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Journal of Alzheimer’s Disease 25 (2011) 679–694 679

DOI 10.3233/JAD-2011-100999
IOS Press

Effects of a Newly Developed Cognitive


Intervention in Amnestic Mild Cognitive
Impairment and Mild Alzheimer’s Disease:
A Pilot Study
Verena C. Buscherta,∗ , Uwe Friesec , Stefan J. Teipeld , Philine Schneidera , Wibke Merenskya ,
Dan Rujescua , Hans-Jürgen Möllera , Harald Hampele and Katharina Buergera,f
a Department of Psychiatry Ludwig-Maximilians University, Munich, Germany
b Department of Psychiatry, University Rostock, Rostock, Germany
c Institute of Psychology, University of Osnabrueck, Osnabrueck, Germany
d DZNE, German Center for Neurodegenerative Disorders, Rostock, Germany
e Department of Psychiatry, Psychosomatic Medicine & Psychotherapy, Goethe University,

Frankfurt/Main, Germany
f Institute for Stroke and Dementia Research, Klinikum Groβhadern, Ludwig-Maximilians

University Munich, Munich, Germany

Accepted 11 February 2011

Abstract. Recent studies have shown that patients with Alzheimer’s disease (AD) and its possible prodromal stage mild cog-
nitive impairment (MCI) benefit from cognitive interventions. Few studies so far have used an active control condition and
determined effects in different stages of disease. We evaluated a newly developed 6-month group-based multicomponent cogni-
tive intervention in a randomized controlled pilot study on subjects with amnestic mild cognitive impairment (aMCI) and mild
AD patients. Forty-three subjects with aMCI and mild AD were recruited. Primary outcome measures were change in global
cognitive function as determined by the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Mini
Mental Status Examination (MMSE). Secondary outcomes were specific cognitive and psychopathological ratings. Thirty-nine
patients were randomized to intervention groups (IGs: 12 aMCI, 8 AD) and active control groups (CGs: 12 aMCI, 7 AD). At
the end of the study, we found significant improvements in the IGMCI compared to the CGMCI in the ADAS-cog (p = 0.02) and
for the secondary endpoint Montgomery Asberg Depression Rating Scale (MADRS) (p < 0.01) Effects on the MMSE score
showed a non-significant trend (p = 0.07). In AD patients, we found no significant effect of intervention on the primary outcome
measures. In conclusion, these results suggest that participation in a 6-month cognitive intervention can improve cognitive and
non-cognitive functions in aMCI subjects. In contrast, AD patients showed no significant benefit from intervention. The findings
in this small sample support the use of the intervention in larger scales studies with extended follow-up period to determine
long-term effects.

Keywords: Alzheimer’s disease, cognitive intervention, cognitive stimulation, cognitive training, mild cognitive impairment,
stage-specific

∗ Correspondence to: Verena Buschert, Dementia Research Sec-


INTRODUCTION
tion and Memory Clinic, Alzheimer Memorial Center and
Geriatric Psychiatry Branch, Department of Psychiatry Ludwig-
The NICE-guidelines (The National Institute for
Maximilians University, Nussbaumstrasse 7, D-80336 Munich,
Germany. Tel.: +49 89 5160 5862; Fax: +49 89 5160 5865; E-mail: Health and Clinical Excellence, http://www.nice.org.
verena.buschert@med.uni-muenchen.de. uk) as well professional societies in the field of

ISSN 1387-2877/11/$27.50 © 2011 – IOS Press and the authors. All rights reserved
680 V.C. Buschert et al. / Cognitive Intervention in MCI and AD

neurology and psychiatry (e.g., the German S3 guide- AD [15], where cognitive stimulation was even more
lines on dementia, http://www.dgn.org/images/stories/ effective than training of specific cognitive functions
dgn/pdf/s3 leitlinie demenzen.pdf) recommend par- [21–23]. In contrast, cognitive training involves guided
ticipation in non-pharmacologic cognitive stimulating practice of a set of standard tasks designed to target
programs for patients with mild-to-moderate AD. Pre- specific cognitive functions such as attention, memory,
vious studies in healthy subjects showed cognitive and problem-solving as well as teaching and practic-
enhancement and a reduced risk of future cognitive ing mnemonic strategies and skills (e.g., restorative
decline after participating in cognitive training [1]. A and compensatory mnemonic techniques) [7, 24]. This
recent meta-analysis covering more than 29,000 indi- approach has been shown to be high effective in people
viduals found an odds ratio (OR) of 0.54 for dementia with MCI [25]. However, classification of the type of
in individuals with a high compared to a low “behav- intervention according to these definitions is often dif-
ioral brain reserve”, indicating a risk reduction of 46% ficult because many studies employ a blend of different
[2, 3]. Mentally stimulating activities were among the intervention strategies that include aspects of cognitive
most robust factors, even after excluding effects of training and cognitive stimulation [20].
education, age, occupation, and other potential con- Clinical, neuropsychological, neuroimaging, and
founds. This effect was sustained over an average neuropathological data indicate that the progression
longitudinal follow-up of 7 years [2]. Because “behav- of AD neuropathology through the brain replicates the
ioral brain reserve”, also referred to as “cognitive ontogenetic brain maturation in reverse order [26]. This
reserve” [4], seems to modulate the clinical expres- theory of retrogenesis provides the theoretical under-
sion of AD pathology, direct modulation of behavioral pinnings of the global deterioration assessment scale
brain reserve using cognitive interventions might help [27], which predicts a stage specific sequence of clin-
to delay the onset and progression of dementia in ical and functional decline in the course of AD. Given
AD. Furthermore, cognition-based interventions have the specific clinical decline sequence in AD patients,
been found to attenuate cognitive decline in amnes- we hypothesize that to obtain best intervention effec-
tic mild cognitive impairment (aMCI) subjects [5–7], tivity, one needs to match cognitive interventions with
which is a transitional stage between normal cogni- the cognitive and global functioning level of the AD
tive aging and AD [8], and in mild-to-moderate stages patient [28]. Otherwise, the intervention is at risk of
of dementia [9–14]. These studies and meta-analyses overstraining or underchallenging the participants and
on cognitive interventions in AD [15, 16] provided may lead to frustration and adverse effects [11, 29].
first evidence of efficacy showing (a) improved global Therefore, we developed a stage-specific multicom-
cognitive functioning, (b) improved abilities of daily ponent cognitive intervention for subjects with aMCI
living, (c) reduced behavioral disturbances, and (d) and mild AD. According to the concept of retrogenesis,
positive effects on the quality of life in MCI subjects the more impaired the participants are, the less use-
and mild AD patients [17]. The findings are promising ful is training of (specific) cognitive functions, and the
but challenges remain for translation to daily routine more meaningful and probably successful are cognitive
because most studies employed relatively small sam- stimulation and activation of everyday functions and
ples and did not focus on specific stages of disease activities. We studied the effects of this newly devel-
[11, 14, 18, 19]. A further limitation is that only a few oped intervention program in subjects with aMCI, who
studies used active control conditions [14, 18, 19] and are at risk to develop AD [30], and patients fulfilling
the cognitive interventions differed between studies criteria for mild stages of clinically probable AD [31,
so that a comparison of treatment effects is challeng- 32] in a 6-month randomized controlled trial.
ing. Therefore, it is desirable to clarify the nature of
related but distinct forms of cognitive interventions and
their target population. A first distinction can be made MATERIALS AND METHODS
between cognitive stimulation and cognitive training
programs. Cognitive stimulation comprises engage- Participants
ment of the participant in a range of activities aimed at
general enhancement of cognitive and social function- A total of 43 subjects (27 aMCI, 16 mild AD)
ing in a non-specific manner [20]. Potential benefits were recruited at the Dementia Research Section and
of this approach have been demonstrated primarily in Memory Clinic of the Alzheimer Memorial Cen-
people with advanced dementia [21]. Positive effects ter and Geriatric Psychiatry Branch, Department of
were also found in patients with mild-to-moderate Psychiatry, Ludwig-Maximilians University, Munich.
V.C. Buschert et al. / Cognitive Intervention in MCI and AD 681

A comprehensive clinical and neuropsychological was used. First of all, subjects were pooled in pairs with
assessment was conducted and global functioning was respect to age, gender, education, and ApoE genotype
assessed by the Global Deterioration Scale (GDS) [27]. (in decreasing degree of priority). A study-independent
Subjects were included if person then randomly assigned pairs to the intervention
or control arm by using a computerized random num-
• aMCI subjects met Petersen’s criteria for amnestic
ber generator. To ensure optimal conditions of work,
single domain MCI or amnestic multiple domain
we considered group sizes of 10–12 aMCI patients
MCI [30] (GDS 3), AD subjects met the DSM-
and 8–10 mild AD patients to be reasonable upper
IV/NINCDS-ADRDA criteria for probable mild
limits.
AD [31, 32] (GDS 4),
There was one baseline test conducted between 1 to
• aMCI subjects scored at least 23 points, AD
4 weeks before the start of the intervention, and one test
subjects at least 19 on the Mini Mental State
administered between 1 to 4 weeks following the end
Examination (MMSE) [33],
of the intervention. The tests were conducted in a fixed
• subjects were at least 50 years old,
order using a standardized case report form (CRF).
• subjects were able to hear and see well enough to
The raters who conducted the testing sessions (ini-
participate in the group activities,
tials: WM, Daniela Otto, see acknowledgement) were
• subjects did not have any major physical illness,
blinded to treatment and different from the instruc-
other mental disorder (e.g., major depression) or
tor who administered the interventions (initials: VCB).
disability which could affect participation,
Participants of the control condition crossed over to the
• subjects were, if treated, on stable medication
intervention condition after 6 months at the end of the
of antidementia, antidepressant or antipsychotic
study.
drugs for at least three months prior to the start of
the study,
Intervention condition
• subjects did not participate in cognitive interven-
tion at least one year prior to the start of the study,
The objective of this project was to conceptualize
• subjects provided written, informed consent.
and evaluate a multicomponent cognitive intervention
With regard to Petersen’s MCI-criterion of normal to preserve, reactivate, and promote cognitive and non-
generalized cognition, aMCI subjects with a MMSE cognitive functions in consideration of stage-specific
score lower than 25 points were only included if needs and capabilities of subjects with aMCI and
their mild cognitive impairments did not interfere sig- patients with mild AD. The program builds on the
nificantly with daily activities or social functioning theory of cognitive reserve [4] and the theory of ret-
verified by a caregiver. The study was performed in rogenesis as basis for intervention task selection [26],
accordance with the Declaration of Helsinki and the and employs already established methods and inter-
Ethics Committee of the Medical Faculty of Ludwig- vention principles (e.g., the face-name association [34]
Maximilians University approved the study. Patients or the errorless learning approach [35]). The inter-
participating in the study gave written informed vention program for subjects with aMCI focused on
consent. The study was officially registered before cognitive training of specific domains such as mem-
first subject joined study (www.clinical.trial.gov; ID: ory function but also included features of cognitive
NCT00544856). stimulation, whereas that for mild AD patients empha-
sized cognitive stimulation and less cognitive training.
Design Table 1 gives an overview of specific features of the
stage-specific cognitive intervention and the control
Of the 43 screened subjects, four dropped out prior condition.
to the randomization procedure (1 concurrent illness, 3 We provided information on meta-cognition (e.g.,
lacking motivation to participate in the intervention). about information processing), age-associated cogni-
39 persons (24 with aMCI, 15 with AD) were ran- tive decline and cognitive changes with AD to enhance
domly assigned to cognitive intervention groups (IGs: motivation of participants [7, 36, 37]. Additionally,
12 aMCI, 8 AD), receiving cognitive intervention, and caregivers were encouraged (contacted by letter) to
active control groups (CGs: aMCI: 12, AD: 7), in which take an active interest in their patient’s participation
participants met monthly and received paper-pencil in the study, e.g., by talking about the contents of the
exercises for self-study. To achieve matched treatment weekly sessions, assisting in the exercises for self-
groups (IG, CG) a blocked randomization procedure study, and applying specific techniques in everyday
682 V.C. Buschert et al. / Cognitive Intervention in MCI and AD

Table 1
Overview of specific features of cognitive intervention and control condition
Target entity
Intervention group (IG) Control group (CG)
aMCI mild AD aMCI mild AD
Treatment Stage-specific cognitive intervention, weekly sessions Paper-pencil exercises for self-study, monthly meetings
Focus Cognitive training/ Cognitive stimulation/ Specific cognitive function: sustained attention
Cognitive stimulation Cognitive training
Expected effects Generalized effects in global cognitive function No generalized effects in global cognitive function
Format Group (max. 12 persons) Group (max. 10 persons) Self-study; meetings in group
Duration 6 month, 20 sessions à 120 min 6 month, 6 meetings à 60 min
aMCI = amnestic mild cognitive impairment; AD = mild AD; IG = intervention group; CG = control group.

situations. Non-cognitive functions such as mood and • teaching and practicing restorative and compen-
quality of life are deemed to be crucial for cognitive satory mnemonic techniques (e.g., visual imagery
performance [7, 25, 38, 39]. To support cognitive and [41], face-name association [34], use of external
additionally non-cognitive functions, we implemented memory aids such as calendar, notes and prompts
components such as reminiscence, psychomotor and [42] and
recreational tasks and conducted the programs in • activation of everyday life activities in house and
groups (aMCI: max. 12 participants, AD: max. 10 par- garden and intellectual and physical leisure activ-
ticipants) to encourage social interaction [7, 11, 14]. ities,
According to the core symptom of AD, however, the
focus lied primarily on cognitive domains. The pro- and topics of common interest such as season, music,
gram was designed to involve a wide range of cognitive and food. Sessions with topics of common interest
functions and was expected to exert generalized effects addressed the natural process of reminiscence but had
on global cognitive functioning. an additional focus on the present situation. Mul-
To detail the process through which the multicom- tisensory stimulation was introduced when possible
ponent intervention leads to a particular outcome, and [11]. Approved memory strategies and principles such
to determine a measurement strategy that enables the as face-name association and the errorless learning
researchers to assess key components of this process, approach were consistently employed. According to
we adapted and applied a methodology for describ- the theory of retrogenesis, units are oriented to the stage
ing and decomposing multidimensional psychosocial of disease and differ concerning difficulty and com-
and behavioral interventions [40]. The aim was to plexity as well as number and duration of trials and
characterize the intervention across a common set of exercises. Differences between the two intervention
dimensions based on the proximal goals and activities programs (aMCI/AD) correspond in fact to a quanti-
of the intervention. Fig. 1 shows goals, activities and tative rather than to a qualitative distinction. However,
measurement instruments of the program according to according to different cognitive and functional sta-
Czaja et al. [40]. tus in MCI and AD, some topics are only covered in
Prior to the start of the study the cognitive inter- the MCI intervention, others only in the AD interven-
vention for subjects with aMCI and patients with tion. Table 2 details similarities and differences of both
mild AD was conceptualized and detailed as a man- interventions with regard to content, target groups, and
ual with reproducible detailed protocols. The program stage-specific topics of units. Note that the design of
particularly aims at global cognitive functioning, but our study is incomplete. A complete design would have
additionally addresses non-cognitive domains (e.g., included AD patients participating in the interventions
mood) that are supposed to be also impaired in designed for MCI patients and vice versa. In addition to
AD and aMCI. Each program consists of 20 units, ethical concerns, we think that participants being sys-
applied weekly for 120 minutes. Units alternate weekly tematically overstrained in one group and participants
between theory based topics such as: being not challenged in the other would have distorted
the results.
• specific cognitive functions following a model of Participants who were present at more than half of
information processing (e.g., attention, percep- the interventions (minimum 11 sessions), were judged
tion, and memory), as compliant and included in the study.
V.C. Buschert et al. / Cognitive Intervention in MCI and AD 683

Stage-specific cognitive intervention


for subjects with aMCI and patients with mild AD

Secondary goal 1 Secondary goal 2


Primary goal
Improvement and stabilisation of specific Improvement and stabilisation of specific
Improvement and stabilisation of global
cognitive functions ((higher) attentional non-cognitive functions (mood, quality of life)
cognitive functioning
and executive functions, memory)

Activities* Activities* Activities*


exercises concerning specific
cognitive functions, e.g. memory, exercises and tasks concerning (short- roundtable and discussions
attentional and executive functions term) memory exercises to stimulate social interaction,
teaching and practising of restaurative exercises and tasks concerning e.g. remote memory, reminiscence,
and compensatory mnemonic techniques, (higher) attention, problem-solving language, imagination & creativity
e.g. visual imagery, face-name association teaching and practising of restaurative psycho-motor/ recreational exercises
use of approved strategies/principles, and compensatory mnemonic techniques, education about age-associated/
e.g. errorless learning e.g. visual imagery, face-name association pathological changes of brain functions
activation of allday activities, e.g. leisure use of approved strategies/principles, (meta-cognition)
discussions e.g. errorless learning oral tasks performed at home
psycho-motor/ recreational exercises detailed exercises for self-study at
detailed exercises for self-study at home
home

Measuring instruments Measuring instruments Measuring instruments


ADAS-cog TMT B MADRS
MMSE RBANS story memory, story recall QoL-AD

*According to the theory of Retrogenesis activities focus on the stage of disease and differ regarding content, difficulty and complexity as well as number and duration of
administered trials and exercises
ADAS-cog = Alzheimer‘s Disease Assessment Scale – cognitive subscale; MMSE = Mini Mental State Examination; RBANS = Repeatable Battery f or the Assessment of
Neuropsychological Status; TMT = Trail Making Test; MADRS = Montgomery and Asberg Depression Rating Scale; QoL-AD = Quality of Life Alzheimer‘ s Disease Scale;

Fig. 1. Goals, activities and measuring instruments of the cognitive intervention.

Table 2
Description and differences of intervention according to functional domains and target entities
Functional domain Target group
aMCI Mild AD
Cognition
Cognitive training (memory
functions)*
Cognitive stimulation**
Meta-Cognition
Activation of all day activities
Mood
(Social-) Behavior
(Psycho-) Motor
Different stage-specific topics Information processing Memory: Everyday life: nutrition
Reminding written information Everyday life: Body & Health
aMCI = amnestic mild cognitive impairment; mild AD = mild Alzheimer’s Disease; *Cognitive training: teaching and
practicing theoretically motivated strategies and skills in order to optimize cognitive functioning; **Cognitive stimulation:
engagement in a range of activities and discussions aimed at general enhancement of cognitive and social functioning;
strong; middle; weak.
684 V.C. Buschert et al. / Cognitive Intervention in MCI and AD

In brief, a typical session included testing) [46], which is a more sensitive scale measuring
cognitive function and including more items that
• a welcome with a short roundtable repeating the assess short-term memory (decreasing scores indicate
contents of the previous session (10 minutes), improvement). The ADAS-cog is frequently used in
• a warm-up-exercise (10 minutes), AD trials as the principal cognitive measure. Both
• oral and/or paper-pencil exercises alone, with a raters (WM, DO) who administered the testing at base-
partner or within a small group (40 minutes) inter- line and end-of-study were blinded to the treatment
mitted by a small break (15 minutes), condition. WM conducted all tests and scales with the
• a psychomotor (e.g., playing with balloons) patients, and DO interviewed the caregivers.
and/or a recreational exercise with music (10 min-
utes), Secondary outcome measures
• exercises targeting primarily social interaction Secondary outcome measures were change in spe-
and mood (25 minutes) and cific cognitive and non-cognitive functions. Immediate
• a conclusion and good-bye at which participants and delayed memory (story memory and story recall)
received both oral (incentive-cards) and paper- from the Repeatable Battery for the Assessment
pencil exercises for self-study (10 minutes). of Neuropsychological Status (RBANS), version A
(pre-testing) and B (post-testing) [47] covered spe-
Control condition cific memory functions (increasing scores indicate
improvement). To determine intervention effects on
To control for effects of an intervention per se, higher attentional and additionally executive function,
such as beneficial effects of social interactions, we Trail Making Test (TMT), Part A and B, commonly
devised an active control condition. Participants of used measurements of attentional functions [48], were
the control group met monthly (6 times in total) and administered (decreasing scores indicate improve-
received paper-pencil exercises for self-study focus- ment). As a non-cognitive domain, mood was assessed
ing primarily on isolated cognitive functions such by the Montgomery Asberg Depression Rating Scale
as sustained attention, which is thought to be rela- (MADRS) [49], a ten-item diagnostic questionnaire,
tively preserved at least in early stages of AD [43] which is sensitive to the changes caused by antidepres-
(see Table 1). We assumed that these kinds of tasks sants and other forms of treatment (decreasing scores
would be of no or only little benefit for improving indicate improvement). Assuming an overlap of cogni-
global cognitive performance in aMCI and AD [44, tive symptoms between “cognitive-inhibition” factors
45]. As with the intervention condition, paper-pencil of the MADRS, such as concentration difficulties [50],
exercises of the control condition were oriented to the and cognitive impairments due to clinical and pre-
patient group (aMCI, AD) and differed concerning dif- clinical AD [51] without diagnosis of depression, we
ficulty, complexity, and number of exercises. In the excluded item 6 (“concentrations difficulties”) of the
course of monthly group-meetings, solutions of the MADRS from analysis [52]. Quality of life of partici-
previous at-home exercises were provided. Comple- pants was assessed by the Quality of Life-Alzheimer’s
tion of paper-pencil exercises for self-study was not Disease (QoL-AD) scale [53] (increasing scores indi-
monitored in order to minimize personal interaction cate improvement).
with the control subjects. The intervention and con-
trol conditions were conducted by the same instructor. Analysis
Participants who took part in at least half of the con- Data were entered into the Statistical Package for
trol sessions (minimum 3 sessions) were judged as the Social Sciences (SPSS), version 15.0 for Win-
compliant and included in the study. dows. We conducted a series of analyses of covariance
(ANCOVA) with treatment (intervention group, IG,
Assessment measures versus control group, CG), and progression (baseline
versus end-of-study) as independent variables. Primary
Primary outcome measures and secondary outcome variables served as depen-
Main outcome measure was change in cognitive dent measures. Furthermore, we entered educational
function determined by the MMSE [33], a brief, level (years of schooling) and patients’ age as covari-
widely used test of cognitive functions (increasing ates into the analysis. We report effect sizes as partial
scores indicate improvement), and the total score of eta squared (η2 ) values. When significant interaction
the ADAS-cog, version B (pre-testing) and C (post- effects between the treatment factor and the progres-
V.C. Buschert et al. / Cognitive Intervention in MCI and AD 685

sion factor indicated that the change of the outcome The average attendance of the control condition (6
measure over time was different for IG and CG, we meetings) was 5.6 (aMCI: 5.5, AD: 5.7). None of the
used post-hoc t-tests to determine differences between participants of the CGs were excluded from the study.
baseline and end-of-study. Unless otherwise noticed,
we report statistical effects associated with p < 0.05 as Sample characteristics
significant, and additionally report effects with p < 0.1
on an exploratory basis. Forty-three persons passed the screening. One AD
patient dropped out due to concurrent physical illness,
and three aMCI-subjects withdrew consent because
RESULTS they found participation in the study too demanding.
Thirty-nine subjects were randomized into interven-
Feasibility and acceptance of program and study tion groups and control groups. Two participants of
the aMCI-IG dropped out of the study because of inter-
The randomized controlled trial was conducted from current illness and lack of compliance. A total of 37
September 2007 to February 2008. Participants of the subjects finally completed the study and were assessed
control group attended the cognitive intervention after at the end of the study. Fig. 2 shows the profile of the
the end of the study. The average attendance of the trial and attrition.
cognitive intervention was 16.7 (83.5%) out of 20 On average, participants were 73.1 years (SD = 7.7)
sessions. Participants with aMCI attended 17.1 times old. There was a tendency for AD patients to be
(85.5%, range of scores: 14–20). For organizational older than aMCI subjects, 75.9 years (SD = 8.1) ver-
reasons, two sessions of the AD intervention had to be sus 71.2 years (SD = 7.7), as revealed by a 2-factorial
administered in one week. Because most of the par- syndrome (aMCI versus AD) by treatment (IG versus
ticipants missed the non-standard scheduled session, CG) analysis of variance (ANOVA) (main effect syn-
participants with AD attended only 16.3 times out of drome: F1,33 = 3.08, p = 0.09). Neither the main effect
19 sessions (85.8%, range of scores: 13–19). One par- of treatment nor the interaction effect were signifi-
ticipant of the aMCI-IG group dropped out of the study cant (all p-values > 0.1). An analogue ANOVA showed
because of intercurrent illness and one was excluded that educational level did not differ between interven-
from the study on the basis of not reaching our com- tion and control groups (all p-values > 0.1). Sample
pliance criteria, which corresponds to a 5.1% drop-out and groups were matched for gender (20 female,
rate. 19 male). All AD patients and one subject of the

Fig. 2. Profile of the trial and attrition. aMCI = amnestic mild cognitive impairment; AD = Alzheimer’s Disease; IG = intervention group; CG
= control group.
686 V.C. Buschert et al. / Cognitive Intervention in MCI and AD

Table 3
Demographic and clinical characteristics of participants at baseline assessment (n = 39)
Variable aMCI mild AD
IG CG Total IG CG Total
Number 12 12 24 8 7 15
Age 71.8 (8.6) 70.7 (5.7) 71.2 (7.0) 77.3 (7.6) 74.2 (9.0) 75.9 (8.1)
min/max 53.2–86.5 62.4–79.3 53.2–86.5 66.9–88.6 57.5–83.7 57.5–88.6
Gender f/m 6/6 6/6 12/12 4/4 4/3 8/7
Education 12.3 (3.6) 13.3 (2.2) 12.9 (2.9) 11.8 (3.2) 13.6 (6.5) 12.6 (4.9)
min/max 8–18.5 11–16.5 8–18.5 8–17 4–21.5 4–21.5
Antidementiva 1 none 1 8 7 15
MMSE 28.1 (1.5) 26.8 (1.5) 27.4 (1.6) 24.5 (1.6) 25.3 (1.5) 24.9 (1.6)
min/max 25–30 24–29 24–30 22–27 23–27 22–27
ADAS-cog 8.7 (2.9) 9.8 (4.3) 9.3 (3.7) 12.1 (5.3) 16.4 (4.8) 14.1 (5.4)
min/max 3–13 5–19 3–19 6–21 13–23 6–23
aMCI = amnestic mild cognitive impairment; AD = Alzheimer’s Disease; IG = intervention group; CG = control
group; MMSE = Mini Mental Status Examination; ADAS-cog = Alzheimer’s Disease Assessment Scale; standard
deviation in ( ); min/max = ranges of scores.

aMCI-IG were on stable medication of antidemen- TMT-B (F1,18 = 3.5, p = 0.08, η2 = 0.16). Moreover,
tia drugs (Acetylcholinesteraseinhibitors (AChE-Is) main effects of treatment were found for MMSE
and/or Memantine). Table 3 shows demographic and (F1,18 = 8.5, p < 0.01, η2 = 0.23), RBANS-story mem-
clinical characteristics as well as initial MMSE and ory (F1,18 = 12.5, p < 0.01, η2 = 0.41), and RBANS-
ADAS-cog scores of all participants at baseline assess- story recall (F1,18 = 9.9, p < 0.01, η2 = 0.36).
ment. For aMCI patients, the difference in MMSE For the AD patients, the interactions between treat-
scores between IG and CG at baseline was associ- ment and progression showed a tendency towards sig-
ated with t22 = 2.6, p = 0.02; ADAS-cog scores did not nificance for TMT-B (F1,11 = 5.1, p = 0.05, η2 = 0.32)
differ (t22 < 1). For AD patients in IG and CG, MMSE- and MADRS (F1,11 = 3.4, p = 0.09, η2 = 0.24) (see
scores and ADAS-cog did not differ at baseline (all Table 4 b for details). For RBANS-story recall
p-values > 0.1). Three aMCI subjects with MMSE- the covariate education was close to significance
sores lower than 25 points (MMSE 23 = 0, MMSE (F1,11 = 4.1, p = 0.07, η2 = 0.27). The ANCOVA with
24 = 2, MMSE 25 = 1) were included as the cognitive TMT-B showed tendencies for an interaction between
impairments did not interfere with activities of daily progression and education (F1,11 = 5.1, p = 0.05,
living and social functioning explicitly verified by a η2 = 0.32) and for a main effect of age (F1,11 = 4.6,
caregiver. p = 0.06, η2 = 0.29).

Effects of treatment Post-hoc tests


We used two-sided pairwise t-tests to additionally
ANCOVAS were conducted for AD and aMCI evaluate differences between baseline and end-of-
separately with treatment (IG versus CG), and pro- study. Owing to the explorative nature of these tests,
gression (baseline versus end-of-study) as independent we did not correct the significance level for multiple
variables; participants’ age and educational level comparisons. For aMCI subjects in the IG, there was a
were treated as covariates. Dependent measures were significant improvement for TMT-B (t9 = 3.0, p = 0.01)
MMSE, ADAS-cog, RBANS story memory and story and MADRS (t9 = 4.0, p < 0.01). aMCI subjects in the
recall, TMT-A and B, MADRS (without item 6 “con- CG showed significant decline in ADAS-cog (t11 = 2.8,
centration difficulties), and QoL-AD. p = 0.02) and MMSE (t11 = 3.1, p = 0.01) (see Table 4 a
For the aMCI subjects, we found significant for details). In the AD groups, only MADRS scores
interactions between treatment and progression of the IG improved significantly between baseline and
for ADAS-cog (F1,18 = 6.2, p = 0.02, η2 = 0.26) end of the study (t7 = 2.6, p = 0.03) (see 4 b for details).
and MADRS (F1,18 = 8.8, p < 0.01, η2 = 0.33) (see
Table 4 a for details). Furthermore, the interac- Number needed to treat
tion was associated with a p-value of p < 0.1 for A number needed to treat (NNT) analysis was
MMSE (F1,18 = 3.8, p = 0.07, η2 = 0.17), RBANS- conducted for an assessment of the effectiveness of
story memory (F1,18 = 3.4, p = 0.08, η2 = 0.16), and the intervention in aMCI. It revealed, that 5 MCI-
V.C. Buschert et al. / Cognitive Intervention in MCI and AD 687

Table 4a
Change from baseline in subgroups of aMCI (n = 22 in measures of efficacy regarding MMSE, ADAS-cog., RBANS story memory and recall,
TMT-A and B, MADRS, and QoL-AD); standard deviation in ( ). Reported are all effects associated with p < 0.1
Outcome Point IGMCI n = 10 CGMCI n = 12 ANCOVA with **η2
ADAS-cog Baseline 8.7 (2.9) 9.8 (4.3) interaction treatment by progression
(F1,18 = 6.2, p = 0.02, η2 = 0.26)
End-of-study 7.3 (3.1) 11.7 (5.6)
t-test* n.s. t(11) = 2.8, p = .02
MMSE Baseline 28.1 (1.5) 26.8 (1.5) interaction treatment by progression
(F1,18 = 3.8, p = 0.07, η2 = 0.17) main
effect treatment (F1,18 = 8.5, p < 0.01,
η2 = 0.32)
End-of-study 28.2 (1.2) 26.0 (1.3)
t-test* n.s. t(11) = 3.1, p = .01
RBANS – Baseline 15.4 (2.8) 13.1 (2, 8) interaction treatment by progression
story memory (F1,18 = 3.4, p = 0.08, η2 = 0.16) main
effect treatment (F1,18 = 12.5, p < 0.01,
η2 = 0.41)
End-of-study 16.4 (3.2) 11.7 (4.2)
t-test* n.s. n.s.
RBANS – Baseline 7.5 (2.4) 4.7 (2.9) main effect treatment (F1,18 = 9.9, p < 0.01,
story recall η2 = 0.36)
End-of-study 7.5 (3.2) 3.4 (3.0)
t-test* n.s. n.s.
TMT-A Baseline 46.1 (27.2) 50.7 (19.8) n.s.
End-of-study 36.5 (9.7) 40.9 (15.1)
t-test* n.s. n.s.
TMT-B Baseline 130. 4 (46.1) 131.4 (34.0) interaction treatment by progression
(F1,18 = 3.5, p = 0.08, η2 = 0.16)
End-of-study 102.0 (28.4) 140.1 (45.0)
t-test* t(9) = 3.0, p = 0.01 n.s.
MADRS Baseline 3.6 (2.6) 3.7 (5.9) interaction treatment by progression
(F1,18 = 8.8, p < 0.01, η2 = 0.33)
End-of-study 0.7 (1.3) 3.8 (6.1)
t-test* t(9) = 4.0, p < 0.01 n.s.
QoL-AD Baseline 35.3 (3.8) 36.6 (5.0) n.s.
End-of-study 35.7 (5.1) 34.7 (5.5)
t-test* n.s. n.s.
ADAS-cog = Alzheimer’s Disease Assessment Scale; MMSE = Mini Mental State Examination; RBANS = Repeatable Battery for the Assessment
of Neuropsychological Status; TMT = Trail Making Test; MADRS = Montgomery Asberg Depression Rating Scale (without item 6 “concentration
difficulties”); QoL-AD = Quality of Life-Alzheimer’s Disease; IG = intervention group; CG = control group; ns = not significant; aMCI =
amnestic mild cognitive impairment; AD = mild AD; ANCOVA = univariate analysis of covariance; columns indicate significant effects of 2 × 2
ANCOVAs (treatment × progression; see text for details).; *t-Test results refer to post-hoc comparisons testing for the effect of progression
(baseline vs. end-of-study) within subgroups (IG, CG).; **η2 = partial eta squared.

participants need to be treated for one to benefit Only aMCI subjects showed significant effects of inter-
compared to controls when calculating a decrease of vention in the primary cognitive outcome variables,
4 or more points on the ADAS-cog total score as an whereas effects in AD patients were limited to sec-
improvement (lower scores indicating improvement) ondary endpoints.
and an increase of 3 points or over as adverse [11]).
Feasibility and acceptance of program and study
DISCUSSION
The cognitive intervention program and the study-
In our randomized controlled trial, we evaluated design were feasible and well accepted by the
the effects of a multicomponent stage-specific cogni- participants. We achieved a very high level of partici-
tive intervention for subjects with aMCI and patients pation in both study arms. Completion of the at-home
with mild AD compared to an active control condi- exercises of the control condition was not monitored,
tion. We found improvement in global cognitive status, but correct solutions of the previous at-home exercises
and specific cognitive and non-cognitive functions. were provided. Furthermore, the aMCI and mild AD
688 V.C. Buschert et al. / Cognitive Intervention in MCI and AD

Table 4b
Change from baseline in subgroups of AD (n = 15 in measures of efficacy regarding MMSE, ADAS-cog., RBANS story memory and recall,
TMT-A and B, MADRS, and QoL-AD); standard deviation in ( ). Reported are all effects associated with p < 0.1
Outcome Point IGAD n = 8 CGAD n = 7 ANCOVAs with**η2
ADAS-cog Baseline 12.1 (5.3) 16.4 (4.8) n.s.
End-of-study 11.4 (6.0) 16.4 (4.9)
t-Test* n.s. n.s.
MMSE Baseline 24.5 (1.6) 25.3 (1.5) n.s.
End-of-study 25.0 (2.7) 24.4 (2.4)
t-Test* n.s. n.s.
RBANS – Baseline 12.4 (4.3) 12.4 (3.9) n.s.
story memory
End-of-study 9.5 (2.9) 10.9 (3.3)
t-Test* n.s. n.s.
RBANS – Baseline 1.9 (2.5) 3.4 (3.6) main effect education (F1,11 = 4.1, p = 0.07,
story recall η2 = 0.27)
End-of-study 2.0 (2.7) 2.1 (2.3)
t-Test* n.s. n.s.
TMT-A Baseline 46.1 (27.2) 50.7 (19.8) n.s.
End-of-study 36.5 (9.7) 40.9 (15.1)
t-Test* n.s. n.s.
TMT-B Baseline 206.9 (42.7) 192.1 (52.1) interaction treatment by progression
(F1,11 = 5.1, p = 0.05, η2 = 0.32) interaction
progression by education (F1,11 = 4.3,
p = 0.06, η2 = 0.28) main effect age
(F1,11 = 4.6, p = 0.06, η2 = 0.29)
End-of-study 178.4 (39.0) 207.9 (43.7)
t-Test* n.s. n.s.
MADRS Baseline 3.1 (4.1) 4.3 (4.0) interaction treatment by progression
(F1,11 = 3.4, p = 0.09, η2 = 0.24)
End-of-study 1.6 (3.4) 4.7 (5.0)
t-Test* t(7) = 2.6, p = 0.03 n.s.
QoL-AD Baseline 39.1 (7.4) 33.5 (4.0) n.s.
End-of-study 38.7 (7.6) 32.6 (3.8)
t-Test* n.s. n.s.
ADAS-cog = Alzheimer’s Disease Assessment Scale; MMSE = Mini Mental State Examination; RBANS = Repeatable Battery for the Assessment
of Neuropsychological Status; TMT = Trail Making Test; MADRS = Montgomery Asberg Depression Rating Scale (without item 6 “concentration
difficulties”); QoL-AD = Quality of Life-Alzheimer’s Disease; IG = intervention group; CG = control group; ns = not significant; aMCI =
amnestic mild cognitive impairment; AD = mild AD; ANCOVA = univariate analysis of covariance; columns indicate significant effects of 2 × 2
ANCOVAs (treatment × progression; see text for details).; *t-Test results refer to post-hoc comparisons testing for the effect of progression
(baseline vs. end-of-study) within subgroups (IG, CG).; **η2 = partial eta squared.

participants were highly compliant and the drop-out The pre-post treatment comparison was significant for
rate was relatively low even though the intervention ADAS-cog, one of the primary outcome-measures, and
was quite demanding. In this context, however, it is to showed a tendency toward significance in MMSE, the
note that sometimes signs of fatigue could be observed other primary outcome variable. Change in ADAS-cog
in the course of the 120-minutes sessions, especially in aMCI indicates improvement insofar as participants
in participants with mild AD. Shortening the length of the CGMCI deteriorated significantly with time,
of weekly sessions is probably advisable. Finally, we whereas participants of the IGMCI showed a tendency
found that the administration of the program by the to improve. This raises the question about whether
same instructor for the whole period proved to be prac- there were simply a greater percentage of aMCI sub-
tical. Thus, the cognitive intervention appears to be a jects with prodromal AD in the control group who may
clinically applicable and feasible intervention program have simply deteriorated over the 6 month follow-up.
for amnestic MCI and mild AD. In our opinion, this seems to be unlikely because inclu-
sion of all aMCI-subjects followed stringent diagnosis
Generalized effects on global cognitive status criteria (see inclusion criteria above), and stratifica-
tion was carried out according to major characteristics
Effects of intervention on the primary outcome such as age, gender, education, and ApoE genotype
variables were detected only in subjects with aMCI. (see randomization procedure, above). Furthermore,
V.C. Buschert et al. / Cognitive Intervention in MCI and AD 689

all MCI-participants showed a similar distribution of considered to be a test of higher level cognitive skills
baseline FDG hypometabolism in AD-typical brain such as mental flexibility within the executive func-
regions [54]. This strongly suggests that MCI patients tion domain [57, 58]. With the exception of the second
in both groups were comparable with respect to intervention-session, divided attention as required in
preclinical AD stage. Moreover, the NNT-analysis the TMT-B was not practiced in the intervention. We
indicates effectiveness of the cognitive intervention. assume the improvement in TMT-B might reflect a
An improvement defined as a 4-point change on generalized effect of the intervention, which addresses
ADAS-cog occurred only in the IGMCI , whereas cog- a high level of attentional performance and linked
nitive decline was observed in both IGMCI and CGMCI . executive functioning due to the group setting (e.g.,
Many regulatory authorities recognize a four-point following conversations involving more than one other
change on the ADAS-cog at 6 months as indicat- person) and a number of distinct exercises (e.g., putting
ing a clinically important difference—a proposal that something in order, finding similarities and differ-
has impacted how clinical trials are interpreted [55]. ences, abstract thinking, and reasoning).
Considering the small sample size, results should be Results of TMT-B in AD patients indicate a tendency
interpreted with caution. The intervention did not train toward a significant interaction between group and pro-
to any item of the ADAS-cog so that findings are prob- gression, which gives weak evidence for an impact
ably not related to practice effects. The positive effects of the intervention on attentional functions. A study
found here suggest that participating in the interven- of cognitive rehabilitation with a comparable sam-
tion induced generalized cognitive benefits in MCI ple size of 6 mild AD-patients in the treatment group
subjects. However, there are a number of concerns (AChE-I combined with cognitive rehabilitation) com-
regarding generalizability of intervention effects to pared to 7 mild AD-patients in the control-group (only
everyday functions and whether a few points improve- AChE-I) with weekly sessions of 90 minutes for 5
ment on a particular test is clinically meaningful month also reported a tendency towards significant
[55]. improvement for participants of the intervention group
The AD patients showed no significant effects of in TMT-B [13]. The statistical power of the present
intervention on the primary outcome variables. It has study might not have been sufficient to detect a modest
been previously hypothesized that brain reserve may be change.
better preserved in mildly impaired subjects at risk for In both groups, intervention had no significant effect
developing dementia than in already demented patients on specific memory performance compared to the
[56]. It is thought that the capability to enhance or active control condition. Recent studies have shown
compensate impaired cognitive functions declines in significant improvements in memory tests in subjects
the course of the disease [4]. Therefore, aMCI and with aMCI and mild AD patients through cognitive
AD participants may benefit differently from cognitive intervention, however, these effects were detected if
interventions. The effect sizes in the AD patients of our specific material or tasks of the intervention were used
study using an active control condition were similar in the subsequent evaluation [7, 59]. Therefore, these
to those in a previous study on 201 patients in mild- effects seem to be specific to the memory material that
to-moderate stages of AD with a care-as usual control was tested in the particular context. Our findings sug-
condition [11] (Cohen’s d 0.37 for MMSE and 0.38 for gest that transfer of utilized mnemonic techniques does
ADAS-cog in [11], and 0.74 and 0.20 in our study). Our not succeed if transferred to tasks and situations other
findings together with these previous findings suggest than directly trained during the intervention [36, 60].
a moderate effect of intervention in AD that requires a This lack of behavioral change could be related to a
sample size of at least 26 subjects per group to detect failure to train participants how to apply established
an effect of intervention with 80% power at p < 0.05. strategies to specific memory problems of daily life
Future studies need to employ larger numbers of sub- [36]. It has been suggested that behavioral change is
jects with an active control condition to finally resolve more likely to be achieved when the participants of a
this question. cognitive intervention have acquired a positive analy-
sis of costs and benefits associated with the behavior in
Effects on specific cognitive functions everyday memory problems [36]. Within this context
it is important to identify those internal and exter-
Amnestic MCI subjects in the IG demonstrated a nal memory strategies which are most effective for
tendency toward significant benefits in higher atten- accomplishing everyday memory tasks, and which are
tional functions as assessed by TMT-B. TMT-B is directly related to functional independence in AD. In
690 V.C. Buschert et al. / Cognitive Intervention in MCI and AD

future studies to investigate the issues of successful TMT-A (see table 4 a), a similar effect cannot be deter-
transfer of mnemonic techniques they may require mined in the present study. Thus, we assume that
from the participants intensive practice of adapting the improvements in TMT-B are rather related to direct
appropriate techniques to daily life. intervention effects on cognition and less mediated by
mood. However, since mood-loaded factors such as
Effects on non-cognitive functions motivation are considered to have an impact on cogni-
tive functioning, we cannot determine to what extent
Significant improvement in mood was found in improvements in non-cognitive depressive symptoms
aMCI-subjects in the IG arm. In patients with mild might have contributed to improvements in higher
AD we observed a tendency towards statistical sig- attentional functions. Studies with long-term observa-
nificance. Participants of the CGMCI and the CGAD tions with greater sample sizes probably will give better
demonstrated no change over the 6 months. Analysis insight into interaction between cognitive intervention,
of MADRS-items of the IGMCI showed that most often attentional functions, and mood.
complaints with “concentration difficulties” (item 6) Although participants of both IGs (aMCI and AD)
were reported (7 of 9 participants, mean 2.3, range benefit from the intervention concerning mood, which
0-4), which improved considerably in the course of is thought to be crucial for self-reported well-being,
the intervention (5 of 9 participants, mean 1.4, range there were no significant intervention effects in qual-
0–3). Cognition-related symptoms measured with a ity of life in both subgroups. In contrast, a study by
depression rating scale may appear to exist in the Spector and colleagues with 115 mild and mild-to-
context of mild cognitive impairment or prodromal moderate patients with AD demonstrated significant
AD. Assuming an overlap of cognitive symptoms improvement in the QoL-AD in the treatment group
between depression and prodromal AD [51], we there- relative to the control group [11, 66]. An interpreta-
fore excluded “concentration difficulties” from the tion of these findings is difficult because the control
analysis of depressive symptoms [61]. All partici- condition in the Spector study was merely the continu-
pants of the present IGMCI scored below a critical ation of “usual activities”. Positive influence of social
cut-off for mild depression (13 to 21 points [49]) or interactions due to the trainer was not considered or
even a cut-off for remission (<9 and <10 [62]) on controlled for. Hence, it remains unclear, to what extent
the MADRS including scores of concentration diffi- the measured benefits on quality of life were due to the
culties at baseline (mean: 5.4 (SD 2.4), range: 1–8). Cognitive Stimulation Therapy in the Spector trial. In
Remaining depression scores were low in all groups contrast, in our study we applied an active control con-
(see table 4 a), thus, improvements in depression scores dition, in which the participants were in contact with
appear not to be clinically significant with regard to the same instructor of the intervention condition.
depression. However, improvements in mood with- In general, intervention-induced effects on quality
out manifest symptoms of depression might suggest of life in AD due to participation in a cognition-
enhancement of self-esteem and well-being [7, 63], based intervention are difficult to achieve owing to
which is thought to be beneficial for cognitive perfor- the complexity of the theoretical construct of qual-
mance [25, 63, 64]. A previous study has shown that ity of life. Cognitive interventions focus primarily on
participation of AD patients in a cognitive intervention cognitive domains, and, if applicable, on additionally
program had a positive impact on global mood [39]. non-cognitive functions such as mood, but they have
Given that a considerable effect of the intervention few or no direct emphasis on several items tested
was on depression scores, it raises the question as to in the QoL-AD such as physical health, living sit-
whether the improvements seen on higher attentional uation, family, marriage, friends, free time activities
functions (see table 4 a) may arise from improved com- or financial status [67]. Administration of a question-
plex attention related to depression. In our opinion, naire concerning satisfaction with one’s own memory
it would be somewhat surprising that improvement ability such as the MMQ-Contentment, a part of the
in mood in absence of depression should affect com- Multifactorial Memory Questionnaire (MMQ) [68],
plex attentional functions to this extent. Moreover, one might probably be more successful for the assessment
might expect that positive effects on mood should not of self-reported benefits. Since interventions target-
only be reflected by improvements in higher atten- ing memory functioning in AD have been criticized
tional functions but also in speed of processing or for negatively affecting well-being [69] it is impor-
sustained attention [65]. Since there were no sig- tant to note that we observed no adverse effects of the
nificant changes in sustained attention assessed with intervention on measures of quality of life.
V.C. Buschert et al. / Cognitive Intervention in MCI and AD 691

Summary Concerning impaired memory functions in AD,


future development of our stage-specific cognitive
In summary, findings of our 6-month randomized intervention should focus strongly on teaching and
controlled pilot study suggest positive effects of a practicing mnemonic strategies which are directly
cognitive intervention in subjects with aMCI. For the related to functional independence in AD (e.g., keep-
AD-patient group we did not find positive intervention ing appointments or remembering to take medications
effects on the primary outcome variables ADAS-cog on time), and which are important for social interac-
and MMSE and only a tendency for improvement on tions (e.g., learning new names or a telephone number)
secondary outcome measures such as higher atten- [36]. In doing so, the program should emphasize cogni-
tional functions and mood. With regard to lack of tive and social resources of the participants providing
improvement in verbal episodic memory but signif- opportunities for (re-) activating largely intact cogni-
icant improvements in higher attentional functions, tive domains. Within this context the Goal Attainment
improvements in global cognitive status seem to rely Scaling might be an appropriate measure to be adminis-
primarily on attentional performance, though interpre- tered in future studies [73]. Finally, sessions, especially
tation of findings should be made with due care with for participants with mild AD, should probably run
regard to limited statistical power. Recent evidence in weekly for less than 120 minutes to minimize partic-
the research on cognitive deficits in AD suggests that ipant fatigue (see also section Discussion, Feasibility
after an initial amnesic stage in AD, attention is the and acceptance of program and study).
first non-memory domain to be affected [43]. It appears
that divided attention is particularly vulnerable while
sustained attention is relatively preserved in the early LIMITATIONS
stages as mentioned above. Improvement of attentional
functions due to practice and experience may lead There are limitations in our study. First, the study
to improved performance in other cognitive domains. included a relatively small number of participants,
Studies examining the neurobiological aspects of prac- which limited the statistical power to detect statistically
tice and experience on cognitive tasks indicate changes significant effects especially for the mild AD patient
of neural networks underlying higher cognitive func- group. In general one has to note that the MCI con-
tions, such as working memory, in healthy humans cept remains controversial, with no generally approved
[70]. Petersen and colleagues [71] suggest that a novel classification system and concerns about reliability and
task requires high cognitive effort during initial perfor- validity [74]. For future studies it may be advanta-
mance for successful performance and training leads geous to define clinical risk groups not only through
to a reduction of cognitive demand. The decrease in neuropsychological status, but also on the basis of bio-
cognitive demand is due to automation of the atten- logical markers [75]. Finally, evidence of long-term
tional and effortful components of the task because the maintenance of benefits in aMCI and mild AD due to
participant becomes an expert in the task with train- intervention is crucial because of the progressive nature
ing [71]. Thus attentional components can be reduced of the disease. A follow-up study is in preparation in
and the participant can focus on the specific cognitive order to detect indications of long-term-efficacy of the
demands of the task. A similar mechanism may also be cognitive intervention focusing on conversion to AD in
activated through cognitive interventions in cognitive MCI-subjects and further deterioration in AD-patients.
impaired subjects.
Basically, the intervention shows evidence of effi- CONCLUSION
cacy in cognitive and non cognitive-domains in
subjects with aMCI. However, there are a number of Our results suggest improvements in cognition and
concerns regarding generalized intervention effects to non-cognitive performance in subjects with aMCI
everyday functions and long-term, disease modifying having attended our 6-month stage-specific cognitive
effects. Thus, future studies with extended follow- intervention, compared to baseline and to an active con-
up periods should focus at global clinical status as a trol condition. Naturally, according to a pilot study, our
primary outcome measure. Additionally, to better esti- results should be viewed as promising findings which
mate whether clinically important goals are met during need to be replicated in larger studies. Given that sub-
cognitive intervention, e.g., Goal Attainment Scaling jects with aMCI are at high risk of developing AD,
[72], might be an appropriate measure which could be and given the lack of disease-modifying pharmacolog-
employed in future studies [73]. ical treatment presently available for this population,
692 V.C. Buschert et al. / Cognitive Intervention in MCI and AD

these results may have important clinical implications [10] Requena C, Maestu F, Campo P, Fernandez A, Ortiz T
for further therapeutic approaches. (2006) Effects of cholinergic drugs and cognitive training on
dementia: 2-year follow-up. Dement Geriatr Cogn Disord 22,
In mild AD patients, trends for a statistically sig- 339-345.
nificant effect of the intervention arm on the outcome [11] Spector A, Thorgrimsen L, Woods B, Royan L, Davies S,
variables were found, indicating the necessity to further Butterworth M, Orrell M (2003) Efficacy of an evidence-
evaluate and specify under which circumstances cog- based cognitive stimulation therapy programme for people
with dementia: randomised controlled trial. Br J Psychiatry
nitive functions can improve in these patients. These 183, 248-254.
findings in a small sample of subjects are promising [12] Requena C, Lopez Ibor MI, Maestu F, Campo P, Lopez Ibor
and support the use of the intervention in larger scale JJ, Ortiz T (2004) Effects of cholinergic drugs and cogni-
studies to confirm the effect in aMCI and AD subjects. tive training on dementia. Dement Geriatr Cogn Disord 18,
50-54.
Long-term-studies with larger samples are required [13] Bottino CM, Carvalho IA, Alvarez AM, Avila R, Zukauskas
to determine the extent to which cognitive interven- PR, Bustamante SE, Andrade FC, Hototian SR, Saffi F,
tion can affect aMCI-subjects’ conversion to AD and Camargo CH (2005) Cognitive rehabilitation combined with
drug treatment in Alzheimer’s disease patients: a pilot study.
progressive deterioration in AD.
Clin Rehabil 19, 861-869.
[14] Olazaran J, Muniz R, Reisberg B, Pena-Casanova J, del
ACKNOWLEDGMENTS Ser T, Cruz-Jentoft AJ, Serrano P, Navarro E, Garcia de
la Rocha ML, Frank A, Galiano M, Fernandez-Bullido Y,
Serra JA, Gonzalez-Salvador MT, Sevilla C (2004) Benefits
The authors thank Arun Bokde, PhD, for critical of cognitive-motor intervention in MCI and mild to moderate
review of the manuscript. Moreover, the authors thank Alzheimer disease. Neurology 63, 2348-2353.
Daniela Otto for administration of tests and scales. [15] Sitzer DI, Twamley EW, Jeste DV (2006) Cognitive training
in Alzheimer’s disease: a meta-analysis of the literature. Acta
Authors’ disclosures available online (http://www.j- Psychiatr Scand 114, 75-90.
alz.com/disclosures/view.php?id=771). [16] Olazaran J, Reisberg B, Clare L, Cruz I, Pena-Casanova J,
Del Ser T, Woods B, Beck C, Auer S, Lai C, Spector A,
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