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Down Syndrome and Alzheimer Disease
Response to Donepezil
Ira T. Lott, MD;
Kathryn Osann, PhD;
Eric Doran, BS;
Linda Nelson, PhD
Arch Neurol. 2002;59:1133-1136.
ABSTRACT
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Background Individuals with Down syndrome who develop Alzheimer disease may show
an improvement in cognitive functioning after treatment with acetylcholinesterase
inhibitors.
Objective To determine whether individuals with Down syndrome and Alzheimer disease
will show improvement after institution of donepezil treatment.
Design A nonrandomized controlled trial using donepezil in a pilot study format.
Setting Academic medical center.
Patients Convenience sample of 6 treated patients with Down syndrome and 9 closely
matched historical control subjects.
Intervention Oral administration of donepezil for a 5-month period.
Primary Outcome Measure The Down Syndrome Dementia Scale.
Results Significant improvement in dementia scores for the treated group during
a 3- to 5-month period (P = .03).
Conclusions Acetylcholinesterase inhibitors may be helpful in reversing the symptoms
of dementia during early and middle stages of cognitive decline. These findings
support the rationale for a more extensive study of the efficacy of acetylcholinesterase
inhibitors in Down syndrome dementia.
INTRODUCTION
PEOPLE WITH Down syndrome (DS) are at risk of developing the dementia
associated with Alzheimer disease (AD). After age 35 years, virtually all
individuals with DS have developed the neuropathologic characteristics of
the disorder, although a smaller percentage undergo symptoms of cognitive
decline.1 The topography of cell loss secondary
to AD in DS parallels the changes seen in AD in the general population and
involves neurons responsible for cholinergic neurotransmission.2
In both AD and DS, a similar cholinergic deficit has been implicated in the
progressive impairment of cognitive, language, and behavioral functioning.3
To date, the most successful clinical strategy to enhance cholinergic
neurotransmission in AD has been through use of acetylcholinesterase inhibitor
drugs.4 The acetylcholinesterase inhibitor
donepezil has been shown to improve language production, comprehension, word
finding, and the ability to follow commands in patients with AD in the general
population.5-6 Despite widespread
use of donepezil for AD in the general population, there are few, if any,
controlled studies of this drug to treat dementia in DS. We present the results
of an open-label pilot study of donepezil to treat symptoms of dementia in
DS.
SUBJECTS AND METHODS
From a database containing data on 46 patients, the study included 9
who were treated with donepezil and 6 who served as nontreated controls. All
subjects in this study lived within community residences. The 9 treated subjects
with DS and dementia received donepezil for up to 6.25 months. Dementia was
assessed before treatment and after a minimum follow-up of 3 months by means
of the Down Syndrome Dementia Scale (DSDS).7
The DSDS is an informant-based measure in which information is gathered on
changes in cognitive and daily living skills. Sixty questions are divided
equally under 3 categories indicating early, middle, and late stages of dementia.
All subjects met middle-stage criteria for dementia according to the DSDS
before initiation of treatment. Specific criteria met by all study subjects
and control subjects included a cognitive cutoff score on the DSDS of 3 or
greater and an early- and a middle-stage tally (EMT) of 17 or greater. Data
available included descriptive age, sex, assessment of dementia at multiple
time points, months of follow-up between assessments, and dose and duration
of treatment with donepezil.
A comparable group of patients with DS and dementia who had not been
treated with donepezil was selected from the database for comparison. Eligible
control subjects were required to meet middle-stage criteria for dementia
according to the DSDS (as described above), to have had at least 2 assessments
for dementia by means of the DSDS, and to have had no previous or concurrent
treatment with donepezil or other psychotropic medications. The comparison
group consisted of 6 subjects who had been studied during a 12-month period
before the approval of donepezil use for treating AD by the Food and Drug
Administration.
The remainder of the patients in the database pool were excluded from
the study for the following reasons: (1) Twelve were excluded because they
had only 1 assessment with the DSDS (mean DSDS EMT at only assessment, 4.00;
SD, 4.75), and this assessment did not meet the criteria for middle-stage
dementia. (2) An additional 14 subjects were excluded because, although they
were tested at multiple time points, none met the middle-stage criteria for
dementia at any of the assessments. In these patients, the mean EMT at baseline
and after an average of 12 months of follow-up was 4.14 (SD, 4.52) and 4.07
(SD, 4.65), respectively. These figures reflected an average change of –0.08
points per month of follow-up. (3) Three subjects were excluded because of
use of tacrine (pre- and post-DSDS EMTs, 17.67 and 16.33, respectively, after
an average follow-up of 11.3 months). (4) Two patients were excluded because
of pseudodementia secondary to other psychotropic medication (pre- and post-DSDS
average EMTs of 7.50 and 3.00, respectively, after 15 months of follow-up).
The group of excluded patients did not differ from the treated or untreated
cohort with respect to age, sex, or concomitant medical conditions, including
seizures. The 3 patients with dementia who were receiving tacrine did not
differ from the study sample in regard to magnetic resonance imaging findings
or pathologic reflexes.
Data were compared by means of nonparametric tests for comparison of
2 groups. Differences between groups for continuous variables were tested
with the Mann-Whitney test. For categorical data, differences were tested
by the Fisher exact test (2-tailed).
RESULTS
Nine patients with DS were treated with donepezil for a mean (SD) of
127.7 (33.9) days (range, 83-182 days; SEM, 11 days). Patients received an
initial daily dose of 5 mg for a mean (SD) of 50.9 (46.6) days and were then
increased to a daily dose of 10 mg for 78.2 (59.5) days.
Treated and control subjects were comparable with respect to initial
level of dementia, length of follow-up, and age. At their pretreatment assessment,
the patients treated with donepezil averaged 52.3 (SEM, 1.4) years of age
compared with an average age of 52.5 (SEM, 2.6) years for the comparison group
(Mann-Whitney test for difference, P = .86). Treated
patients were followed up for a mean of 136.0 (SEM, 11.3) days before reassessment,
whereas control subjects were followed up for 147.2 (SEM, 8.6) days (Mann-Whitney
test for difference, P = .41). At baseline, patients
who were subsequently treated with donepezil received an averaged assessment
for early plus middle dementia of 30.4 (SEM, 2.3) on the DSDS compared with
an initial level of dementia of 29.0 (SEM, 2.6) (Mann-Whitney test for difference, P = .72).
Subjects were reassessed by means of the DSDS after an average time
interval of 5 months (Table 1).
Patients treated with donepezil improved in terms of dementia test scores
(mean, 24.3; SEM, 4.0) relative to control subjects, who failed to demonstrate
a significant change in scores over time (mean, 30.7; SEM, 3.0). When the
change in DSDS over time was compared between donepezil-treated patients and
control subjects, the difference was statistically significant (P = .03).
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Table 1. DSDS Scores for Treated and Nontreated Patients*
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Results of independent clinical evaluation of the entire sample generally
confirmed the results of the DSDS assessment. Six of 8 patients were judged
to have improved by clinical impression of the neurologist (I.T.L.), who was
blind to the DSDS results. None of the 4 patients examined in the comparison
group was judged as improved. Clinical evaluations were not available on all
patients; hence, numbers were small and the difference was of borderline statistical
significance (Fisher exact test, P = .06).
As part of our ongoing assessment of dementia in DS, many of the subjects
included in this study had been assessed by means of the DSDS questionnaire
at additional time points before the beginning of the treatment period. A
dementia assessment was completed an average of 4.1 times (range, 0-9) from
1 to 18 months before baseline study assessment (time 0). Because of the variable
length of time between early measurements and start date for the study, all
past measurements on the DSDS were averaged to give 1 prestudy composite score
of dementia for each patient. As reflected in Table 2, the level of dementia increased in both groups during the
period preceding the initiation of medication and increased at the same rate
during this period. The mean change from prestudy to baseline for the donepezil-treated
group was 7.19 (SEM, 1.45) during an average of 11.9 months, or 0.61 points
per month. By contrast, the mean level of dementia scores in the control group
increased by 3.65 (SEM, 0.96) during an average of 5.8 months (0.62 points
per month) (P = .89 for difference between groups
in rate of increase). In the approximately 5 months after the study start
date, the level of dementia in the subjects treated with donepezil improved,
reflected in an average decline of 1.36 points per month of follow-up, while
the control group continued to demonstrate higher measures of dementia over
time (an increase of 0.32 point on the DSDS per month; P = .04 for the difference in rate between the treated and control
groups).
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Table 2. DSDS Scores Over Time*
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COMMENT
Results showed that, in a small sample of individuals with DS, the use
of donepezil in an open-label pilot trial was associated with a significant
improvement in cognitive functioning, as reflected by lower scores on the
DSDS, compared with a closely matched control group. All subjects met the
criteria for middle-stage dementia on the DSDS, indicating that the disease
was moderately advanced. This improvement held not only at the 5-month time
points but also when composite scores of test results before the use of donepezil
were compared between the 2 groups. There was no evidence that the treated
and control patients differed in their rate of decline before treatment was
begun. Improvement in patient status was also demonstrated by the results
of clinical neurologic examination by global impression of the neurologist.
Our clinical and psychological assessment of dementia in DS addressed
the International Classification of Diseases, 10th Revision, criteria for the diagnosis of AD in DS as reviewed by Aylward et
al.8 The DSDS was chosen as an informant-based
measure to document the degree of dementia and possible changes within the
time span of the study. This scale has been used to identify cognitive decline
in DS during a period of 6 months to 3 years.9-10
In a comparison of a clinician's diagnosis of dementia in DS and the DSDS,
a specificity of 0.89 and a sensitivity of 0.85 were found for a group of
62 adults with DS, 26 of whom were demented.11
In this study, a good correlation was found between the DSDS and other observer
scales for dementia in DS.
After the use of donepezil, Kishnani et al12
reported an improvement in physician's global impression, diaries of caregivers,
and the Vineland Adaptive Behavioral Scale in 2 patients with DS who met Diagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, criteria for dementia. In keeping with Kishnani and coworkers'
observations, no adverse events related to cholinergic side effects were observed
with the medication in our treatment group. Specifically, we did not observe
adverse effects of peripheral cholinergic overstimulation that were described
by Hemingway-Eltomey and Lerner13 in 3 patients
with DS treated with donepezil.
The purpose of the present study was to observe the short-term efficacy
of donepezil for treating symptoms of dementia in DS. In a study of 282 patients
in the general population with AD, Evans et al6
found improved cognitive functioning in more than 65% of patients with AD
reaching 3 months or more of treatment with donepezil. Kishnani et al12 noted that most improvement in 2 patients with Down
syndrome and dementia occurred in the first 3 months.
In a cohort of patients from the general population with moderate to
severe AD, Feldman et al14 found that the donepezil-treated
group was significantly improved compared with control subjects at least up
to week 24. Doody et al15-16 reported
that donepezil showed efficacy during at least the first year of therapy.
It is not yet clear whether the more sustained cognitive improvement noted
in patients with AD but no Down syndrome will be seen in DS.
The drawbacks of this study included small sample size, nonblinded observations
of the raters, criteria-based selection of subjects from a larger database,
and historical controls. However, based on the initial response of this cohort
of patients with DS, further placebo-controlled trials of donepezil are indicated
for the treatment of dementia in DS.
AUTHOR INFORMATION
Accepted for publication February 26, 2002.
Author contributions: Study concept and design (Dr Lott); acquisition of data (Drs Lott
and Nelson and Mr Doran); analysis and interpretation of data (Drs Lott and Osann and Mr Doran); drafting of the manuscript (Drs Lott, Osann, and Nelson); critical revision of the
manuscript for important intellectual content (Drs Lott
and Osann and Mr Doran); statistical expertise (Dr
Osann); obtaining funding (Dr Lott); administrative,
technical, or material support (Drs Lott and Nelson);
study supervision (Dr Lott).
This study was supported in part by grants AG 05142 and HD 94020 from
the National Institutes of Health, Bethesda, Md.
Corresponding author and reprints: Ira T. Lott, MD, University of
California, Irvine Medical Center, 101 The City Dr S, Bldg 2, Third Floor,
Orange, CA 92868-4482 (e-mail: Itlott{at}uci.edu).
From the Departments of Pediatrics (Dr Lott and Mr Doran), Medicine
(Dr Osann), and Neurology (Drs Lott and Nelson), University of California,
Irvine.
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