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Box 1 | Definition of cognitive interventions25 with clinical cognitive deficits or dementia have been
considered in this Review.
Cognitive training Cognition-related intervention strategies can be
■ Guided practice on a set of standard tasks designed to increase particular divided into two basic categories: compensatory strat-
cognitive functions; for example attention, memory and problem-solving egies and restorative strategies.4 The aim of compensatory
■ By improving cognitive abilities, accomplishment of everyday tasks and strategies is to teach patients with cognitive deficits new
independent living are supported ways of performing cognitive tasks by changing every-
■ Generalized effects beyond the immediate training context are envisaged day memory behavior, so that they can ‘work around’
Cognitive rehabilitation their cognitive deficits. This approach emphasizes the
■ Individualized approach in which personally relevant goals are identified, and
use of internal strategies such as organizing information
the therapist works with the patient and their family to devise strategies to to be remembered, or encoding information through
address these goals multiple sensory modalities such as visual and auditory
■ Emphasis is placed on improving performance in everyday life rather than on senses, but also includes the use of electronic and non-
cognitive tests, thereby building on the individual’s strengths and developing electronic memory aids, as well as procedural training
ways of compensating for impairment (Box 2). By contrast, the aim of restorative strategies is to
■ Changes instituted in one setting would not necessarily generalize to another enhance functioning in specific cognitive domains, with
the goal of returning cognitive function to premorbid
Cognitive stimulation
levels.4 These two approaches can be used separately
■ Engagement in a range of activities aimed at general enhancement of cognitive or in combination. For example, the errorless learning
and social functioning in a nonspecific manner
approach is often combined with the spaced retrieval
■ Usually administered in a group setting technique (Box 2). some evidence indicates that restora-
tive strategies used in cognitive intervention programs
for the treatment of patients with mild-to-moderate AD
Box 2 | Compensatory and restorative cognitive intervention strategies4 achieve greater improvements in cognitive functioning
than do compensatory approaches.4,26
Compensatory strategies
■ Encoding specificity:77 interactive encoding and retrieval by encoding further Cognitive training in healthy elderly
cues such as semantic classification within the context (for example, target Numerous studies have shown that cognitive training
word: carrot; additional cue: vegetable) benefits healthy elderly individuals. 27,28 However, the
■ Visual imagery:78 simultaneous association of new verbal material (semantic opinion that commercially available computerized brain-
memory) and visual information during encoding training programs improve general cognitive function in
■ External memory aids: electronic notebook,79 notes, calendars and prompts80 the wider population lacks empirical support.29 Regard-
■ Dyadic approach: instructing the patient’s caregiver to carry out various ing the potential use of cognitive training in patients with
memory and cognitive improvement strategies AD, the few clinical trials that have been conducted to date
Restorative strategies have addressed two key issues: persistence of effect over
time, and transfer of effect to non-trained domains.11
■ Spaced retrieval technique:81 repeated recalling of information at short but
gradually increasing time intervals The sIMA (Maintaining and supporting Independent
Living in old Age) study demonstrated that a combina-
■ Vanishing cues technique:82 gradually giving as many letter prompts as required
by adding (forward cueing) and removing (backward chaining) cues until target tion of memory and psychomotor training significantly
word is correctly identified improved cognitive status in healthy elderly people
■ Errorless learning approach:83 elimination of incorrect or inappropriate
(75–89 years) after 1 year of training.16 This effect was
responses (interferences) during the learning process, and avoiding frustration stable for 5 years, and immediate and long-term transfer
and decreased motivation effects on non-trained cognitive functions were demon-
■ Sensorimotor skill stimulation: training of simple daily activities such as strated. In addition, all participants (aged 65–94 years)
grooming, preparing and eating meals and using a telephone, to improve in the ACTIvE (Advanced Cognitive Training for
daily living Independent and vital Elderly) study showed significant
■ Reality orientation therapy84 and reminiscence therapy:85 aims to improve improvements in distinct cognitive functions—memory,
temporal, local and personal orientation by proposal of orientation information, reasoning, problem solving and speed of processing—
either throughout the day or in group meetings on a regular basis after receiving >2 years of cognitive intervention therapy.30
11 month follow-up booster training sessions, which
were administered to over 60% of the study participants,
engagement in a range of activities that aim to enhance successfully improved reasoning and speed of processing
general cognitive and social functioning. Cognitive abilities. Improvements in these cognitive functions were
training, however, is a more specific approach, which stable for over 5 years. In addition, the 5 year follow-up
involves teaching patients strategies and skills in order revealed that reasoning training resulted in a reduced
to optimize specific cognitive functions. Cognitive reha- decline in ‘everyday’ functions.31 The positive effects of
bilitation is broadly defined as the use of any interven- cognitive training, such as delaying cognitive and func-
tion strategy that enables patients and their families to tional decline in healthy elderly adults, have substantial
manage the patient’s cognitive deficits.25 only approaches ramifications for its potential application in patients
that have been used to target cognitive deficits in patients with MCI.
with MCI. overall, the article highlights the need for The National Institute for Health and Clinical Excel-
randomized controlled trials to evaluate the efficacy of lence in the uK, as well as numerous professional
cognitive intervention in MCI. societies in the fields of neurology and psychiatry,
studies have shown that cognitive intervention recommends that patients with mild-to-moderate AD
approaches in which patients with MCI acquire and apply should participate in cognitive stimulation programs.
learning strategies to optimizing ‘everyday’ memory per- The largest and most extensive randomized controlled
formance have beneficial effects.42,43 The results indicate trial to assess the use of cognitive intervention in AD
that patients with MCI can acquire and maintain know- used a global cognitive stimulating approach based on
ledge about memory strategies. Furthermore, by employ- reality orientation therapy.6,47 The aim of the study was
ing these strategies the patients can modify their everyday to determine whether presentation and repetition of
memory behavior. By including these strategies in their orientation information could increase cognition and
daily routines, patients affected by memory problems quality of life of patients with mild-to-moderate AD.
could potentially maintain their independence, an issue The results of this study revealed that participating in
that needs to be addressed in future research.42 cognitive stimulation therapy significantly enhanced the
global cognitive status and quality of life of the inter-
Alzheimer disease vention group when compared with the control group
A number of articles have reviewed the randomized (Table 2). A number-needed-to-treat analysis of the
controlled trials that were conducted to assess the use data indicated that cognitive therapy was as effective
of cognitive intervention in AD.6,38,44–46 In general, the as antidementia drugs (ChEIs) at relieving cognitive
studies found that specific cognitive intervention strat- symptoms—memory and orientation—associated with
egies could be clinically effective or practically benefi- AD and seemed to potentiate the beneficial cognitive
cial in patients with AD. Furthermore, a meta-analysis effects provided by ChEI treatment.44–46,48 Nevertheless,
designed to assess the use of cognitive interventions in long-term cognitive deterioration in patients with AD
AD provided evidence that restorative strategies seem cannot be stopped even with 2 years of pharmacological
to be more efficacious than compensatory strategies for and/or non-pharmacological treatment, but deterioration
alleviating memory deficits (Box 2).4 Global cognitive is greater and progresses faster in patients not receiving
stimulation was shown to be more efficacious at improv- any treatment at all.49 Results of two studies, one compar-
ing cognitive functioning in patients with AD than were ing stimulation of procedural memory with training of
cognitive interventions involving training of specific cog- partially spared cognitive functions,50 and one compar-
nitive functions.4 However, owing to the fact that substan- ing the effects of ‘recreational activities’ against a specific
tial methodical differences existed between the studies, cognitive program on global stimulation in patients with
these results should be interpreted with caution. AD,51 provide further support for the use of cog nitive
intervention therapies in this condition. Immediate and Training seems to have three general effects on the
3–6 month follow-up assessments indicated that the cog- brain:55 it increases or decreases brain activity in speci-
nitive interventions significantly improved functional fic brain regions, and causes long-term global changes
competence in daily living in patients with AD, as well in brain activity when a specific task is being performed.
as alleviating caregiver distress. Global stimulation pro- Two possible scenarios could account for the changes
grams that aim to improve activities of daily living might in global brain activity that are associated with train-
be more beneficial to patients with AD than intervention ing: either specific regions of the brain that are activated
programs that stimulate specific cognitive functions. during the performance of a specific task before training
In summary, cognitive interventions can improve show altered levels of activity after training, or cognitive
global cognitive status, abilities of daily living and training causes additional cortical regions to be recruited
quality of life, and reduce behavioral disturbances, in after training. These changes in brain activity associated
patients with mild-to-moderate AD. The potential bene- with training reflect a qualitative shift—known as process
fits of cognitive stimulation have been demonstrated in switching—in the cognitive processes that underlie the
both patients with moderate-to-severe dementia,52 and performance of a given task.56 Thus, the cognitive pro-
patients with mild-to-moderate AD. Cognitive inter- cesses underpinning the performance of a task after train-
vention programs focusing on global cognitive stimu- ing are different from those used to complete the same
lation were found to be more effective at enhancing task before training. For example, brain activity could
cognitive and non-cognitive functioning than programs decrease in response to a particular stimulus when an
that trained specific cognitive functions.4 By contrast, individual becomes accustomed to, and better at, perceiv-
patients with MCI seem to benefit more from cognitive ing the information. At the cellular level, this net change
training than from global cognitive stimulation.32,53 in neuronal activity could reflect a minority of neurons
The findings mentioned above do not provide informa- being activated more strongly by the stimulus, and other
tion regarding the underlying biological mechanisms that neurons that were previously activated by the stimulus
are responsible for the improvements in global cognitive becoming unresponsive. Neural activity associated with
status. one study investigated the effects of cognitive– the performance of a cognitive task might also decrease as
motor intervention in patients with MCI or mild-to- a consequence of training, as the response time to perform
moderate AD, and found that participants with fewer the task decreases with practice and experience, meaning
years of formal education responded more strongly to that less neural processing is required to perform the
the cognitive intervention than patients deemed to have exercise. Furthermore, training and learning might alter
had more years of formal education.38 To explain this the level of awareness an individual requires to perform a
finding, the authors suggest that at a given level of clini- task, thereby altering the pattern of brain activity required
cal severity the underlying pathology is more advanced to accomplish the feat. Process switching might also evoke
in patients with AD with higher educational levels changes in task monitoring. For example, performing a
than in patients with lower educational levels. There- task might be challenging before training, but would
fore, the highly educated patients might be at the limit of become easier as the individual practices, thus requiring
their compensatory capacity and, thus, benefit less from less task monitoring—and fewer executive resources—for
cognitive interventions. This explanation is consistent the same level of performance after training.
with findings from another study, which reported that Decreased brain activity after training is observed in
although education delays the onset of cognitive decline, most studies of cognitive training, generally in paral-
once cognitive deficits become clinically apparent cog- lel to alterations to the neural processes underpinning
nitive decline is more rapid in individuals judged to be the performance of the task, as detailed in the previous
highly educated than in those with fewer years of formal paragraph. Functional MRI has shown decreases in brain
education.54 Better insights into how neuronal plasticity activity after training in the sternberg verbal task,57 in a
and cognitive reserve might affect the efficacy of cog- spatial working memory task,58 and in the n-back working
nitive intervention strategies in patients with cognitive memory task.59 A PET study of verbal recall also revealed
deficits could be provided by neuroimaging studies. reduced brain activity after training.60 In a further study
that examined the effects of training on completing a
Neuroimaging studies video game, researchers found that after a few weeks of
studies that have examined the neurobiological basis of practice, brain activity in the parietal cortex when playing
training programs have typically focused on examin- the game was decreased, and that decreased activity in
ing the effects of training on changes in brain activity in this brain region positively correlated with improved task
young, healthy individuals. These studies indicate that performance.61 This finding is consistent with the hypo-
training can alter brain function at the molecular and thesis that functional decreases in brain activity reflect
synaptic levels, as well as at the neural network level.7 more-efficient information processing in the brain.
Interestingly, these changes in neurobiological function Increased brain activity after training has been demon-
might underlie the increases in cognitive performance strated during the performance of cognitively taxing
that are associated with cognitive intervention strategies. tasks, such as playing musical instruments.62 In a study of
Both PET and functional MRI studies might further our working memory, increased activity in frontal and pari-
understanding of how brain activity changes in response etal cortices correlated with increased working memory
to cognitive intervention therapies. capacity after training.63
As mentioned above, changes in brain activity after capacity to enhance or compensate for impaired cog-
training reflect parallel increases and decreases of acti- nitive functions seems to decline. Therefore, patients
vation in the neuronal network underlying the perfor- with MCI and patients with mild AD could benefit
mance of the task. In general, these changes probably differently from cognitive interventions. These initial
reflect decreases in the attentional demand required studies indicate that cognitive intervention can alter
by the task and increases in task-specific domains such neuronal function, and these functional changes can be
as memory. 64 Petersen and colleagues 64 argue that a measured with neuroimaging tools.
novel task requires high cognitive effort for successful
performance, and that training leads to a reduction in Implications for future studies
the cognitive activity required to successfully perform In general, most studies that have investigated the
this task. The increased brain activity associated with effects of cognitive interventions in AD and MCI have
performing a novel task is typically localized in brain involved relatively small numbers of patients and con-
areas associated with visual processing and memory.64 trols. Furthermore, owing to the wide range of cognitive
similar patterns of altered brain activity have also been interventions that have been implemented in these
observed in individuals who have successfully acquired a trials, comparisons of the data are problematic. Further
new motor skill.65,66 The key insight from these studies is studies with larger sample sizes are warranted to establish
that attentional processes are associated with decreases whether cognitive intervention programs can improve
in brain activity, whereas task-specific brain regions are and stabilize global cognitive functioning and delay
associated with increased brain activity after training. further disease progression.
only a few neuroimaging studies have investigated Most studies have failed to consider potentially con-
the effects of cognitive training or cognitive stimu- founding effects that could arise from the social inter-
lation in patients with AD. one of the earliest PET action with a trainer or instructor. Hence, the extent to
studies of patients with mild AD reported that a com- which the observed training benefits are actually due to
bination of cognitive training and phosphatidylserine cognitive intervention is unclear. Furthermore, studies
or pyritinol drug therapy was associated with increased investigating the effects of cognitive intervention in AD
brain glucose metabolism in temporal–parietal brain or MCI are typically relatively short in duration and,
areas during a continuous visual recognition task. 67 therefore, do not provide any information on the possible
Furthermore, patients receiving combined cognitive mid-term and long-term effects of this therapy on global
and drug therapies showed increased glucose metabo- cognitive functioning. Another issue worthy of investi-
lism and improved cognitive performance compared gation is whether cognitive intervention might delay
with control groups receiving either drug or cognitive the need for help and care dependency in the mid term
intervention alone.67 A PET study of elderly patients and long term. Finally, as the heterogeneous underlying
with memory impairments that investigated the effects causes of MCI and the various types of dementia could
of a 14 day mental exercise program in combination substantially affect the ability of cognitive interventions
with physical exercise, stress reduction and a healthy to provide benefits to patients with cognitive deficits,
diet showed that the inter vention substantially reduced better patient stratification is needed.36,69,70 Assessment
resting glucose metabolism in the dorsolateral pre- of neuropsychological status, multimodal biological
frontal cortex in the intervention group compared with markers,71 patterns of progressive regional brain atrophy,
the control group. The study participants receiving the and regional changes in brain metabolism72,73 will all aid
intervention were also shown to have increased verbal patient stratification and assist the development of cog-
fluency.68 The decreased resting glucose metabolism in nitive interventions that target patients with different
the dorsolateral prefrontal cortex might reflect increased levels of cognitive and global functioning.
cognitive efficiency, as no changes in brain glucose In summary, large, long-term (18–24 months in
metabolism were evident in the control group. duration) cognitive intervention studies that document
A randomized controlled trial has tested a 6 month information regarding the study participant’s neuro-
stage-specific cognitive intervention designed to increase psychological, neurogenetic and biomarker status are
cognitive and non-cognitive functions, which was required to establish whether cognitive intervention can
administered weekly in a group environment and com- positively affect global cognitive functioning in patients
pared with active control groups (v. Buschert, unpub- with MCI or AD.74 studies examining the neurobiologi-
lished work). In patients with amnestic MCI, greater cal effects of cognitive training in healthy individuals
cognitive bene fits were seen in those receiving the indicate that this intervention can substantially affect
intervention than in controls. Patients with mild AD also neural activity in brain areas associated with perfor-
benefitted from the intervention, but to a lesser degree mance of the cognitive function in question. We feel,
than those with amnestic MCI (s. Foerster, unpublished therefore, that future functional and anatomical studies
work). The gains in cognition were shown by PET to be should examine in detail how cognitive training influ-
associated with an attenuation in the decline in glucose ences the neural networks affected by the pathological
metabolism in cortical regions typically affected by AD. processes associated with both MCI and AD. In addi-
Cognitive reserve might be better preserved in patients tion, neuroimaging studies could identify which specific
with MCI who are at risk of developing dementia than neural networks in patients with MCI might respond
in patients with AD.14 As the disease progresses, the positively to cognitive training.75
Recommendations for practice studies in MCI and AD could have important clinical
varying levels of cognitive functioning exist during implications. At present, however, no standardized,
the progression of AD, so matching appropriate cogni- replicable intervention programs have been designed for
tive interventions to patients with different cognitive the treatment of patients at different stages of AD.
and global functioning levels is desirable. Patients with Cognitive interventions that support global function-
advanced symptoms will receive fewer benefits from ing could delay the onset of AD by 5 years in patients
cognitive interventions that target specific cognitive who will eventually develop this condition. As a result,
functions than patients with preclinical or mild AD. the prevalence of AD could decrease by 50%, leading
By contrast, global cognitive stimulation and cognitive to substantial personal, social and economic benefits.
intervention strategies that aid performance of activities Compared with the pharmacological treatments cur-
of daily living might provide greater benefits to patients rently available for the treatment of AD—namely, ChEIs
with advanced AD. 52 A meaningful cognition-based and memantine—non-pharmacological cognitive inter-
intervention should focus on the distinct stages of the ventions have a number of advantages. With regard to
disease and aim to improve cognitive functions that health insurance costs, cognitive intervention programs,
increase the patient’s independence and autonomy. when administered in groups in the course of outpatient
Throughout the intervention, confrontation of indivi- treatment, seem to be highly attractive, as they are associ-
dual cognitive deficits should be avoided to prevent the ated with lower costs and higher cost-effectiveness than
participant from becoming disillusioned, which might have pharmacological treatments. 5 Furthermore, cognitive
a negative impact on the success of the therapy.68 Cognitive interventions are thought to cause no undesirable adverse
intervention places high demands on the therapist, and events, unlike antidementia drugs.
requires the application of current knowledge concerning The implementation of adequate intervention pro-
intervention techniques, content and strategy. grams for the treatment of AD requires the availability of
sufficient numbers of medical practitioners and specia-
Conclusions lists (and suitable institutions) to diagnose and treat all
Cognitive interventions have been shown to improve patients with this serious condition. Considering that the
global cognitive functioning and abilities of daily living, number of patients with dementia worldwide is expected
reduce behavioral disturbances, and have positive to increase dramatically from 35 million today to
effects on quality of life in patients with MCI or mild- 115 million in 2050,76 efforts to advance the development
to-moderate AD. Neuroimaging results indicate that and implementation of cognition-based interventions for
changes in attention underpin many of the improvements the treatment of AD must definitely be pursued.
in cognitive performance.
Evidence suggests that physical activity slows down cog- Review criteria
nitive decline and delays the onset of dementia in healthy PubMed was searched for articles published in English,
elderly adults. At present, however, the importance of with the following search terms: “cognitive training/”,
physical activity in the framework of non-pharmacological “cognitive stimulation”, “cognitive intervention”, “healthy
approaches to the treatment of AD remains unclear. elderly”, “mild cognitive impairment”, “Alzheimer’s
Given that patients with MCI have an increased risk disease”, “neuroimaging”, “DTI”, “SPECT”, “fMRI” and
of developing AD, and considering that no approved “PET”. In addition, we identified papers from references in
disease-modifying drugs are currently available for AD, the articles retrieved by the initial searches and selected
articles from our own archives.
the encouraging results from cognitive intervention
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