Sex-specific Proteomic Signatures of the SUR1-TRPM4 Pathway in Plasma and Cerebrospinal Fluid after Aneurysmal Subarachnoid Hemorrhage
Erin McNally1, Aurelia Cors2, Shreya Satheesh3, Aditya Kumar1, Thomas Donovan4, Ethan Gaskin4, Semeon Afework1, Joshua Catapano5, Adam Eberle6, Sirin Gandhi1, Jane Hwang1, Kaitlyn Hebig1, Raemier Javelosa1, Margaux Miller7, Diana Monge Sanchez1, NASATHAPOT NAMPHOL1, Anupama Rani1, Felipe Albuquerque1, Andrew Ducruet1, Ashutosh Jadhav1, Michael Lawton1, Patrick Kochanek4, Ruchira Jha1, Dhivyaa Rajasundaram4
1Barrow Neurological Institute, 2Yale University, 3Arizona State University, 4University of Pittsburgh, 5University of Pennsylvania, 6The Icahn School of Medicine at Mount Sinai, 7Lewis Katz School of Medicine at Temple University
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.
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.