Neuroinflammation and postoperative cognitive dysfunction: to resolve or not?

Neuroinflammation and postoperative cognitive dysfunction: to resolve or not?

  • Issue 61

Niccolò Terrando | Member of EuroSTAR Working Group
niccolo.terrando@duke.edu

It has long been known that surgery and trauma can lead to cognitive impairments[1]. With the increase in our ageing population postoperative cognitive dysfunction (POCD) is becoming a common complication with significant implications for our patients and the overall healthcare system[2]. Extensive surgical procedures are increasingly being offered to older and sicker patients due to the continuing improvements in surgical technology and anesthetic care. Although many patients regain full control of their lives after an operation (pain is relieved, organ function reestablished, professional and leisurely activities reinstated), some individuals experience complications in the perioperative period, including thinking and memory deficits. POCD is generally defined through a set of neuropsychological tests as a change in cognitive performance (affecting domains like learning, memory and attention) from before to after a surgical procedure. While often reversible, POCD has been reported to affect up to 30% of middle age and elderly patients at one week after non-cardiac surgery, and remains present in 10% of elderly surgical patients at three months or even later[3], potentially predisposing to permanent dementia[4].

The pathophysiology of POCD is unclear, but evidence from both preclinical and recent clinical studies implicates inflammation as a possible contributing factor. Surgery and tissue damage engage with the innate immune system and trigger an inflammatory response that promotes systemic inflammation, which can affect brain function[5]. Typically, surgical trauma activates a distinct cascade of pro- and anti-inflammatory molecules that have direct and unique actions on receptor systems in the brain. If poorly controlled, this inflammatory response leads to more extensive tissue injury and can become potentially fatal (such as in the case of septic shock).

Endogenous regulation of inflammatory processes is of considerable translational interest and clinical relevance. It is now appreciated that resolution of inflammation is an active process involving a class of specialized pro-resolving lipid mediators (SPM), which exert potent stereoselective actions during acute inflammation and restore homeostasis[6]. Resolvins, protectins and maresins are three major families of SPM biosynthesized from the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which display potent anti-inflammatory and pro-resolving effects[7]. Through a research grant from the European Society of Anaesthesiology we have described for the first time the effects of aspirin-triggered resolvin D1 (AT-RvD1) in preventing surgery-induced neuroinflammation and cognitive decline in a mouse model of POCD[8]. Aspirin, in addition to reducing prostaglandin levels, also triggers the release of endogenous lipid mediators, such as resolvins. We have shown that AT-RvD1, a novel mediator found in the resolution of inflammation, prevents cognitive decline by modulating central nervous system function. Using a combination of methods including cell cultures, immunoassays, electrophysiology and behavior, we further defined the underlying mechanisms whereby inflammation leads to memory dysfunction after sterile injury: peripheral trauma affects synaptic plasticity, glia function, and impairs long-term potentiation (a cellular correlate of long term memory) in hippocampal neurons (figure). Overall, these results indicate that modulating pro-resolving processes after surgery may offer a safe and effective treatment for POCD and perhaps other neurodegenerative conditions.

Although it is evident that some patients experience postoperative cognitive deficits, the pathophysiology of POCD remains unclear, we do not know which patients are at highest risk of POCD, and it is debated how to prevent it[9]. Current efforts are aiming at translating preclinical findings into surgical patients using pre- and post-operative imaging, for example using PET and/or fMRI scans, combined with assessments of cellular and humoral biomarkers for neuroinflammation and neurodegeneration. These studies shall provide novel insights into the pathophysiology of cognitive decline and ultimately may lead to approaches to treat POCD.

Figure: proposed POCD model and resolution of neuroinflammation.

 

References

  1. Bedford, P.D., Adverse cerebral effects of anaesthesia on old people. Lancet, 1955. 269(6884): p. 259-63.
  2. Terrando, N., et al., Perioperative cognitive decline in the aging population. Mayo Clin Proc, 2011. 86(9): p. 885-93.
  3. Moller, J.T., et al., Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study. ISPOCD investigators. International Study of Post-Operative Cognitive Dysfunction. Lancet, 1998. 351(9106): p. 857-61.
  4. Chen, C.W., et al., Increased risk of dementia in people with previous exposure to general anesthesia: a nationwide population-based case-control study. Alzheimers Dement, 2014. 10(2): p. 196-204.
  5. Lord, J.M., et al., The systemic immune response to trauma: an overview of pathophysiology and treatment. Lancet, 2014. 384(9952): p. 1455-65.
  6. Serhan, C.N., et al., Resolution of inflammation: state of the art, definitions and terms. FASEB J, 2007. 21(2): p. 325-32.
  7. Serhan, C.N., Pro-resolving lipid mediators are leads for resolution physiology. Nature, 2014. 510(7503): p. 92-101.
  8. Terrando, N., et al., Aspirin-triggered resolvin D1 prevents surgery-induced cognitive decline. FASEB J, 2013. 27(9): p. 3564-71.
  9. Terrando, N., L.I. Eriksson, and R.G. Eckenhoff, Perioperative neurotoxicity in the elderly: summary of the 4th International Workshop. Anesth Analg, 2015. 120(3): p. 649-52. 4SdPm781018

ESA Grants Programme 2016

The ESA Research Grants promote anaesthesiology–related research in Europe and encourage anaesthesiologists to go beyond their existing practice and understanding.

Applications are called for in the following areas: Clinical Research, Experimental Research, Patient Safety and in line with the H2020 Funding programme. The submissions deadline is 4 September 2015, 23:59 CET.

More information? Visit the ESA website or contact us at research@esahq.org.