SEARCH

SEARCH BY CITATION

Summary

  1. Top of page
  2. Summary
  3. Postoperative cognitive dysfunction: type of surgery and incidence
  4. Genetic markers of postoperative cognitive dysfunction
  5. Previous hypotheses
  6. Introduction to the central cholinergic system functions
  7. Molecular pathology of Alzheimer’s disease
  8. Action of amyloid β peptide on the cholinergic system: the role of anaesthetics
  9. Cholinergic system and anaesthetics
  10. Anaesthetics and cell apoptosis
  11. Why is age an important risk factor?
  12. Does the molecular size of the anaesthetic matter?
  13. Conclusions
  14. Acknowledgements
  15. References

With longevity, postoperative cognitive decline in the elderly has emerged as a major health concern for which several factors have been implicated, one of the most recent being the role of anaesthetics. Interactions of anaesthetic agents and different targets have been studied at the molecular, cellular and structural anatomical levels. Recent in vitro nuclear magnetic resonance spectroscopy studies have shown that several anaesthetics act on the oligomerisation of amyloid β peptide. Uncontrolled production, oligomerisation and deposition of amyloid β peptide, with subsequent development of amyloid plaques, are fundamental steps in the generation of Alzheimer’s disease. Amyloid β peptide is naturally present in the central nervous system, and is found at higher tissue concentrations in the elderly. We argue that administering certain general anaesthetics to elderly patients may worsen amyloid β peptide oligomerisation and deposition and thus increase the risk of developing postoperative cognitive dysfunction. The aim of this review is to highlight the clinical aspects of postoperative cognitive dysfunction and to find plausible links between possible anaesthetic effects and the molecular pathological mechanism of Alzheimer’s disease. It is hoped that our hypothesis will stimulate further enquiry, especially triggering research into elucidating those anaesthetics that may be more suitable when cognitive dysfunction is a particular concern.

The therapeutic objective of general anaesthesia is to produce analgesia, amnesia, hypnosis, and muscle relaxation to facilitate surgery while keeping the incidence of undesirable side effects low. In pharmacological terms, this can be achieved by using drugs with very specific sites of action and keeping tissue and receptor drug concentrations at effective levels, but lower than those that produce unacceptable toxicity. It is assumed that the effects are reversible [1–3].

As the nature of molecular action of general anaesthetics is probably both widespread across several types of body tissue and complex in terms of cellular processes affected, any impairment of these functions could be reflected as an alteration in mood, memory, motor function and/or behaviour [2–4]. Furthermore, anaesthetic drugs could have longer lasting effects on the brain than previously imagined [2, 4, 5].

Postoperative cognitive dysfunction (POCD) is now recognised as one such complication, often detected by an abnormality on neuropsychological testing [6–8]. It may manifest clinically as memory loss, psychomotor derangement, dementia, delirium or depression, difficulties with fine-motor coordination and impaired higher-level cognitive functions [9, 10]. However, the severity of impairment is variable and is often detected only by neuropsychological testing after surgery and anaesthesia. Cognitive changes are usually transient, returning to normal function in a few days [11], but evidence exists that cognition may be impaired for weeks after anaesthesia [12] and, in some cases, cognitive dysfunction may persist after surgery and may be a precursor for further deterioration [11].

Postoperative cognitive dysfunction is often related to a higher risk of postoperative complications and long-term disability [13]. The International Study of Postoperative Cognitive Dysfunction (ISPOCD) group has confirmed that POCD is associated with reduced daily activities, stopping work earlier in life, increased dependency on social support and increased mortality [7, 14]. About 70% of patients with POCD die within 5 years, as compared to about 35% of patients without postoperative delirium [15].

As overall life expectancy has increased, an increasing number of elderly patients are undergoing anaesthesia [5, 8], so much so that half of all people reaching the age of 65 may have had one or more operations [16, 17]. Therefore, POCD could pose a major global health concern [18, 19].

In this review, we develop a hypothesis for a link between POCD, Alzheimer’s disease and use of anaesthetic agents. First, we outline the mechanisms proposed for POCD and Alzheimer’s and we demonstrate similarities between the candidate pathways for both conditions. Then, we show what is known about interaction of anaesthetics with these pathways. This enables us to formulate a hypothesis, involving some specific compounds that could help identify those patients at risk of POCD, and also suggest some anaesthetic techniques that might minimise this disabling condition.

Postoperative cognitive dysfunction: type of surgery and incidence

  1. Top of page
  2. Summary
  3. Postoperative cognitive dysfunction: type of surgery and incidence
  4. Genetic markers of postoperative cognitive dysfunction
  5. Previous hypotheses
  6. Introduction to the central cholinergic system functions
  7. Molecular pathology of Alzheimer’s disease
  8. Action of amyloid β peptide on the cholinergic system: the role of anaesthetics
  9. Cholinergic system and anaesthetics
  10. Anaesthetics and cell apoptosis
  11. Why is age an important risk factor?
  12. Does the molecular size of the anaesthetic matter?
  13. Conclusions
  14. Acknowledgements
  15. References

There may be differences between cardiac and non-cardiac surgery in terms of incidence, genesis and risk factors for POCD.

In non-cardiac surgery, the probable incidence of POCD depends on the extent of surgery undertaken. With minor surgery, the incidence of POCD at intervals up to 3 months postoperatively is reported as 6.6% (95% CI 4.1–10.0) [20]. After major non-cardiac surgery, however, POCD appears detectable in approximately 26% of patients 7 days postoperatively but in approximately 10% of patients 3 months after surgery [7]. Across the subspecialties, orthopaedic surgery has been described as a high-risk procedure for POCD: in patients > 75 years old with hip fractures, the cumulative incidence of POCD was approximately 11% [21].

Cognitive dysfunction is well documented after cardiac surgery [22–24]. The use of cardiopulmonary bypass is suspected as a causative factor, with the incidence of postoperative cognitive impairment as high as 70–90% [25]. It has usually been attributed to the adverse effects of surgery-related trauma, microembolisation, temperature changes, levels of mean arterial pressure used, or changes in jugular bulb oxygen saturation with bypass [9, 26]. However, demographic predictors of cognitive decline also exist and include patients' age and years of education (i.e. secondary and beyond). Furthermore, coronary artery bypass grafting may be an additional independent risk factor [9]; before discharge, approximately 67% of patients suffer from POCD, whereas 1 year after operation approximately 20% of patients have experienced deterioration in their quality of life, exacerbations related to self-confidence and increased dependence on others [9, 27].

Genetic markers of postoperative cognitive dysfunction

  1. Top of page
  2. Summary
  3. Postoperative cognitive dysfunction: type of surgery and incidence
  4. Genetic markers of postoperative cognitive dysfunction
  5. Previous hypotheses
  6. Introduction to the central cholinergic system functions
  7. Molecular pathology of Alzheimer’s disease
  8. Action of amyloid β peptide on the cholinergic system: the role of anaesthetics
  9. Cholinergic system and anaesthetics
  10. Anaesthetics and cell apoptosis
  11. Why is age an important risk factor?
  12. Does the molecular size of the anaesthetic matter?
  13. Conclusions
  14. Acknowledgements
  15. References

Possessing the apolipoprotein E ɛ-4 (APOE, gene or ApoE, protein) allele has been implicated as a predictor of postoperative cognitive decline [9, 26, 28]. Apolipoprotein E ɛ-4 is the major genetic susceptibility locus for the common forms of Alzheimer’s, and a multifunctional role of ApoE in the brain implicates isoform-specific differences in interactions with several brain proteins, including Aβ and τ proteins [28] associated with sporadic forms of Alzheimer’s [9, 26].

Other studies have highlighted a crucial role for interleukin 18 (IL-18) in mediating neuroinflammation and neurodegeneration in the central nervous system under pathological conditions [29]. Patients with defects in IL-18 cytokine promoter gene polymorphisms have high circulating concentrations of serum amyloid peptides, which are implicated in Alzheimer’s disease [30].

General anaesthesia is associated with persistent changes in gene expression in the brain for at least 72 h postoperatively, and this might also be relevant for genesis of POCD [31].

Previous hypotheses

  1. Top of page
  2. Summary
  3. Postoperative cognitive dysfunction: type of surgery and incidence
  4. Genetic markers of postoperative cognitive dysfunction
  5. Previous hypotheses
  6. Introduction to the central cholinergic system functions
  7. Molecular pathology of Alzheimer’s disease
  8. Action of amyloid β peptide on the cholinergic system: the role of anaesthetics
  9. Cholinergic system and anaesthetics
  10. Anaesthetics and cell apoptosis
  11. Why is age an important risk factor?
  12. Does the molecular size of the anaesthetic matter?
  13. Conclusions
  14. Acknowledgements
  15. References

The aetiology of POCD remains unclear. More than 50 potential causes of delirium suggested in the literature from the last few decades have been listed [32]. Investigations have focused on the anaesthetic agent, general vs regional anaesthesia, use of anticholinergic agents such as atropine, or the physiological effects of the anaesthetic, such as hypoxia, hypotension, hypertension or hyperventilation [18, 33]. Also, the patient’s medical conditions as potential risk factors for long-term POCD have been investigated. In hypertensive patients, for example, there is a significant relationship between minimum intra-operative mean arterial pressure and decline in cognitive function after surgery [33]. Or, modifications in thyroid hormone functioning, often a consequence of psychophysical stress caused by surgery and probably by reduced conversion of T4 into T3 by the liver engaged in metabolising anaesthetic drugs, may play an important role in the pathogenesis of POCD [34].

Introduction to the central cholinergic system functions

  1. Top of page
  2. Summary
  3. Postoperative cognitive dysfunction: type of surgery and incidence
  4. Genetic markers of postoperative cognitive dysfunction
  5. Previous hypotheses
  6. Introduction to the central cholinergic system functions
  7. Molecular pathology of Alzheimer’s disease
  8. Action of amyloid β peptide on the cholinergic system: the role of anaesthetics
  9. Cholinergic system and anaesthetics
  10. Anaesthetics and cell apoptosis
  11. Why is age an important risk factor?
  12. Does the molecular size of the anaesthetic matter?
  13. Conclusions
  14. Acknowledgements
  15. References

The central cholinergic system has been identified as probably a key neurotransmitter system involved in regulating consciousness, memory and learning [35, 36]. Nicotinic acetylcholine receptors (nAChRs) are a family of ligand-gated cation channels, characterised by a pentameric structure composed of α and β subunits. After agonist binding, the receptor changes conformation opening the inner pore, permitting cations to flow [37]. Different receptor subtypes are likely to be involved in various ways in the pathogenesis of Alzheimer's disease, Parkinson’s disease, pain sensitivity, analgesia, anxiety and neuroprotection [38–40].

Muscarinic acetylcholine receptors (mAChRs) are a family of ligand-gated K+ channels mediating metabolic functions. They can be classified into five different subtypes (M1–M5), according to their primary structure, and propriety of activating/inhibiting cation transmembrane current. Both nAChRs and mAChRs are coupled with G protein that generates second messengers and regulates cation channel and the transmembrane ionic flux [32]. Receptor binding by agonists causes the activation of several cytoplasmic and nuclear factors, such as specific tyrosine kinases, focal adhesion kinase (FAK), MAPK, extra cellular signal-regulated kinases (ERKs) and c-Jun N-terminal kinases (JNKs, or stress-activated protein kinases) [32].

Molecular pathology of Alzheimer’s disease

  1. Top of page
  2. Summary
  3. Postoperative cognitive dysfunction: type of surgery and incidence
  4. Genetic markers of postoperative cognitive dysfunction
  5. Previous hypotheses
  6. Introduction to the central cholinergic system functions
  7. Molecular pathology of Alzheimer’s disease
  8. Action of amyloid β peptide on the cholinergic system: the role of anaesthetics
  9. Cholinergic system and anaesthetics
  10. Anaesthetics and cell apoptosis
  11. Why is age an important risk factor?
  12. Does the molecular size of the anaesthetic matter?
  13. Conclusions
  14. Acknowledgements
  15. References

We now turn to the likely mechanisms underlying Alzheimer’s disease, showing some similarities with postoperative cognitive decline.

Alzheimer’s disease is the most common form of brain dementia characterised by the accumulation of amyloid β peptide and loss of forebrain cholinergic neurons [41, 42]. It is clinically characterised by progressive memory loss, which begins early in the disease process, decline in cognitive functions and behavioural disturbances. Other cognitive (disorientation, confusion and problems with reasoning) and behavioural (agitation, anxiety, delusions, depression and insomnia) disturbances appear as the disease progresses and impair functions in daily activities [43].

The brain of an affected individual exhibits profound loss of basal forebrain cholinergic neurons that innervate the hippocampus and the neocortex, possibly leading to progressive decline in cognitive functions and behavioural disturbances [43]. The degeneration of cell bodies in the nucleus basalis magnocellularis leads to the loss of neuronal projection to the cortex, impairing the mechanism of cortical activation, probably involved in attention, learning and memory. Furthermore, progressive neuronal loss results in a reduction of the brain levels of acetylcholine and enzyme choline acetyltransferase that correlates with the severity of cognitive dysfunction [41–44].

Data suggest that very low concentrations of amyloid β peptide can inhibit various cholinergic neurotransmitter functions independent of its apparent neurotoxicity [45]. Conversely, activation of selected cholinergic receptors is involved in the regulation of amyloid precursor protein metabolism to amyloid β peptide production [46].

Amyloidβ peptide concentration is related to the impairment of learning and memory, and neurodegeneration [47]. Continuous infusion of amyloid β peptide results in learning and memory deficits in rats [48].

The similarity of the mechanisms proposed for POCD and Alzheimer’s disease, and the fact that similar compounds appear key to both disorders, suggest a functional interrelation between amyloid β peptide and the central cholinergic system. Better understanding of these relationships may help us understand on the one hand, the mechanisms of POCD, and on the other hand, how anaesthetics interfere with Alzheimer’s disease [49].

Action of amyloid β peptide on the cholinergic system: the role of anaesthetics

  1. Top of page
  2. Summary
  3. Postoperative cognitive dysfunction: type of surgery and incidence
  4. Genetic markers of postoperative cognitive dysfunction
  5. Previous hypotheses
  6. Introduction to the central cholinergic system functions
  7. Molecular pathology of Alzheimer’s disease
  8. Action of amyloid β peptide on the cholinergic system: the role of anaesthetics
  9. Cholinergic system and anaesthetics
  10. Anaesthetics and cell apoptosis
  11. Why is age an important risk factor?
  12. Does the molecular size of the anaesthetic matter?
  13. Conclusions
  14. Acknowledgements
  15. References

A direct interaction between amyloid β peptide and nAChRs has been demonstrated. Physiologically relevant concentrations of amyloid β peptide have acute, adverse effects on multiple aspects of acetylcholine synthesis and release [43].

Neuronal nAChRs may serve as important targets that mediate amyloid β peptide neurotoxicity [41]. Treatment with very small concentrations of amyloid β peptide significantly decreased the number of nicotinic receptor binding sites in cell lines [50] and, after long-term exposure, induced cholinergic cell toxicity [43].

These effects may be affected by ageing. Higher levels of amyloid β peptide were observed in the aged rat hippocampus than were found in young adult rats, and the cholinergic neurons of aged, cognitively impaired rats may be more sensitive to amyloid β peptide-mediated inhibition of hippocampal acetylcholine release than either cognitively unimpaired, aged rats or young adult rats [43]. Overexpression of amyloid precursor protein or amyloid β peptide profoundly affects learning and memory and hippocampal volume [51].

Different anaesthetic agents act differently on the central cholinergic system. Clinical concentrations of isoflurane cause altered processing of amyloid precursor protein and increase amyloid β peptide production in both human neuroglioma and mice brain cell lines [52, 53]. Similarly, desflurane can induce amyloid β peptide production, but only in the presence of hypoxia [54], whereas propofol and thiopental do not significantly change amyloid precursor protein protein in phaeochromocytoma cells, indicating that both propofol and thiopental are considered to be relatively safe with respect to amyloid precursor protein metabolism [55]. Moreover, propofol does not enhance amyloid β peptide toxicity [56]. Since altered processing of amyloid precursor protein and its neurotoxic derivatives plays key roles in the development of Alzheimer's disease these findings may have implications for use of this anaesthetic agent in individuals with excessive levels of cerebral amyloid β peptide, and elderly patients at increased risk for POCD [52–55].

In vitro experimental studies have suggested that the inhaled anaesthetics desflurane and isoflurane, at clinically relevant concentrations, encourage clumping of amyloid β peptide protein. Propofol, at very high concentrations, in nuclear magnetic resonance spectroscopic studies, induces structural alteration of amyloid β peptides from the soluble monomeric α-helical form to oligomeric β-sheet conformation oligomerisation (micro-aggregation) [57, 58].

Cholinergic system and anaesthetics

  1. Top of page
  2. Summary
  3. Postoperative cognitive dysfunction: type of surgery and incidence
  4. Genetic markers of postoperative cognitive dysfunction
  5. Previous hypotheses
  6. Introduction to the central cholinergic system functions
  7. Molecular pathology of Alzheimer’s disease
  8. Action of amyloid β peptide on the cholinergic system: the role of anaesthetics
  9. Cholinergic system and anaesthetics
  10. Anaesthetics and cell apoptosis
  11. Why is age an important risk factor?
  12. Does the molecular size of the anaesthetic matter?
  13. Conclusions
  14. Acknowledgements
  15. References

Activation of selected cholinergic muscarinic M1 receptors is involved in the regulation of amyloid precursor protein metabolism to amyloid β peptide production [46], as well as phosphorylation of the τ-protein. Selective agonists of M1 receptors lead to the processing/transformation of amyloid precursor protein into non-amyloidogenic products [59], suggesting that M1 receptors might mediate a dual action of increasing amyloid precursor protein release and decreasing Aβ formation to modify the Alzheimer's disease process [60]. M1 agonists also decrease the phosphorylation of τ-proteins, also involved in the pathogenesis of Alzheimer's disease [43, 59].

The central cholinergic system plays a major role in regulation of cognitive functions: agonists of central nAChRs and mAChRs may improve, whereas antagonists impair, performance in cognitive tasks, learning and memory [44, 61]. Anaesthetics affect the cholinergic system: volatile anaesthetics and ketamine are potent inhibitors of nAchRs; desflurane selectively binds M1 receptor subtype enhancing the signal for low concentrations and depressing the pathway for higher doses; sevoflurane depresses M1 and M3 signalling in a dose-dependent manner, while isoflurane interferes only with M3 [32].

Barbiturates are strong competitive antagonists of mAChRs, but propofol acts on nAChRs and mAChRs only at concentrations much higher than used clinically. Opiods (morphine, fentanyl) depress cholinergic signals mediated by nAChRs and mAChRs; remifentanil does not alter acetylcholine release in cholinergic synapses [62]. Other drugs administered during anaesthesia, such as anticholinesterase drugs and neuromuscular blocking agents, exert an ambiguous pattern of effects on cholinergic transmission depending on drug characteristics and cerebrospinal fluid concentrations. Physostigmine activates only the M1 receptor, neostigmine activates only M3, while pyridostigmine activates both subtypes [63]. Cholinergic dysfunction in the basal forebrain may potentiate the effects of propofol [64]. Thus we can formulate a hypothesis that anaesthetic agents that inhibit central cholinergic transmission, diverted by age-related changes and with an unstable homeostasis, influence the possible pathogenesis of POCD [32].

Anaesthetics and cell apoptosis

  1. Top of page
  2. Summary
  3. Postoperative cognitive dysfunction: type of surgery and incidence
  4. Genetic markers of postoperative cognitive dysfunction
  5. Previous hypotheses
  6. Introduction to the central cholinergic system functions
  7. Molecular pathology of Alzheimer’s disease
  8. Action of amyloid β peptide on the cholinergic system: the role of anaesthetics
  9. Cholinergic system and anaesthetics
  10. Anaesthetics and cell apoptosis
  11. Why is age an important risk factor?
  12. Does the molecular size of the anaesthetic matter?
  13. Conclusions
  14. Acknowledgements
  15. References

Cell death (apoptosis) is distinct from disturbance of function, and clinically relevant concentrations of isoflurane induce apoptosis both in a human neuroglioma cell line and in the mouse brain [52, 53]. This appears independent of changes in amyloid β peptide and amyloid precursor protein levels. However, it is potentiated by increased levels of amyloid precursor protein C-terminal fragments [52, 53]. Isoflurane can induce apoptosis, which, in turn, increases β- and γ-secretase levels, promoting the two sequential cleavages of the amyloid precursor protein to amyloid β peptide. Isoflurane also promotes amyloid β peptide aggregation, which can cause apoptosis. Therefore a vicious cycle can result: isoflurane-induced apoptosis; amyloid β peptide generation and aggregation; and further apoptosis [65]. Recently, it has been demonstrated that isoflurane activates endoplasmic inositol 1,4,5-trisphosphate (IP3) receptors producing excessive calcium release, which is apoptotic. Interestingly, neurons with enhanced IP3 receptor activity (as in certain cases of familial Alzheimer’s or Huntington's disease) may be especially vulnerable to isoflurane cytotoxicity [66]. However, the N-methyl-d-aspartic acid receptor partial antagonist, memantine, can prevent isoflurane-induced apoptosis in vivo and in vitro, suggesting that isoflurane-induced apoptosis is dependent on cytosolic calcium levels [67]. Desflurane can also induce amyloid β peptide production and caspase activation, but only in the presence of hypoxia [54].

Why is age an important risk factor?

  1. Top of page
  2. Summary
  3. Postoperative cognitive dysfunction: type of surgery and incidence
  4. Genetic markers of postoperative cognitive dysfunction
  5. Previous hypotheses
  6. Introduction to the central cholinergic system functions
  7. Molecular pathology of Alzheimer’s disease
  8. Action of amyloid β peptide on the cholinergic system: the role of anaesthetics
  9. Cholinergic system and anaesthetics
  10. Anaesthetics and cell apoptosis
  11. Why is age an important risk factor?
  12. Does the molecular size of the anaesthetic matter?
  13. Conclusions
  14. Acknowledgements
  15. References

Age is the only universally accepted risk factor for the development of prolonged/irreversible POCD [2, 3, 7]. The aged human brain differs from the younger adult brain in several respects, including size, distribution and type of neurotransmitters, metabolic function, and capacity for plasticity, suggesting that it might be more susceptible to anaesthetic mediated changes [8]. Ageing involves some progressive loss of adaptive capability, yet in many ways the environment imposes greater demands (occurrence of life events or psychological traumas) and this imbalance may contribute to dementia [68].

As stated above, the pathogenic mechanisms of Alzheimer’s include uncontrolled oligomerisation and deposition of amyloid β peptide [69, 70]. Since amyloid β peptide is naturally present in the central nervous system, with higher levels in the elderly, it is logical that higher amounts of amyloid β peptide are available in the aging brain to interact with anaesthesia during long exposure to anaesthesia. Therefore, administration to elderly patients of certain general anaesthetics that directly affect the rate at which amyloid β peptides bind together could increase their risk of developing POCD [44]. Since amyloid β peptide is known to be involved in Alzheimer’s disease, there would appear to be a plausible link between this disease and POCD in the elderly.

Does the molecular size of the anaesthetic matter?

  1. Top of page
  2. Summary
  3. Postoperative cognitive dysfunction: type of surgery and incidence
  4. Genetic markers of postoperative cognitive dysfunction
  5. Previous hypotheses
  6. Introduction to the central cholinergic system functions
  7. Molecular pathology of Alzheimer’s disease
  8. Action of amyloid β peptide on the cholinergic system: the role of anaesthetics
  9. Cholinergic system and anaesthetics
  10. Anaesthetics and cell apoptosis
  11. Why is age an important risk factor?
  12. Does the molecular size of the anaesthetic matter?
  13. Conclusions
  14. Acknowledgements
  15. References

The molecular volumes of agents given during general anaesthesia are in the following order: halothane > isoflurane > sevoflurane > propofol > thiopental > diazepam. Nuclear magnetic resonance spectroscopic studies suggest that smaller-sized volatile agents will promote amyloid β peptide oligomerisation by interacting with key residues (G29, A30 and I31) of the peptide chain [71, 72]. In contrast, the larger-sized intravenous agents do not access these regions and no amyloid β peptide oligomerisation is observed [71, 72]. Figure 1 shows a schematic presentation of how isoflurane and/or desflurane may interact with amyloid β peptide and its subsequent oligomerisation [71].

image

Figure 1.  Schematic interaction of amyloid β peptide (Aβ) with inhaled anaesthetics isoflurane/desflurane and subsequent aggregation (oligomerisation). The figure is based on nuclear magnetic resonance spectroscopic studies, and shows how smaller sized inhaled anaesthetics could interact with critical residues (G29, A30 and I31) of Aβ, promoting oligomerisation. This figure has been adapted and revised from our earlier work [71]. APP; amyloid precursor protein.

Download figure to PowerPoint

Conclusions

  1. Top of page
  2. Summary
  3. Postoperative cognitive dysfunction: type of surgery and incidence
  4. Genetic markers of postoperative cognitive dysfunction
  5. Previous hypotheses
  6. Introduction to the central cholinergic system functions
  7. Molecular pathology of Alzheimer’s disease
  8. Action of amyloid β peptide on the cholinergic system: the role of anaesthetics
  9. Cholinergic system and anaesthetics
  10. Anaesthetics and cell apoptosis
  11. Why is age an important risk factor?
  12. Does the molecular size of the anaesthetic matter?
  13. Conclusions
  14. Acknowledgements
  15. References

Knowledge of the pathophysiology of neurodegenerative disorders has dramatically accelerated with progress in genetics and molecular biology. In vitro experiments suggest that some anaesthetics act in the processing of amyloid β peptide directly (i.e. production and oligomerisation) and/or indirectly (i.e. via interaction with central cholinergic system and therefore on amyloid precursor protein metabolism), providing a plausible link between effects of anaesthetics and postoperative cognitive sequelae.

If similar processes occurred in vivo, anaesthetics (especially volatile agents) could lead to persistent increases in concentrations of Alzheimer’s-associated peptides [2, 3]. Since many elderly patients undergo anaesthesia with volatile agents, this raises the possibility of a mechanistic association between anaesthesia, POCD and neurodegenerative disorders [44].

The crux of our hypothesis is:

  • • 
    Alzheimer’s disease and POCD appear to share a similar mechanism, involving aberrant function of the cholinergic system in the brain.
  • • 
    Amyloid β peptide production and oligomerisation is important in both Alzheimer’s disease and POCD and might explain the propensity for the elderly to suffer from both disorders.
  • • 
    Some anaesthetic agents (e.g. volatile agents) cause amyloid β peptide oligomerisation. This propensity may indicate a link between anaesthetics, POCD and Alzheimer’s disease.

High levels of cerebral amyloid β peptide may be a marker for risk of POCD in elderly patients [52–54, 58, 67], making the development of preventive or therapeutic interventions possible. As our hypothesis is based on evidence obtained primarily from animal and in vitro studies, clinical studies that seek to investigate the purported association between the type of anaesthetic agent used, POCD and Alzheimer’s disease would be valuable.

Acknowledgements

  1. Top of page
  2. Summary
  3. Postoperative cognitive dysfunction: type of surgery and incidence
  4. Genetic markers of postoperative cognitive dysfunction
  5. Previous hypotheses
  6. Introduction to the central cholinergic system functions
  7. Molecular pathology of Alzheimer’s disease
  8. Action of amyloid β peptide on the cholinergic system: the role of anaesthetics
  9. Cholinergic system and anaesthetics
  10. Anaesthetics and cell apoptosis
  11. Why is age an important risk factor?
  12. Does the molecular size of the anaesthetic matter?
  13. Conclusions
  14. Acknowledgements
  15. References

PKM's research was supported by the National Brain Research Centre, Department of Biotechnology, Government of India. This research is also supported by the Italian Ministry for University and Research, Program for the Development of Research of National Interest (PRIN Grant N.2007H84XNH – Scientific coordinator: V. Fodale). We thank Dr. Subbulakshmy Natarajan, Consultant Neurologist for valuable suggestions and Ms Manisha Ahuja, Project Assistant, National Brain Research Centre, for editorial assistance.

References

  1. Top of page
  2. Summary
  3. Postoperative cognitive dysfunction: type of surgery and incidence
  4. Genetic markers of postoperative cognitive dysfunction
  5. Previous hypotheses
  6. Introduction to the central cholinergic system functions
  7. Molecular pathology of Alzheimer’s disease
  8. Action of amyloid β peptide on the cholinergic system: the role of anaesthetics
  9. Cholinergic system and anaesthetics
  10. Anaesthetics and cell apoptosis
  11. Why is age an important risk factor?
  12. Does the molecular size of the anaesthetic matter?
  13. Conclusions
  14. Acknowledgements
  15. References