Biomarkers for prediction of chronic traumatic encephalopathy-like pathology following repeated mild traumatic brain injury in rats are partially sex- and age-dependent.

Abstract

INTRODUCTION: Repeated mild traumatic brain injuries (rmTBIs) pose a high risk of developing chronic traumatic encephalopathy (CTE). Since this neurodegenerative disease is diagnosed only post-mortem, new biomarkers for early detection are needed. Although age at injury and biological sex are important factors in many brain pathologies, little is known about their relevance to rmTBI-induced CTE-like consequences. Hence, this study explored how biological sex and age at the time of impact affect progression and changes in biomarker candidates after experimental rmTBI. METHODS: Rats of both sexes, aged 7 weeks (adolescent) or 14 weeks (adult), were subjected to three mTBIs at 5-day intervals. Neurological, behavioral and cognitive impairments, as well as changes in potential plasma and brain biomarkers, were assessed up to 12 weeks post-injury. The generalized estimating equation model was used to compare sexes and age groups. RESULTS: RmTBI induced ongoing neurological impairment. While no depressive-like behavior was observed, long-term, age-specific changes in anxiety were observed after rmTBI. A short-term increase in plasma p-tau was found after rmTBI only in male and adolescent rats. Plasma neuron-specific enolase (NSE) levels were elevated in adolescent animals at both 2 weeks and 12 weeks post-rmTBI. An increase in brain neurofibrillary tangles (NFT) was detected 12-weeks after rmTBI. Correlation analyses suggested NSE as a prospective biomarker for anhedonia-like behavior, and brain NFT as an indicator of neurological impairment. DISCUSSION: We found that behavioral outcomes and biomarker changes following rmTBI in rats were both age- and sex-dependent. This information will help in developing translatable diagnostics to guide CTE treatment in clinical settings.