet, MD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Penumbra. Andrew Ducruet, MD has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Grace Therapeutics. The institution of Andrew Ducruet, MD has received research support from National Institute of Health.
Ashutosh P. Jadhav, MD, FAAN (Barrow Neurological Institute) Dr. Jadhav has nothing to disclose.
Michael T. Lawton, MD The institution of Dr. Lawton has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Zeiss. Dr. Lawton has received intellectual property interests from a discovery or technology relating to health care. Dr. Lawton has received personal compensation in the range of $500-$4,999 for serving as a Visiting Professor with Visiting Professor Honorariums.
Patrick M. Kochanek, MD, MCCM (University of Pittsburgh) Patrick M. Kochanek, MD, MCCM has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for University of Washington. Patrick M. Kochanek, MD, MCCM has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Johns Hopkins Health System. Patrick M. Kochanek, MD, MCCM has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for de Boisblanc Law Firm. The institution of Patrick M. Kochanek, MD, MCCM has received research support from Chuck Noll Foundation. The institution of Patrick M. Kochanek, MD, MCCM has received research support from NIH. Patrick M. Kochanek, MD, MCCM has received publishing royalties from a publication relating to health care.
Dhivyaa Rajasundaram (University of Pittsburgh) Dhivyaa Rajasundaram has nothing to disclose.
Ruchira M. Jha, MD (Barrow Neurological Institute) Dr. Jha has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. An immediate family member of Dr. Jha has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Legal fees. The institution of Dr. Jha has received research support from NIH/NINDS, Chuck Noll Foundation, University of Pittsburgh, Barrow Neurological Foundation.