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Ann Thorac Surg 2009;88:1426-1432. doi:10.1016/j.athoracsur.2009.07.003
© 2009 The Society of Thoracic Surgeons
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Original Articles: Adult Cardiac

Plasma Amyloid β42 and Amyloid β40 Levels Are Associated With Early Cognitive Dysfunction After Cardiac Surgery

Lisbeth A. Evered, BS, MBiostata, Brendan S. Silbert, FANZCAa,b,*, David A. Scott, PhDa,b, Paul Maruff, PhDc, Katrina M. Laughton, BSc,d, Irene Volitakis, BSc,d, Tiffany Cowie, BS, MBAc, Robert A. Cherny, PhDc,d, Colin L. Masters, MDc,d, Qiao-Xin Li, PhDc,d

a Centre for Anaesthesia and Cognitive Function, Department of Anaesthesia, University of Melbourne, Melbourne, Australia
b Department of Surgery, St. Vincent's Hospital, University of Melbourne, Melbourne, Australia
c Department of Pathology and Centre for Neuroscience, University of Melbourne, Parkville, Australia
d The Mental Health Research Institute, University of Melbourne, Parkville, Australia

Accepted for publication July 1, 2009.

* Address correspondence to Dr Silbert, Department of Anaesthesia, St. Vincent's Health, PO Box 2900, Fitzroy, Victoria, 3065, Australia (Email: brendan.silbert{at}svhm.org.au).


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Decreased cognitive function associated with coronary artery bypass graft surgery is common. These deficits may be similar to the cognitive dysfunction seen in the spectrum of mild cognitive impairment to Alzheimer's disease, which are believed to result from the accumulation of amyloid beta (Aβ) peptide in the brain. We measured cognition both before and after coronary artery bypass graft surgery and assayed Aβ levels to investigate whether the cognitive dysfunction of cardiac surgery was associated with Aβ levels.

Methods: The plasma of 332 patients, who had undergone neuropsychological testing before and 3 and 12 months after coronary artery bypass graft surgery, was analyzed for Aβ42 and Aβ40. Patients were classified as having preexisting cognitive impairment if cognitive function was decreased in two or more tests compared with a healthy control group, and postoperative cognitive dysfunction was defined as a decline in two or more tests compared with the group mean baseline score.

Results: Preexisting cognitive impairment was present in 117 patients (35.2%), and postoperative cognitive dysfunction was present in 40 (12%) at 3 months and 41 (13%) at 12 months after surgery. Both plasma Aβ42 and Aβ40 levels assessed before the surgery were significantly lower in patients who later had postoperative cognitive dysfunction at 3 months.

Conclusions: Decreased preoperative plasma levels of Aβ42 and Aβ40 in patients who exhibit postoperative cognitive dysfunction at 3 months suggest that postoperative cognitive dysfunction at this time may share a common mechanism with mild cognitive impairment and Alzheimer's disease. This process may be exacerbated by anesthesia.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 
Decreased cognitive function in patients undergoing elective coronary artery bypass graft (CABG) surgery has been described both before and after surgery. The prevalence of preexisting cognitive impairment (PreCI) before surgery is 35% to 45% [1, 2], whereas the incidence of postoperative cognitive dysfunction (POCD) has been identified in more than 40% of patients 5 years after surgery [3]. Despite numerous investigations, the exact cause of these cognitive changes remains unknown [4].

Because CABG surgery generally takes place in the aged, the possibility exists that PreCI is a form of mild cognitive impairment (MCI), a subtle decline in cognition that is prevalent in 17% to 34% of the elderly population [5]. Clinically, the cognitive dysfunction associated with CABG surgery and MCI is identified by cognitive testing, although both entities fall short of affecting activities of daily living or frank dementia. A large proportion of MCI is understood to be a precursor to Alzheimer's disease (AD), and both are believed to originate from the same pathophysiology [5]. Both conditions are associated with an increased prevalence of apolipoprotein E e4 allele. Attempts to support a parallel between the cognitive dysfunction associated with CABG surgery and that of MCI/AD have centered on demonstrating an increased prevalence of the apolipoprotein E e4 allele in both conditions. Although a previous study [6] suggested a relationship between the apolipoprotein E e4 allele and cognitive dysfunction in cardiac surgery we have been unable to confirm this [7].

Both MCI and AD are believed to originate from the neurotoxic accumulation of amyloid beta (Aβ) peptide in the central nervous system. Laboratory studies have shown that inhalational anesthetics both increase Aβ generation [8] and promote oligomerization in cell cultures [9]. Thus anesthesia may influence Aβ processing and play a role in the evolution of cognitive dysfunction in the clinical setting, in common with MCI/AD.

Blood and cerebrospinal fluid levels of Aβ vary during the evolution of AD. The more pathogenic peptide Aβ42 has a tendency to decline in the cerebrospinal fluid such that the ratio of Aβ42/Aβ40 decreases in AD. Blood Aβ, which is derived in part from cerebral sources, also varies in time and cellular compartment, but only preliminary studies of its diagnostic/prognostic value have been undertaken owing to technical limitations of assay methods.

To investigate a relationship between plasma Aβ and cognitive decline related to CABG surgery, we measured plasma Aβ42 and Aβ40 levels in patients scheduled for CABG surgery who underwent extensive neuropsychological testing both before and after the surgery.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Comment
 Acknowledgments
 References
 
Study Participants
The study group consisted of 332 patients from the 349 patients who participated in the Australian Trial Investigating Postoperative Cognitive Deficit, Early Extubation and Survival (ANTIPODES) Trial, investigating the effects of high-dose opioids on cognitive outcome [10]. Institutional ethics committee approval was granted, and written informed consent was obtained from all patients. Eligible patients were aged 55 years or older, with no prior neurologic deficit, suitable for neuropsychological testing and scheduled to undergo elective first-time CABG surgery. Because there was no difference in cognitive outcome between patients, regardless of opioid dose, when tested at 3 and 12 months after surgery, all patients were treated as a single group for the purpose of POCD at these testing times. Fasting venous blood was taken before induction of anesthesia and stored at 4°C before processing. Blood was not drawn or analyzed for Aβ peptide for logistic reasons in 17 patients.

Preexisting cognitive impairment was defined by using the cognitive test results from 170 control subjects without cardiovascular disease. Ninety control subjects free of cardiovascular disease comprised friends and family members of patients undergoing CABG surgery at one hospital [11], and the remaining 80 control subjects had responded to general advertisements to be involved in a study of healthy aging [12]. The control participants completed the same neuropsychological test battery (with the exception of one test—see below) as the CABG surgery group.

Neuropsychological Testing
All patients completed a battery of eight neuropsychological tests administered by a trained interviewer. The tests were administered at baseline and at 3 and 12 months after surgery. The test battery consisted of the CERAD Auditory Verbal Learning test, Digit Symbol Substitution test, Trail Making test parts A and B, Controlled Oral Word Association Test (COWAT), Semantic Fluency test, and the Grooved Pegboard test (dominant and nondominant hands) [11]. Absolute test scores were reversed for timed tasks so that a decrease relative to an earlier assessment implied cognitive decline for every test.

For assessing baseline PreCI, decreased cognitive function for each test was defined if the test score was at least two standard deviations less than the mean of the healthy control group for that test [2]. As the Semantic Fluency test was not administered to the control group, PreCI was assessed on seven tests and defined for each individual patient when decreased cognitive function was present in two or more tests of the seven measures of performance according to the method of Silbert and associates [1] and Hogue and colleagues [2].

For assessing POCD, decreased postoperative cognitive function for each test was defined as a decrease of an individual's score of at least one standard deviation of the baseline mean for all patients for the relevant test (after adjusting for systematic factors such as learning and practice effects). Postoperative cognitive dysfunction in each patient was defined as decreased postoperative function on two or more test results. Tests not attempted were treated as omissions and not as failures, and if fewer than two tests were completed at one time, assessment for deficit at that time was omitted. The process of testing and the analysis of the results have been described in detail elsewhere [10].

The National Adult Reading Test (NART) was administered at the time of preoperative testing and used to estimate intelligence quotient (IQ) [13]. Anxiety and depression were measured at all times of neuropsychological testing, using visual analog scales, which are simple, quick, and reliable tools in the perioperative period [14].

All patients were tested for postoperative stroke using the National Institutes of Health Stroke Scale (NIHSS) at baseline and at 1 week after surgery [15].

Analysis of Amyloid β42 and Amyloid β40 Levels
The blood was taken before induction of anesthesia, transported on ice to the laboratory within 2 to 4 hours, and immediately spun, and the plasma was stored at –70°C. Plasma Aβ levels were measured using double antibody capture enzyme-linked immunoabsorbent assay for Aβ detection as previously described [16]. Plates were coated with monoclonal antibody G210 (for Aβ40) or monoclonal antibody G211 (for Aβ42). After washing the plates, Aβ40 and Aβ42 peptide standards and plasma (50 µL) along with WO2-Biotin were added to the wells in triplicate, and the plates were incubated overnight at 4°C. The plates were washed, streptavidin-labeled europium was added, and the plates were then developed with enhancement solution. The plates were read on the Wallac Victor 1420 Multilabel Plate Reader (PerkinElmer, Melbourne, Australia) with excitation at 340 nm and emission at 613 nm.

Patient samples were assayed with samples of known concentrations at regular intervals in each assay plate. Each assay plate run generated its own standard curve against which unknowns were measured for determination of Aβ concentration; the results reflect a series of Aβ concentrations that demonstrate variability relative to each other in an accurate and reproducible manner.

Levels of Aβ42 and Aβ40 that fell below the limit of detection for the assay were imputed at 50% of this value [17].

Statistical Analyses
Group comparisons were made using unpaired Student's t tests for continuous variables, the Mann-Whitney U test for ranked data, and {chi}2 or Fisher's exact test for dichotomous variables. Incidence analysis was used to examine cognition after patients were classified as having PreCI or POCD [18, 19]. Amyloid β was considered as a continuous variable, and logarithmic transformation was performed to approximate a normal distribution before analysis.

Associations were determined using univariable analysis and multivariable linear and logistic regression with a probability value of less than 0.2 set for entry into the multivariable regression models. Analysis was undertaken using STATA version 10.0 (StataCorp, College Station, TX), and a probability value of less than 0.05 was taken to indicate significance.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Comment
 Acknowledgments
 References
 
There was no significant difference between age, sex, and estimated IQ for patient and control groups (Table 1).


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  		Table 1 Control Group Demographics
 
Patient demographics, cardiovascular risk factors, and medications are shown in Table 2. Hypertension was defined if patients were taking antihypertensive medication. A total of 332 patients had their plasma taken before surgery for analysis. The lower limit of detection for Aβ42 ranged from 137.32 to 108.53 pmol/L and for Aβ40, from 25.40 to 12.93 pmol/L. For Aβ42, 46 samples (13.9%) fell below the limits of detection and for Aβ40, 68 samples (20.5%) fell below the limits of detection.


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  		Table 2 Demographics, Baseline Characteristics, Cardiovascular Risk Factor, and Medications a
 
The overall median (interquartile range) levels of Aβ42 and Aβ40 were 145.7 pmol/L (59.5 to 281.9 pmol/L) and 35.6 pmol/L (12.7 to 85.1 pmol/L), and the median (interquartile range) Aβ42/Aβ40 ratio was 4.4 (3.1 to 5.2).

Preexisting cognitive impairment was identified in 117 (35.2%) of the 332 patients. There was no significant difference between the levels of Aβ42, Aβ40, or Aβ42/Aβ40 ratio in patients with PreCI and those without PreCI (Table 3).


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  		Table 3 Plasma Amyloid β and Preexisting Cognitive Impairment a
 
There were 309 and 307 patients who completed testing at 3 and 12 months, respectively. Postoperative cognitive dysfunction was present in 40 (13%) patients at 3 months and 41 (13%) patients 12 months after surgery. Only 7 patients with POCD at 3 months displayed POCD at 12 months. Plasma levels of both Aβ42 and Aβ40 were significantly lower in patients with POCD at 3 months than those without POCD (Table 4). The plasma level of either Aβ42 or Aβ40 was below the median in 28 of the 40 patients (70%) with POCD at 3 months; 26 (65%) patients were below the median values for both Aβ42 and Aβ40 (Fig 1). At 12 months, there was no significant difference in plasma levels of Aβ42 and Aβ40 in patients with POCD compared with those without POCD (Table 5).


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  		Table 4 Plasma Amyloid β and Postoperative Cognitive Dysfunction at 3 Months a
 

Figure 1
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  		Fig 1. Plasma amyloid β42 (Aβ42) and amyloid β40 (Aβ40) levels (in pmol/L) before surgery and postoperative cognitive dysfunction (POCD). The lines indicate the median levels of Aβ42 and Aβ40. Twenty-eight of the 40 patients (70%) who had postoperative cognitive dysfunction at 3 months were below the median values for either Aβ42 or Aβ40 and 26 (65%) of patients were below the median values for both Aβ42 and Aβ40.

 

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  		Table 5 Plasma Amyloid β and Postoperative Cognitive Dysfunction at 12 Months a
 
There were 2 patients with postoperative strokes, one presenting as hemianopia and the other as mild hemiparesis. Both these patients were still able to complete all cognitive assessments. Five patients died, 4 of whom completed cognitive assessments at 3 months after surgery.

Univariable and multivariable analysis of plasma Aβ42, Aβ40, and ratio Aβ42/Aβ40 levels was performed for the presence of PreCI, POCD (at 3 and 12 months), age, sex, IQ, anxiety, depression, clinical risk factors for cardiovascular disease, and perioperative indicators of severity of cardiovascular disease (number of distal grafts, a history of myocardial infarction, and left ventricular function). The results of the analyses are shown in Table 6. Hypertension and myocardial infarction were associated with lower plasma Aβ42 on univariable and multivariable analysis. Postoperative cognitive dysfunction at 3 months was associated with both Aβ42 and Aβ40.


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  		Table 6 Multivariable Analysis of Amyloid β42, Amyloid β40, and Amyloid β42/Amyloid β40
 
Predictors of POCD at 3 months were assessed using univariable and multivariable analysis (Table 7). Both plasma Aβ42 and Aβ40 levels were associated with POCD at 3 months on both univariable and multivariable analysis.


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  		Table 7 Predictors of Postoperative Cognitive Dysfunction at 3 Months
 

   Comment
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
Acknowledgments
 References
 
Patients with POCD at 3 months after elective CABG surgery had significantly lower levels of Aβ42 and Aβ40 before surgery than those who did not demonstrate POCD. Multivariable analysis confirmed an independent association between POCD at 3 months with both Aβ42 and Aβ40 levels. There was no relationship between Aβ levels and either PreCI or POCD at 12 months.

The association at 3 months implicates Aβ proteins in the pathogenesis of early POCD, at least at this particular time interval. The cause of POCD has remained elusive, and in the absence of a specific cause, multifactorial mechanisms have been postulated. This has included cerebral hypoperfusion, cerebral embolism, and the systemic inflammatory response [20]. Furthermore, the statistical analysis of POCD is a complex issue, which has been the subject of various definitions [21, 22]. We chose the one standard deviation definition because it provides fewer false-positive results [23]. The current finding suggests that mechanisms associated with MCI/AD (ie, related to Aβ) may play a prominent part. Previous attempts to link these two entities by implicating a common genetic predisposition through the apolipoprotein E 4 allele have been unsuccessful. Other investigations into homocysteine and C-reactive protein have also been negative [24].

The current finding is underscored by the stronger association with Aβ42, which is known to be the more pathogenic of the Aβ peptides. The result provides clinical reinforcement of laboratory findings in which anesthetic agents have been shown to promote Aβ cytotoxicity [8, 9]. Carnini and coworkers [25] have hypothesized that anesthesia-facilitated disinhibition of protein binding helps Aβ monomers oligomerize to protofibrils that are neurotoxic. Lowering the threshold for oligomerization by anesthetic agents may initiate cytotoxicity and synaptic damage in a transient fashion.

Hypertension was independently associated with plasma Aβ42 levels (Table 6). Beta amyloid may play a role in vascular abnormalities in addition to neurodegeneration [26]. Low levels of Aβ42 (but not the less pathogenic Aβ40) have been shown to correlate with increased body fat, and it is hypothesized that cardiovascular risk factors may have modulatory effects on the parent molecule, the Aβ protein precursor [27].

The failure to find associations with PreCI and POCD at 12 months requires explanation. Certainly, cognitive testing before exposure to the anesthetic agents indicates that cognitive performance may be related to other factors such as vascular disease [1]. The lack of association of Aβ levels to POCD at 12 months suggests that there may be a different mechanism at play producing POCD over the longer term. The 3-month testing time may highlight the interaction between anesthetic agents and Aβ demonstrated in cell cultures. This transient form of cognitive impairment may imply a reversible form of neurotoxicity independent of long-term POCD. The alternative explanation, that the finding of an association between low levels of Aβ and POCD at 3 months is a type 1 error, is unlikely given the high degree of statistical significance.

Plasma and serum Aβ levels have been measured in several population studies of dementia and cognitive impairment with variable results [28]. Graff-Radford and associates [29] found that subjects with low plasma Aβ42/Aβ40 ratios were at increased risk for MCI and AD. They hypothesized that lower plasma levels of Aβ indicated premorbid neurodegenerative disease as Aβ deposited selectively in the brain; the initial decline was in the Aβ42 component, thus the Aβ42/Aβ40 ratio was a sensitive measure. We hypothesize that higher brain levels would be susceptible to oligomerization by anesthetic agents as demonstrated in cell cultures [9]. Such a hypothesis could be confirmed by using Pittsburgh Compound-B radiotracer studies in the future. This radiotracer binds with high affinity and specificity to neuritic Aβ plaques [30].

The present study provides definitive evidence linking POCD to the neurodegenerative changes of MCI/AD. Previous attempts to link these two entities have been mixed. In a retrospective study by Lee and colleagues [31] the adjusted risk for AD associated with CABG versus percutaneous coronary angioplasty was 1.71. Silverstein and associates [32] failed to show that memory, which often deteriorates in MCI/AD, was not a major component of POCD. We have recently shown that the apolipoprotein E4 allele, which is known to be associated with MCI/AD, is also not associated with the cognitive changes of CABG surgery [33].

The relationship of preoperative Aβ42 and Aβ40 levels to POCD at 3 but not 12 months may have important clinical implications. First, Aβ levels may provide a mechanism for screening susceptible patients before they undergo CABG surgery. Second, if POCD does result from mechanisms related to MCI/AD, then these patients may provide a suitable group for testing prophylactic therapies against MCI/AD because effects would be seen in 3 months instead of over many years.

In conclusion, we have shown an inverse relationship between plasma Aβ42 and Aβ40 levels and POCD at 3 months. This observation may provide clinical evidence of an interaction between anesthetic agents and Aβ, which has been observed in animal studies. It may also offer the potential for using a biomarker for cognitive impairment after surgery. Further research is warranted to confirm these findings.


   Acknowledgments
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
References
 
This work was supported by the National Health and Medical Research Council, Canberra, Australian Capital Territory, Australia (Project Grant No. 140510). We would like to thank Darryl Carrington and Christine Mavros for blood processing and Konrad Beyreuther for provision of antibodies.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Comment
 Acknowledgments
 References
 

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