Alzheimer's disease and anaesthesia
Harrogate, UK
* E-mail: tomcollyer{at}doctors.org.uk
Editor—It was with particular interest that we read the review article by Fodale and colleagues1 on Alzheimer's disease (AD) and anaesthesia. In the same month, our department received a letter from the family of an 80-yr-old lady diagnosed 4 yr previously with AD. She had undergone an elective hip replacement in 1998. The patient received a general anaesthetic using isoflurane and the operation, lasting 2 h, was unremarkable. At around this time, the family report that the patient started experiencing increasing problems with her memory. Having read a recent article2 in the New Scientist titled ‘Alzheimer's alert over anaesthetics’, in which Mandal is quoted as saying ‘It's a seriously deadly combination when an older person receives halothane’, the family were inquiring as to whether the volatile anaesthetic administered in 1998 could have lead to the development of the patient's AD.
Mandal and colleagues3 have shown experimentally a molecular pathway by which halothane induces structural alterations of the amyloid beta peptide resulting in oligomerization, a risk factor for AD. This interaction of inhaled anaesthetics is also noted in Fodale's review article.1 Both Mandal and Fodale acknowledge studies disproving an association between the number of anaesthetics received and the development of AD,4 but Mandal contends that it is the duration of anaesthesia that is critical for the onset of AD, not the number of anaesthetics.
On review of the evidence to date, Fodale and colleagues concluded that the relationship between general anaesthesia and AD has not yet been clarified. They do, however, acknowledge the potential neurotoxic effects of several anaesthetic agents and suggest that further epidemiological prospective studies are required examining the link between general anaesthesia and AD. Fodale and colleagues also highlight the inhibitory interaction of anaesthetic drugs on central cholinergic transmission in the brain and support the hypothesis linking anaesthetic agents with the pathogenesis of postoperative cognitive dysfunction. Given this emerging knowledge and the ageing population, Fodale and colleagues consider a careful mental state evaluation mandatory for all elderly patients undergoing general anaesthesia. This has potentially huge implications. Just how the mental state evaluation is to be conducted is not clear. The limitations of tests assessing cognitive decline and the misuse of simple test such as the Mini-Mental State Examination have previously been highlighted.5 Any test introduced must therefore be appropriately validated. Additionally, who would conduct the mental state evaluation? If the anaesthetist, would we receive appropriate training and have sufficient time to conduct the evaluation before operation? What would be the costs involved? Finally, in the climate of empowering patients and informed consent, should we be consenting elderly patient to the risks of postoperative cognitive dysfunction?
A review of the admission clerking of our patient interestingly noted the patient to be ‘a bit forgetful’. Whether a formal mental state evaluation would have indicated our patient as having early cognitive decline, and allowed us to tailor our anaesthetic, we will not know. It does, however, seem likely that this letter may be one of many to come and the excellent review article of Fodale and colleagues, puts us in a stronger position to answer such inquiries.
Messina, Italy
E-mail: vfodale{at}unime.it
Editor—We appreciate the interest expressed by Drs Collyer and Frater in our article,1 since it gives us another possibility of discussing this intriguing issue. Patients' acceptance of general anaesthesia is founded on the assumption that its effects are totally reversible. But researchers from many centres have convincingly demonstrated that measurable cognitive dysfunctions, called postoperative cognitive dysfunctions (POCD), are a common complication after anaesthesia.6 Cognitive dysfunctions may manifest both as memory loss and as psychomotor derangement.7
AD is the most common dementia disorder characterized by multiple pathological changes in the brain, leading to a progressive memory loss and other cognitive symptoms producing occupational and social disabilities.8 Genetic evidence, confirmed by neuropathological and biochemical studies, indicates that excessive beta-amyloid protein (Aß) generated by amyloidogenic processing of the beta-amyloid precursor protein (APP) plays a fundamental role in AD neuropathogenesis. In addition, Aß clearance and APP adaptor proteins can contribute to AD neuropathogenesis by affecting Aß levels.9
Current literature suggests the potential involvement of AD neuropathogenesis in POCD.9 Aß, the major constituent of senile plaques in the brains of patients with AD, is related to the impairment of learning and memory, and neurodegeneration,10 and its continuous infusion results in learning and memory deficits in rats.11 Beta-amyloid directly inhibits human cholinergic 
4ß2-nicotinic acetylcholine receptors.12 Treatment with Aß at very low concentrations for 7 days significantly decreased the number of nicotinic receptor binding sites and mRNA levels.8 We know that the central cholinergic system plays a major role in regulation of cognitive functions: agonists of central nicotinic acetylcholine receptors and muscarinic acetylcholine receptors may improve, whereas receptor antagonists impair performance in cognitive tasks. Inhibition also contributes to learning and memory impairment and delirium.13 14
Inhaled anaesthetic agents remain the mainstay for patients undergoing major surgical operations, especially in elderly patients. Clinically, relevant concentrations of isoflurane induce apoptosis, alter APP processing, and increase Aß production in human cell lines. Because altered processing of APP leading to accumulation of Aß is a key event in the pathogenesis of AD, these findings may have implications for use of this anaesthetic agent in individuals with excessive levels of cerebral Aß, and elderly patients at increased risk for postoperative cognitive dysfunction.15 In addition, isoflurane interacts with Aß40 peptides and promotes Aß oligomerization and cytotoxicity.16 17
On the basis of his experimental published data, Mandal2 suggested that ‘the inhaled anaesthetics halothane and isoflurane encourage clumping of beta amyloid protein. Halothane interacts directly with a pocket in the beta amyloid protein, changing its shape and encouraging neighbouring proteins to bind. Giving elderly patients certain general anaesthetics could increase their risk of developing Alzheimer's disease and other memory and attention problems'. Therefore, anaesthesia for elderly patients is considered as a risk factor in AD as they frequently experience deterioration in cognitive function with long exposure to anaesthetics during surgery.3
Previous retrospective studies had concluded that it seems unlikely that multiple exposures to general anaesthesia increase the risk of AD,4 18 but today the knowledge of the pathophysiology of neurodegenerative disorders has been dramatically improved, and now we should keep in mind that anaesthesia drugs are not totally safe.
Drs Collier and Frater rightly suggest that the relationship between general anaesthesia and AD has not yet been clarified, but all these aspects, taken together, open new, intriguing, and maybe challenging, scenarios for our clinical practice. In addition, we should be aware that these findings may have implications for the information given to elderly patients before surgery and, therefore, we should be prepared to answer many inquiries, and possible legal implications, in the near future.
References
1 Fodale V, Quattrone D, Trecroci C, Caminitii V, Santamaria LB. Alzheimer's disease and anaesthesia: implications for the central cholinergic system. Br J Anaesth (2006) 97:445–52.
2 Philips H. Alzheimer's alert over anaesthetics. New Scientist (2006) 2575:12.
3 Mandal P, Pettegrew J, McKeag D, Mandal R. Alzheimer's disease: halothane induces Aß peptide to oligomeric form-solution NMR studies. Neurochem Res (2006) 31:883–90.[CrossRef][Web of Science][Medline]
4 Gasprini M, Vanacore N, Schiaffini C, et al. A case control study on Alzheimer's disease and exposure to anaesthesia. Neurol Sci (2002) 23:11–4.[CrossRef][Web of Science][Medline]
5 Hanning CD. Postoperative cognitive dysfunction. Br J Anaesth (2005) 95:82–7.
6 Moller JT, Cluitmans P, Rasmussen LS. Long-term postoperative cognitive dysfunction in the elderly ISPOCD1 study: ISPOCD investigators—International Study of Post-Operative Cognitive Dysfunction. Lancet (1998) 351:857–61.[CrossRef][Web of Science][Medline]
7 Raja PV, Blumenthal JA, Doraiswamy P. Cognitive deficits following coronary artery bypass grafting: prevalence, prognosis, and therapeutic strategies. CNS Spectr (2004) 9:763–72.[Web of Science][Medline]
8 Nordberg A. Neuroprotection in Alzheimer's disease—new strategies for treatment. Neurotox Res (2000) 2:157–65.[Medline]
9 Xie Z, Tanzi RE. Alzheimer's disease and post-operative cognitive dysfunction. Exp Gerontol (2006) 41:346–59.[CrossRef][Web of Science][Medline]
10 Nabeshima T, Nitta A. Memory impairment and neuronal dysfunction induced by beta-amyloid protein in rats. Tohoku J Exp Med (1994) 174:241–9.[Web of Science][Medline]
11 Yamada K, Tanaka T, Mamiya T, Shiotani T, Kameyama T, Nabeshima T. Improvement by nefiracetam of beta-amyloid-(1-42)-induced learning and memory impairments in rats. Br J Pharmacol (1999) 126:235–44.[CrossRef][Web of Science][Medline]
12 Wu J, Kuo YP, George AA, Xu L, Hu J, Lukas RJ. J Biol Chem (2004) 279:37842–51.
13 Fodale V, Santamaria LB. The inhibition of central nicotinic nAch receptors is the possible cause of prolonged cognitive impairment after anesthesia. Anesth Analg (2003) 97:1207.
14 Pratico C, Quattrone D, Lucanto T, et al. Drugs of anesthesia acting on central cholinergic system may cause post-operative cognitive dysfunction and delirium. Med Hypotheses (2005) 65:972–82.[CrossRef][Web of Science][Medline]
15 Xie Z, Dong Y, Maeda U, et al. The common inhalation anesthetic isoflurane induces apoptosis and increases amyloid beta protein levels. Anesthesiology (2006) 104:988–94.[CrossRef][Web of Science][Medline]
16 Eckenhoff RG, Johansson JS, Wei H, et al. Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiology (2004) 101:703–9.[CrossRef][Web of Science][Medline]
17 Mandal PK, Williams JP, Mandal R. Molecular understanding of Aß peptide interaction with isoflurane, propofol, and thiopental: NMR spectroscopic study. Biochemistry. (in press).
18 Bohnen NI, Warner M, Kokmen E, Beard CM, Kurland LT. Alzheimer's disease and cumulative exposure to anesthesia: a case-control study. J Am Geriatr Soc (1994) 42:198–201.[Web of Science][Medline]
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