Plasma Proteins in the SUR1–TRPM4 Pathway are Associated With Cerebral Edema and Contusion Expansion after Traumatic Brain Injury
Diana Monge Sanchez1, Nasathapot Namphol1, Aditya Kumar1, Shreya Satheesh2, Aurelia Cors3, Anupama Rani1, Margaux Miller4, Erin McNally1, Raemier Javelosa1, Jane Hwang1, Kaitlyn Hebig1, Sirin Gandhi1, Adam Eberle5, Joshua Catapano6, Semeon Afework1, Thomas Donovan7, Ethan Gaskin7, Laura Snyder1, Patrick Kochanek7, H.E. Hinson8, Dhivyaa Rajasundaram7, Ruchira Jha1
1Barrow Neurological Institute, 2Arizona State University, 3Yale University, 4Temple University, 5Icahn School of Medicine at Mount Sinai, 6University of Pennsylvania, 7University of Pittsburgh, 8University of California, San Francisco
Objective:
To identify plasma biomarkers within the Sulfonylurea-receptor-1(SUR1)—transient-receptor-potential-cation-channel-M-member-4 (TRPM4) pathway associated with cerebral-edema and contusion-expansion after traumatic brain injury (TBI).
Background:
Cerebral edema and contusion-expansion are devastating secondary injuries in TBI, associated with death and disability. The SUR1-TRPM4 pathway has been mechanistically implicated in these processes, representing a promising therapeutic target. However, no clinically available biomarkers currently exist to predict/monitor these secondary injuries and their underlying molecular processes. Plasma is a minimally-invasive, clinically-practical biofluid; it can serve as a valuable generalizable platform for biomarker translation.
Design/Methods:
In a prospectively enrolled cohort of ‘severe’ TBI (GCS 3-8), we used SomaScan to quantify 175 plasma proteins identified in the SUR1-TRPM4 pathway (63 samples: 48 TBI, 15 uninjured-control, two timepoints/patient). Outcomes included cerebral-edema, contusion-expansion, and discharge disposition. An initial screen of differential expression was assessed via t-tests (Benjamini-Hochberg correction). 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 age, Glasgow Coma Scale score, sex.
Results:
Thirty-three proteins were elevated post-TBI vs controls (all-padj=0.049-0.0002); ≥20% increase was seen in twenty-six proteins, several (IL6, HMOX1, ITGA1, CASP3, RELA, LMNA, PPP1R10, GHRL) had ≥50% increase; overlap was noted with aneurysmal subarachnoid hemorrhage (separate study), including APOE isoforms. Twenty-eight proteins increased between 24h-72h post TBI (all-padj=0.049-0.01). Sixteen proteins were positively associated with cerebral-edema requiring hypertonic therapy and thirteen with contusion-expansion (threshold contribution-importance>10%). KRAS, S100A8, and MSR1-ECD were associated with ≥1% increased odds of death at discharge per-unit increase (all-padj<10-6), and six proteins were protective at this threshold.
Conclusions:
SUR1-TRPM4-linked plasma protein signatures are quantifiable post-TBI and associated with secondary injury. Overlap with markers in other forms of acute brain injury identifies potentially common molecular pathways contributing to similar secondary injuries and high-yield targets for minimally-invasive biomarker development.
Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff.