The response of the brain to traumatic injury and genetic influences

Smith, Colin (2004) The response of the brain to traumatic injury and genetic influences. MD thesis, University of Glasgow.

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Traumatic brain injury (TBI) remains a significant cause of morbidity and mortality, and is one of the commonest causes of disability in young people. Increasingly evidence is emerging to suggest that TBI results in long-term neurodegeneration and is a risk factor for the subsequent development of Alzheimer's disease (AD) in later life. The mechanisms underlying the association between head injury and AD are unknown, although the response to TBI and the pathology of AD have some features in common not only in terms of a cellular and protein response but also striking parallels in the genetic influences. Statement of aims; This studied aimed to assess the potential contribution of cytoskeletal pathology and neuroinflammation to long-term outcome after head injury, and influence of genetic factors in determining outcome. Methodology: Archived human brain tissue was used for this study. Both cytoskeletal pathology and neuroinflammation were assessed by immunohistochemistry. Cytoskeletal pathology was assessed semi-quantitatively while neuroinflammation was assessed using image analysis. Genotyping of cases used a PCR based technique. Standard statistical methods were used to assess the data. Neurofibrillary tangles were not seen in acute fatal TBI cases but they may be an important feature of neurodegeneration in long-term survivors. Cytoskeletal neurodegenerative pathology has been demonstrated after repetitive mild head injury in humans and a single head injury in animals, and is a major component of the neurodegenerative pathology associated with AD. This study assessed tau-associated cytoskeletal pathology in individuals dying after a single episode of TBI. Subtle alterations in tau immunoreactivity, for example in oligodendrocytes, were present in some head injury cases but not controls. However, neurofibrillary tangles did not appear more prevalent after TBI when compared with age-matched controls. Although alterations in tau immunoreactivity may occur which warrant further study, neurofibrillary tangles were not more prevalent after a single fatal episode of TBI. Possession of APOE epsilon4 was associated with more severe vascular related pathology after fatal TBI (contusions, global cerebral ischaemia) and this may be relevant to the relatively poor outcome from TBI in patients with APOE epsilon4 identified in clinical studies. APOE has genetic polymorphisms which may increase susceptibility to AD. Possession of APOE epsilon4 has been shown to increase susceptibility to AD. In addition possession of APOE epsilon4 is associated with a worse outcome after TBI. This study demonstrated that possession of APOE epsilon4 is associated with the greatest incidence of moderate/severe contusional injury and severe ischaemic brain damage in fatal cases of TBI. There does appear to be an increased neuroinflammatory response after TBI particularly in cases with diffuse traumatic axonal injury. This increased neuroinflammatory response may be associated with greater neurotoxicity. Neuroinflammation has been implicated as a potential cause of neurodegeneration both in AD and in the response to brain injury. There have been few studies looking at the neuroinflammatory response after acute head injury or in long-term survivors. Possession of IL-1A allele 2 is not associated with a greater neuroinflammatory response. Interleukin-1 (IL-1) is the main controller of neuroinflammation and homozygosity for IL-1A allele 2 has been shown to increase susceptibility to AD. This study has demonstrated no association between possession of IL-1A allele 2, either heterozygosity or homozygosity, and an increased inflammatory response (identified by expression of MHC class II molecules) after TBI. However, the neuroinflammatory response is most pronounced in cases with diffuse white matter damage (diffuse traumatic axonal injury). Conclusion: This study has demonstrated that possession of APOE ? 4 is associated with the greatest incidence of moderate/severe contusional injury and severe ischaemic brain damage in fatal cases of TBI and that this may account for the over-representation of APOE epsilon4 in severe outcome after head injury. With regard to neurodegeneration after head injury there is increased neuroinflammation, particularly in cases with diffuse TAI, but this did not appear to be modified by genetic influences although the number of cases studied was small. Cytoskeletal pathology was limited to subtle glial alterations although the study only looked at a survival of less than 12 months.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Additional Information: Adviser: David Graham
Keywords: Neurosciences
Date of Award: 2004
Depositing User: Enlighten Team
Unique ID: glathesis:2004-74190
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 23 Sep 2019 15:33
Last Modified: 23 Sep 2019 15:33

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