Biomarkers of Moderate/severe Traumatic Brain Injury in a Preclinical Model: Brain or Peripheral?
Abstract number :
1.222
Submission category :
2. Translational Research / 2C. Biomarkers
Year :
2024
Submission ID :
913
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Aristea S. Galanopoulou, MD, PhD – Albert Einstein College of Medicine
Anna Maria Katsarou, MD – Albert Einstein College of Medicine
Idrish Ali, PhD – Monash University
Adeboye Bamgboye, PhD student – University of Minnesota
Jesse McCullough, PhD – Uniformed Health Services
Jesus-Servando Medel-Matus, PhD – University of California, Los Angeles
Cindy Santiago-Castaneda, PhD – Albert Einstein College of Medicine
Wei Liu, MD – Department of Neurosurgery, Ruijin Hospital
Michael Eklund, PhD – Uniformed Health Services
Hsuan Lin, PhD – Uniformed Health Services
Peravina Thergarajan, PhD – Monash University
Yifan Huang, PhD – Monash University
Emma Braine, PhD – Monash University
Julia Frostholm, Student – University of California, Los Angeles
Don Shin, BSc – University of California, Los Angeles
Raman Sankar, MD, PhD – University of California, Los Angeles
Pablo Casillas-Espinosa, PhD – Monash University
Nigel Jones, Professor – Monash University
Solomon L. Moshé, MD – Albert Einstein College of Medicine and Montefiore Medical Center
Terence J O'Brien, MBBS MD – School of Translational Medicine, Monash University, The Alfred Centre
Richard Staba, PhD – University of California, Los Angeles
Cesar Santana-Gomez, PhD – University of California, Los Angeles
Wenzhu Mowrey, PhD – Albert Einstein College of Medicine
Andrey Mazarati, PhD – University of California, Los Angeles
Denes V. Agoston, MD, PhD – Uniformed Services University
Lisa Coles, PhD – University of Minnesota
Rationale: Moderate/severe traumatic brain injury (sTBI) increases risk for post-traumatic epilepsy (PTE). Biomarkers that stratify and predict post-sTBI outcomes are essential in efforts to prevent post-sTBI outcomes, including PTE. We used the lateral fluid percussion injury (LFPI) rat model of sTBI/PTE across 3 preclinical sites to identify panels of brain and plasma biomarkers of LFPI and post-LFPI outcomes, comparing with naïve or sham-craniotomy rats. We used 2 biomarker platforms to compare the predictive value of brain vs plasma biomarkers of LFPI severity and treatment exposure. We selected levetiracetam (LEV), used for prophylactic seizure control, and deferiprone (DEF), which is used in the management of hemorrhagic pathologies.
Methods:
Sprague-Dawley rats underwent craniotomy only (Sham, n=16) or left LFPI (n=60) at 3 sites (Einstein, Monash, UCLA); 11 naïve rats were also used. LFPI rats received LEV and/or DEF or vehicle (VEH) for 7d. Plasma was collected at baseline and terminally at: 2hr, 1 day (1d), 2d, or 7d after craniotomy/LFPI, before collecting left (LCCX) or right parietal cortical (RCCX) samples. Multiplex ELISA assays were used for inflammatory markers: interleukin-1a (IL-1a), IL-1b, IL2, IL-6, IL-10, interferon gamma (IFNg), tumor necrosis factor (TNF), MIP1a, vascular endothelial growth factor (VEGF), RANTES) (Coles lab). Reverse-phase protein microarrays (RPPM, Agoston lab) analyzed plasma protein markers: GFAP, HMGB1, HSP70, interferon gamma (IFNg), IL-1b, IL-6, neurofilament L (NFL), phosphorylated TAU (pTAU), S100B, TAU, TNF, UCHL1. Statistics included mixed model analyses with repeated measures, nominal logistic fit for ROC analyses.
Results:
A strong intracortical inflammatory response was noted (2hr≥1d >2d post-LFPI), ipsi- or bi-lateral to LFPI, with the increase in IL-1a, MIP1a, IL-6, TNF and/or decrease in IL-2, IFNg, VEGF cortical concentrations. Brain inflammatory markers between 2hr-2d strongly differentiated LFPI from naïve (ROC AUC 0.914-0.887) or sham (ROC_AUC 0.898 – 0.784) rats. At the same timepoints, plasma IL-10, VEGF, IL-2 and RANTES levels best differentiated LFPI from naive (ROC_AUC 0.955-0.822) but only modestly differentiated LFPI from sham (ROC_AUC 0.775 – 0.684). A subgroup of the RPPM biomarker panel (IL-6, pTAU, S100B, TAU, NFL, HSP70, GFAP), achieved excellent, but delayed, differentiation of LFPI from controls between 1d-7d (ROC_AUC 0.869 – 0.974) but only moderate differentiation from sham (ROC_AUC 0.777, 2d only). LEV treatment exposure was predicted by 1d-plasma IL-1a, IL-6, IL-10, IFNg (ROC_AUC 0.738) and 2hr-brain inflammatory markers including IL-1a, TNF, and IL-6 (ROC_AUC 0.728). DEF treatment exposure was predicted by 2hr-plasma VEGF (ROC_AUC 0.72).
Conclusions: LFPI elicits different albeit overlapping brain and peripheral inflammatory responses. Brain inflammatory biomarkers are more sensitive for differentiating sTBI from sham craniotomy than peripheral biomarkers. Different panels of peripheral biomarkers may track acute vs subacute LFPI and predict treatment exposure.
Funding: NINDS R01 NS127524; DoD W81XWH2210210 & W81XWH2210510, N & V Harinarayan Charitable Fund (UCLA)
Translational Research