We wish to thank Dr Perouansky for his interest in our editorial and we appreciate the opportunity to comment on his letter point by point.
As a general preamble to this response, it appears necessary to clarify that the editorial format demands brevity in conveying the essence of the literature on the subject, highlighting the salient points and succinctly expressing the authors' views. On the part of the reader who wishes appropriately to comment on the editorial, it is mandatory to be aware of the current scientific context, and meticulously analyse the citations quoted in the editorial. In his urgency to publish, perhaps Dr Perouansky has skipped (e.g. Planel et al.1) this essential exercise.
The correspondent's ingenious attempt to close the wide chasm separating his views and the harsh realities of global literature in the field, in order to disenchant the reader with the editorial, is, borrowing from the correspondent's own term, a veritable ‘tour de force’.
The studies on the influence of anaesthetics on amyloid-beta (Aβ) peptide are important and timely. Recent literature from the Journal of the American Medical Association has stated: ‘Some of the commonly used inhaled anaesthetics may cause brain damage that accelerates the onset of Alzheimer disease, according to recent findings from two separate groups of scientists. It's a vicious cycle between apoptosis induced by isoflurane and also increased by amyloid β levels. …patients and physicians should not panic about the potential damaging effects of these drugs. It is alarming …'.2 Dr Perouansky's3 review ‘Liaisons dangereuses? General anaesthetics and long-term toxicity in the CNS’ is a rethink on the subject, an alarming (not necessarily alarmist!) wake up call to the scientific community.
In the wake of recognition of postoperative cognitive decline (POCD), especially in the elderly, as a definite ‘clinical entity’3 (Dr Perouansky's review, p. 113, line 42, column 1), the International Study of POCD strongly recommended a strict anaesthesia protocol, from choice of drug to anaesthetic technique. This was a prudent move and our concern for the vulnerable surgical patient was a reminder on similar lines. But why this sudden change of heart by Dr Perouansky to claim that POCD is ‘only a research entity with widely varying study-specific definitions’, contradicting what he mentioned (‘clinical entity’) in his review3 (only in 2007, not so long ago!) or other literature to substantiate the statement?
POCD is a reality and engages scientific groups and clinicians globally in unravelling the role of anaesthetics in this process. The editorial attempts no ‘coherent body of incremental response’, as suggested by Dr Perouansky, but traces the converging results from various groups, which may lead to better understanding of the pathomechanism of POCD and closer monitoring of anaesthetic protocol.
Subsequently, Dr Perouansky criticizes our affirmation that ‘current literature supports the potential involvement of the mechanism of Alzheimer's disease [AD] neuropathogenesis in the genesis of POCD’. However, researchers have hypothesized the same ‘…anaesthetics may be associated with AD and render POCD via triggering AD neuropathogenesis’.4 Dr Perouansky's referred study,5 in his letter also stated ‘there is a strong public perception supported by a body of scientific research suggesting that cognitive decline with lasting and noticeable impact on daily function is common in elderly patients after surgery. Recent in-vitro and animal in-vivo research provides biologic plausibility for the pathogenesis and evolution of POCD and even suggests that general anaesthetic agents have the potential to precipitate or exacerbate Alzheimer's disease’.5
The correspondent's cynicism regarding an ‘ex-vivo study’, which is not conducted in a natural environment, comes through, but our results must make him ponder on its positive contribution to the bulk of the literature. The biophysical studies were conducted in an environment mimicking in-vivo conditions6 and experiments were performed at a clinically relevant concentration of anaesthetics (not Aβ peptide!). The central theme of this biophysical study, using state-of-the-art NMR spectroscopy, is that certain anaesthetics (smaller sized) do interact with specific amino acid residues (G29, A30 and I31) of Aβ peptide and promote oligomerization of Aβ peptide. However, larger sized anaesthetics could not fit in the helix–loop–helix region containing those specific amino acid residues (G29, A30 and I31) of Aβ peptide; hence, no Aβ oligomerization is initiated by those large sized anaesthetics. The ‘size factor’ of these anaesthetics and its role in Aβ oligomerization is a thought-provoking and exciting concept and constituted the title of our editorial.
It is a strange phenomenon that, in his letter, Dr Perouansky claimed our ‘(mis)interpretation of important published work’. In the editorial, regarding the halothane/isoflurane effect on Aβ peptide, we wrote that ‘our results are in accordance with some animal model studies, which showed that isoflurane and halothane increase the plaque load in a mouse model with Alzheimer's disease pathology’, a concise (p. 1002, line 77 and p. 618, line 138) presentation from the two published studies7,8 and certainly not a study by Planel et al.,9 as erroneously mentioned by Dr Perouansky in his letter.
Dr Perouansky made another claim that ‘Bianchi et al.7 does not provide any direct link between anaesthetics, increased plaque load and neurocognitive dysfunction in either wild-type or AD-mutant mice’ but, it has no basis as the same study7 (p. 1002, line 7) clearly stated ‘halothane-exposed Tg2576 mice had more amyloidopathy than the isoflurane-treated mice or the nonexposed transgenic mice. These findings indicate that inhaled anaesthetics influence cognition and amyloidogenesis, but that the mechanistic relationship remains unclear’.7 Recently, Dr Mena and her group have investigated the effects of repetitive anaesthesia, twice a week, for 3 months, from 7 to 10 months of age, on WT and APPswe mice, and reported that a ‘deleterious impact of isoflurane on behavior, survival, neuronal cell death, and processing of proteins involved in neurodegeneration is restricted to subjects with special susceptibility but does not affect normal subjects’.10
Regarding isoflurane effect on tau protein, we also stated ‘very recently, it was reported that isoflurane induced acceleration of neurofibrillary disorder in a mouse model of tauopathy’, from a recent research study.1
It is clearly evident that the scientific content of these important research studies1,7,8 were not reviewed by the respondent. We are amazed by the incredible double (mis)interpretation of our editorial due to lack of analysis of the cited papers by Dr Perouansky, who also erroneously cited a different reference9 in his letter proving his ‘misleading behavior’.
Biophysical ‘in-vitro’ studies provide crucial information and promote further investigation both in animal models and at clinical level. The purpose is to find converging views, if any, between studies from different research groups, which should add new knowledge and value to this area of research.
1 Planel E, Bretteville A, Liu L, et al.
Acceleration and persistence of neurofibrillary pathology in a mouse model of tauopathy following anesthesia. Faseb J
2 Kuehn BM. Anesthesia-Alzheimer disease link probed. JAMA 2007; 297:1760.
3 Perouansky M. Liaisons dangereuses? General anaesthetics and long-term toxicity in the CNS. Eur J Anaesthesiol 2007; 24:107–115.
4 Xie ZC, Tanzi RE. Alzheimer's disease and postoperative cognitive dysfunction. Exp Gerontol 2006; 41:346–359.
5 Avidan MS, Searleman AC, Storandt M, et al
. Long-term cognitive decline in older subjects was not attributable to noncardiac surgery or major illness. Anesthesiology 2009; 111:964–970.
6 Mandal PK, Fodale V. Isoflurane and desflurane at clinically relevant concentrations induce amyloid beta-peptide oligomerization. An NMR study. Biochem Biophys Res Commun 2009; 379:716–720.
7 Bianchi SL, Tran T, Liu C, et al
. Brain and behavior changes in 12-month-old Tg2576 and nontransgenic mice exposed to anesthetics. Neurobiol Aging 2008; 29:1002–1010.
8 Xie Z, Culley DJ, Dong Y, et al
. The common inhalation anesthetic isoflurane induces caspase activation and increases amyloid beta-protein level in vivo. Ann Neurol 2008; 64:618–627.
9 Planel E, Richter KEG, Nolan CE, et al
. Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J Neurosci 2007; 27:3090–3097.
10 Perucho J, Rubio I, Casarejos MJ, et al.
Anesthesia with isoflurane increases behavioral abnormalities and amyloid pathology in mice models of Alzheimer's disease. J Alzheimer Dis
2009. [Epub ahead of print]