Genetic predictors of perioperative neurological and cognitive injury and recovery

In most investigations, genetic and environmental factors have been shown to interact in altering the progression of ageing related disease including stroke and cognitive decline. The peri-operative period appears to be no different, with environmental (operative) and genetic factors interacting to determine the presence, absence or severity of neurological outcomes. In our initial work we confirmed that apolipoprotein E4 (apoE4) alters cognitive function after coronary artery bypass graft (CABG), the mechanism of this association apparently being related to atherosclerosis and inflammatory factors. These findings are consistent with multiple studies that have shown an important role of apoE in the modulation of neurological injury and recovery following a variety of acute ischaemic insults including intra-cerebral haemorrhage, closed head injury, acute stroke and dementia pugilistica. More recently we have found that polymorphism of the GPIIIa constituent of the platelet integrin receptor, GPIIb/IIIa (PLA2) polymorphism is also associated with early post-operative cognitive decline. The association of multiple genetic factors with the incidence or severity of neurological injury is not surprising, since the factors that alter cerebral injury and recovery are complex. Similarly, there are genetic factors that determine the occurrence of tissue injury and its recovery, including genes that modulate atherosclerosis, emboli, inflammation, thrombosis and vascular reactivity. We have only begun to scratch the surface in our understanding of functional genomics as it applies to peri-operative outcomes. Functional genomics, as applied to complex human disease, will require a unique combination of cutting-edge genetics and large, highly phenotyped patient populations in order to further our understanding of the complex genetic–environmental interactions. This chapter will concentrate initially on the broad classes of genetic factors that may play a role in neurological injury and recovery, and will conclude with our current data on those genetic factors that predict neurocognitive decline after cardiac surgery and the potential mechanisms driving these associations.