Genetic Predictors of Perioperative Neurologic and Neuropsychological Injury and Recovery

Abstract

Central nervous system (CNS) dysfunction after cardio pulmonary bypass represents a continuum from coma and focal stroke to cognitive deficits after surgery. Despite the marked increase in investigation of neuro logic and neurocognitive deficits after cardiac surgery, causative factors fail to predict the majority of the variance in the observed incidence of both early and late neurocognitive decline pointing to some inherent indi vidual susceptibility to injury. The authors' investigative team recently discovered a genetic association be tween late-onset Alzheimer's disease and the apolipo protein E (APOE, gene; apoE, protein) ∈-4 gene. This finding triggered many recent studies that have shown an important role of apoE in the determination of neurologic injury and recovery following a variety of acute ischemic insults including intracerebral hemor rhage, closed-head injury, as well as acute stroke and dementia pugilistica. Most important to the current discussion is the authors' recent report documenting preliminary evidence of an association of APOE4 with neurocognitive decline after cardiac surgery. This re view discusses the authors' hypothesis that the bio chemical products coded by this gene are not available to protect and repair the neurons of the CNS during cardiac surgery resulting in deficits of memory, atten tion, and concentration. Potential mechanisms of apoE's association with acute neurologic injury are discussed including regulation of the inflammatory response. The authors have recently determined that apoE, in vivo, modulates the release of nitric oxide and tumor necro sis factor a. This may compound the autonomic dysreg ulation recently reported in the aging population. The authors' preliminary data associating APOE4 with cogni tive impairment after cardiac surgery support this hy pothesis. The different potential mechanisms of apoE function in neuronal injury and recovery are not mutu ally exclusive, and it is likely that apoE modulates the CNS injury response at several functional levels.