Response to: Kapila et al. (2014) J Alzheimers Dis, doi: 10.3233/JAD-132258

6 May 2014

It was with great interest that we encountered the recent article by Kapila et al. [1]. The preclinical studies from this group have contributed significantly to our understanding of the relationship between the perioperative period and cognitive loss. However, with respect to translation, we believe that a much more cautionary note is due here than presented by the article. First, the evidence in humans that the perioperative period is linked to incident dementia is weak at best. Many contradictory clinical studies exist and there is simply no consensus at this point. Second, the mechanism of post-operative cognitive decline (POCD) in people is unknown, and any relationship between POCD and dementia, although suspected, is unproven, so statements like ‘Neuroinflammatory processes as a result of surgical trauma and anesthetic insult are, as aforementioned, major factors in the pathogenesis of POCD and resulting AD’ are premature. Finally, and most concerning in our view, are the comments regarding mitigation. It is entirely premature, and perhaps perilous, to promote one anesthetic, or perioperative management strategy, as being of lower risk for the development of POCD or incident dementia. This is simply not known at this point, and the even the preclinical evidence is only suggestive at best. What we need are well-designed, adequately powered, prospective studies, so that the presence and nature of any association between anesthesia, surgery and Alzheimer’s disease can be clarified. The conversion of, what are essentially hypotheses, in the Kaplia et al. paper, to conclusions and recommendations requires a far more substantive body of such research.Lis Evered, Associate Professor, Melbourne Medical School, University of Melbourne; Centre for Anaesthesia and Cognitive Function, St. Vincent’s Hospital, Melbourne; lis.evered@svhm.org.auRod Eckenhoff, Vice Chair for Research, Austin Lamont Professor of Anesthesiology & Critical Care, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USAJeff Silverstein, Professor of Anesthesiology, Surgery, and Geriatrics & Palliative Care, Icahn School of Medicine at Mount Sinai, New York, NY, USAGreg Crosby, Associate Professor, Harvard Medical School, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham & Women's Hospital, Boston, MA, USADavid Scott, Associate Professor, Department of Surgery, University of Melbourne; Director, Department of Anaesthesia, St. Vincent’s Hospital, Melbourne, AustraliaEsther Oh, Assistant Professor, Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, MD, USAStacie Deiner, Associate Professor of Anesthesiology, Neurosurgery, Geriatrics and Palliative Care, The Icahn School of Medicine, Mt. Sinai, NY, USAReference: [1] Kapila AK, Watts HR, Wang T, Ma D (2014) The impact of surgery and anesthesia on post-operative cognitive decline and Alzheimer’s disease development: biomarkers and preventive strategies. J Alzheimers Dis, doi: 10.3233/JAD-132258.

Comments

Reply

Thank you for giving us the opportunity to respond to the comments about our work [1] raised by Dr. Eckenhoff and colleagues. We would like to address these points one by one. Firstly, “evidence that the perioperative period is linked to incident dementia is weak at best.”; we certainly agree and had tried to convey this idea in our review. We reviewed the literature and found that while a number of clinical studies suggest this link [2-4], others do not. In addition, we emphasized the controversy surrounding the impact of anesthesia on Alzheimer’s disease (AD) [5,6], which could be viewed as accentuating the link between surgery and AD. Regardless, we intended for readers to understand that this is a field in need of further research. This was repeated throughout the review paper and in the conclusions. Secondly, “the mechanism of POCD in people is unknown, and any relationship between POCD and dementia, although suspected, is unproven”; we absolutely agree with this and this is clearly stated in our review several times, e.g., “Nevertheless, the link between POCD toward AD development is still a developing research area and warrants further studies before any conclusions can be made.” and “Hence, inflammatory markers post-surgery in old age may not be predictors of AD, but could merely be the result of ageing and stress triggered by surgery. Clearly, further studies with large sample sizes comparing young and old AD patients are the need of the hour.” We realize that our sentence, when quoted in isolation, may make it seem that we rushed into making conclusions; however, if taken in the context of the whole review, this was not the case. Not only did we make a careful assessment of every single research topic brought forward in the review, but also repeatedly reminded the reader that further research is warranted. Thirdly, “It is entirely premature, and perhaps perilous, to promote one anesthetic, or perioperative management strategy, as being of lower risk for the development of POCD or incident dementia.”; again we totally agree with this and are dismayed that readers interpreted our statements otherwise. For example, we stated in the review that “It is important to appreciate, however, that anesthesia is not administered as a sole procedure and is always paired with surgical stress. Therefore, improved and safer anesthetic management may not be sufficient in protecting patients who are already susceptible. The best choice of anesthetics for preventing AD onset in the elderly and susceptible patients requires further analysis and new experimental evidence". Lastly, we sincerely thank Dr. Eckenhoff and colleagues for their scientific remarks which could likely contribute to better designed clinical trials as suggested in the letter to clarify “the presence and nature of any association between anesthesia, surgery and AD”.

Ayush K Kapila, BSc (Hons) and Daqing Ma, MD PhD
Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea & Westminster Hospital, London, UK; Tel: +44 020 3315 8495, d.ma@imperial.ac.uk

References
[1] Kapila AK, Watts HR, Wang T, Ma D (2014) The impact of surgery and anesthesia on post-operative cognitive decline and Alzheimer’s disease development: biomarkers and preventive strategies. J Alzheimers Dis, doi: 10.3233/JAD-132258.
[2] Lee TA, Wolozin B, Weiss KB, Bednar MM (2005) Assessment of the emergence of Alzheimer's disease following coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty. J Alzheimers Dis 7, 319-324.
[3] Plassman BL, Langa KM, Finlayson EVA, Rogers MAM (2009) Surgery using general anesthesia and risk of dementia in the Aging, Demographics and Memory Study. Alzheimers Dement 5, 3-153.
[4] Vanderweyde T, Bednar MM, Forman SA, Wolozin B (2010) Iatrogenic risk factors for Alzheimer's disease: surgery and anesthesia. J Alzheimers Dis 22 Suppl 3, 91-104.
[5] Sprung J, Jankowski CJ, Roberts RO, Weingarten TN, Aguilar AL, Runkle KJ, Tucker AK, McLaren KC, Schroeder DR, Hanson AC, Knopman DS, Gurrieri C, Warner DO (2013) Anesthesia and incident dementia: a population-based, nested, case-control study. Mayo Clin Proc 88, 552-561.
[6] Sztark F, Le Goff M, André D, Ritchie K, Dartigues J, Helmer C (2013) Exposure to general anaesthesia could increase the risk of dementia in elderly: 18AP1‐4. Eur J Anaesthesiol 30, 245-245.