Abstract Details

Title Sex-specific Proteomic Signatures of the SUR1-TRPM4 Pathway in Plasma and Cerebrospinal Fluid after Aneurysmal Subarachnoid Hemorrhage

Topic Neuro Trauma and Critical Care

Presentation(s) P9 - Poster Session 9 (5:00 PM-6:00 PM)

Poster/Presentation
Number 18-005

Objective To identify sex-specific plasma and/or cerebrospinal fluid (CSF) protein biomarkers within the Sulfonylurea-receptor-1(SUR1)—transient-receptor-potential-cation-channel-M-member-4 (TRPM4) pathway after aneurysmal-subarachnoid hemorrhage (aSAH).

Background Women are at higher risk for aSAH, and may also be more susceptible to secondary injuries (cerebral-edema, vasospasm, delayed cerebral ischemia (DCI)) and unfavorable outcomes. The SUR1-TRPM4 pathway has been mechanistically implicated in these secondary injuries, with preclinical data suggesting sex-specificity after acute brain injury. Clinical sex-specific biomarkers may facilitate risk-stratification and precision-therapies.

Design/Methods We quantified 175 proteins in the SUR1-TRPM4 pathway in plasma and CSF in a prospectively enrolled cohort of aSAH patients (aSAH total=161, 92 CSF samples; Control total=29, 15 CSF samples). T-tests with Benjamini-Hochberg correction identified differentially expressed proteins as an initial screen. Multivariate integrative sparse partial least squares discriminant analysis (MINT-sPLS-DA, R-mixOmics) identified the most discriminative proteins across sex and confirmed robustness.

Results MINT-sPLS-DA identified 73 (CSF) and 51 (plasma) proteins correlated with sex, discriminating between female vs male aSAH patients. 27.4% of sex-associated proteins in CSF were also discriminatory in plasma. Proteins spanned multiple biological processes including energy metabolism, inflammation, extracellular matrix re-modelling, neurodegeneration, cell death, reactive oxygen species, and ion/water channels. Contribution importance thresholds of 10% identified a subset (including IL1A, S100A3, TRADD, S100A8, CTNNB1, IL12A, IL12B, NPY, LGALS3, LRPAP, PPARG, IL6, POMC, STXA1, TNFSF14, GHRL, NFATC1, SNC1, KRAS, ADA, SIRT6) that had large differences across sex. Higher levels of IL6, CTNNB1, PPARG and ADA were strongly associated with males. Several identified proteins overlapped with markers of secondary injury (cerebral-edema, vasospasm, DCI) and discharge disposition (separate study).

Conclusions Sex-based differences in SUR1-TRPM4 pathway proteins were noted post-aSAH in both CSF and plasma, several of which overlap with secondary injury associations. Validation of these markers may valuably inform sex-based differences in aSAH mechanisms underlying secondary injury, as well as potential precision-therapies.

Authors/Disclosures
Erin McNally, BS PRESENTER	Miss McNally has nothing to disclose.
Aurelia Cors	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.
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.
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.
Dhivyaa Rajasundaram (University of Pittsburgh)	Dhivyaa Rajasundaram has nothing to disclose.

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