Traumatic brain injury in humans and animal models

Abstract

Traumatic brain injuries (TBI) are receiving increasing attention due to a combination of injuries related to war and sports, as well as to an increasing number of traffic accident survivors. Today the leading cause of death in young adults in industrialized nations is traumatic brain injury and in the population under 35 years, the death rate is 3.5 times that of cancer and heart disease combined. Despite a major improvement in the outcome of TBI in the acute setting, the assessment, therapeutic interventions and prevention of long-term complications remain a challenge. The challenges today are primarily related to a rapid diagnosis, identification of patient’s pathophysiological heterogeneity and to limit the secondary injuries. TBI is a complex condition that can be caused by focal or diffuse primary impacts that may initiate complex secondary neurochemical processes that proceeds over hours and days. The major secondary events include neuronal death, ischemia, excitotoxicity, mitochondrial failure, oxidative stress, oedema and inflammation. In addition, the brain’s restorative capacity involving neurotrophins, in particular brain derived neurotrophic factor (BDNF), is triggered. Animal models are necessary to gain a deeper insight into the events that follow a TBI, and to ultimately apply the findings to the clinical setting.

The aim of this thesis was to identify distinct pathological processes in different types of TBI by using animal models that mimic distinct types of TBI found in patients. We investigated alterations in gene expression, serum biomarkers and secondary processes such as inflammatory response involving the complement cascade. In addition we aimed to assess the effects of heterogeneity of TBI patients, based on their genetic background, on the outcome of TBI, with specific focus on BDNF. We used animal models to mimic three major types of TBI; blast wave, penetrating and rotational acceleration TBI. We found distinct profiles of alteration in gene expression in these models. The histological findings in blast and rotational TBI indicated these injuries to be mild. The hallmark of the rotational TBI was axonal injuries found in anatomical locations comparable with clinical findings in diffuse axonal injuries (DAI) in humans. Despite the mild type of injury displayed in the histology and behavioural outcome, significant increases in the serum biomarkers Tau, S100B, NF-H and MBP were observed up to 2 weeks following the injury. The complement cascade was initiated in both penetrating and rotational TBI, detected by C1q and C3. However, the terminal pathway that generates cell death, detected by C5b9, was only activated in the penetrating TBI. This suggests that axonal injuries and secondary axotomy found in the rotational TBI are not complement mediated. In order to investigate whether genetic heterogeneity can be used to predict injury outcome and brain plasticity following TBI, we targeted the ApoE ε4 allele and the BDNF gene. We investigated whether there was an association between the presence of the ApoE ε4 allele and BDNF polymorphisms and cognitive outcome in veterans who had suffered penetrating head injury. We found that the genetic polymorphisms of BDNF predict general intelligence following penetrating TBI. Subsequently we investigated the expression of BDNF and its receptors TrkB-full length, TrkB-truncated and p75NTR, in animals exposed to penetrating TBI. The expression of TrkB truncated and p75NTR was altered in the chronic phase.

In summary, these results show the importance of categorizing the different types of TBI, not only through the use of animal models but also in the clinical setting. Each type of TBI shows distinct patterns of gene expression, behavioural outcome, and morphological changes that may be reflected in the release of serum biomarkers. In the clinical setting, the situation is further complicated by the coexistence of different types of injuries. In addition to this, the genetic background of each patient contributes to the heterogeneity of TBI pathology as well as their ability to recover. The use of distinct types of TBI models will provide essential information about the underlying pathology, which can then be applied to the clinical setting. This will contribute to the establishment of better diagnostic tools as well as more individualized treatment approaches.