Why do older people develop dementia after surgery?

Research project: Novel strategies to prevent the early onset of Alzheimer's disease induced by surgery.

Lead Investigator: Dr Daqing Ma
Institution: Imperial College London
Grant type: Project
Grant amount: £139,418
Start date: December 2010
Completion date: April 2013

What was the project and what did the researchers do?

Major surgery that involves general anaesthetic, such as for knee and hip replacements or for heart conditions, is common for many older adults. After general anaesthesia there is an increased risk of developing prolonged problems with thinking that go beyond the short period of temporary disorientation that is typical after surgery.

This long-lasting disorder is known as post-operative cognitive decline and is thought to be associated with inflammation in the brain, similar to that seen in Alzheimer's disease. There is a need to understand how this cognitive decline develops and ways to prevent it, since it poses a particularly high risk to the ageing population. 

What were the key results and how will this help in the fight against dementia?

Dr Daqing Ma and his research team used a mouse model of Alzheimer's disease and compared these with normal mice. The researchers found that although anaesthesia alone can suppress the brain's immune support cells (glial cells), this does not result in any lasting adverse effects on memory – even for very old or Alzheimer's disease model mice – providing that good anaesthetic techniques are employed. These techniques include ensuring that the depth of anaesthesia and total exposure time are kept to a minimum, as is standard practice in UK hospitals.

Inflammation occurs during surgery to combat any danger produced by the surgical wound, but this quickly serves its purpose and resolves itself in normal mice. However in Alzheimer's disease model mice, the inflammation increases in response to feedback from previous inflammation even after the danger has passed, as though without a 'stop button'.

Left to its own devices this surgery-induced cellular stress could hasten cognitive decline and the onset of dementia. However, the researchers found that short-term treatment with either atorvastatin (a drug used to lower blood cholesterol) or celastrol (the active ingredient of a Chinese herbal remedy) appeared to prevent these changes in Alzheimer's disease model mice. Since the inflammation is a common characteristic of Alzheimer's disease, any treatment that combats or prevents this is promising for individuals affected by Alzheimer's disease and those at risk of developing the disease.

Further research is now needed to understand why these particular drugs had these effects and how they might be used safely in people to prevent the development of post-operative cognitive decline. 

What happened next? Future work and additional grants:

Dr Dafydd Lloyd, a researcher on this project, is continuing research on the impact of surgery and anaesthesia on inherited Alzheimer's disease, as work towards a PhD at Imperial College London.

The post-doctoral researcher on this grant, Dr Helena Watts has been awarded a Research Fellowship by Alzheimer's Society to explore strategies to prevent surgery-induced cognitive decline in a novel model of sporadic Alzheimer's disease.

How were people told about the results? Conferences and papers: 

Conferences

Xenon reduces apoptosis, gamma- and beta-secretase expression in an in vitro model of Alzheimer's disease. Lloyd D, Vizcaychipi M, Pac-Soo C, Ma D. Br. J. Anaesth. (2011) 106 (3): 428-446. Abstract & Oral Presentation.

The anaesthetic agent Xenon down-regulates a pathway of Alzheimer's pathogenesis and shows cytoprotection in vitro. Lloyd D, Vizcaychipi M, Ma D. Medical Research Society meeting (2011) Abstract and plenary talk.

Can Anaesthesia accelerate Alzheimer's?  Lloyd D, Watts H, Vizcaychipi M, Ma D.  National Institute of Academic Anaesthesia, Royal College of Anaesthetists (2011) Abstract and poster presentation.

Metabolome changes induced by anaesthetic in an in vitro Alzheimer model. Lloyd D, Spurr S, Li J, Watts H, Vizcaychipi M, Xie Z and Ma D.  Alzheimer's Association International Conference, Paris (2011). Poster presentation.

Does surgery accelerate Alzheimer's? Watts H, Vizcaychipi M, Lloyd D, Ma D. Alzheimer's Society research conference, Birmingham (2011). Poster.

'Surgery accelerates Alzheimer's:  Fact or fiction?'  27th International Conference of Alzheimer's Disease, London, UK. (2012). Poster.

4th UCL Perioperative & Critical Care Research Forum, National Hospital for neurology and neurosurgery, Queens Square, London (2012). Effects of Anaesthesia on Alzheimer's Disease. Oral Presentation 

'Surgery-induced Cognitive Decline: implications for Alzheimer's'. Watts HR, Vizcaychipi M, Lloyd D, Ma D. Alzheimer's Society research conference, Leeds (2012). Poster.

'Neuroinflammation following surgery: implications for Alzheimer's' Watts HR. Neuroinflammation, Prague, Sept 2013. Invited speaker.

Publications:

C Pac-Soo, D Lloyd, M Vizcaychipi, D Ma.  Statins: The Role in the Treatment and Prevention of Alzheimer's Neurodegeneration. Journal of Alzheimer's Disease 27; 1-10 (2011) doi: 10.3233/JAD-2011-110524. 

D Lloyd, D Ma, M Vizcaychipi. Cognitive decline after surgery and critical illness. Continuing Education in Anaesthetics, Critical Care and Pain Medicine.  BJA publications.  Continuing Education in Anaesthesia, Critical Care and Pain (2012) doi: 10.1093/bjaceaccp/mks004. 

Fung A, Vizcaychipi M, Lloyd D, Wan Y, Ma D. Central nervous system inflammation in disease related conditions: mechanistic prospects. Brain Res. 2012 Mar 29; 1446:144-55. doi: 10.1016/j.brainres.2012.01.061.

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