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

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.