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Original Articles: Adult Cardiac

Subjective Memory Symptoms in Surgical and Nonsurgical Coronary Artery Patients: 6-Year Follow-up

^a Johns Hopkins University School of Medicine, Baltimore, Maryland
^b The Zanvyl Krieger Mind Brain Institute, Baltimore, Maryland
^c Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland

Accepted for publication September 10, 2008.

^_* Address correspondence to Dr McKhann, 338 Krieger Hall, Johns Hopkins University, 3400 N. Charles St, Baltimore, MD 21218 (Email: guy.mckhann{at}jhu.edu).

	Abstract

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Background: Self-reported cognitive and memory complaints after coronary artery bypass graft (CABG) operations are common. Several studies have attempted to quantify the incidence of such complaints and to examine the relationship between subjective and objective cognitive functioning, but the etiology and longitudinal course of these self-reports remain unclear.

Methods: Measures of subjective memory complaints were compared in two groups: 220 CABG patients and 92 nonsurgical cardiac patients at 3 months, and 1, 3, and 6 years. At 6 years, additional measures were used to quantify memory self-assessment. The frequency of subjective complaints at each time point was determined, and associations with objective cognitive performance as well as depression were examined.

Results: At early (3-month or 1-year) follow-up, subjective memory complaints were reported more often by the CABG than the nonsurgical group (45.5% vs 17.0%, p < 0.0001). By 6 years, the frequency of complaints was similar (52%) in both groups. Subjective memory ratings were significantly correlated with performance on several memory tests at 6 years. This relationship was not confounded by depression.

Conclusions: Subjective memory complaints are more frequent early in follow-up in patients undergoing CABG than in controls, but are similar by 6 years. The increase in subjective complaints over time may be related to progression of underlying cerebrovascular disease. Unlike previous studies, we found that subjective memory assessments were correlated with objective performance on several memory tests. Although subjective memory complaints are more common in patients with depression, they cannot be explained by depression alone.

	Introduction

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Complaints of cognitive problems, especially memory, are frequently reported by patients who have had coronary artery bypass grafting (CABG). In part on the basis of the lack of correlation between subjective symptoms and objective neuropsychologic test findings, previous studies have suggested that self-reported memory symptoms reflect underlying depression [1, 2]. Nonetheless, because most of these studies involved only patients undergoing CABG, the possibility that memory symptoms might also develop in patients with coronary artery disease who did not have an operation was not examined. Therefore, in a previous study [3] we compared subjective memory complaints during a 12-month period in patients undergoing CABG with those in patients with angiographically proven coronary artery disease but without surgical intervention. Those undergoing CABG were more likely to report memory changes at 3 and 12 months after baseline; moreover, these differences remained even after adjustment for demographic variables and for depression.

In attempting to define further the time course and mechanism underlying subjective complaints among CABG patients, the present report is an extension of our previous study by continuing to evaluate their memory complaints in greater detail. Among several questions raised by the previous study, we considered whether the difference in subjective memory complaints between the CABG and nonsurgical comparison group persisted over time (primary outcome), and if so, were subjective memory complaints a manifestation of depression. We also considered the possible predictive value of early subjective complaints with respect to long-term outcome and cognitive decline. Lastly, because we previously reported no differences in cognitive change at 6 years between the CABG and nonsurgical comparison patients [4], we wished to determine whether there were correlations between subjective memory reports and the level of cognitive performance at 6 years or a change in cognitive performance from baseline to 6 years, as measured by objective tests (secondary outcome). Answers to these questions may provide insight into the origin of the memory complaints that are of considerable concern to patients undergoing CABG procedures.

	Patients and Methods

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Patients
Three groups of patients with coronary artery disease were included in this observational, longitudinal study: 152 patients who underwent CABG with cardiopulmonary bypass (on-pump), 68 CABG patients without cardiopulmonary bypass (off-pump), and 92 nonsurgical cardiac comparison patients. The nonsurgical comparison patients, recruited from the cardiology group at our institution, all had stable, diagnosed, medically managed coronary disease but had not undergone cardiac surgical intervention at the time of enrollment. These populations are described elsewhere in detail [5]. The study was originally approved by the Institutional Review Board on July 14, 1997, to include baseline, and 3- and 12-month visits, and all patients gave written informed consent. The 3-year follow-up was approved on September 22, 2000, and the 6 year follow-up on July 28, 2003.

Study Design and Cognitive Testing
All patients were seen on the timeline of baseline, 3 months, and 1, 3, and 6 years. Subjective memory symptoms, our primary outcomes, were assessed in three ways: yes/no complaint, Likert scale, and Lund questionnaire. At the 3-month and 1-, 3-, and 6-year follow-up visits, patients were asked if they felt as though their memory had become worse (yes/no complaint) since their previous visit. This question was asked before cognitive testing. In addition at 6 years, a more extensive evaluation of subjective complaints was given. This included a Likert scale, in which patients were asked to rank their memory (as it is today) on a scale of 1 to 10 (10 being the best memory score). This ranking was completed before the actual cognitive testing.

After the cognitive test battery, patients completed a seven-item memory questionnaire (from the Lund questionnaire) [6]. Patients were asked if each of the following memory items had become better (score of +1), worse (score of –1), or remained the same (score of 0) when comparing their memory today to 6 years ago, before the study started. The seven memory items were remembering appointments, remembering whether you've taken your medication, remembering names of persons and places, remembering items on a grocery list, remembering telephone numbers, walking into a room and forgetting what you wanted to do there, and the question, is it easier to remember things today than before the start of our study (6 years ago)? The scores to these seven items were summed for a total memory score and were therefore focused on change in memory from baseline to the 6-year follow-up. Thus, a negative score indicated that overall the patient's memory was worse over time.

Patients completed a cognitive test battery (16 tests/subtests as summaized in Table 1), that measured eight cognitive areas: verbal memory, visual memory, visuoconstruction, language, motor speed, psychomotor speed, attention, and executive function [7]. Additional questionnaires that were completed at all study time points included The Center for Epidemiological Study of Depression (CES-D) [8], a measure of depression; the Mini-Mental Status Exam [9], a global measure of cognitive function; and the Beth Israel Functional Status questionnaire [10], which measured physical functioning. At the 6-year time point, we included the Letter-Number sequencing test, which is a measure of working memory [11].

For our primary outcome, we estimated the frequency of subjective memory complaints at each follow-up time point for the two groups with 95% confidence intervals (CI) and the odds ratio at each time with its CI using logistic regression and generalized estimating equations [12] to account for the correlation among repeated measures on a person. In this analysis we controlled for age, gender, education level, and baseline depression score. This is an analysis of variance model with treatment group, time, and the time by treatment interaction, controlling for potential confounders because this is an observational rather than randomized study.

At 6 years, we measured the strength of linear association between subjective complaints as measured by the Likert scale, and each objective cognitive test by estimating the Pearson correlation coefficient between these two continuous measures. Because we have previously determined that there are no differences in objective cognitive test performance between the CABG and nonsurgical comparison patients at 6 years [4], we then combined these groups, and correlations were calculated for both the Likert score and the change in z score from baseline to 6 years on each cognitive test (secondary outcome). To assure that the correlation was not affected by depression, we also calculated the Pearson correlation after both measures were linearly adjusted for the CES-D score at the 6-year time point.

	Results

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Comparison of On-Pump and Off-Pump Patients
The frequencies of subjective complaints were essentially the same in the two surgical groups at all time points, as follows:

• 3 months: on-pump, 27.0% (33 of 122); off-pump, 26.4% (14 of 53).

• 1 year: on-pump, 37.8% (48 of 127); off-pump, 31.4% (16 of 51).

• 3 years: on-pump, 47.4% (36 of 76); off-pump, 41.4% (12 of 29).

• 6 years: on-pump, 51.5% (50/97); off-pump 56.1% (23 of 41).

Because none of these differences were statistically significant, these two surgical groups were combined for all the further analyses and will be referred to as the CABG group.

Demographic Comparison and Frequency of Subjective Complaints by Study Group
There were some differences in medical history variables between the CABG and nonsurgical comparison group at baseline as summarized in Table 2. At each follow-up time point, the frequency of memory complaints is reported on the following schedule (3 months, 1, 3, and 6 years): CABG was 26.9%, 36.0%, 45.7%, and 52.9%; and for the nonsurgical comparison, 6.0%, 15.3%, 29.0%, and 51.6%. These differences between the groups are statistically significant (Table 3), except at 6 years. When the early complaints were examined together at 3 months or 1 year, or both, the CABG patients had more subjective complaints (45% vs 17%; p < 0.0001). The number of complaints increased for both groups over time. The probabilities of subjective complaints at each follow-up point are shown by group in Figure 1. In addition, the mean scores for the Likert scale memory ranking and Lund questionnaire were not significantly different between the groups at 6 years. Therefore, these data show that although the CABG group has more complaints in the early (3-month and 1-year) time periods, the frequency of memory complaints in both groups equalizes over time.

View larger version (13K): [in this window] [in a new window]   Fig 1. Risk-adjusted probability of having a (yes/no) memory complaint at each study follow-up time point in the coronary artery bypass grafting (CABG) group (white circles), a combination of conventional and off-pump surgical patients, and the nonsurgical comparison group (NSCC, black circles). Odds ratios are shown above the bars and 95% confidence intervals are shown in parentheses. In all situations, except at 72 months (6 years), the CABG group has greater odds of a memory complaint than the nonsurgical comparison group. Data are adjusted for age, gender, education and Center for Epidemiological Study of Depression score at baseline.

Early Subjective Memory Complaints and Long-term Cognitive Outcomes
Using Pearson correlation coefficients, we asked whether or not early subjective memory complaints predict late cognitive decline at 6 years. For each cognitive test, the z score changes from the 1- to 6-year follow-up were compared between those with and without early complaints. There were no statistically significant correlations. Therefore, despite some nonsignificant trends, we were not able to demonstrate that early memory complaints predicted late cognitive decline.

Correlation of Subjective Memory Ratings and Objective Cognitive Tests at 6 Years
We sought to determine if correlations existed between subjective memory scores and specific cognitive tests. The cognitive test scores were adjusted for baseline age, gender, and education level. First, when the correlations between the Likert scale score and cross-sectional cognitive test scores at 6 years were examined (Table 1), there were statistically significant positive correlations with five memory tests: Total Rey Auditory Verbal Learning Test (RAVLT) score, delayed recall on the RAVLT, Rey Complex Figure-retention, Rey Complex Figure-delayed recall, and Letter-Number Sequencing [13] (Table 4). Correlations were also found with tests of language (Boston Naming Test) and attention (RAVLT-Trial 1). After adjusting for depression, two of the five memory tests remained statistically significant (Total RAVLT and RAVLT Trial 1) as well as the Boston Naming Test.

Second, we compared the Likert scale score with the cognitive test z scores examining cognitive change from baseline to 6 years. Statistically significant positive correlations were found between the Likert scale scores and change on multiple cognitive tests, not only memory tests (data not shown). Therefore, patients rating themselves lower on the Likert scale tended to have a negative change in the z score indicating cognitive decline, whereas those rating themselves higher on the Likert scale tended to have a positive change in the z score, indicating improvement in cognitive scores. These relationships remained statistically significant even after adjusting for depression scores (CES-D) at 6 years.

In addition, we tested the associations between the Lund memory questionnaire score and change (from baseline to 6 years) in cognitive tests (see Table 1). Because the Lund questions are designed to measure change, we found significant correlations between the Lund memory scores and change in cognitive test scores for 3 of the 6 memory tests in our cognitive battery (RAVLT total, RAVLT delayed recall, and RAVLT retention).

	Comment

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In a previous study, we compared self-reported subjective memory problems at 3 months and 1 year in patients who had undergone on-pump CABG with those in patients with stable coronary artery disease but without surgical intervention. We reported that the frequency of memory problems was significantly higher in the CABG patients than in the nonsurgical group [3]. The reasons for this were not entirely clear, but may have included effects of general anesthesia, postoperative pain, and narcotic use, as well as interactions with depression. In part due to increased media attention to postoperative cognitive complications, these symptoms are of considerable concern to patients.

In the present study, we evaluated a larger group of surgical patients, including those with on-pump and off-pump treatment as well as a nonsurgical group, at 3 and 6 years later. We found no differences between the on-pump and off-pump patients, which suggests that subjective memory symptoms are not specific to the use of cardiopulmonary bypass. Unlike the differences in the frequency of memory complaints that existed between the surgical and nonsurgical groups at the early time points, by 6 years the groups were similar although with a greatly increased frequency of complaints. The question remains, however, about the reasons for these increases in subjective complaints.

The increase in memory complaints over a 6-year time period has several plausible explanations, including aging, progression of cerebrovascular disease, and depression. The gradual increase in memory complaints over time may possibly be related to aging during the 6 years of the study. Nonetheless, aging and vascular disease changes in this cohort of patients with diagnosed coronary disease may be interrelated and therefore may not represent normal aging. In addition, the increase in complaints may be related to the progression of underlying cerebrovascular disease. We have shown that at baseline, the surgical groups have more hypertension, diabetes mellitus, previous strokes, peripheral vascular disease, and three-vessel disease, all risk factors or characteristics of significant vascular disease [5]. Thus, we postulate that the CABG patients may have begun the study having already reached their vascular disease threshold with associated lower cognitive function, but over time the nonsurgical patients reach a similar threshold, although it may have developed on a slightly different time course.

Previous cross-sectional studies that comprised only CABG patients [14] suggested that subjective memory complaints are all related to or explained by underlying depression [15]. The results from our longitudinal study indicate that depression alone cannot explain the subjective symptoms. First, our results show that the percentage of patients reporting memory complaints is increasing, but the percentage of those with depression is decreasing over time. Second, when we adjust for depression levels, the probability of reporting a subjective complaint persists. Thus, consistent with findings from a recent study that highlights the very complex relationship of depression with other disease processes [16], our work shows that depression alone does not account for the increased frequency of complaints, but other interactions may be present.

In assessing the possible predictive value of whether early subjective memory complaints predict long-term memory complaints, and whether such complaints predict late cognitive change, we found that patients with memory complaints at early time points were more likely to rank their memory lower at 6 years on the Likert scale and to report changes over time on the Lund questionnaire. This suggests that subjective memory complaints may reflect a progressive underlying pathology, as would be expected with cerebrovascular disease.

Some studies in the general population have reported associations with early cognitive complaints and future cognitive disease diagnoses [17, 18]. Although in our study, early complaints predicted (late) 6-year memory complaints, they did not predict actual late cognitive decline from 1 to 6 years. This finding may highlight the multiple reasons for memory complaints; that is, the interactions of a patient's perception, depression, and poor physical well-being, at the four times that we have measured them in this study. Early complaints may be more closely related to a person's perception of worse physical functioning and depression status, which are both at their peak in the early time points, whereas later complaints may more accurately reflect actual cognitive functioning at the time. Indeed, we found a correlation with subjective symptoms at 6 years and actual cognitive and memory performance at 6 years (cross-sectional comparison). Performance on other measures of cognition frequently associated with subcortical disease, such as executive function and psychomotor speed, do not appear to be correlated with memory self-reports at 6 years.

We believe that our study has significant strengths: It is a prospective longitudinal evaluation comparing CABG with nonsurgical patients with known coronary artery and presumed cerebrovascular disease. In addition, we used multiple subjective and objective measures to evaluate patients. Among the limitations are that we did not obtain data on memory complaints at baseline; therefore, we do not know whether there were subjective differences between the groups at the start of the study. Moreover, we did not have imaging studies to assess the degree of underlying cerebrovascular disease. Other studies, however, have reported an association of self-reported cognitive complaints with white matter lesions [19, 20] as well as severity of lesions [21]. These studies suggest that self-reported cognitive symptoms may reflect the severity of underlying cerebrovascular disease.

The mechanism underlying the progression of memory complaints among patients with cardiovascular disease remains elusive. From these findings we conclude that subjective complaints reflect, at least in part, changes in underlying cognitive performance, are not solely a manifestation of depression, and do not appear to be related to treatment group. We speculate that the longitudinal increase in subjective complaints may be a manifestation of increasing cerebrovascular disease. It may also be important for future candidates for cardiac operations to know that they are no more likely than nonsurgical patients to have changes in memory over time.

	Acknowledgments

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This study was supported by grant 35610 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland; by the Dana Foundation, New York, New York, and the Johns Hopkins Medical Institution GCRC grant RR 00052. We thank Pamela Talalay, PhD, Rebecca Gottesman, MD, and Charles Hogue, MD, for their help during the preparation of this article. Louis M. Borowicz Jr helped with the data acquisition. We also thank the cardiologists, cardiac surgeons, and anesthesiologists at our institution as well as Johns Hopkins Bayview Medical Center, who helped with this study. Special thanks are extended to our study participants who volunteered their time and energy to make this study possible.

	References

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