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RESEARCH ARTICLE |
1 Palo Alto Veterans Affairs Health Care System, Palo Alto, California.
2 Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California.
Address correspondence to Jerome A. Yesavage, MD, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305-5550. E-mail: yesavage{at}stanford.edu.
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Abstract |
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Key Words: Acetylcholinesterase inhibitor • Cognitive training • Donepezil
The purpose of this study was to determine if an acetylcholinesterase inhibitor (AChI) would improve the effectiveness of cognitive training designed to enhance memory performance in nondemented older adults. The use of AChIs is based on the cholinergic hypothesis that the memory deficit seen in patients with Alzheimer's disease (AD) and the memory decrements associated with normal aging are due to a relative deficit in cholinergic function (Bartus, Dean, Beer, & Lippa, 1982
; McGeer & McGeer, 1976). Prior studies support the theory that AChIs can enhance memory function in normal adults (Bentley, Husain, & Dolan, 2004; Bentley, Vuilleumier, Thiel, Driver, & Dolan, 2003; Davis et al., 1978; Freo et al., 2005; Furey, Pietrini, & Haxby, 2000; Furey et al., 1997). Our own research that suggested improved assimilation and retention of a complex aviation task with low-dose (5 mg/day) donepezil treatment also supported the relevance of the cholinergic hypothesis for normal aging (Yesavage et al., 2002).
Cognitive training has been used in attempts to attenuate age-related cognitive deficits. Training programs have succeeded in improving memory and other cognitive functions (Backman, Mantyla, & Herlitz, 1990; Ball et al., 2002; Brooks et al., 1999; Verhaeghen, Marcoen, & Goossens, 1992; Willis, 1987; Willis & Nesselroade, 1990; Willis et al., 2006); however, not all participants benefit from training. Greater improvement has been associated with better initial abilities (Hill, Yesavage, Sheikh, & Friedman, 1989). Some nondemented participants in prior studies might have suffered from mild cognitive impairment (MCI), which is a strong risk factor for AD. Such patients might actually have incipient AD and thus be relatively unresponsive to training.
The main hypothesis of the current study was that pharmacologic treatment would augment cognitive training effects so that the donepezil + cognitive training group would perform better than the placebo + cognitive training group (Hypothesis 1). Primary outcome measures were measures of delayed recall. Exploratory hypotheses proposed the examination of several potential moderators or predictors of treatment response (gain in recall scores), including demographic (age, education), biological (apolipoprotein E, or APOE, status), and baseline cognitive function measures (Hypothesis 2). Finally, this study tested whether changes in performance on cognitive measures were mediated by changes in levels of acetylcholinesterase (AChE) inhibition or changes in working-memory ability (Hypothesis 3).
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METHODS |
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Inclusion and exclusion criteria allowed entry of the usual spectrum of cognitive abilities found in community-dwelling individuals but excluded participants with various forms of dementia. Our inclusion–exclusion criteria, enumerated in the following paragraphs, were based on those described by Petersen and associates (2005) to include a broad range of community-dwelling older adults, from those with normal function to those with MCI.
Inclusion criteria
Participants had to be in good general health—they could have no additional diseases that we expected would interfere with the study. They had to have normal B12 levels, resting blood pressure levels, and thyroid function tests or be without any clinically significant abnormalities that would interfere with the study. They had to have normal general clinical chemistry results and complete blood count results. They could have self-reported memory complaints, but they had to score between 24 and 30 on the Mini-Mental State Examination (Folstein, Folstein, & McHugh, 1975). They had to have a sufficiently preserved general cognition level to function in the community.
We included both individuals with MCI and individuals with normal age-adjusted scores on the Logical Memory II subscale of the revised Wechsler Memory Scale (Wechsler, 1987). Following criteria presented in Petersen and colleagues (2005), we considered scores below an education-adjusted cutoff on the Logical Memory II subscale (Delayed Paragraph Recall) to be indicative of MCI. The cutoff was as follows: with a maximum score of 25 (Part A), the cutoff was 
8 for 
16 years of education, 4 for 8 to 15 years of education, and 2 for 0 to 7 years of education. Participants could have no significant cerebrovascular disease (modified Hachinski score of 4), and they had to have visual and auditory acuity that would be adequate for neuropsychological testing and benefit from cognitive training. On the 17-item Hamilton Depression Scale, they had to have a score of 12. We did permit participants to take some medications: they could take 1 month of a stable dose of antidepressants lacking significant anticholinergic side effects; they could be on estrogen replacement therapy; or they could take ginkgo biloba.
Exclusion criteria
We excluded participants if they had significant neurologic disease (other than suspected incipient AD), such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or a history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities. To determine this, a senior staff physician reviewed the medical history, list of current medications, and lab test data collected for each participant and conducted a physical examination that included testing basic neurological signs. Using criteria set from the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, 1994), we also excluded participants if they had a history of alcohol or substance abuse or dependence in the past 2 years, major depression in the past 2 years, or significant systemic illness or an unstable medical condition that which could lead to difficulty in complying with the protocol.
The protocol received approval by the Institutional Review Board of Stanford University. Participants gave informed, written consent and were compensated $200 for their participation at completion of the year-long study. Compensation was prorated for participants who did not complete the protocol.
Pharmacologic Treatment
Drug administration and dosage
Participants meeting study criteria received, in a randomized double-blind fashion, either donepezil or placebo (kindly provided by Eisai Inc., Woodcliff Lake, New Jersey) for 52 weeks. All participants started at 5 mg/day for 6 weeks before moving to 10 mg/day (schedule recommended by Doody, 1999). The 10-mg dose was provided as two 5-mg pills. However, if patients could not tolerate 10 mg of donepezil or placebo, they were allowed (in consultation with the monitoring physician) to continue with 5 mg. Participants were encouraged to take the medication before noon but were allowed to take the medication at their preferred time, if consistent. Personal contact was maintained by a blinded research assistant who issued medication, inquired about possible side effects, and conducted pill counts. Participants were seen 14 times over the year: once every 3 weeks for the initial 12 weeks and then monthly after the start of cognitive training. If a participant missed three or more consecutive doses in any 1-month period, we withdrew the participant as a treatment failure but included the participant in our random regression (intent-to-treat) analyses.
Adverse events
We recorded adverse events throughout the year until 1 week after medication discontinuation. A physician monitored reported side effects.
Withdrawal of participants
We withdrew participants from the study if it was medically necessary, if they wished to withdraw, or if they did not comply with study protocol (e.g., used prohibited medication).
Blinding
All participants and research staff were blinded. We accomplished the medication blinding by using identical donepezil and placebo tablets. Randomization and allocation to treatment was performed by the pharmacy through the use of random-number-generated codes. Pharmacy staff was not aware of any other participant data.
Cognitive Training
For 2 weeks, that is, during Weeks 13 and 14, the participants had 2 hours of cognitive training every morning, Monday through Friday. The training for all classes was conducted by the same experienced teacher and took place in a classroom adjacent to our laboratory. The training followed the format of a "comprehensive extended" training developed in earlier work (Brooks, Friedman, Pearman, Gray, & Yesavage, 1999). This consisted of supplemental nonmnemonic "pretraining," including visualization techniques, combined with mnemonic training. This program has been shown in controlled trials to be effective in improving list learning and name–face recall in nondemented older adults. The list-learning task made use of visual associations of to-be-remembered items to a permanent list of locations or loci (usually locations in each participant's living room). The name–face recall technique similarly used visual associations between a facial feature and a transformation of the person's name to an image placed on the feature (Brooks et al.; Hill, Sheikh, & Yesavage, 1988; Yesavage, 1983, 1985; Yesavage & Rose, 1984). Primary outcome measures were readministered prior to training on Day 1 of the cognitive training program (T2). Pretraining started on Day 2 and lasted through Day 4. Mnemonic training started on Day 5 and lasted through Day 9. A test was administered on Day 10 at the end of the second training week (i.e., Week 14, or T3; see Figure 2).
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Word list recall
Participants received individual copies of a list of 16 words; they had 4 minutes to memorize the words in order. We tested short-term recall after a 5-minute distracter task, and we tested delayed recall after 30 minutes. At recall, participants were asked to write as many words as they could remember in the order they were presented. Equivalent alternate lists of words were used and counterbalanced.
Name–face recall
We had pictures of faces projected one at a time onto a screen with the associated name (first and last) read aloud and presented underneath the face. Participants studied the name–face pair for 1 minute. Immediately after the 12 name–face pairs were presented, the same set of faces was presented again without the names, one per minute, in a different random order. Participants were asked to write down both names associated with each face.
Secondary outcome measures
We used the core subset of the Medical Outcomes Study Functioning and Well-Being Profile (Stewart, 1992) to measure quality of life. We used the Everyday Problems Test (Willis & Marsiske, 1993) to measure functional capacities.
Measures: Hypothesis 2 (Moderators)
We selected the following measures to test whether demographic, baseline cognitive, and biological (APOE) characteristics of participants would predict treatment response.
Demographics
We tested specific hypotheses regarding basic demographic variables (age and education) as relevant predictors of differential treatment response (McKitrick et al., 1999).
Cognitive measures
We used a battery of widely used cognitive measures to test baseline cognitive functions that were likely to moderate response to the intervention (Table 1).
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), we extracted genomic DNA from frozen whole blood samples. We performed APOE genotyping according to the restriction isotyping protocol of Hixson and Vernier (1990).
Measures: Hypothesis 3 (Mediators)
We hypothesized and measured two potential mediators of drug response: change in an index of working memory and change in red blood cell (RBC) AChE activity.
Working memory
We used change scores of the Digit Span (Wechsler, 1987) and the Symbol Digit modalities (Smith, 1991) as indicators of working memory and mediators of drug response. We computed change scores both from baseline to Week 13 and from baseline to Week 52.
RBC AChE activity
We tested RBC AChE inhibition as a mediator variable (Rogers, Doody, Mohs, & Friedhoff, 1998; Rogers & Friedhoff, 1996). To determine AChE activity in RBC membranes, we collected a 5-ml venous blood sample at baseline, Week 13, and Week 52. We analyzed the blood with a specific radioenzyme assay, applying the methods used by Rogers (Hulse, Rogers, Friedhoff, Sukovaty, & Pedersen, 1992; Rogers & Friedhoff).
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RESULTS |
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4 carrier distributions, although, by chance, 50% of placebo MCI participants were APOE 4 carriers, versus 30% of the drug group. Dropout rates and several side effects were significantly higher in the drug group than in the placebo (Table 2). These side-effect data (the 10 mg/day dosage caused more side effects) are similar to those of a controlled trial with 468 patients that examined both 5- and 10-mg dosages (Rogers et al., 1998). In our study, dose reductions occurred in 14 of 83 donepezil participants (16.9%) and 4 of 85 placebo participants (4.7%).
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At the end of Week 14, participants were asked several questions about the mnemonic test they had just completed. They scored an average of 6.32 (1.23) on a 7-point scale (ranging from 1, not at all, to 7, very much) in response to a question asking if, during the test, they employed the list-learning technique they were taught. When asked whether they understood the list-learning technique, they scored an average of 6.45 (1.10); and on a question asking whether they would apply the mnemonic techniques to their everyday lives, they scored 6.20 (1.33).
Statistical Analysis
Hypothesis 1: Efficacy
The primary analysis compared gain in list learning and name–face recall from baseline to after cognitive training (Week 14). We also examined gain in list learning and name–face recall from baseline to after the 12 weeks of pharmacologic treatment alone and retention of list learning and name–face recall skills from end of cognitive training to follow-up (Week 52). Although the overall effects of cognitive training were uncontrolled, they were similar to those reported in prior controlled trails. In other words, i.e., gain scores improved in a manner similar to that in our prior controlled trials (Yesavage, 1985); there were no significant effects associated with donepezil treatment at any measurement point either alone or as an augmentation of the effects of cognitive training (Table 3a). Similarly, there were no differences between treatments on measures of quality of life (Medical Outcomes Study Functioning and Well-Being Profile) or functional capacity (Everyday Problems Test; see Table 3b).
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Hypothesis 3: Mediators—Change in working memory and change in AChE inhibition under the initial 12 weeks of donepezil therapy
The first step in a mediator analysis is to demonstrate that the potential mediator changes during treatment. If the change is statistically significant, then the second step is to demonstrate that the change in the mediator explains some portion of the treatment effect on clinical outcome measures. There were no significant changes with donepezil versus placebo on the working-memory mediator measures (i.e., Symbol Digit Substitution and Digit Span; see Table 4). Thus, the "drug response" was absent and we could not perform the first step in the mediational analyses. However, increased levels of AChE inhibition would be expected in the active treatment versus control. We performed a set of correlations to determine if the level of AChE inhibition was related to gain on memory scores. After 12 weeks, the level of RBC AChE inhibition, 69% at 5 mg/day and 70% at 10 mg/day, was similar to that found by Rogers (1998) and there were no significant correlations between AChE inhibition levels and memory performance gain scores. Those participants who had their dosage reduced to 5 mg had similar levels of AChE inhibition to those who could tolerate 10 mg.
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DISCUSSION |
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A possible solution to identifying the optimal dosage for each individual was suggested by the original studies of physostigmine, conducted about 30 years ago. Davis and his collaborators (Davis, Hollister, Overall, Johnson, & Train, 1976; Davis et al., 1978) performed a series of experiments that defined an individual's "optimal" dosage not in terms of milligrams or measures of cholinergic inhibition but by using a proxy measure of central cholinergic function: improvement of performance on a memory task. In an attempt to determine whether or not dosage was a factor, we studied an additional cohort of 30 participants dosage was adjusted to 2.5 mg, 5.0 mg, or 7.5 mg on the basis of their optimal list-learning test performance. An analysis of gain in cognitive scores after cognitive training while receiving these "optimally" adjusted dosages showed no advantage from dose optimization. These results as well as results for the participants in the main experiment who did not advance beyond 5 mg provided no evidence that dosage was a factor that could be adjusted to improve outcome. This is consistent with the finding that the level of RBC AChE inhibition on 5-mg and 10-mg dosages was virtually identical in the main study.
Physiological tolerance to the effects of donepezil is another factor that may affect the benefit from donepezil that an individual receives. In other words, AChE levels may increase with chronic treatment, thereby reducing the potential for long-term clinical benefit. Although the literature is not consistent, this might explain why some short-term studies have shown the benefit of AChIs in nondemented populations whereas chronic administration to similar populations has failed to enhance cognition. For example, some researchers found cerebrospinal fluid levels of AChE to be significantly elevated after participants received donepezil treatment for 6 months (Davidsson et al., 2001; Parnetti et al., 2002). In contrast, using positron emission tomography techniques, other researchers showed cortical AChE activity to be reduced after participants received 12 weeks of treatment (Bohnen et al., 2005). A study using rats also showed decreased cortical AChE activity that was unchanged in magnitude after 14 days of treatment (Haug, Bogen, Osmundsen, Walaas, & Fonnum, 2005). Thus, although some studies suggest that physiological tolerance to the effects of donepezil may occur, the literature is not consistent and does not provide a convincing explanation for the lack of effects of donepezil found in the experiment reported herein.
Davis and Sadik (2006) offered the disruption of circadian rhythms as another explanation for the lack of effect of donepezil on chronically treated nondemented patients. They argued that several studies have suggested that the chronic dosing of an AChE inhibitor around the clock will have adverse effects on sleep and other circadian parameters that interfere with consolidation of memory. Their proposed solution is more frequent treatment with AChE inhibitors having a short half-life that thus do not carry their inhibitory effects over into sleep periods, instead of treatment with donepezil, which has a long half-life.
In conclusion, the results of this study of 168 community-dwelling older adults with memory complaints suggest that a 10-mg treatment of donepezil will not improve the cognitive function of most of these individuals, with or without adjunctive cognitive training. Despite considerable rationale that such agents may work in the short term, successful long-term treatment in nondemented populations remains elusive. Problems include establishing the proper dosage, the potential for the development of physiological tolerance, and interference with circadian rhythms with an associated disruption of the process of memory consolidation. Until these challenges are met, the use of donepezil as an augmentation of memory in nondemented populations is not warranted.
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Acknowledgments |
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Footnotes |
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Received for publication August 17, 2007. Accepted for publication March 11, 2008.
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