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A randomised pilot study to assess the efficacy of
an interactive, multimedia tool of cognitive
stimulation in Alzheimer’s disease
L Tárraga, M Boada, G Modinos, A Espinosa, S Diego, A Morera, M Guitart, JBalcells, O L López and J T Becker
2006;77;1116-1121; originally published online 4
J. Neurol. Neurosurg. Psychiatry
Jul 2006; doi:10.1136/jnnp.2005.086074
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A randomised pilot study to assess the efficacy of an
interactive, multimedia tool of cognitive stimulation
in Alzheimer’s diseaseL Ta´rraga, M Boada, G Modinos, A Espinosa, S Diego, A Morera, M Guitart, J Balcells,O L Lo´pez, J T Becker. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
J Neurol Neurosurg Psychiatry 2006;77:1116–1121. doi: 10.1136/jnnp.2005.086074
Objective: To determine the usefulness of an interactive multimedia internet-based system (IMIS) for the
cognitive stimulation of Alzheimer’s disease.
Methods: This is a 24-week, single-blind, randomised pilot study conducted on 46 mildly impaired
. . . . . . . . . . . . . . . . . . . . . . .
patients suspected of having Alzheimer’s disease receiving stable treatment with cholinesterase inhibitors
(ChEIs). The patients were divided into three groups: (1) those who received 3 weekly, 20-min sessions of
IMIS in addition to 8 h/day of an integrated psychostimulation program (IPP); (2) those who received only
IPP sessions; and (3) those who received only ChEI treatment. The primary outcome measure was the
Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-Cog). Secondary outcome measures were: Mini-
Mental State Examination (MMSE), Syndrom Kurztest, Boston Naming Test, Verbal Fluency, and the
Rivermead Behavioral Memory Test story recall subtest.
Results: After 12 weeks, the patients treated with both IMIS and IPP had improved outcome scores on the
ADAS-Cog and MMSE, which was maintained through 24 weeks of follow-up. The patients treated with
IPP alone had better outcome than those treated with ChEIs alone, but the effects were attenuated after
24 weeks. All patients had improved scores in all of the IMIS individual tasks, attaining higher levels of
Accepted 20 June 2006Published Online First
Conclusion: Although both the IPP and IMIS improved cognition in patients with Alzheimer’s disease, the
IMIS program provided an improvement above and beyond that seen with IPP alone, which lasted for
. . . . . . . . . . . . . . . . . . . . . . .
Alzheimer’s disease is the most frequent form of Despitetheprogressivenatureofthedegenerativeprocess,
dementia in elderly people,1 2 and its current treatment
patients with Alzheimer’s disease also seem to retain the
includes cholinesterase inhibitors (ChEIs),3–5 and N-
physiological capacity to alter brain structure and function.
methyl-D-aspartate receptor blockers (eg, memantine).6
Recent studies have shown cognitive plasticity and learning
However, symptomatic treatment often entails non-pharma-
potential not only in patients with Alzheimer’s disease but
cological treatments as well, and adequate dementia manage-
also in healthy elders.22 23 Positron emission tomography
ment requires a wide range of intervention to help maximise
studies that used activation paradigms24 25 have found that
the patient’s independence, increase their self-confidence
people with Alzheimer’s disease have a greater activation
and relieve burden to the care giver.
than those without dementia in the brain regions usually
Current symptomatic treatment of Alzheimer’s disease can
associated with memory tasks, as well as in the frontal lobes
improve cognition and functionality.3–6 However, before the
that were activated only with increasing difficulty of tasks.
emergence of these drugs, non-pharmacological treatments
Pathological studies conducted on biopsy specimens of
had already been evaluated and cognitive stimulation had
patients with Alzheimer’s disease with mild or moderate
been found to be potentially beneficial for patients with
dementia have shown increased synaptic contact size.26 Thus,
dementia.7–9 Although these non-pharmacological treatments
the brain may be able to compensate during the early stages
do not always seem efficacious, methodological problems
of Alzheimer’s disease, suggesting that there may be some
may limit the validity of some studies.10 A recent Cochrane
utility to non-pharmacological adjunctive interventions.
review11 emphasised caution when interpreting the results of
Although studies on cognitive stimulation show that it is
non-pharmacological treatments, but suggested that certain
possible to stimulate the memory of patients with Alzheimer’s
cognitive domains could, in fact, benefit from these types of
disease, the results are often modest. Because of methodolo-
gical limitations, there is a need to conduct more randomised-
Clinical and laboratory studies have shown that mental
controlled trials with larger samples to validate this therapeutic
and physical activity can positively influence cognition in
approach. Computerised systems27 and internet-based distance
normal elderly people and people with dementia. Education12
programs offer one potential mechanism by which non-
and lifestyle choices (eg, occupation and leisure activities)13–15
pharmacological cognitive stimulation can be conducted in
can modulate the risk of developing dementia, and psycho-motor stimulation improves cognition in patients withAlzheimer’s disease.16 17 Environmental enrichment can
Abbreviations: ADAS-Cog, Alzheimer’s Disease Assessment Scale-
Cognitive; BNT, Boston Naming Test; ChEIs, cholinesterase inhibitors;
improve cognition in transgenic mice.18 19 Despite the
GDS, Global Deterioration Scale; IMIS, interactive multimedia internet-
continued deposition of b-amyloid, exercise can increase
based system; IPP, integrated psychostimulation program; MMSE, Mini-
the levels of brain-derived neurotrophic factor20 and may
Mental State Examination; RBMT, Rivermead Behavioral Memory Test;
Multimedia tool of cognitive stimulation in Alzheimer’s disease
patients with dementia. In this study, we evaluated an
N Experimental group: These patients received the IMIS, as
interactive multimedia internet-based system (IMIS) as an
adjunct to ChEI treatment and classic psychostimulation
N IPP control: These patients received IPP and ChEIs.
N ChEIs control: These patients received only ChEIs.
The ChEIs group comprised of patients who were
diagnosed with Alzheimer’s disease, but who were living at
Forty six patients suspected of having Alzheimer’s disease28
home, and never received the IPP or the IMIS. These patients
were recruited for the study through a referral clinic and
either did not want to come to the daycare centre, although
they agree to be followed clinically, or were on a waiting list
`ncies Aplicades, Barcelona, Spain). The Institut
for admission to the daycare centre. The experimental and
`ncies Aplicades is a referral diagnostic
the IPP control groups were participants in the daycare
clinic for community-dwelling people with dementia, and
centre, and the only difference between these two groups was
also provides adult daycare services to these patients. All of
that the experiment group received the IMIS. Written
the patients had been treated with ChEIs for at least 1 year
informed consent was obtained from all the participants
before inclusion to the study. The inclusion criteria were:
enrolled in the study and their legal representative before the
Three patients in the experimental group dropped out of
the study: one because of rapid progression of the disease and
a Mini-Mental State Examination (MMSE)29 30 score
two because of institutionalisation. Consequently, from the
initial sample of 46, 43 patients completed the study: 15 in
N a Global Deterioration Scale (GDS)31 score of 3 or 4;
the experimental group, 16 in the IPP control group and 12 in
N absence of uncontrolled disruptive behaviours (eg, aggres-
sion, delusions, hallucinations and agitation) that couldinterfere with program administration and/or neuro-
These patients received the IMIS, IPP and ChEIs.
N absence of major depression, current or partial remission32;N
absence of structural lesions in the computed tomogram or
These patients received IPP and ChEIs.
N absence of history of alcohol or other substance abuse; and
N absence of severe auditory, visual or motor deficits that
may interfere with cognitive testing.
No significant differences were observed between the
groups in terms of age (F2,41 = 0.72) or level of education
None of the participants had previous experience with a
(x2 = 5.513, df = 4, p = 0.239). There was a tendency for a
personal computer and all attended the daycare centre
difference in the proportion of male patients, primarily
5 days/week. Participants were allowed to be on stable doses
because all the patients in the ChEI group were female;
however, the difference was not significant (x2 = 5.70, df = 2,p = 0.06).
Patients were assessed at study entry, and after 12 and
The IMIS was conducted using Smartbrain (http://www.
24 weeks of treatment. The primary outcome measure was
educamigos.com), an interactive multimedia tool that allows
the Alzheimer’s Disease Assessment Scale-Cognitive (ADAS-
patients to carry out a variety of different stimulation
Cog) section.33 This is a standardised measure of cognitive
programs, at different levels of difficulty and at various
function that examines components of memory, language,
times during the day. Briefly, the IMIS program consists of 19
visuoconstructional and ideational praxis, and orientation.
separate ‘‘tasks’’ or stimulation exercises across the domains
High ADAS-Cog scores indicate worse performance. The
of attention, calculation, gnosis, language, memory and
orientation. All participants began at the lowest level of
N MMSE: This is a global measure of cognitive function that
difficulty (first of 15 levels) and the program monitored
examines orientation to time and place, immediate and
activity at each level. Difficulty increased automatically after
delayed recall of three words, attention and calculation,
three consecutive performances within a single task without
language and visuoconstructional functions.
error, or when a patient was 80% correct over six consecutive
N Syndrom Kurztest (SKT)34: This is a short cognitive perfor-
sessions. A patient’s level of difficulty decreased when his or
mance test that examines memory and attentional
her performance fell below 15% correct for three consecutive
sessions or ,20% correct for six consecutive sessions. All
patients were trained before the study with the use of the
Boston Naming Test (BNT)35: Patients must name 60 large
computer mouse, especially on how to ‘‘click and drag’’.
ink drawings that are presented to them by the examiner.
Table 1 Demographic characteristics of the patients
The IPP is a daily program in the daycare centre that includes
cognitive stimulation tasks, workshops (eg, music therapy,
art and crafts, and physical activity) and reinforcement of
instrumental activities of daily living.17 The IPP is integrated
into the daycare centre activities, and it takes 2 h in the
morning and 1.5 h in the afternoon out of the 8 h that the
Each patient was randomly assigned to one of three study
ChEI, cholinesterase inhibitor; IPP, integrated psychostimulationprogram.
The test is discontinued after eight consecutive failures.
differed from each other on the MMSE (D-lysergic acid
When the patient fails to name the drawing, the examiner
diethylamide test, p,0.05). After 24 weeks, group differences
provides a semantic cue; if still unable to name the
were still apparent on the ADAS-Cog (F2,42 = 3.08, p = 0.06,
drawing, a phonemic cue is provided.
N Verbal fluency: This includes letter generation (letter P) and
Reanalyses showed that the experimental group was better
than the ChEI control group on the ADAS-Cog (p,0.05),
N The story recall subtest from the Rivermead Behavioral Memory
whereas the experimental and IPP control groups differed
Test (RBMT)36: Patients listen to a short passage of a prose
from the ChEIs control group on the MMSE (p,0.05; fig 2).
being read aloud and then recall as much as they can.
There was no significant change in SKT scores over 24 weeks
Rapid Disability Rating Scale—2 (RDRS-2)37: This is an
assessment of three functional and behavioural areas:
Measures at week 12 and 24 are shown as compared with
(a) help with activities of daily living, (b) degree of
disability, and (c) degree of special problems (ie, mental
No significant differences were observed in the functional
confusion, uncooperativeness and depression). The RDRS-2
assessments, as measured by the RDRS-2 at baseline
was administered at baseline and at 24-week follow-up
examination (experimental group mean: 26.6 (SD 0.96),
IPP control: 27.3 (0.93), ChEI control: 24.4 (1.0); F2,42 = 2.16,
GDS31: This is a staging system of seven distinguishable
p = 0.12, r = 0.32), or after 24 weeks of follow-up (experi-
cognitive and functional stages, ranging from normal
mental group: 25.3 (1.1), IPP control: 25.6 (1.0), ChEI
(stage 0) to severe dementia (stage 7). All patients in the
control: 23.7 (1.2); F2,42 = 0.76, p = 0.47 , r = 0.14). The GDS
stage was 4 in all patients at baseline and in all follow-upevaluations.
The primary and secondary outcome measures were
Figure 3 shows the mean difficulty level obtained by the
administered to all participants in the experimental and IPP
patients over the course of the 24 weeks of treatment in each
control groups at all visits. Owing to manpower limitations,
of the six cognitive domains of the IMIS. Performance in all
the BNT, verbal fluency tests and RBMT (all secondary
cognitive domains showed an improvement, but most
outcome measures) were not administered to the ChEI
especially in the measures of attention and memory. In no
case did a patient’s performance level for any individualactivity actually decline over the course of the 24 weeks.
INTERACTIVE MULTIMEDIA INTERVENTIONPatients in the experimental group received a total of 72 IMIS
sessions, three times a week for 24 weeks. All of the patientsin the experimental group had the same computerised
This study shows that both classic cognitive stimulation
activities, order of presentation and session length. During
treatment and computer-based treatment improved cognition
the first 24 sessions, the IMIS sessions lasted only 15 min.
in patients who were treated with a stable dose of ChEI,
Sessions 25–28 lasted 20 min, and sessions 29–72 lasted
compared with those who were treated only with ChEIs. In
25 min. Because this was the first time that such a
addition, the IMIS program provided an improvement above
computerised multimedia program was applied for the
and beyond that seen with classic cognitive stimulation, with
cognitive stimulation of these patients, it was necessary to
improvement lasting 24 weeks. Not only did ADAS-Cog and
ensure tolerability and adequate dose to avoid fatigue or
MMSE scores fail to decline (as was seen in the ChEIs control
other possible negative effects that might arise from exposure
group) but scores also actually improved, and the improve-
to a PC. A minimum requirement was that the participants
ment was maintained over the 24 weeks that the IMIS was
completed 58 of 72 (80%) sessions, with an interruption of no
more than 10 days between sessions; all participants met this
The progression of illness observed in the ChEI control
group is consistent with what has previously been describedin subjects with prolonged exposure to ChEIs (.1 year).38 Onaverage, this group declined at a rate of approximately 2–3
MMSE points per year, which is slightly slower than is
The data were analysed using SPSS V.12. Descriptive
typical, but falls within the range of expected decline in mild
statistics were prepared at baseline, 12 weeks and 24 weeks.
Outcomes were assessed using one-way analysis of variance
These results show that it is possible to augment the effects
at each of the three critical time points.
of cholinesterase inhibition using cognitive stimulationprocedures, with the result that patients have improved
outcomes. These findings from the experimental group
Table 1 shows the characteristics of the groups.
cannot be explained simply by increased social contact or
No significant differences were observed between the three
interactions, as the experimental group and the IPP control
study groups on the ADAS-Cog (F2,42 = 0.67) or SKT
group attended the daycare centre. The IMIS greatly
(F2,42 = 0.84) at baseline, although the experimental group
augmented the traditional psychomotor stimulation, because
had slightly lower MMSE scores than the other groups
when both treatments were used together efficacy was
(F2,42 = 3.33, p = 0.046; table 2). There were no differences
extended to 24 weeks. Thus, it seems that an individually
between the experimental and the IPP control groups on the
constrained cognitive stimulation program such as the IMIS
other neuropsychological measures at baseline examination
used here is more efficacious than treatment only with drugs,
(the ChEI control group did not receive these additional four
and at least augments traditional psychostimulation. In
regard to the possible effects of IMIS-alone treatment, we
After 12 weeks of treatment, the three study groups
hypothesise that it would represent an improvement com-
differed in terms of the ADAS-Cog (F2,42 = 7.05, p = 0.002,
pared with non-treated patients and also with patients
r = 0.50) and the MMSE (F2,42 = 10.3, p,0.001, r = 0.57;
treated with ChEIs alone, as shown in previous studies.27 40
fig 1). Both experimental and IPP control groups were
The degree of difficulty of the problems is individually
superior to the ChEI control group on the ADAS-Cog (D-
adjusted to maximise success (and increase the challenges)
lysergic acid diethylamide test, p,0.05), and all three groups
for each patient. Although an understanding of the
Multimedia tool of cognitive stimulation in Alzheimer’s disease
Table 2 Neuropsychological characteristics at baseline, and at 12 and 24 weeks follow-up examination
ADAS-Cog, Alzheimer’s Disease Assessment Scale-Cognitive; BNT, Boston Naming Test; ChEI, cholinesterase inhibitor; IPP, integrated psychostimulationprogram; MMSE, Mini-Mental State Examination; RBMT, Rivermead Behavioral Memory Test; SKT, Syndrom Kurztest.
physiological basis of the efficacy of these individualised
other cognitive functions43 or activities of daily living
cognitive stimulation programs is beyond the scope of this
initial study, our findings and data from others suggest that
N training in ADLs (procedural memory stimulation) and its
plasticity remains possible in patients with Alzheimer’s
disease at the cellular level, and that these changes can
N psychosocial intervention programmes (ie, reality orienta-
modify disease progression.22–26 Cellular plasticity could thus
provide a substrate on which the improvements observed
combination of cognitive stimulation and counselling(patients and care givers)47;
No functional improvement was noted among the three
groups. This may be explained by the fact that these were
combination of cognitive rehabilitation with mental
mildly impaired patients (mean MMSE was 22.0), who
retained the physical or functional ability to participate in a
N combination of cognitive enhancers and computerised
cognitive or motor stimulation program, and did not exhibit
disruptive behaviours. Similarly, the ChEI control group was
N comprehensive cognitive and motor stimulation pro-
only mildly impaired, and they had sufficient support from
their care giver to come to the clinic for frequent evaluations.
Therefore, any change in functional capacity could have been
Although these approaches show varying degree of benefits
more difficult to measure in this cohort than in patients in
from non-pharmacological interventions in patients with
moderate or severe stages of dementia. In addition, it is
Alzheimer’s disease, it is difficult to establish comparisons
possible that the functional measures used in this study were
among studies, as the outcome measures and duration of the
not sensitive enough to detect subtle change.
interventions were not the same, especially when compared
There have been multiple methodological approaches to
with drug trials. Studies of non-pharmacological interven-
explore the benefits of non-pharmacological treatments in
tions should, therefore, use the same outcome measures and
patients with Alzheimer’s disease. These included studies of:
study duration as the pharmacological trials to provide abetter perspective of the effects of non-pharmacological
N memory training in one specific task (eg, errorless learning
treatments. This study used the ADAS-Cog and MMSE,
paradigm) and its effects on memory function,41 42 or on
which are the standard cognitive measures used in drugtrials; participants who had cognitive or motor stimulation
Figure 1 Mini-Mental State Examination mean change at 12 and
Figure 2 Alzheimer’s Disease Assessment Scale-Cognitive mean
24 weeks. ChEI, cholinesterase inhibitor; IPP, integrated
change after 12 and 24 weeks. ChEI, cholinesterase inhibitor; IPP,
integrated psychostimulation program.
Table 3 Mean change in cognitive measures at 12 and 24 weeks follow-up
ADAS-Cog, Alzheimer’s Disease Assessment Scale-Cognitive; BNT, Boston Naming Test; ChEI, cholinesterase inhibitor; IPP, integrated psychostimulationprogram; MMSE, Mini-Mental State Examination; RBMT, Rivermead Behavioral Memory Test; SKT, Syndrom Kurztest; 0, baseline.
*Lower scores indicate cognitive improvement.
treatment had improved scores, and this effect was enhanced
Although this was a trial of a non-pharmacological
by the use of a computerised program.
intervention, one way to conceptualise the design is to
One of the limitations of the study is that we were unable
consider that we were able to evaluate ‘‘dose’’ and ‘‘toler-
to complete the neuropsychological battery (secondary out-
ability’’. In this context, the ‘‘dose’’ refers to the amount of
comes) in the ChEI control group. Therefore, we could not
time each day that a patient could engage in the IMIS.
further expand our analysis to specific cognitive domains.
Similarly, we could consider the patient’s willingness to
The improvement seen with the ADAS-Cog and the MMSE
complete the assigned tests on schedule as a measure of
was not seen with the SKT. This discrepancy could be
‘‘tolerability’’. Therefore, we started with sessions of 15 min
explained by assessing whether these treatments have
of duration and increased them to 25 min, and all patients
beneficial effects in some cognitive domains, and not in
completed the minimum requirement of 58 sessions.
others. However, the limited scope of the cognitive functions
Future research is needed to evaluate the efficacy of the
assessed by the SKT, and a possible ceiling effect in mildly
IMIS-type programs in larger, more diverse populations to
impaired patients can also explain these findings.
understand factors that may modify the response, as well as
The patients in the experimental and the IPP control
to establish its long-term effects (.1 year). The IMIS should
groups were in the daycare centre; the only difference
be tested outside the controlled clinical environment (ie,
between the groups was that the experimental group received
home-based) to determine the efficacy of ‘‘distance therapy’’
the IMIS. Patients in these groups were drawn from the same
in Alzheimer’s disease. Nevertheless, the results of this study
institution, where the IPP program is used in all patients.
suggest that this is a promising avenue of approach to help
Therefore, we could not create a group of patients receiving
maximise a patient’s cognitive functions in the context of a
daycare only, as patients could not be isolated from their
progressive degenerative disease, potentially altering the
daily stimulation routines (which are an integral part of the
effect of the condition on both the patients and the caregivers.
ACKNOWLEDGEMENTThis study was conducted with an unrestricted grant from Fundacio
. . . . . . . . . . . . . . . . . . . . .
L Ta´rraga, M Boada, G Modinos, A Espinosa, S Diego, A Morera,M Guitart, J Balcells, Fundacio´ ACE. Institut Catala` de Neurocie`nciesAplicades, Barcelona, SpainO L Lo´pez, J T Becker, Departments of Neurology and Psychiatry,University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania,USA
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Studienliste für das Tumorboard: Brusttumore Breast cancer A randomized, phase 2 trial of AEZS-108 in chemotherapy refractory triple negative (ER/PR/HER2-negative) LHRH-R positive metastatic breast cancer – AEZS-108-049 local PI: email@example.com http://www.uni-frauenklinik-goettingen.de/ ->Studienangebot Follow-up Studies: Breastcancer
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