Inflammation resolving mechanism dysregulation in postoperative cognitive decline

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DESCRIPTION (provided by applicant): There is a concern that surgical patients of advanced age may develop problems processing information ("cognitive dysfunction") that persist long after the operation. Apart from age a recent study revealed that surgical patients with the Metabolic Syndrome (a clustering of conditions that include visceral obesity, insulin resistance, dyslipidemia and hypertension) are particularly prone to develop postoperative cognitive dysfunction occurring with a frequency of almost one in three. Over the last 5 years we have accumulated data from a series of published studies involving healthy rodents undergoing surgery that reveal the development of short-lived inflammation in the hippocampus, a brain region that is vital for cognitive function. As a consequence acute recall of memories, acquired immediately before the surgery, is disrupted. Normally, both the brain inflammation and the memory decline are repaired within days with no long-lasting consequence. However, if the processes involved in resolving the inflammation are disabled then restoration of normal cognitive function will not occur. We have undertaken postoperative studies involving a rat model of the Metabolic Syndrome in which both the influences of nature and nurture contribute to serious consequences including a considerably shorter life expectancy. Acutely postoperatively, these rats develop exaggerated cognitive decline, and remotely a persistent, rather than short-lived, cognitive decline that is associated with more severe brain inflammation. We noted that the cognitive deterioration was associated with abnormalities in the manner that these animals resolve the inflammation that follows the trauma of surgery. Our new project tests the hypothesis that the abnormalities in inflammation-resolution are the cause for the exaggerated and persistent postoperative cognitive decline in this rat model of the Metabolic Syndrome. As we test this cause and effect relationship we will uncover possible targets in the immune system that will allow us to intervene and hopefully interrupt the abnormality. In particular, we are encouraged that some of the abnormalities that we have noted are potentially reversible with exercise and therefore we will also explore the effect of exercise training on the mechanisms and expression of postoperative cognitive decline. Because of the similarity between the rat model and the human condition of Metabolic Syndrome we subsequently plan to study whether surgical patients with this condition exhibit the same abnormalities as we noted in the rat; if so, we can extend to humans successful therapeutic interventions noted in this study, in particular pre-operative exercise.