The objective of this Project is to determine the effect of survival time and of genetic factors on the manifestation of Alzheimer-type pathology in the brains of patients who die as a result of a series head injury. The hypothesis to be tested is that the genotype of an individual modulates the extent of Abeta deposition and expression of glia-derived cytokines seen in the brain following injury. A large cohort of head injury patients representing various ages and survival times will be genotyped with respect to those genes which have been identified as being important in the development of Alzheimer's disease. This will include apolipoprotein I and IL-1A/IL-1B allelotypes. To examine mechanisms by which these genes modulate neuropathology sequelae of head injury, the presence and levels of the mRNA and protein products of these genes and other cytokine cycle proteins will be determined by hybridization and immunoblot analyses, and by immunocytochemistry. The temporal course for the expression of these molecules will be assessed by looking at patients with different survival times. Results will be quantified using previously constructed computer image analysis algorithms. The topographical relationships between these proteins and Abeta or glial-derived cytokines will also be studied. Using the data accrued from these experiments, it will be possible to determine if the genotype of an individual affects the post-traumatic expression of """"""""genetic-risk"""""""" proteins and/or cytokines. The advantage of studying head injury cases is that they provide an insight into the early events involved in the pathogenesis of Abeta deposits which cannot be gained from studying patients with established Alzheimer's disease. The effects of genotype on the extent of inflammatory activity in the grain are a potentially important factor in predicting long term sequelae of head injury (i.e. Alzheimer's disease) in individual patients, and in tailoring therapeutic or preventative strategies.
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