Abstract Details

Title Plasma Proteins in the SUR1–TRPM4 Pathway are Associated With Cerebral Edema and Contusion Expansion after Traumatic Brain Injury

Topic Neuro Trauma and Critical Care

Presentation(s) P1 - Poster Session 1 (8:00 AM-9:00 AM)

Poster/Presentation
Number 18-005

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-p_adj=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-p_adj=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-p_adj<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.

Authors/Disclosures
Diana L. Monge Sanchez, MD PRESENTER	Dr. Monge Sanchez has received research support from Barrow Neurological Foundation.
NASATHAPOT NAMPHOL, MD	Dr. NAMPHOL has nothing to disclose.
Aditya Kumar, MD (Barrow Neurological Institute)	Dr. Kumar has nothing to disclose.
Shreya Satheesh, Student	Ms. Satheesh 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.
Anupama Rani, PhD	Dr. Rani has nothing to disclose.
Margaux Miller	Ms. Miller has nothing to disclose.
Erin McNally, BS	Miss McNally has nothing to disclose.
Raemier Javelosa	Ms. Javelosa has nothing to disclose.
Jane Hwang	Ms. Hwang has nothing to disclose.
Kaitlyn Hebig	Ms. Hebig has nothing to disclose.
Sirin Gandhi, MD	Dr. Gandhi has nothing to disclose.
Adam Eberle	Mr. Eberle has nothing to disclose.
Joshua Catapano, MD	Dr. Catapano has nothing to disclose.
Semeon Afework	Mr. Afework has nothing to disclose.
Thomas Donovan, MSc	Mr. Donovan has nothing to disclose.
Ethan Gaskin, MS	Mr. Gaskin has nothing to disclose.
Laura Snyder, MD	Dr. Snyder has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Medtronic. Dr. Snyder has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Globus.
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.
H. E. Hinson, MD, MCR, FAAN (UCSF/Zuckerberg San Francisco General Hospital)	Dr. Hinson has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology. Dr. Hinson has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for American Heart Association.
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.

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