Cognitive intervention in Alzheimer disease

REVIEWS Cognitive intervention in Alzheimer disease Verena Buschert, Arun L. W. Bokde and Harald Hampel Abstract | Alzheimer disease (AD) is one of the most prevalent chronic medical conditions affecting the elderly population. The effectiveness of approved antidementia drugs, however, is limited—licensed AD medications provide only moderate relief of clinical symptoms. Cognitive intervention is a noninvasive therapy that could aid prevention and treatment of AD. Data suggest that specifically designed cognitive interventions could impart therapeutic benefits to patients with AD that are associated with substantial biological changes within the brain. Moreover, evidence indicates that a combination of pharmacological and non-pharmacological interventions could provide greater relief of clinical symptoms than either intervention given alone. Functional and structural MRI studies have increased our understanding of the underlying neurobiological mechanisms of aging and neurodegeneration, but the use of neuroimaging to investigate the effect of cognitive intervention on the brain remains largely unexplored. This Review provides an overview of the use of cognitive intervention in the healthy elderly population and patients with AD, and summarizes emerging findings that provide evidence for the effectiveness of this approach. Finally, we present recommendations for future research on the use of cognitive interventions in AD and discuss potential effects of this therapy on disease modification. Buschert, V. et al. Nat. Rev. Neurol. 6, 508–517 (2010); published online 17 August 2010; doi:10.1038/nrneurol.2010.113

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Dementia Research Section and Memory Clinic, Alzheimer Memorial Center and Research Section, Department of Psychiatry, LudwigMaximilian University, Nussbaumstrasse 7, D-80366 Munich, Germany (V. Buschert). Discipline of Psychiatry, School of Medicine & Trinity College Institute of Neuroscience, Cognitive Systems Group, Trinity College Dublin, Lloyd Building, Dublin 2, Ireland (A. L. W. Bokde). Department of Psychiatry, Psychosomatic Medicine & Psychotherapy, Johann Wolfgang Goethe University, HeinrichHoffmann-Straße 10, 60528 Frankfurt, Germany (H. Hampel). Correspondence to: V. Buschert verena.buschert@ med.uni-muenchen.de

Medscape, LLC designates this educational activity for a maximum of 1.0 AMA PRA Category 1 CreditsTM. Physicians should only claim credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test and/or complete the evaluation at http://www.medscapecme.com/journal/ nrneuro; and (4) view/print certificate.

Learning objectives Upon completion of this activity, participants should be able to: 1 Identify the factor that is associated with the maintenance of cognitive reserve and incorporate this knowledge into strategies for the prevention of dementia. 2 Examine cognitive interventions for the management of Alzheimer’s disease, and develop treatment strategies that correctly incorporate these interventions.

Introduction

Alzheimer disease (AD) is one of the most devastating and prevalent chronic medical conditions in elderly individuals.1 At present, no approved disease-modifying drugs are available for this condition. Licensed antidementia drugs, such as cholinesterase inhibitors (ChEIs) and memantine—an N-methyl-d-aspartate Competing interests The authors, the journal Chief Editor H. Wood and the CME questions author C. P. Vega declare no competing interests.

receptor antagonist—provide only limited relief from clinical symptoms and, on average, delay cognitive decline by only 6–12 months.2 Thus, new therapeutic strategies are urgently needed that robustly inhibit the clinical symptoms of AD and attenuate disease progression. Cognitive intervention seems to be an emerging therapeutic approach that could aid prevention and treatment of this disease. Research suggests that regular activation of various brain networks by cognitive and/or physical stimulation could considerably contribute to brain health and cognitive status.3,4 Moreover, approaches that combine pharmacological and non-pharmacological interventions might effectively support cognitive, affective and functional abilities in patients with preclinical or clinical AD. Compared with pharmacological treatment of AD, cognitive interventions are likely to be less expensive and more costeffective,5 in addition, cognitive intervention is thought to cause no adverse events.6 In this article, we review the use of cognitive intervention in healthy elderly individuals and patients with preclinical or clinical AD, and provide an overview of recent studies that suggest that cognitive intervention provides substantial benefits for patients with this condition. We also present recommendations for future research on the use of cognitive interventions in AD and discuss how this nonpharmacological treatment can modify clinical symptoms associated with this disease.

Neuronal plasticity

Evidence for the usefulness of cognitive interventions in AD originates from several different areas of research, and the assertion that cognition-based interventions could impart therapeutic benefits to patients with this disease derives from the concept of neuronal plasticity. Neuronal

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ReVieWs plasticity can be defined as the ability of the nervous system to adapt its structural organization in response to changes in the environment, as well as other factors such as injuries, which affect the integrity and functioning of the nervous system.7 Neuronal plasticity is considered to be an essential process that endows animals—in particular, humans and other primates—with the ability to adapt to new cognitive or behavioral stresses. A high level of neuronal plasticity, although deemed integral to brain evolution, has been shown to be associated with increased neuronal vulnerability in regions of the brain that are typically affected in AD.8 This finding suggests that a complex relationship exists between this agingassociated, chronically progressive disease of the CNs and the genetic, epigenetic, functional, metabolic and structural changes that have taken place throughout the evolution of the human brain.9 Although a high degree of neuronal plasticity could contribute to the clinical symptoms associated with AD, enhancing neuronal plasticity, especially in higher-order frontal, parietal and temporal association cortices might improve neurological functioning and could prevent the loss of neuronal processes that typically occurs in AD.10

Cognitive reserve and brain reserve

Meta-analyses have provided strong evidence that specifically designed cognitive training programs can attenuate the risk of cognitive decline in healthy elderly patients.11 The beneficial effects of cognitive training are thought to reflect increases in cognitive reserve. Cognitive reserve relates to the brain’s ability to perform cognitive tasks adequately despite neuropathological damage,12 and is thought to represent either an enhanced ability to recruit alternative brain networks or a more efficient utilization of brain networks in general.13 These proposed mechanisms are both considered to require neuronal plasticity. Education, mentally demanding occupations and mentally stimulating lifestyle pursuits are all thought to increase cognitive reserve.14 Individuals deemed to have greater reserves have been shown to have a reduced risk of developing dementia compared with individuals judged to have low reserves,13 and studies have demonstrated that higher cognitive reserve is associated with increased cognitive performance in healthy elderly people.12,15,16 The effects of cognitive reserve can be substantial. A meta-analysis including over 29,000 individuals has shown that individuals with high cognitive reserve had a 46% reduced risk of developing dementia compared with individuals with low cognitive reserve.14 of all the factors that influence cognitive reserve, mentally stimulating activities were shown to have the largest effect on dementia risk. The effect of cognitive reserve was sustained over a median longitudinal follow-up of 7 years. As cognitive reserve seems to have such a large effect on the risk of developing dementia, cognitive interventions—secondary prevention or rehabilitative measures—might attenuate cognitive decline in patients with dementia. Moreover, cognitive interventions could potentially delay the onset of dementia and might also be able to partially reverse neurodegenerative-related

Key points ■ No disease-modifying drugs are available for the treatment of Alzheimer disease (AD) and the effectiveness of approved antidementia drugs is still not satisfactory ■ Non-pharmacological interventions could aid the prevention and treatment of AD, and combining pharmacological and non-pharmacological interventions might substantially alleviate the clinical symptoms associated with the disease ■ Neuroimaging studies could further our understanding of the neurobiological mechanisms underlying the effects of cognitive intervention on the brain ■ Health-care professionals must base recommendations concerning the use of cognitive intervention in mild cognitive impairment and AD on robust experimental evidence ■ No standardized intervention programs are currently available for the treatment of the diverse cognitive and functional impairments associated with the different stages of AD

cog nitive decline once dementia has been clinically diagnosed. In fact, findings from neuroimaging studies support the concept that cognitive reserve can attenuate the clinical symptoms associated with dementia and contribute to the neurophysiological heterogeneity observed in AD.8 Brain reserve is also hypothesized to affect an individual’s risk of cognitive decline. In contrast to cognitive reserve, brain reserve is considered to be a passive quality, and is thought to be directly related to brain size or neuronal cell count. Brain reserve influences the amount of brain damage that can be sustained before clinical symptoms develop.13

Physical exercise

Physical exercise seems to have a beneficial effect on cognition.16 Accumulating evidence from animal studies and epidemiological studies in humans indicates that moderate exercise improves cognitive function in normal individuals,3 is neuroprotective in healthy animals and humans, and can prevent cognitive decline in patients with AD.17–22 Nevertheless, owing to the limited number of randomized controlled trials that have been conducted to investigate the effects of physical activity on cognition, the authors of a systematic review on this subject have concluded that insufficient evidence exists to suggest that physical activity is beneficial for people with dementia.23 Additional studies are necessary before any potential effects of exercise on cognition in patients with AD or mild cognitive impairment (MCI) are recognized. We believe that comparing the efficacy of physical exercise programs with cognitive intervention programs in clinical and preclinical AD and evaluating the combination of both interventions would be extremely instructive.

Terms and definitions

With regard to the use of cognition-based activities in AD, terms like cognitive training, cognitive rehabilitation and cognitive stimulation have been used almost interchangeably in the literature. Although cognitive training and cognitive rehabilitation are related, they are, in fact, two different forms of cognitive intervention, both of which are also distinct from cognitive stimulation (Box 1).24 Cognitive stimulation comprises

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ReVieWs Box 1 | Definition of cognitive interventions25 Cognitive training ■ Guided practice on a set of standard tasks designed to increase particular cognitive functions; for example attention, memory and problem-solving ■ By improving cognitive abilities, accomplishment of everyday tasks and independent living are supported ■ Generalized effects beyond the immediate training context are envisaged

Cognitive rehabilitation ■ Individualized approach in which personally relevant goals are identified, and the therapist works with the patient and their family to devise strategies to address these goals ■ Emphasis is placed on improving performance in everyday life rather than on cognitive tests, thereby building on the individual’s strengths and developing ways of compensating for impairment ■ Changes instituted in one setting would not necessarily generalize to another

Cognitive stimulation ■ Engagement in a range of activities aimed at general enhancement of cognitive and social functioning in a nonspecific manner ■ Usually administered in a group setting

Box 2 | Compensatory and restorative cognitive intervention strategies4 Compensatory strategies ■ Encoding specificity:77 interactive encoding and retrieval by encoding further cues such as semantic classification within the context (for example, target word: carrot; additional cue: vegetable) ■ Visual imagery:78 simultaneous association of new verbal material (semantic memory) and visual information during encoding ■ External memory aids: electronic notebook,79 notes, calendars and prompts80 ■ Dyadic approach: instructing the patient’s caregiver to carry out various memory and cognitive improvement strategies

Restorative strategies ■ Spaced retrieval technique:81 repeated recalling of information at short but gradually increasing time intervals ■ Vanishing cues technique:82 gradually giving as many letter prompts as required by adding (forward cueing) and removing (backward chaining) cues until target word is correctly identified ■ Errorless learning approach:83 elimination of incorrect or inappropriate responses (interferences) during the learning process, and avoiding frustration and decreased motivation ■ Sensorimotor skill stimulation: training of simple daily activities such as grooming, preparing and eating meals and using a telephone, to improve daily living ■ Reality orientation therapy84 and reminiscence therapy:85 aims to improve temporal, local and personal orientation by proposal of orientation information, either throughout the day or in group meetings on a regular basis

engagement in a range of activities that aim to enhance general cognitive and social functioning. Cognitive training, however, is a more specific approach, which involves teaching patients strategies and skills in order to optimize specific cognitive functions. Cognitive rehabilitation is broadly defined as the use of any intervention strategy that enables patients and their families to manage the patient’s cognitive deficits.25 only approaches that have been used to target cognitive deficits in patients

with clinical cognitive deficits or dementia have been considered in this Review. Cognition-related intervention strategies can be divided into two basic categories: compensatory strategies and restorative strategies.4 The aim of compensatory strategies is to teach patients with cognitive deficits new ways of performing cognitive tasks by changing everyday memory behavior, so that they can ‘work around’ their cognitive deficits. This approach emphasizes the use of internal strategies such as organizing information to be remembered, or encoding information through multiple sensory modalities such as visual and auditory senses, but also includes the use of electronic and nonelectronic memory aids, as well as procedural training (Box 2). By contrast, the aim of restorative strategies is to enhance functioning in specific cognitive domains, with the goal of returning cognitive function to premorbid levels.4 These two approaches can be used separately or in combination. For example, the errorless learning approach is often combined with the spaced retrieval technique (Box 2). some evidence indicates that restorative strategies used in cognitive intervention programs for the treatment of patients with mild-to-moderate AD achieve greater improvements in cognitive functioning than do compensatory approaches.4,26

Cognitive training in healthy elderly

Numerous studies have shown that cognitive training benefits healthy elderly individuals. 27,28 However, the opinion that commercially available computerized braintraining programs improve general cognitive function in the wider population lacks empirical support.29 Regarding the potential use of cognitive training in patients with AD, the few clinical trials that have been conducted to date have addressed two key issues: persistence of effect over time, and transfer of effect to non-trained domains.11 The sIMA (Maintaining and supporting Independent Living in old Age) study demonstrated that a combination of memory and psychomotor training significantly improved cognitive status in healthy elderly people (75–89 years) after 1 year of training.16 This effect was stable for 5 years, and immediate and long-term transfer effects on non-trained cognitive functions were demonstrated. In addition, all participants (aged 65–94 years) in the ACTIvE (Advanced Cognitive Training for Independent and vital Elderly) study showed significant improvements in distinct cognitive functions—memory, reasoning, problem solving and speed of processing— 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, successfully improved reasoning and speed of processing abilities. Improvements in these cognitive functions were stable for over 5 years. In addition, the 5 year follow-up revealed that reasoning training resulted in a reduced decline in ‘everyday’ functions.31 The positive effects of cognitive training, such as delaying cognitive and functional decline in healthy elderly adults, have substantial ramifications for its potential application in patients with MCI.



ReVieWs Table 1 | Cognitive intervention in patients with MCI and AD Reference

intervention (treatment vs control)

Participants

Duration

Results

Olazaran et al. (2004)38

Cognitive (memory, attention, language, visuoconstructive abilities and executive functions) and motor intervention plus psychosocial activities vs psychosocial support only

Total 84: 12 MCI, 48 mild AD, 24 moderate AD; 44 TG, 40 CG

1 year (103 twiceweekly 310 min sessions); no follow-up

TG maintained cognitive status at 6 months; significant deterioration of CG at 6 months; TG maintained or improved affective status (GDS) at month 12

Belleville et al. (2006)53

Teaching episodic memory strategies, metacognition and computer-based training of attention vs waiting-list group

Total 47: 20 MCI, 9 healthy (TG) vs 8 MCI, 8 healthy (CG); note discrepancy between number of participants reported in each group and total number of participants reported

Weekly 120 min sessions for 8 weeks; no follow-up

Improvement of TG in delayed list recall and face–name association; improved subjective memory and well-being

Cipriani et al. (2006)41

Individualized computer-based cognitive training (no control group)

Total 23: 10 MCI, 10 mild AD, 3 MSA; 20 TG, 3 CG*

Weekly sessions (13–45 min per day for 4 days) for 8 weeks; no follow-up

MCI: improvement in tasks concerning working memory and psychomotor function, improvement in behavioral memory; AD: improved global cognitive status (MMSE), improved verbal production and executive functions; MSA: no improvement

Rozzini et al. (2007)39

Computer-based cognitive training (memory, attention and language training, abstract reasoning, thinking, visuoconstructive abilities) and ChEIs vs ChEIs or NT

Total 59 MCI: 15 TG + ChEIs, 22 ChEIs alone, 22 NT

Weekly sessions (60 min per day for 5 days) for 12 weeks; 3 month follow-up

After 3 months follow-up, TG + ChEIs: improvements in two different cognitive areas (memory, abstract reasoning) and behavioral disturbances (depressive symptoms); ChEIs alone: improvement in depressive symptoms; NT: cognitive, functional and behavioral status remained unchanged

Talassi et al. (2007)40

Computerized cognitive training, occupational therapy and behavioral training vs physical rehabilitation, occupational therapy and behavioral training

Total 66: 30 MCI, 24 mild AD (TG) vs 7 MCI, 5 mild AD (CG)

Weekly sessions (30–45 min per day for 4 days) for 3 weeks; no follow-up

MCI TG: improvement in constructive apraxia and long-term visuospatial memory, reduced symptoms of depression and anxiety; mild AD TG: improved global cognitive status (MMSE), reduced symptoms of depression and anxiety; AD CG: improved word fluency

Troyer et al. (2008)42

Evidenced-based memory training aimed at teaching and practicing of compensatory memory strategies and lifestyle education vs waiting-list group

Total 54 MCI: 27 TG, 27 CG

10 sessions (120 min each) over 6 months; 3 month follow-up

TG: improved memory-strategy knowledge and use; no improvement in memory beliefs or objective memory performance

Kinsella et al. (2009)43

Evidenced-based memory rehabilitation aimed at teaching and practicing of all-day memory strategies

Total 47 MCI: 22 MCI vs 25 MCI

Weekly 90 min sessions for 5 weeks; 4 month follow-up

Improvements in performance on prospective memory tasks and knowledge and use of memory strategies

*MSA group served as the control group. Abbreviations: AD, Alzheimer disease; CG, control group; ChEIs, cholinesterase inhibitors; GDS, Geriatric Depression Scale; MCI, mild cognitive impairment; MMSE, Mini Mental State Examination; MSA, multiple system atrophy; NT, no treatment; TG, treatment group.

Cognitive intervention Mild cognitive impairment Beneficial effects of cognition-based interventions on cognitive decline have been reported in patients with MCI.32 MCI is defined as a subjective complaint of memory impairment with demonstrated objective memory deficits that does not interfere notably with activities of daily life or psychosocial competence. Importantly, MCI does not fulfill the currently accepted clinical criteria for dementia, as defined by either the Diagnostic and statistical Manual of Mental Disorders (edition Iv) or the International Classification of Diseases (10th edition).33 According to population-based epidemiological studies, the prevalence of MCI ranges from 3–19% in the adult population aged >65 years in the Western world.34 Furthermore, a meta-analysis has shown that 5–10% of patients with MCI, notably those who have amnestic impairments in single or multiple

domains,35 develop dementia within 1 year after being diagnosed with this condition.36 Thus, compared with healthy individuals of the same age, patients with MCI who have noticeable deficits in memory37 can be regarded as having an increased risk of developing dementia. The use of cognitive training in MCI has typically focused on enhancing episodic memory by teaching patients learning strategies,27 making them perform cognitive exercises, and increasing their levels of social and psychomotor activity (Table 1).38–41 A review on cognitive intervention in MCI indicates that cognitive training is an efficient method of delaying cognitive decline in patients with MCI, and suggests that, following training, episodic memory improves, as does mood and behavior.32 However, the few studies that were reviewed in the article had limited power owing to small sample sizes, and even fewer evaluated long-term effects or the global functional impact of cognitive training on patients



ReVieWs Table 2 | Cognitive intervention in subjects with mild-to-moderate AD Reference

Conditions (treatment vs control)

Participants

Duration

Results and comments

Spector et al. (2003)6

CS therapy (reality orientation) vs usual activities

Total 201: 115 TG, 86 CG

Two 45 min sessions per week for 7 weeks; no follow-up

TG showed improved global cognitive functions (MMST, ADAS-cog) and quality of life; number needed to treat (6) (≥4 points on ADAS-cog) results compare favorably with trials of dementia drugs

Requena et al. (2004)45

ChEIs and CS involving images of everyday life and reminiscent music vs ChEI only vs CS only vs watching television

Total 86: 20 ChEI + CS, 30 ChEI only, 18 CS only, 18 NT

12 months, weekly (5 days each 45 min); 1 year follow-up

ChEI + CS and CS only: improved MMSE, ADAS-cog and FAST; ChEI only: improvement in affective symptoms (GDS); NT: poor scores in all measures compared with other groups

Requena et al. (2006)49

ChEIs and CS involving images of everyday life and reminiscent music vs ChEIs only vs CS only vs watching television

Total 68: 14 ChEIs + CS, 20 ChEIs only, 14 CS only, 30 NT

2 years, weekly (5 days each 45 min)

Gradual deterioration in all groups; greater and faster progress in patients not receiving any treatment

Farina et al. (2002)50

Procedural memory training (activities of daily living) vs training of partially spared cognitive functions

Total 22: 11 TG, 11 CG

Weekly sessions (each two 45 min sessions a day for 3 days) for 5 weeks; 3 month follow-up

Both groups improved functional living skills; slightly improved performance in specific cognitive functions (attention, verbal fluency); training in activities of daily living might be more effective than stimulating ‘residual’ cognitive functions

Farina et al. (2006)51

Recreational activities, for example, crafts, games, pets and ROT (global stimulation) vs combination of procedural memory training on activities of daily living and neuropsychological rehabilitation of ‘residual’ functions (cognitive-specific)

Total 32: 16 TG, 16 CG

6 weeks (15 sessions each 180 min); 6 months follow-up

Global stimulation group: reduced behavioral disturbances (NPI); reduced memory behavioral problems; improved functional living skills; improved verbal fluency; at 6 months follow-up, alleviation of caregiver distress (NPI) associated with global stimulation group

Abbreviations: AD, Alzheimer disease; ADAS-cog, Alzheimer’s Disease Assessment Scale Cognitive Subscale; ADL, activities of daily living; CG, control group; ChEIs, cholinesterase inhibitors; CS, cognitive stimulation; GDS, Geriatric Depression Scale; FAST, Functional Assessment Staging of Alzheimer’s Disease; MMSE, Mini Mental State Examination; NPI, Neuropsychiatric Inventory; NT, no treatment; ROT, reality orientation therapy; TG, treatment group.

with MCI. overall, the article highlights the need for randomized controlled trials to evaluate the efficacy of cognitive intervention in MCI. studies have shown that cognitive intervention approaches in which patients with MCI acquire and apply learning strategies to optimizing ‘everyday’ memory performance have beneficial effects.42,43 The results indicate that patients with MCI can acquire and maintain knowledge about memory strategies. Furthermore, by employing these strategies the patients can modify their everyday memory behavior. By including these strategies in their daily routines, patients affected by memory problems could potentially maintain their independence, an issue that needs to be addressed in future research.42

Alzheimer disease A number of articles have reviewed the randomized controlled trials that were conducted to assess the use of cognitive intervention in AD.6,38,44–46 In general, the studies found that specific cognitive intervention strategies could be clinically effective or practically beneficial in patients with AD. Furthermore, a meta-analysis designed to assess the use of cognitive interventions in AD provided evidence that restorative strategies seem to be more efficacious than compensatory strategies for alleviating memory deficits (Box 2).4 Global cognitive stimulation was shown to be more efficacious at improving cognitive functioning in patients with AD than were cognitive interventions involving training of specific cognitive functions.4 However, owing to the fact that substantial methodical differences existed between the studies, these results should be interpreted with caution.

The National Institute for Health and Clinical Excellence in the uK, as well as numerous professional societies in the fields of neurology and psychiatry, recommends that patients with mild-to-moderate AD should participate in cognitive stimulation programs. The largest and most extensive randomized controlled trial to assess the use of cognitive intervention in AD used a global cognitive stimulating approach based on reality orientation therapy.6,47 The aim of the study was to determine whether presentation and repetition of orientation information could increase cognition and quality of life of patients with mild-to-moderate AD. The results of this study revealed that participating in cognitive stimulation therapy significantly enhanced the global cognitive status and quality of life of the intervention group when compared with the control group (Table 2). A number-needed-to-treat analysis of the data indicated that cognitive therapy was as effective as antidementia drugs (ChEIs) at relieving cognitive symptoms—memory and orientation—associated with AD and seemed to potentiate the beneficial cognitive effects provided by ChEI treatment.44–46,48 Nevertheless, long-term cognitive deterioration in patients with AD cannot be stopped even with 2 years of pharmacological and/or non-pharmacological treatment, but deterioration is greater and progresses faster in patients not receiving any treatment at all.49 Results of two studies, one comparing stimulation of procedural memory with training of partially spared cognitive functions,50 and one comparing the effects of ‘recreational activities’ against a specific cognitive program on global stimulation in patients with AD,51 provide further support for the use of cog nitive



ReVieWs intervention therapies in this condition. Immediate and 3–6 month follow-up assessments indicated that the cognitive interventions significantly improved functional competence in daily living in patients with AD, as well as alleviating caregiver distress. Global stimulation programs that aim to improve activities of daily living might be more beneficial to patients with AD than intervention programs that stimulate specific cognitive functions. In summary, cognitive interventions can improve global cognitive status, abilities of daily living and quality of life, and reduce behavioral disturbances, in patients with mild-to-moderate AD. The potential benefits of cognitive stimulation have been demonstrated in both patients with moderate-to-severe dementia,52 and patients with mild-to-moderate AD. Cognitive intervention programs focusing on global cognitive stimulation were found to be more effective at enhancing cognitive and non-cognitive functioning than programs that trained specific cognitive functions.4 By contrast, patients with MCI seem to benefit more from cognitive training than from global cognitive stimulation.32,53 The findings mentioned above do not provide information regarding the underlying biological mechanisms that are responsible for the improvements in global cognitive status. one study investigated the effects of cognitive– motor intervention in patients with MCI or mild-tomoderate AD, and found that participants with fewer years of formal education responded more strongly to the cognitive intervention than patients deemed to have had more years of formal education.38 To explain this finding, the authors suggest that at a given level of clinical severity the underlying pathology is more advanced in patients with AD with higher educational levels than in patients with lower educational levels. Therefore, the highly educated patients might be at the limit of their compensatory capacity and, thus, benefit less from cognitive interventions. This explanation is consistent with findings from another study, which reported that although education delays the onset of cognitive decline, once cognitive deficits become clinically apparent cognitive decline is more rapid in individuals judged to be highly educated than in those with fewer years of formal education.54 Better insights into how neuronal plasticity and cognitive reserve might affect the efficacy of cognitive intervention strategies in patients with cognitive deficits could be provided by neuroimaging studies.

Neuroimaging studies

studies that have examined the neurobiological basis of training programs have typically focused on examining the effects of training on changes in brain activity in young, healthy individuals. These studies indicate that training can alter brain function at the molecular and synaptic levels, as well as at the neural network level.7 Interestingly, these changes in neurobiological function might underlie the increases in cognitive performance that are associated with cognitive intervention strategies. Both PET and functional MRI studies might further our understanding of how brain activity changes in response to cognitive intervention therapies.

Training seems to have three general effects on the brain:55 it increases or decreases brain activity in specific brain regions, and causes long-term global changes in brain activity when a specific task is being performed. Two possible scenarios could account for the changes in global brain activity that are associated with training: either specific regions of the brain that are activated during the performance of a specific task before training show altered levels of activity after training, or cognitive training causes additional cortical regions to be recruited after training. These changes in brain activity associated with training reflect a qualitative shift—known as process switching—in the cognitive processes that underlie the performance of a given task.56 Thus, the cognitive processes underpinning the performance of a task after training are different from those used to complete the same task before training. For example, brain activity could decrease in response to a particular stimulus when an individual becomes accustomed to, and better at, perceiving the information. At the cellular level, this net change in neuronal activity could reflect a minority of neurons being activated more strongly by the stimulus, and other neurons that were previously activated by the stimulus becoming unresponsive. Neural activity associated with the performance of a cognitive task might also decrease as a consequence of training, as the response time to perform the task decreases with practice and experience, meaning that less neural processing is required to perform the exercise. Furthermore, training and learning might alter the level of awareness an individual requires to perform a task, thereby altering the pattern of brain activity required to accomplish the feat. Process switching might also evoke changes in task monitoring. For example, performing a task might be challenging before training, but would become easier as the individual practices, thus requiring less task monitoring—and fewer executive resources—for the same level of performance after training. Decreased brain activity after training is observed in most studies of cognitive training, generally in parallel to alterations to the neural processes underpinning the performance of the task, as detailed in the previous paragraph. Functional MRI has shown decreases in brain activity after training in the sternberg verbal task,57 in a spatial working memory task,58 and in the n-back working memory task.59 A PET study of verbal recall also revealed reduced brain activity after training.60 In a further study that examined the effects of training on completing a video game, researchers found that after a few weeks of practice, brain activity in the parietal cortex when playing the game was decreased, and that decreased activity in this brain region positively correlated with improved task performance.61 This finding is consistent with the hypothesis that functional decreases in brain activity reflect more-efficient information processing in the brain. Increased brain activity after training has been demonstrated during the performance of cognitively taxing tasks, such as playing musical instruments.62 In a study of working memory, increased activity in frontal and parietal cortices correlated with increased working memory capacity after training.63



ReVieWs As mentioned above, changes in brain activity after training reflect parallel increases and decreases of activation in the neuronal network underlying the performance of the task. In general, these changes probably reflect decreases in the attentional demand required by the task and increases in task-specific domains such as memory. 64 Petersen and colleagues 64 argue that a novel task requires high cognitive effort for successful performance, and that training leads to a reduction in the cognitive activity required to successfully perform this task. The increased brain activity associated with performing a novel task is typically localized in brain areas associated with visual processing and memory.64 similar patterns of altered brain activity have also been observed in individuals who have successfully acquired a new motor skill.65,66 The key insight from these studies is that attentional processes are associated with decreases in brain activity, whereas task-specific brain regions are associated with increased brain activity after training. only a few neuroimaging studies have investigated the effects of cognitive training or cognitive stimulation in patients with AD. one of the earliest PET studies of patients with mild AD reported that a combination of cognitive training and phosphatidylserine or pyritinol drug therapy was associated with increased brain glucose metabolism in temporal–parietal brain areas during a continuous visual recognition task. 67 Furthermore, patients receiving combined cognitive and drug therapies showed increased glucose metabolism and improved cognitive performance compared with control groups receiving either drug or cognitive intervention alone.67 A PET study of elderly patients with memory impairments that investigated the effects of a 14 day mental exercise program in combination with physical exercise, stress reduction and a healthy diet showed that the inter vention substantially reduced resting glucose metabolism in the dorsolateral prefrontal cortex in the intervention group compared with the control group. The study participants receiving the intervention were also shown to have increased verbal fluency.68 The decreased resting glucose metabolism in the dorsolateral prefrontal cortex might reflect increased cognitive efficiency, as no changes in brain glucose metabolism were evident in the control group. A randomized controlled trial has tested a 6 month stage-specific cognitive intervention designed to increase cognitive and non-cognitive functions, which was administered weekly in a group environment and compared with active control groups (v. Buschert, unpublished work). In patients with amnestic MCI, greater cognitive bene fits were seen in those receiving the intervention than in controls. Patients with mild AD also benefitted from the intervention, but to a lesser degree than those with amnestic MCI (s. Foerster, unpublished work). The gains in cognition were shown by PET to be associated with an attenuation in the decline in glucose metabolism in cortical regions typically affected by AD. Cognitive reserve might be better preserved in patients with MCI who are at risk of developing dementia than in patients with AD.14 As the disease progresses, the

capacity to enhance or compensate for impaired cognitive functions seems to decline. Therefore, patients with MCI and patients with mild AD could benefit differently from cognitive interventions. These initial studies indicate that cognitive intervention can alter neuronal function, and these functional changes can be measured with neuroimaging tools.

Implications for future studies

In general, most studies that have investigated the effects of cognitive interventions in AD and MCI have involved relatively small numbers of patients and controls. Furthermore, owing to the wide range of cognitive interventions that have been implemented in these trials, comparisons of the data are problematic. Further studies with larger sample sizes are warranted to establish whether cognitive intervention programs can improve and stabilize global cognitive functioning and delay further disease progression. Most studies have failed to consider potentially confounding effects that could arise from the social interaction with a trainer or instructor. Hence, the extent to which the observed training benefits are actually due to cognitive intervention is unclear. Furthermore, studies investigating the effects of cognitive intervention in AD or MCI are typically relatively short in duration and, therefore, do not provide any information on the possible mid-term and long-term effects of this therapy on global cognitive functioning. Another issue worthy of investigation is whether cognitive intervention might delay the need for help and care dependency in the mid term and long term. Finally, as the heterogeneous underlying causes of MCI and the various types of dementia could substantially affect the ability of cognitive interventions to provide benefits to patients with cognitive deficits, better patient stratification is needed.36,69,70 Assessment of neuropsychological status, multimodal biological markers,71 patterns of progressive regional brain atrophy, and regional changes in brain metabolism72,73 will all aid patient stratification and assist the development of cognitive interventions that target patients with different levels of cognitive and global functioning. In summary, large, long-term (18–24 months in duration) cognitive intervention studies that document information regarding the study participant’s neuropsychological, neurogenetic and biomarker status are required to establish whether cognitive intervention can positively affect global cognitive functioning in patients with MCI or AD.74 studies examining the neurobiological effects of cognitive training in healthy individuals indicate that this intervention can substantially affect neural activity in brain areas associated with performance of the cognitive function in question. We feel, therefore, that future functional and anatomical studies should examine in detail how cognitive training influences the neural networks affected by the pathological processes associated with both MCI and AD. In addition, neuroimaging studies could identify which specific neural networks in patients with MCI might respond positively to cognitive training.75



ReVieWs Recommendations for practice

varying levels of cognitive functioning exist during the progression of AD, so matching appropriate cognitive interventions to patients with different cognitive and global functioning levels is desirable. Patients with advanced symptoms will receive fewer benefits from cognitive interventions that target specific cognitive functions than patients with preclinical or mild AD. By contrast, global cognitive stimulation and cognitive intervention strategies that aid performance of activities of daily living might provide greater benefits to patients with advanced AD. 52 A meaningful cognition-based intervention should focus on the distinct stages of the disease and aim to improve cognitive functions that increase the patient’s independence and autonomy. Throughout the intervention, confrontation of individual cognitive deficits should be avoided to prevent the participant from becoming disillusioned, which might have a negative impact on the success of the therapy.68 Cognitive intervention places high demands on the therapist, and requires the application of current knowledge concerning intervention techniques, content and strategy.

Conclusions

Cognitive interventions have been shown to improve global cognitive functioning and abilities of daily living, reduce behavioral disturbances, and have positive effects on quality of life in patients with MCI or mildto-moderate AD. Neuroimaging results indicate that changes in attention underpin many of the improvements in cognitive performance. Evidence suggests that physical activity slows down cognitive decline and delays the onset of dementia in healthy elderly adults. At present, however, the importance of physical activity in the framework of non-pharmacological approaches to the treatment of AD remains unclear. Given that patients with MCI have an increased risk of developing AD, and considering that no approved disease-modifying drugs are currently available for AD, the encouraging results from cognitive intervention 1.

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studies in MCI and AD could have important clinical implications. At present, however, no standardized, replicable intervention programs have been designed for the treatment of patients at different stages of AD. Cognitive interventions that support global functioning could delay the onset of AD by 5 years in patients who will eventually develop this condition. As a result, the prevalence of AD could decrease by 50%, leading to substantial personal, social and economic benefits. Compared with the pharmacological treatments currently available for the treatment of AD—namely, ChEIs and memantine—non-pharmacological cognitive interventions have a number of advantages. With regard to health insurance costs, cognitive intervention programs, when administered in groups in the course of outpatient treatment, seem to be highly attractive, as they are associated with lower costs and higher cost-effectiveness than pharmacological treatments. 5 Furthermore, cognitive interventions are thought to cause no undesirable adverse events, unlike antidementia drugs. The implementation of adequate intervention programs for the treatment of AD requires the availability of sufficient numbers of medical practitioners and specialists (and suitable institutions) to diagnose and treat all patients with this serious condition. Considering that the number of patients with dementia worldwide is expected to increase dramatically from 35 million today to 115 million in 2050,76 efforts to advance the development and implementation of cognition-based interventions for the treatment of AD must definitely be pursued. Review criteria PubMed was searched for articles published in English, with the following search terms: “cognitive training/”, “cognitive stimulation”, “cognitive intervention”, “healthy elderly”, “mild cognitive impairment”, “Alzheimer’s disease”, “neuroimaging”, “DTI”, “SPECT”, “fMRI” and “PET”. In addition, we identified papers from references in the articles retrieved by the initial searches and selected articles from our own archives.

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Acknowledgments Charles P. Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

Author contributions V. Buschert, A. L. W. Bokde and H. Hampel all researched the data for the article, made substantial contributions to discussions of the content, and contributed equally to writing the article and to reviewing and/or editing of the manuscript before submission.
