Proteomic Profiling of Inflammation Following Traumatic Brain Injury and Cerebral Insults : Decoding Molecular Signatures for Therapeutic Insights

Traumatic brain injury (TBI) is a complex and diverse condition influenced by various factors, all of which contribute to a wide range of outcomes for the patients. The initial injury renders the brain susceptible to secondary molecular and pathophysiological events, with neuroinflammation considered a crucial secondary mechanism. In this thesis, we investigated the inflammatory response following TBI and drew comparisons with central nervous system (CNS) inflammatory disorders. The aim was to identify distinct inflammatory responses specific to TBI pathology, ultimately contributing to precision medicine and advancing the development of individualized therapies. We used cerebral microdialysis (CMD) and proximity extension assay (PEA) to analyze protein expressions in patients with acute severe TBI. Additionally, we conducted mass-spectrometry (MS) analysis on cerebrospinal fluid (CSF) collected from patients with TBI and individuals with various types of encephalitis. Paper I - The PEA technique revealed the presence of inflammatory proteins in the brain interstitium during the initial days following severe TBI. Diverse temporal patterns were observed, with some proteins peaking early, others showing middle or late peaks, and some exhibiting biphasic or steady patterns. Notably, while these temporal patterns varied among proteins, unique and consistent patterns were discerned for the same proteins across different patients. Paper II - 21 proteins were selected for a customized panel to explore their temporal dynamics in patients suffering from acute TBI. This structured approach brought the method closer to clinical application and identified proteins of interest for monitoring in this patient group. Paper III - Patients had their CSF analyzed with the use of MS. The resulting protein findings from patients with acute severe TBI were then compared to findings from patients with non-infectious inflammatory CNS disorders, infectious inflammatory CNS disorders and controls. We found distinct proteomic profiles in the CSF of TBI patients compared with the healthy controls and different disease controls, indicating a specific interplay between inflammatory factors, metabolic response, and cell integrity. In relation to primarily infectious or inflammatory disorders, unique inflammatory pathways seem to be engaged and could potentially serve as future treatment targets. Paper IV - CSF from patients with acute severe TBI and COVID-19 patients with neurological symptoms were analysed using MS. Neurofilament light chain (NFL) levels were measured separately. Distinct inflammatory profiles in severe TBI and COVID-19 patients were identified. Elevated NFL levels in both groups indicated white matter injury. The discovery of novel biomarkers specific to each pathology, provide valuable insights into the inflammatory mechanisms and may serve as targets for therapeutic interventions. A more comprehensive understanding of the unique inflammatory response within the CNS following TBI could potentially reveal valuable therapeutic targets. By mapping specific molecular pathways, researchers can develop precise interventions and more effective treatments, tailored to the distinct challenges posed by different conditions.