Volume 22, Supplement 3, November 2010 - "Anesthetics and Alzheimer's Disease" (Guest Editors: Pravat K. Mandal and Vincenzo Fodale)

Pages 1-3
Vincenzo Fodale, Karen Ritchie, Lars S. Rasmussen, Pravat K. Mandal
Anesthetics and Alzheimer's Disease: Research and Background

Page 5-19
Verena H. Finder
Alzheimer’s Disease: A General Introduction and Pathomechanism
Abstract: Alzheimer’s disease (AD) is the most common form of dementia, which affects more than 35 million people worldwide with increasing tendency. Satisfying therapies and prevention are not available. Since the first description of the fatal progressive neurodegenerative disease in 1907, however, major findings on the molecular mechanisms have been reported. Current clinical trials target diverse aspects and principles of AD, such as the generation and aggregation of amyloid-β (Aβ). Extracellular amyloid plaques, predominantly consisting of Aβ and intracellular neurofibrillar tangles, formed by hyperphosphorylated tau, are the major pathological hallmarks in the brain of AD patients. AD is consequently one of about 40 identified amyloidosis—protein misfolding diseases, which share as their main pathogenic mechanism the aberrant deposition of endogenous proteins as amyloid fibrils. This article aims principally to introduce AD and its identified key players, to summarize classic and recent publications on the complex molecular mechanisms underlying the disease, and to discuss challenges that need to be faced for the development of improved therapeutic strategies.

Pages 21-26
Barbara Eckel, Manfred Blobner, Gerhard Rammes
Anesthetics Promoting in vitro AβPP Metabolism and Amyloid-β Toxicity
Abstract: At present, more than 35 million people worldwide have Alzheimer’s disease (AD). With increasing incidence and a growing number of aged patients undergoing surgery, the relevance of a possible interaction between anesthetics and AD is growing as well. Below, we review in vitro studies investigating the effects of anesthetics on the metabolism of amyloid precursor protein and its metabolite amyloid-β.

Pages 27-34
Pravat K Mandal, Manisha Ahuja
Comprehensive Nuclear Magnetic Resonance Studies on Interactions of Amyloid-β with Different Molecular Sized Anesthetics
Abstract: Laboratory research on anesthetic-induced structural changes of amyloid-β (Aβ) peptide has generated much interest in the scientific community, as Aβ oligomerization is considered a key step in Alzheimer’s diseasepathogenesis. A comprehensive review of the molecular interactions of Aβ with anesthetics of different molecular sizes, published in biophysical studies from year 2004 until the present date, leads to results that may be summarized as follows. Smaller sized anesthetics can access and perturb the cavity in the Aβ peptide-containing crucial amino acid residues G29, A30, and I31, which leads to Aβ oligomerization. However, bulkier sized anesthetics are sterically hindered from accessing the cavity containing these crucial residues and do not initiate Aβ oligomerization. Notably, when a small sized anesthetic is co-administered with a larger sized one, the latter does not prevent access of the small sized anesthetic to the cavity. The results of these biophysical studies are supported by animal model studies which report that inhaled anesthetics induce enhanced plaque load. In this review, a molecular pathway is envisaged for the Aβ-anesthetics interaction at the atomic level.

Pages 35-41

Daniela Schifilliti, Letterio B. Santamaria, Giovanni Rosa, Gianfranco Di Nino, Pravat K. Mandal, Vincenzo Fodale
Cholinergic Central System, Alzheimer’s Disease, and Anesthetics Liaison: a Vicious Circle?
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation and aggregation of amyloid-β peptide and loss of forebrain cholinergic neurons, resulting in progressive loss of memory and irreversible impairment of higher cognitive functions. Several studies have accounted for the close relationship between AD and the central cholinergic system, suggesting that a dysfunction of acetylcholine containing neurons in the brain contributes significantly to the cognitive deficit of individuals with AD. The aim of the present review is to survey current literature on this topic in order to provide a clear understanding of the role of the cholinergic system in the development and neurodegenerative process of AD. The implications for anesthesia are also discussed. This kind of knowledge could be a basic valuable support to improve anesthesia performance and patient safety.

Pages 43-48
María Ángeles Mena, Juan Perucho, Isabel Rubio, Justo Garcia de Yébenes
Studies in Animal Models of the Effects of Anesthetics on Behavior, Biochemistry, and Neuronal Cell Death
Abstract: Recent clinical studies have suggested that there is an increased risk of Alzheimer’s disease (AD) in patients undergoing surgical interventions, but it is unknown whether this effect is related to anesthesia, cardiovascular complications of surgery, or associated conditions such as hypothermia. In addition, many patients, especially the elderly, present persistent post-operative cognitive deterioration after anesthesia, without clear complications during surgery. Experimental studies in animals may be helpful to dissect the pathogenic role of the different factors involved in surgery. Here, we review studies on the effects of anesthesia on neuronal function performed in tissue culture and in experimental animals. Several studies have shown that a small inhalation of anesthetics induces activation of caspases and cell toxicity on glioma and pheochromocitoma cells in culture, which is prevented by treatment with the metal chelating agent clioquinol. Exposure of old rodents to anesthesia produced memory deficits and increased levels of amyloid-β (Aβ) peptide and phosphorylated tau in brain. The effects of long term or short term repetitive exposure to small molecular weight anesthetics are more severe in transgenic AβPPswe than in wild type mice. In the former, low molecular weight increased the number of TUNEL+ apoptotic cells and the ratio of pro-apoptotic proteins in hippocampus; reduced astroglial and increased microglial responses; increased Aβ aggregates and high molecular weight peptides; abnormal chaperone responses and reduced autophagy. In conclusion, anesthetic gases induce changes which may reproduce AD pathology in mice with mutations which produced AD. It would be interesting to know whether anesthetics are risky for subjects with special genetic risk factors.

Pages 49-55
Xiaoqin Run, Zhihou Liang, Cheng-Xin Gong
Anesthetics and Tau Protein: Animal Model Studies
Abstract: Recent studies have suggested that general anesthesia may initiate or accelerate cognitive impairment and Alzheimer’s disease (AD). To understand the possible underlying mechanisms, several studies have been carried out in animal models. In this review, we first briefly discuss the mechanisms leading to neurodegeneration and cognitive impairment in AD, with an emphasis on tau abnormalities in this pathological process. Subsequently, we review the role of anesthesia in inducing tau abnormalities and the possible mechanisms. Recent studies suggest that anesthesia may accelerate the development of AD by promoting abnormal hyperphosphorylation of tau. Further studies are certainly needed to understand the molecular mechanism by which anesthesia may initiate or accelerate cognitive impairment and AD. An understanding of the mechanism will help develop strategies for preventing or eliminating this adverse effect of anesthesia.

Pages 57-65
Manjari Tripathi, Deepti Vibha
Unusual Risk Factors for Cognitive Decline
Abstract: The evaluation and management of patients with cognitive decline pose many diagnostic and therapeutic challenges. While most cognitive disorders need a standard screening for common reversible causes, the diagnosis of ‘not so usual’ causes are delayed and often missed. It is important to be aware of such clinical scenarios, especially since a lot of these are reversible. Many coexisting metabolic, nutritional, endocrinal, toxic, and infectious causes mask the subtle and progressive cognitive changes that become apparent with stress and in the post operative period, often after a major surgery. Many more metabolic, nutritional, endocrinal, toxic, post operative, autoimmune, cerebrovascular, genetic, infectious, and hemorheological factors are now emerging as unusual causes. This review deals with the recognition and evaluation of these unusual causes of cognitive decline.

Pages 67-79
Sam Ewan Mason, Anna Noel-Storr, Craig William Ritchie
The Impact of General and Regional Anesthesia on the Incidence of Post-Operative Cognitive Dysfunction and Post-Operative Delirium: a Systematic Review with Meta-Analysis
Abstract: Post-operative cognitive complications such as delirium have been consistently associated with poor short and long term outcomes, and the role of anesthesia, particularly the role of general versus regional anesthesia, remains unclear. The objective of this systematic review with meta-analysis was to compare the influence of general, regional, or a combination of anesthesia on the development of Post-Operative Cognitive Dysfunction (POCD) and Post-Operative Delirium (POD). Standard bibliographic databases were searched and complimented by hand searching of original and review article references. Included studies were randomized controlled trials comparing general to regional (spinal, epidural, or intravenous block) or a combination of these in a cohort who were pre-operatively cognitively normal and had an average age exceeding fifty. Where POD was the principle outcome, studies must have employed the DSM or ICD criteria. Where POCD was the principal outcome, this was defined as any objective cognitive impairment. Twenty one studies were considered suitable for inclusion. There was no effect of anesthesia type on the odds ratio of developing POD (0.88, 0.51-1.51 with 95% confidence) however general anesthesia was marginally non-significantly associated with POCD (odds ratio of 1.34, 0.93-1.95 with 95% confidence). There was no evidence of publication bias. In conclusion, it appears that general anesthesia, compared to others, may increase the risk of developing POCD; however this has not been shown for POD. Possible reasons for this finding have been explored. This data would advocate for the use of regional anesthesia wherever possible especially in people otherwise vulnerable to developing cognitive symptoms.

Pages 81-89
Federico Bilotta, Andrea Doronzio, Elisabetta Stazi, Luca Titi, Vincenzo Fodale, Gianfranco Di Nino, Giovanni Rosa
Postoperative Cognitive Dysfunction: Toward the Alzheimer’s Disease Pathomechanism Hypothesis
Abstract: Alzheimer’s disease (AD), a chronic and progressive deterioration of memory and other cognitive domains, is the most common form of dementia. Because of related health and social impact, there is growing interest in assessing potential relationship between anesthesia and the onset and progression of chronic neurodegenerative disorders, including AD. Currently, preclinical and clinical research is addressed to identify underlying pathomechanisms, patient risk factors, and the use of the least provocative drugs and techniques, to minimize the incidence of chronic neurodegenerative disorders. Preclinical studies are providing an increasing body of evidences on some of the mechanisms that link anesthetics to neuronal programmed cell death (apoptosis) and accumulation of misfolded proteins in the aging brain. Therefore, risk factors and pathomechanisms of chronic neurodegenerative disorders, including AD, and persistent postoperative-postanesthesia cognitive dysfunction may overlap.

Pages 91-104
Tara Vanderweyde, Martin M. Bednar, Stuart A. Forman, Benjamin Wolozin
Iatrogenic Risk Factors for Alzheimer’s Disease: Surgery and Anesthesia
Abstract: Increasing evidence indicates that patients develop post-operative cognitive decline (POCD) following surgery. POCD is characterized by transient short-term decline in cognitive ability evident in the early post-operative period. This initial decline might be associated with increased risk of a delayed cognitive decline associated with dementia 3 to 5 years post-surgery. In some studies, the conversion rate to dementia are up to 70% in patients who are 65 years or older. The factors responsible for the increased risk of dementia are unclear; however, clinical studies investigating the prevalence of POCD and dementia following surgery do not show an association with the type of anesthesia or duration of surgery. Epidemiological studies from our group support this observation. The adjusted Hazard Ratios for developing dementia (or AD specifically) after prostate or hernia surgery were 0.65 (95% CI, 0.51 to 0.83, prostate) and 0.65 (95% CI, 0.49 to 0.85, hernia) for cohorts of subjects exposed to general anesthesia compared to those exposed only to local anesthesia. Animal studies suggest that prolonged exposure to some volatile-inhalational anesthetics increase production of amyloid-β and vulnerability to neurodegeneration, but these results are weakened by the absence of clinical support. Inflammation and a maladaptive stress response might also contribute to the pathophysiology of this disorder. Future research needs to identify predisposing factors, and then strategies to protect against POCD and subsequent dementia. The field also needs to adopt a more rigorous approach to codifying the frequency and extent of early and delayed post-operative cognitive decline.

Pages 105-113
Marie-Laure Ancelin, Guilhem de Roquefeuil, Jacqueline Scali, François Bonnel, Jean-François Adam, Jean-Claude Cheminal, Jean-Paul Cristol, Anne-Marie Dupuy, Isabelle Carrière, Karen Ritchie
Long-Term Post-Operative Cognitive Decline in the Elderly: The Effects of Anesthesia Type, Apolipoprotein E Genotype, and Clinical Antecedents
Abstract: Cognitive dysfunction in the elderly commonly observed following anesthesia has been attributed to age-related neuronal changes exacerbated by pharmacotoxic effects. However, the extent to which these changes may persist following recovery from surgery is still largely unknown. This study investigates the long-term effects of anesthesia on cognitive functioning after orthopedic surgery in 270 elderly patients over the age of 65 who completed a computerized cognitive battery before and 8 days, 4 and 13 months after surgery. Their performance was compared to those of 310 elderly controls who completed the same neuropsychiatric evaluation at baseline and one-year interval. Multivariate analyses adjusted for socio-demographic variables, depressive symptomatology, vascular pathology as well as baseline cognitive performance. We found early and transient post-operative decline in reaction time and constructional praxis. With regard to long-term changes we observed improvement compared to controls in most verbal tasks (probably due to learning effects). On the other hand, a clear dissociation effect was observed for several areas of visuospatial functioning which persisted up to the 13-month follow-up. This specific pattern of visuospatial deficit was found to be independent of apolipoprotein E genotype and closely resembles what has recently been termed vascular mild cognitive impairment, in turn associated with subtle sub-cortical vascular changes. The observation of only minor differences between persons operated by general and regional anesthesia makes it difficult to attribute these changes directly to the anesthetic agents themselves, suggesting that cognitive dysfunction may be attributable at least in part to peri-operative conditions, notably stress and glucocorticoid exposure.

Pages 115-120

Yatin Mehta and Raveen Singh
Cognitive Dysfunction after Cardiac Surgery
Abstract: Both short and long term cognitive changes occur after cardiac surgery but the pathophysiology of these neurobehavioral changes remain incompletely understood. The cause of cognitive decline is most likely multifactorial and probably represents a complex interaction between cerebral microemboli, global cerebral hypoperfusion, inflammation, and genetic susceptibility. The problem of cognitive decline after cardiac surgery continues to increase as the surgical population becomes older and has more prevalent comorbid diseases. A better understanding of the etiology is essential to finding new preventive strategies as no definitive therapy exists for cognitive dysfunction.

Pages 121-127
Gianfranco Di Nino, Marco Adversi, Boaz G. Samolsky Dekel, Vincenzo Fodale, Giovanni Rosa, Rita M. Melotti
Peri-Operative Risk Management in Patients with Alzheimer’s Disease
Abstract: The aim of this review is to identify an evidence-based perioperative management for patients affected by Alzheimer’s disease (AD) that are scheduled to undergo surgery. Such would minimize the negative effects of anesthesia and postoperative sedation and correct those perioperative variables possibly responsible for a decline in cognitive status and a worsening of AD. We here gather evidence on the importance of correct preoperative assessment regarding cognitive and functional status and the presence of preoperative delirium. The potential role of anesthesia, surgery, and postoperative analgosedation as risk factors for development of delirium are herein outlined. Finally, pain assessment instruments, as well as principles of management strategies for postoperative delirium in subjects with AD, are suggested.

Pages 129-134
Kamilia S. Funder, Jacob Steinmetz and Lars S. Rasmussen
Anesthesia for the Patient with Dementia
Abstract: With a growing aging population, more patients suffering from dementia are expected to undergo surgery, thus being exposed to either general or regional anesthesia. This calls for specific attention ranging from the legal aspects of obtaining informed consent in demented patients to deciding on the use of premedication, choice of anesthetics, and management of postoperative pain. This review reflects on both general considerations concerning geriatric patients but also on the specific features of perioperatively used drugs and anesthetics that might have an impact on patients with Alzheimer’s disease (AD).

Pages 135-136

Pravat K. Mandal and Vincenzo Fodale