The research also reveals for the first time that a specific inflammatory response in the brain may explain why many patients experience memory loss or other forms of cognitive dysfunction after surgery or critical illness.
The findings, from research in mouse models, could lead to human clinical trials within a year, the authors say. Their work is published today in the journal Proceedings of the National Academy of Sciences.
For years, anesthesiologists and neurologists have struggled to explain why some patients, especially the elderly, experience confusion, learning disorders and memory loss after surgery – a condition clinicians call post-operative cognitive decline. While typically short-term, this delirium occurs widely in intensive care units, affecting between 28 and 92 per cent of hospitalized patients, depending on their age, health status and type of surgery. It also has been linked to poorer surgical outcomes, as well as an increased risk of mortality, inability to cope and possible permanent dementia.
Until now, researchers have not clearly understood what causes the disorder or how to treat it. The new research suggests that it is caused by cell-to-cell signalling molecules called cytokines released by cells of the immune system. There are drugs already in use that target the activity of cytokines so it is possible that these drugs could be effective against cognitive decline.
The senior author of the study is Mervyn Maze, MB ChB, Professor and Chair of the Department of Anesthesiology and Perioperative Care at UCSF and a Visiting Professor in the Department of Surgery and Cancer at Imperial College London.
“Antibody therapies already are widely used against cytokines to prevent or treat inflammation, so we know that these are effective in humans,” said Professor Maze, who began the research at Imperial before moving to UCSF. “This study suggests that one day we also might be able to use these therapies as a single, pre-surgical dose to prevent cognitive decline in susceptible patients.”
Previous studies have linked post-operative cognitive decline with the rise in blood levels of a cytokine called interleukin-1 beta (IL-1β), which is involved in inflammation. For this study, Maze and his colleagues studied another cytokine called tumour necrosis factor (TNF-α), which is known to regulate the immune system’s inflammatory response before interleukin-1 is produced.
Working with Professor Sir Marc Feldmann – a pioneer in cytokine research in inflammatory disorders and Head of the Kennedy Institute of Rheumatology at Imperial College London – the team gave a single dose of anti-TNF antibody to mice before giving them surgery. They found that the treatment decreased blood levels of IL-1β, limited inflammation in the brain and prevented the mice from showing behavioural signs of cognitive decline.
The research suggests that TNF acts “upstream” of IL-1 and triggers a cascade of immune responses during surgery that provokes the production of IL-1 in the brain, Professor Maze said. That in turn contributes to cognitive decline after surgery or critical illness.
“This is an important observation, as it demonstrates that cytokines are potential therapeutic targets in a wider range of diseases, not just autoimmune disease and cancer for which they are known targets,” Professor Feldmann said. “Moreover, effective therapeutics already are available, with a known safety profile and modest cost if used short term.”
The study was supported by the Westminster Medical School Research Trust, in London, the Mathilda and Terence Kennedy Institute of Rheumatology Trust, and Arthritis Research UK.
Arthritis Research UK-funded research at its Kennedy Institute of Rheumatology was instrumental in showing the substantial health benefits of anti-TNF therapy in patients with rheumatoid arthritis and has transformed the lives of millions of people worldwide. Medical director of the charity Professor Alan Silman said: “This research shows the potential that these drugs have in other areas of health.”
1. Journal reference
N Terrando et al. Tumor necrosis factor-α triggers a cytokine cascade yielding postoperative cognitive decline. Proceedings of the National Academy of Sciences, 1 November 2010.