PREDICTING THE UNPREDICTABLE: BIOMARKER EXPLORATION FOR POST-TRAUMATIC EPILEPSY

Abstract

Background: Traumatic brain injury (TBI) is a major health concern, affecting more than 69 million individuals annually. The majority of TBI cases are mild TBI, which typically present with only mild symptoms. However, symptoms may persist without complete recovery and can be associated with brain damage. TBI can lead to the development of delayed brain pathologies, including post traumatic epilepsy (PTE). The prevalence of PTE following mild TBIs is not well-established and a relationship between repetitive mild TBIs (rmTBIs) and PTE has been infrequently investigated. Problem: Currently, no biomarkers are available to predict individuals at risk of developing PTE. Goal: In this thesis, I established an animal model of post-rmTBI epilepsy and investigated potential predictive and diagnostic biomarkers. I also evaluated the efficacy of TGF-β inhibition in preventing post-rmTBI epilepsy. Methods: For five consecutive days, a single closed-head mild injury was administered to 8-10 weeks-old male rats. To uncover potential biomarkers for PTE, a battery of neurobehavioral and cognitive tests was conducted in combination with electrocorticography (ECoG) recordings. Additionally, I tested the antiepileptogenic effects of a 9-day post-rmTBI treatment of IPW-5371, a specific TGF-β receptor inhibitor. Results: My study revealed that at 6 months post-rmTBI, epilepsy can be detected in ~70% of animals and was associated with memory impairment. Acute neurobehavioral assessments and cognitive performance did not predict the risk of PTE. However, I identified the occurrence of an ECoG feature, paroxysmal slow wave events (PSWEs), as a reliable biomarker for predicting PTE. Treatment with IPW-5371 delayed, but did not prevent, PTE at 6 months following rmTBI. Memory impairment was prevented after IPW-5371 treatment. Furthermore, preliminary data from human EEG recordings shows that PSWEs may become a potential biomarker in the diagnosis of PTE. Conclusions: PTE is a common long-term complication in a rat model of rmTBIs, with PSWEs emerging as a non-invasive, cost-effective diagnostic and predictive biomarker. The TGF-β inhibitor IPW-5371 shows promise as a novel treatment strategy for preventing PTE and associated memory impairments.