Surgical patients expect to return to their pre-morbid state after the procedure for their underlying condition; unfortunately, perioperative neurocognitive disorders (PNDs) may complicate their recovery resulting in a spectrum of conditions ranging from early-onset delirium to dementia in the longer term. The surgical populations that are most at risk for developing PNDs are the aged and those with existing cognitive decline, which most often is due to Alzheimer’s Disease (AD). The proportion of surgical patients with these risks is rising steadily. While neuroinflammation plays a pivotal role in the development of PNDs, it remains unknown which inflammatory cytokines are acting on which cell types to produce the clinical syndrome. Recently, interleukin 6 (IL-6), a pleiotropic cytokine, has come to the fore as a leading candidate for provoking PNDs. Our central hypothesis to be tested, using animal models of aging and AD, is that vulnerability to PNDs is due to an increase in hippocampal (hc) neuronal IL-6 trans-signaling, which can be assessed perioperatively and can be attenuated with sgp130Fc, a selective blocker. We will test this hypothesis by addressing the following 5 questions: (1) Is the vulnerability to PNDs in aged and AD mouse models associated with upregulation of IL-6 trans-signaling/neurodegeneration in a part of the brain that contains circuitry involved in memory? (2) What are the antecedents and/or surrogates of postoperative upregulated IL-6 trans-signaling? (3) What are the genetic consequences of postoperative IL-6 trans-signaling in hc cells? (4) Can vulnerability to PNDs be overcome prophylactically, and therapeutically, with blockade of IL-6 trans-signaling? (5) Is blockade of IL-6 trans-signaling safe for perioperative use? Answers to these questions will inform on critically needed therapies for safe prevention and/or reversal of postoperative cognitive impairments in older adults and subjects with neurodegenerative disorders and possibly for treating delirium and cognitive impairment associated with neuroinflammation in non-surgical settings.
