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1177/0269215510376004
Received 11th January 2010; returned for revisions 10th April 2010; revised manuscript accepted 1st May 2010.
Introduction
inhibitor (donepezil) for at least three months. Of Patients were evaluated at the beginning
the 32 subjects on donepezil, 20 subjects were and at the end (after 10 weeks of training)
taking 10 mg and 12 were taking 5 mg. of the study by an independent psychiatrist,
blind to neuropsychological test results and
patients’ treatment groups.
Assessment instruments
Procedures
1) Psychopathological assessment was based on
Thirty-two participants were arranged in years
the Neuropsychiatric Inventory21 interview
and allocated to the two study groups according to
with a caregiver within the four weeks prior a computerized block randomization process after
to the study. Total caregiver distress score was baseline ratings were made (block randomization
obtained from the sum of distress scores was used to keep the age of participants in the
across all 10 subscales. different groups closely balanced). Sixteen partic-
The Neuropsychiatric Inventory, developed ipants were assigned to each of the two groups.
to assess behavioural disturbances in demen- During the 10-week period, intervention sessions
tia patients and behaviour-related caregiver were conducted individually twice a week by two
distress, consists of 10 domains/subscales trained activity therapists. Each session was
that are designed to rate specific behavioural 45 minutes long. There were no missed interven-
characteristics (delusions, hallucinations, agi- tion visits in either condition. The dosage of done-
tation/aggression, depression/dysphoria, anx- pezil was unchanged during the study period. The
iety, elation/euphoria, apathy/indifference, intake of psychoactive medications was not per-
disinhibition, irritability/lability, and aberrant mitted during the study period (Figure 1).
motor behaviour). For each domain, fre-
quency is rated from 1 (occasional, less than
once per week) to 4 (very frequent, daily or
continuous). Severity is rated from 1 (mild) to Cognitive stimulation therapy
3 (severe). If the symptom is absent, the Cognitive stimulation therapy was administered
domain score is zero (0). The product of individually and focused on a set of tasks requiring
severity and frequency ranges from 1 to 12 executive functions and working memory. An
points for each behaviour assessed with a appropriate level of difficulty was selected for
total score for all 10 behaviours ranging each patient on each set of tasks as described
from 1 to 120 points; higher scores indicate below.
more severe psychopathology. In addition,
the caregiver is asked to score his or her
own distress level as it relates to the patient’s The Reality Orientation Task
behaviour on an anchored 0–5 point rating Widely used in the rehabilitation of subjects
scale. The total caregiver distress score is with dementia, the Reality Orientation Task may
generated by adding the distress-related item delay nursing home placement and slow down the
scores (total possible score ¼ 50). Evaluations progression of cognitive decline in patients with
were based on both clinical impressions and mild to moderate Alzheimer’s disease. Verbal ori-
information provided by a caregiver who had entation is the ability to answer questions relating
daily contact with the patient and was famil- to time, place, and person orientation. The cogni-
iar with the patient’s behaviour. Caregivers tive stimulation therapy session always started
were encouraged to use weekly diaries as a with the Reality Orientation Task.
memory aid to record neuropsychiatric or
other symptoms.
2) The Mini Mental State Examination23 score The Fluency Task
was used to identify clinically significant The Fluency Task included verbal fluency
decline in cognitive functioning. (based on the Direct Assessment of Functional
4 Y-X Niu et al.
Analysis (n = 16, for clinical tests) Analysis (n = 16, for clinical tests)
Status (DAFS)) and category fluency. The verbal The Photo-Story Learning Task
fluency task required participants to list as many This task is intended to stimulate the encoding
words as possible starting with a Chinese verb and retrieval of episodic memory, one of the most
(‘Cai’, ‘Pin’ or ‘Fa’) within a time limit, while the impaired cognitive functions in Alzheimer’s dis-
category fluency task required participants to ease. In addition, the summarizing component is
recite as many words as possible from a specified related to abstract thinking, which is an important
category during a 1-minute interval. These tasks element of executive function. A set of photos
require cognitive flexibility in organizing and was used for training working memory and for
selecting lexical information, generation of a producing short stories. Several questions (with
search strategy and the ability to switch from two levels of difficulty) related to the photos
one category to another while inhibiting the pre- were asked. The difficult questions were more
ceding category. abstract (e.g. ‘What familiar relationship do
these people have?’) while the simpler questions
were more concrete (e.g. ‘How many boys are in
the picture?’).
The Overlapping Figure Task Task difficulty was adapted to individual
The Overlapping Figure Task demands partici- performance level based on the errorless learning
pants to identify and name as many figures as paradigm24,25 which has been shown to decrease
possible from a black and white array of many frustration and increase success during cogni-
overlapping figures. Numbers, letters, animals tive stimulation therapy sessions, leading to
and objects of different dimensions can be recog- enhanced learning in Alzheimer’s disease
nized and selected. The aim of this task is to facil- patients. If a patient stumbled over performance
itate the ability to identify, select and recognize of a task, the therapist would give sufficient
shapes from a background; to increase cognitive clues to ensure successful performance. If
flexibility in identifying different overlapping the patient appeared frustrated, priority was
shapes; and to inhibit those shapes already recog- given to psychological support over cognitive
nized from the same pattern. stimulation.
Cognitive stimulation therapy in Alzheimer’s disease 5
Placebo condition (mock intervention) Table 1 Baseline demographic and clinical characteristics of
As the control group, patients in the placebo the participants
condition participated in a communication exer- Characteristics CST (n ¼ 16) Control (n ¼ 16) P-value*
cise (controlling for time and attention). The com-
munication exercise was administered individually Age (years) 80.56 (4.23) 79.13 (4.38) 0.352
and focused on: (1) discussing recent topics (e.g. Female 2 (12.5%) 5 (31.3%) 0.394
Education (years) 10.56 (1.90) 10.81 (1.87) 0.710
activities from the day prior) and important life MMSE scores 16.93 (3.02) 17.31 (3.24) 0.737
events (e.g. hobbies and enjoyable activities) and NPI-total 14.06 (5.69) 13.69 (4.60) 0.839
(2) learning about progress in current Alzheimer’s NPI-distress 8.88 (4.00) 8.56 (3.24) 0.810
disease research and external memory aids that
may be effective. The exercises focused on conver- Data are presented as mean (SD) or n (%).
sational interaction and psychological support CST, cognitive stimulation therapy; MMSE, Mini Mental
State Examination; NPI, Neuropsychiatric Inventory.
rather than practice or drills (as with the experi- *Based on the independent t-test or Fisher’s exact test.
mental cognitive stimulation therapy condition)
and were unstructured and relaxed (e.g. watching
television games and having the caregiver read
news items to the patient without encouraging from the study (two from the cognitive stimulation
discussion). therapy group and one from the control group),
one post-baseline efficacy assessment had been
done. All patients who had a baseline evaluation,
completed one post-baseline efficacy assessment,
Statistical analyses and fulfilled intent-to-treat criteria were included
T-tests, and Fisher’s exact test when appropriate, in the intent-to-treat population for analysis.
were employed to compare the demographic and Table 2 compares changes in patient and care-
clinical characteristics of groups. The two groups giver outcomes between the two study groups.
were compared at baseline to confirm that success- Cognitive stimulation therapy appeared to have
ful randomization had been achieved. Data were an additive beneficial effect on neuropsychiatric
analysed based on intention to treat. Pre- and post- symptoms and cognition: in the treatment group,
treatment group data and change in scores were the Neuropsychiatric Inventory total score showed
compared using the Mann–Whitney U-test, and,
a significant improvement (–2.06 points,
when appropriate, T-tests for independent samples.
SE ¼ 0.35) compared with a slight decline (0.00
Baseline versus post-baseline assessments were
points, SE ¼ 0.26) in the control group
compared using the Wilcoxon text and pairwise
(t ¼ 4.766, P50.001). Similarly, the Mini
t-test for related samples when appropriate. All
Mental State Examination score improved by
tests were two-tailed, using a probability level of
0.81 points, (SE ¼ 0.28) in the treatment group
0.05 as an indicator of statistical significance.
and declined by 0.19 points (SE ¼ 0.16) in the con-
Correlativity between change in the Mini Mental
trol group (t ¼ 3.106, P ¼ 0.004). The initial
State Examination score and change in the total
Neuropsychiatric Inventory score was assessed by descriptive analysis showed outliers change from
Pearson’s correlation coefficients. baseline on the 10 individual Neuropsychiatric
Inventory domains, Therefore, a non-parametric
test, the Mann–Whitney U-test for independent
samples, was used to compare the treatment
Results groups on the change from baseline in
Neuropsychiatric Inventory domains. Analysis of
The baseline measures of common demographic the 10 individual Neuropsychiatric Inventory
variables, the Mini Mental State Examination, domains from baseline to endpoint revealed
and Neuropsychiatric Inventory scores did not sig- a statistically significant benefit of cognitive stim-
nificantly differ between the two treatment groups ulation therapy treatment in the domains of
(Table 1). Subject disposition is detailed in the apathy (Z ¼ 2.594, P ¼ 0.017) and depression
flow chart (Figure 1). As three patients withdrew (Z ¼ 2.437, P ¼ 0.047). There were no significant
6 Y-X Niu et al.
Table 2 Mini Mental State Examination and Neuropsychiatric Inventory scores and analyses showing changes from baseline
to week 10
MMSE 16.94 (3.02) 17.31 (3.23) 0.737 0.81 (1.11) –0.19 (0.66) 0.004
Del 1.06 (1.44) 1.13 (1.26) 0.897 0.13 (0.34) 0.06 (0.25) *0.780
Del-distress 0.94 (1.18) 1.00 (1.10) *0.867 0.06 (0.25) –0.13 (0.34) *0.402
Hal 0.63 (1.20) 0.38 (0.81) *0.724 0.00 (0.00) 0.00 (0.00) *1.000
Hal-distress 0.63 (1.15) 0.44 (0.96) *0.752 –0.06 (0.25) 0.00 (0.00) *0.780
Agit 2.50 (2.48) 2.13 (2.13) 0.649 –0.50 (0.97) –0.13 (0.50) *0.381
Agit-distress 1.38 (1.31) 1.38 (1.31) 1.000 –0.25 (0.58) –0.06 (0.25) *0.361
Dys 1.75 (1.61) 1.88 (1.71) 0.833 –0.50 (0.73) 0.06 (0.68) *0.047
Dys-distress 1.00 (0.89) 1.06 (0.93) 0.848 –0.06 (0.25) 0.00 (0.37) *0.780
Anx 1.63 (1.67) 1.93 (1.65) 0.598 –0.19 (0.75) 0.13 (0.34) *0.423
Anx-distress 0.94 (0.93) 1.19 (0.91) 0.448 0.00 (0.37) –0.06 (0.57) *0.985
Euph 0.25 (0.68) 0.13 (0.50) *0.780 0.00 (0.00) 0.00 (0.00) *1.000
Euph-distress 0.31 (0.87) 0.19 (0.75) *0.780 0.00 (0.00) 0.00 (0.00) *1.000
Apa 3.50 (1.86) 3.25 (1.61) 0.688 –1.06 (0.85) –0.31 (0.60) *0.017
Apa-distress 1.44 (1.03) 1.06 (0.85) 0.271 –1.19 (5.04) –0.13 (0.34) *0.642
Dis 0.63 (1.20) 0.38 (0.81) *0.724 0.00 (0.37) 0.06 (0.25) *0.780
Dis-distress 0.56 (1.03) 0.31 (0.70) *0.696 0.00 (0.37) 0.06 (0.25) *0.780
Irrit 1.13 (1.26) 1.69 (1.62) 0.282 0.06 (0.44) 0.06 (0.44) *1.000
Irrit-distress 0.94 (1.06) 1.19 (1.11) 0.520 0.06 (0.44) 0.06 (0.44) *1.000
Motor 1.00 (1.26) 0.81 (0.98) *0.809 0.00 (0.00) 0.06 (0.25) *0.780
Motor-distress 0.75 (0.93) 0.75 (1.00) *0.985 0.00 (0.00) –0.06 (0.25) *0.780
Total-NPI 14.06 (5.69) 13.69 (4.60) 0.839 –2.06 (1.39) –0.00 (1.03) 50.001
Total-NPI-distress 8.88 (4.00) 8.56 (3.24) 0.810 –0.31 (0.79) –0.31 (1.01) 1.000
improvements associated with cognitive stimula- cholinesterase inhibitor can benefit from cognitive
tion therapy treatment in the remainder of the stimulation therapy. We found not only a signifi-
Neuropsychiatric Inventory domains or in the cant effect on cognition but also a highly significant
caregiver distress score. effect on two domains of neuropsychiatric distur-
In the cognitive stimulation therapy group, there bance. Analysis of the ten Neuropsychiatric
was a trend towards negative correlation between Inventory domains separately showed that cogni-
change in the Mini Mental State Examination score tive stimulation therapy improves scores on
and change in the total Neuropsychiatric Inventory apathy and depression.
score (r ¼ 0.658, df ¼ 16, P ¼ 0.06). However, To our knowledge, this is the first randomized
there was no evidence of such an association in controlled clinical trial to analyse the effects of
the control group (r ¼ 0.493, df ¼ 16, P ¼ 0.53). cognitive stimulation/training interventions com-
bined with cholinesterase inhibitor therapy on
neuropsychiatric outcomes, and in particular the
Discussion ten individual Neuropsychiatric Inventory
domains. This study is also novel in its inclusion
The current findings indicate that mild to moderate of a comparison condition (i.e. the communication
Alzheimer’s disease patients on a stable dose of a exercise) that allowed the examination of the
Cognitive stimulation therapy in Alzheimer’s disease 7
impact of non-specific variables (e.g. therapist may be accounted for by differences in cultures
contact, familiarity with tests in follow-up assess- and residential status29 which may have an effect
ments) on outcome. on outcomes in assessing the effect of treatment on
Previous studies have shown that social contact behaviour.
intervention may reduce disturbing behav- Apathy and depression in Alzheimer’s disease
iours.26,27 We controlled for the effects of social patients are related to underlying neurobiological
contact experienced in cognitive stimulation ther- changes in the brain. Recent neurobiological stud-
apy by providing a control group that experienced ies30–32 have implicated hypoperfusion in the ante-
time and attention from a therapist. We found a rior cingulate gyrus and dorsolateral prefrontal
significant effect of cognitive stimulation therapy regions in depressive symptomatology. In addi-
compared with the control experience on apathy, tion, Holthoff et al.32 found hypometabolism in
depression and cognition, suggesting that the the orbitofrontal regions in Alzheimer’s disease
effects were not mediated through social contact patients with apathy. Moreover, both the anterior
or attention. Participants entering the study had cingulate gyrus and the prefrontal cortical regions
received treatment with donepezil for at least may play an important role in monitoring control
three months, the time required for maximum over conflicting response systems and task diffi-
drug efficacy.28 Therefore, the results from the culty (‘executive function’).33,34 Thus, both the
study also cannot be attributed to the effects of behavioural symptoms (apathy and depression)
medication. Since psychotropic medications were and some specific executive functions (inhibitory
unchanged before and during participation, it is control and divided attention) may have an over-
unlikely that improvements of cognition and neu- lapping anatomical basis in the frontal lobe.35–37
ropsychiatric symptoms were brought about by In the cognitive stimulation therapy group, the
pharmacological treatment. Moreover, all partici- presently observed trend towards negative correla-
pants lived in a specific region under relatively tion between change in the Mini Mental State
similar environmental conditions. Therefore, the Examination score and change in the total
effect of environmental conditions in the study Neuropsychiatric Inventory score, with no appar-
results can also be excluded. ent association in the control-treated group, is
Several published studies agree with the present consistent with the possibility.
results showing a positive effect of specific cognitive Previous studies have shown that increases in
rehabilitation procedures on neuropsychiatric regional cerebral blood flow and metabolism are
symptoms. Yet, there are noteworthy differences linked to performance of cognitive tasks.38,39 cog-
between our findings and prior findings. For exam- nitive stimulation therapy stimulates brain func-
ple, Talassi demonstrated that mild Alzheimer’s dis- tions such as complex attention, working
ease patients enrolled in a computerized cognitive memory, flexibility, self-monitoring abilities, and
training programme significantly improved in anx- reasoning and abstract thinking, which are espe-
iety and depression symptoms.20 A survey study19 cially vulnerable in mild Alzheimer’s disease
concerning the rehabilitation of mild to severe patients.40 These elements are important features
Alzheimer’s disease patients in a specialized unit of executive functioning. Moreover, cognitive
suggested that a comprehensive rehabilitation treat- stimulation therapy may be associated with neuro-
ment programme may have beneficial effects on biological changes in extensive association corti-
neuropsychiatric outcomes, particularly with ces, especially in the frontal lobe region,41 an
respect to apathy and agitation. In our study, a area associated with apathy and depression.32
difference in inclusion criteria could account for Activating these association cortices by cognitive
the discrepancy. While other studies have not stimulation therapy may partly enhance metabo-
used the presence or absence of neuropsychiatric lism and regional cerebral blood flow,38,39 thus
symptoms as inclusion criteria, the participants in leading to the beneficial effects and improvement
the present study all had a total Neuropsychiatric in the functioning of these cortices. Future
Inventory score greater than 5 points arising from research should include neurobiological correlates
at least two domains of behaviour at baseline. of neuropsychological benefits resulting from cog-
Another possible explanation for discrepancies nitive stimulation therapy.
8 Y-X Niu et al.
The psychological mechanisms underlying the as a decrease in the apathy and depression
beneficial effects of cognitive stimulation therapy domains than did patients receiving the control
may also provide important insight. The errorless treatment. This analysis suggests that cognitive
learning paradigm24,25 was used during cognitive stimulation therapy should be considered as a
stimulation therapy sessions in the present study, therapeutic option for patients with mild to mod-
favouring the elimination or reduction of incorrect erate Alzheimer’s disease with neuropsychiatric
or inappropriate responses. The errorless learning disturbances.
paradigm decreases patient frustration and errors
during cognitive stimulation therapy. Learning,
retention and retrieval during the exercise should Clinical messages
therefore be easy, making the patient feel more
successful. It has been proposed42 that depression Cognitive stimulation therapy has signifi-
in Alzheimer’s disease patients arises as a reaction cant efficacy in lowering apathy and depres-
to the mourning of cognitive deficits. It is possible, sion symptomatology and in the Mini
therefore, that the increase in successful experi- Mental State Examination in patients with
ences through cognitive stimulation therapy may mild to moderate Alzheimer’s disease.
have enhanced the patient’s self-confidence or psy- Cognitive stimulation therapy should be
chological well-being and in turn decreased his or considered as a therapeutic option for
her psychological distress, leading to the improve- patients with mild to moderate Alzheimer’s
ment in Neuropsychiatric Inventory scores. disease with neuropsychiatric disturbances.
Some methodological considerations have to be
taken into account in the interpretation of the pre-
sent findings. First, our sample size is small. The Acknowledgements
limitation of a small sample size is the increased This research was supported by China
possibility of detecting small and clinically insig- Postdoctoral Science Foundation (Grant No.
nificant results. Our results require replication in a 20090461434).
larger sample. Second, we could not control the
effects of either care services or social networks
on the Neuropsychiatric Inventory of the References
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