Circulating Brain Injury Exosomal Proteins following Moderate-To-Severe Traumatic Brain Injury: Temporal Profile, Outcome Prediction and Therapy Implications

Abstract

Brain injury exosomal proteins are promising blood biomarker candidates in traumatic brain injury (TBI). A better understanding of their role in the diagnosis, characterization, and management of TBI is essential for upcoming clinical implementation. In the current investigation, we aimed to explore longitudinal trajectories of brain injury exosomal proteins in blood of patients with moderate-to-severe TBI, and to evaluate the relation with the free-circulating counterpart and patient imaging and clinical parameters. Exosomal levels of glial (glial fibrillary acidic protein (GFAP)) and neuronal/axonal (ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), neurofilament light chain (NFL), and total-tau (t-tau)) proteins were measured in serum of 21 patients for up 5 days after injury using single molecule array (Simoa) technology. Group-based trajectory analysis was used to generate distinct temporal exosomal biomarker profiles. We found altered profiles of serum brain injury exosomal proteins following injury. The dynamics and levels of exosomal and related free-circulating markers, although correlated, showed differences. Patients with diffuse injury displayed higher acute exosomal NFL and GFAP concentrations in serum than those with focal lesions. Exosomal UCH-L1 profile characterized by acutely elevated values and a secondary steep rise was associated with early mortality (n = 2) with a sensitivity and specificity of 100%. Serum brain injury exosomal proteins yielded important diagnostic and prognostic information and represent a novel means to unveil underlying pathophysiology in patients with moderate-to-severe TBI. Our findings support their utility as potential tools to improve patient phenotyping in clinical practice and therapeutic trials.