Anti-inflammatory drugs currently used to treat diseases such as rheumatoid arthritis may also help prevent cognitive problems after surgery, according to a new study by researchers at Imperial College London and University of California, San Francisco (UCSF).
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."
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Imperial College London
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Notes to editors:
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.
A copy of the paper can be downloaded from https://fileexchange.imperial.ac.uk/files/e0d383fa682/pnas201014557_pvqearNT11.13.pdf
2. About Imperial College London
Consistently rated amongst the world's best universities, Imperial College London is a science-based institution with a reputation for excellence in teaching and research that attracts 14,000 students and 6,000 staff of the highest international quality. Innovative research at the College explores the interface between science, medicine, engineering and business, delivering practical solutions that improve quality of life and the environment - underpinned by a dynamic enterprise culture.
Since its foundation in 1907, Imperial's contributions to society have included the discovery of penicillin, the development of holography and the foundations of fibre optics. This commitment to the application of research for the benefit of all continues today, with current focuses including interdisciplinary collaborations to improve global health, tackle climate change, develop sustainable sources of energy and address security challenges.
In 2007, Imperial College London and Imperial College Healthcare NHS Trust formed the UK's first Academic Health Science Centre. This unique partnership aims to improve the quality of life of patients and populations by taking new discoveries and translating them into new therapies as quickly as possible.
Website: www.imperial.ac.uk
3. About University of California, San Francisco
UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care.
Website: www.ucsf.edu.
4. About Arthritis Research UK
Arthritis Research UK is the leading authority on arthritis in the UK, conducting scientific and medical research into all types of arthritis and musculoskeletal conditions. It is the UK's fourth largest medical research charity and the only charity solely committed to funding high quality research into the cause, treatment and cure of arthritis.
Website: www.arthritisresearchuk.org
5. About the Mathilda and Terence Kennedy Institute of Rheumatology Trust
The Mathilda and Terence Kennedy Institute of Rheumatology Trust (the KIR Trust) was founded in 1965/66. It is committed to supporting research into rheumatism and allied diseases which it does by means of grants.
Website www.kirtrust.org
Journal
Proceedings of the National Academy of Sciences