Biomarkers of Vascular Integrity in Traumatic Brain Injury and Correlation with Cerebrovascular Reactivity

Objective: Several plasma proteins, such as Angiopoietins (Ang), Tumor Necrosis Factor (TNF), Serum Amyloid A (SAA), Soluble Intercellular Adhesion Molecule (sICAM-1), Von Willebrand Factor (vWF), and Tie2, have been implicated as potential biomarkers of vascular integrity and angiogenesis in traumatic brain and vascular injuries (TBI and TVI). Our goal is to test the hypothesis that (1) plasma biomarkers of vascular integrity and angiogenesis can assess TVI during chronic TBI; (2) Cerebrovascular Reactivity (CVR) may be a sensitive biomarker in chronic TBI and TVI and may correlate with the plasma biomarkers. Design: Plasma levels of 18 proteins were measured using high sensitivity electro-chemiluminescent sandwich immunoassays (Meso Scale Discoveries, LLC). Subjects were 23 patients with chronic TBI and persistent post-concussive symptoms (PCS, TBI-Sx), 9 chronic TBI patients without PCS (recovered TBIs or TBI-Rec), and 21 healthy controls (HC). TVI was assessed using MRI by measuring CVR-CO2 by assessing the BOLD response to hypercapnia. All subjects underwent MRI with hypercapnia challenge. Nominal a=0.05 was judged to be statistically significant. Results: Plasma concentration of Ang-1 was decreased in patients with chronic TBI with symptoms (TBI-Sx) compared to HC or TBI-Rec (p<0.05), as was the ratio of Ang-1/Ang-2 (p<0.05). SAA was decreased in TBI-Rec patients compared to the TBI-Sx group (P<0.01). CVR-CO2 was decreased in TBI-Sx group compared to HC (P<0.05). Baseline CVR-CO2 correlated with plasma levels of VEGF, VEGF-C, and P-selectin in all TBI patients, but not in HC group. Conclusions: A panel of plasma biomarkers (Ang-1/Ang-2, SAA, VEGF, P-selectin, and vWF) and assessment of CVR may be useful as predictive biomarkers for therapies designed to improve cerebrovascular function after TBI.


Yunhua Gong, Franck Amyot, Baoxi Qu, Kimbra Kenney, Carol Moore, Tanya Bogoslovsky, Gregory Mueller, Erika Silverman and Ramon Diaz-Arrastia


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